Method of and system for characterizing at least one biomedical potentiometric electrochemical sensor

Abstract

A method of characterizing at least one biomedical potentiometric electrochemical sensor (110) is proposed. The biomedical potentiometric electrochemical sensor (110) comprises at least one main electrode (112) with at least one ion-selective membrane, at least one reference electrode (114), and at least one counter electrode (116). The method comprises: (120) connecting the main electrode (112) with the reference electrode (114); (122) determining a potential between the main electrode (112) and the reference electrode (114) by a high-impedance potentiometric measurement; (124) connecting the one main electrode (112) with the counter electrode (116) and applying the determined potential between the main electrode (112) and the counter electrode (116); (126) recording electrochemical impedance data by performing an electrochemical impedance spectroscopy measurement (EIS), wherein the electrochemical impedance spectroscopy measurement comprising applying an alternating voltage; (128) de-connecting the main electrode (112) from the counter electrode (116) after applying the alternating voltage; and (130) characterizing the biomedical potentiometric electrochemical sensor (110) based on the recorded electrochemical impedance data.

Description

[0001] Roche Diagnostics GmbH

[0002] Method of and system for characterizing at least one biomedical potentiometric electrochemical sensor

[0003] Technical Field

[0004] The invention relates to a method of characterizing at least one biomedical potentiometric electrochemical sensor and a system for characterizing at least one biomedical potentiometric electrochemical sensor. The system may be applied in the field of blood gas analyzer, continuous monitoring blood parameters, specifically for handheld devices or for laboratory analyzers. Other applications, however, are also feasible.

[0005] Background art

[0006] Monitoring one or more blood parameters such as one or more electrolytes, e.g. Na+, K+, Ca2+, C1-, Urea, pH, Li+, Mg2+, Ammonium, in a body fluid of a subject plays an important role in the prevention and treatment of various diseases.

[0007] Generally potentiometric sensors are known, e.g. from EP 3 594 671 Al. Potentiometric electrochemical sensors are generally known, such as for continuous monitoring systems, to measure specific blood parameters. Potentiometric sensors may be coated with an ion selective membrane for the specific parameters that need to be measured. If the sensor is introduced to a blood sample or implanted into the body (interstitial fluid), the sensor supplies a voltage. The voltage corresponds to an analyte concentration. However, effects like sensor aging, wetting or clotting through the blood and fluid sample can lead to a shift or attenuation of the sensor voltage that can result in false measurements without knowing. In addition, potentiometric sensors may not be polarized to a divergent voltage. Although, this is a requirement for impedance measurements.

[0008] For quality control of blood gas cartridges usually random sample tests are performed. A single measured variable, e.g. the sensor potential vs. reference electrode, may be recorded for one electrode and may then be used to perform a quality control for a batch, e.g. of 1200 cartridges. If this value is conspicuous several times, the entire batch may be discarded. However, this measured variable can already become conspicuous if there is an air bubble in the cartridge in front of an electrode. If, for example, fluidic artifacts, in particular air bubbles, are present in the cartridge, conspicuous values can occur and entire batches are incorrectly discarded as a result.

[0009] US 2009 / 0157338 Al discloses a method for measuring, monitoring and analyzing a condition of a potentiometric measuring probe. The method utilizes the potentiometric measuring probe to provide measurement of the potential difference of electrodes.

[0010] For different sensor technologies and parameters, in particular for measuring the concentration of glucose, several electrochemical sensors are known by the skilled person such as from EP 3 158 934 Bl or US 10,004,442 B2.

[0011] Problem to be solved

[0012] It is therefore desirable to provide a method of characterizing at least one biomedical potentiometric electrochemical sensor and a system for characterizing at least one biomedical potentiometric electrochemical sensor which at least partially address the abovementioned technical challenges. Specifically, improvement of techniques for characterizing at least one biomedical potentiometric electrochemical sensor is desirable.

[0013] Summary This problem is addressed by a method of characterizing at least one biomedical potentiometric electrochemical sensor and a system for characterizing at least one biomedical potentiometric electrochemical sensor with the features of the independent claims. Advantageous embodiments which might be realized in an isolated fashion or in any arbitrary combinations are listed in the dependent claims as well as throughout the specification.

[0014] As used in the following, the terms “have”, “comprise” or “include” or any arbitrary grammatical variations thereof are used in a non-exclusive way. Thus, these terms may both refer to a situation in which, besides the feature introduced by these terms, no further features are present in the entity described in this context and to a situation in which one or more further features are present. As an example, the expressions “A has B”, “A comprises B” and “A includes B” may both refer to a situation in which, besides B, no other element is present in A (i.e. a situation in which A solely and exclusively consists of B) and to a situation in which, besides B, one or more further elements are present in entity A, such as element C, elements C and D or even further elements.

[0015] Further, it shall be noted that the terms “at least one”, “one or more” or similar expressions indicating that a feature or element may be present once or more than once typically will be used only once when introducing the respective feature or element. In the following, in most cases, when referring to the respective feature or element, the expressions “at least one” or “one or more” will not be repeated, non-withstanding the fact that the respective feature or element may be present once or more than once.

[0016] Further, as used in the following, the terms "preferably", "more preferably", "particularly", "more particularly", "specifically", "more specifically" or similar terms are used in conjunction with optional features, without restricting alternative possibilities. Thus, features introduced by these terms are optional features and are not intended to restrict the scope of the claims in any way. The invention may, as the skilled person will recognize, be performed by using alternative features. Similarly, features introduced by "in an embodiment of the invention" or similar expressions are intended to be optional features, without any restriction regarding alternative embodiments of the invention, without any restrictions regarding the scope of the invention and without any restriction regarding the possibility of combining the features introduced in such way with other optional or non-optional features of the invention.

[0017] In a first aspect, a method of characterizing at least one biomedical potentiometric electrochemical sensor is disclosed.

[0018] The term “characterizing” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a process of categorizing the biomedical potentiometric electrochemical sensor into at least two categories with respect to quality and / or a process of quantification of sensor lifetime. The term “quality” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a measure for reliability of a signal determined by the biomedical potentiometric electrochemical sensor. Specifically, the quality may be classified as good for reliable measurement results and as bad for non-reliable measurement results. The quality may relate to sensor aging, wherein an aged sensor may be characterized as bad and a non-aged sensor is characterized as good. The characterizing may comprise quantitatively determining an age of the biomedical potentiometric electrochemical sensor and / or remaining sensor lifetime. The characterizing may further comprise determining structural and material changes of the biomedical potentiometric electrochemical sensor. Using electrochemical impedance data, as will be outlined in detail below, can allow determining and / or predicting sensor age and / or sensor aging. Real part and / or imaginary part of impedance change, e.g. in case used membranes become leaky, if electrolyte leaks, if water penetrates into the reference electrolyte, if membranes are clogged.

[0019] The term “sensor” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element or device configured for one or more of detecting, measuring or monitoring at least one condition or for measuring at least one measurement variable. Specifically, the sensor may be capable of generating at least one signal, such as a measurement signal, which is a qualitative or quantitative indicator of the measurement variable and / or measurement property. The sensor may be capable of qualitatively or quantitatively determining the presence and / or the concentration of at least one analyte. The determination may be or may comprise a qualitative detection, simply determining the presence of the analyte or the absence of the analyte, and / or may be or may comprise a quantitative detection, which determines the quantity and / or the concentration of the analyte.

[0020] The term “analyte” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary element, component or compound which may be present in a sample and the concentration of which may be of interest. For example, the sample may be a fluid, wherein the fluid comprises at least one of: an aqueous solution; a buffer solution; a quality control sample; a calibrator sample; a stand-by solution for keeping the at least one biomedical potentiometric electrochemical sensor wetted; a sample fluid, specifically a bodily fluid, more specifically whole blood and / or a component of whole blood, specifically blood serum and / or blood plasma; and / or cerebrospinal fluid (CSF); and / or interstitial fluid. For example, the analyte may be a blood gas parameter. As an example, the analyte may be at least one analyte selected from the group consisting of: pH; pCO2; an electrolyte such as Na+, K+, Ca2+, C1-, Urea Ammonium, Li+, Mg2+. However, other analytes may be possible.

[0021] The term “biomedical” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a suitability of the sensor for one or more of detecting, measuring or monitoring at least one biological measurement variable or biological measurement property which is indicative of a health condition of a subject. The biomedical electrochemical sensor may be configured for qualitatively and / or quantitatively determining at least one health condition and / or at least one measurement variable indicative of a health condition of a subject.

[0022] The term “subject” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically relates to a human being or an animal, independent from the fact that the human being or animal, respectively, may be in a healthy condition or may suffer from one or more diseases. The subject may be a patient. The biomedical sensor may be configured for detecting and / or measuring either quantitatively or qualitatively at least one biological and / or physical and / or chemical parameter of the subject and for transforming the detected and / or measured parameter into at least one signal such as for further processing and / or analysis.

[0023] The term “electrochemical sensor” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a sensor based on electrochemical measurement principles, such as by using a potentiometric measurement principle. The electrochemical sensor may be configured for a detection of an electrochemically detectable property of the analyte, such as an electrochemical detection reaction. For example, the electrochemical detection reaction may be detected by applying and comparing one or more electrode potentials. Specifically, the electrochemical sensor may be adapted to generate at least one measurement signal which may, directly or indirectly, indicate a presence and / or an extent of the electrochemical detection reaction, such as at least one current signal and / or at least one voltage signal. The measurement signal may be or may comprise at least one electronic signal. The measurement signal may be or may comprise at least one analogue signal and / or may be or may comprise at least one digital signal. The sensor may be configured for generating and evaluating a plurality of measurement signals, wherefrom the desired information is determined.

[0024] The term “potentiometric” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a measurement principle in which a measurement signal is measured as the potential difference between a main electrode and a reference electrode. The potential of the main electrode may depend on the concentration of the analyte in the gas or solution phase. The reference electrode may be used to provide a defined reference potential. The biomedical potentiometric electrochemical sensor comprises at least one main electrode with at least one ion-selective membrane, at least one reference electrode, and at least one counter electrode, in particular at least one low impedance counter electrode.

[0025] The term “electrode” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a, generally arbitrary shaped, electrical conductor.

[0026] The term “main electrode” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an electrode configured for performing detecting the at least one analyte of interest, in particular for measuring the concentration of the at least one analyte of interest. The main electrode may be contactable with a sample, e.g. an electrolyte solution suspected to comprise the analyte of interest. The sample may be held by a vessel, e.g. a disposable vessel. The method may comprise contacting the main electrode with the sample. The main electrode may be designed such that an electrochemical reaction may take place at the electrode. The main electrode may also be named as sensing electrode, detection electrode or working electrode. The at least one main electrode may comprise and / or may be coated with at least one of the following components: gold, platinum, carbon, carbon paste. The main electrode may comprise a contact area of 0.1 mm2to 2 cm2. The contact area may be configured for contacting the bodily fluid.

[0027] The main electrode may be an ion-selective electrode (ISE). The main electrode may be an ion selective electrode configured for measuring a concentration of the analyte of interest. The potential measured between the main electrode and the reference electrode gives a potential value which can be used to calculate the concentration of the analyte using the equation of Nernst.

[0028] The main electrode comprises the ion-selective membrane. The term “membrane” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to at least one element configured for controlling and / or limiting diffusion of the analyte to the electrode to which the membrane is applied. The term “ion-selective membrane” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to permeability for the at least one analyte of interest and diffusion limiting for other analytes and / or constituents of the sample. The membrane may be configured for allowing only the specific ion to pass through. For example, the at least one ion-selective membrane may be selective for at least one of Na+, K+, Ca2+, C1-, Urea, pH, Li+, Mg2+, Ammonium. For example, the membrane may be selective for a particular ion, such as hydrogen ions (pH) or sodium ions (Na+). The ions having passed the membrane may generate a measurable potential change that is proportional to the ion concentration. Depending on the application, the membrane may comprise different materials. The membrane may comprise at least one polymer or a glass. For example, the polymer may be or may comprise poly(3,4-ethylenedioxythiophene) (PEDOT), polypyrrole, and poly(3 -octylthiophene) (POT), Poly(vinyl chloride) (PVC), polyurethane derivatives, poly(ethylene oxide) derivatives, carboxylated PVC, hydroxylated PVC, silicone-rubber, sol-gel glass, poly(2-methoxyethylacrylate), heparin-attached cellulose triacetate membrane, NO-releasing polymer films, polymers containing phospholipid polar group, 2-methacryloyloxyethyl phosphorylcholine (MPC), PVC membranes coated by biocompatible copolymers of MPC and an alkyl methacrylate. For example, the membrane may comprise at least one material as described in Setsuko Yajima, Yuri Sonoyama, Ken Suzuki, Keiichi Kimura’Ton-sensor property and blood compatibility of neutral-carrier-type poly(vinyl chloride) membranes coated by phosphorylcholine polymers”, Analytica Chimica Acta, Volume 463, Issue 1, 16 July 2002, Pages 31-37, https: / / doi.oi I ‘1J ' ' J / S0003-2670t02)0l 1• H • < The at least one ion-selective membrane may have a capacity in the range of 10 pF to 100 pF. The membrane may have even more functionalities, such as providing biocompatibility.

[0029] For example, the biomedical potentiometric electrochemical sensor may be a pH sensor. The main electrode may be embodied as a glass pH electrode. The pH electrode may comprise a glass shaft. Inside the glass shaft an electrical conductor may be arranged. The electrical conductor is connected via a cable to a measurement engine. The membrane, in this case a glass membrane, may be embodied as a, e.g. hemi spherically shaped, electrode tip. The electrode tip may be in contact with the sample. The glass of the membrane may be made from hydrogen ion sensitive glass. The membrane may be fused to the shaft. The pH electrode may be partly filled with a buffer solution. The buffer solution may have a pH value of 7. Depending on the sample, H+ ions may diffuse either into or out of the electrode tip leading to a measurable potential change.

[0030] The term “reference electrode” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an electrode which is configured to provide an electrochemical reference potential which, at least widely, is independent of the presence or absence or concentration of the analyte. The reference electrode may be configured for providing a stable potential, at least within tolerances, which should not vary when the concentration of analyte changes. The reference electrode may be configured for being or providing a reference for measuring a potential of the main electrode. The method may comprise contacting the reference electrode with the sample.

[0031] The reference electrode may comprise a housing, e.g. a glass shaft, in which an internal electrode is arranged. The housing and internal electrode may be similar to the design of the main electrode. The internal electrode may be immersed into a defined electrolyte. The electrolyte may be in contact with the sample via a liquid junction e.g. via a porous ceramic diaphragm. The liquid junction may allow diffusing of electrolyte out of the housing into the sample, thereby generating an electrical path between the inside of the reference electrode and the main electrode. The main electrode and the reference electrode may be designed as separate elements having two separate housings or as combined element wherein the main electrode and the reference electrode are installed in the same housing.

[0032] The reference electrode may consist of a metal and a poorly soluble salt of the same metal. The reference electrode may be a so-called reference electrode of second order. For example, the reference electrode may be at least one electrode selected from group consisting of: a Hydrogen (H2 / H+) electrode, Silver / Silver Chloride (Ag / AgCl) electrode, Silver / Silver Sulfate (Ag / Ag2SO4) electrode, Calomel (Hg / Hg2C12) electrode, Mercury / Mercurous Sulfate (Hg / Hg2SO4) electrode, Mercury / Mercury Oxide (Hg / HgO) electrode. Other embodiments may be possible. For example, calibration-free potentiometric sensors with solid-contact can be used as reference electrode(s) or as ion-selective electrode(s). For example, the ion-selective electrode may be designed as described in Celeste R. Rousseau, Philippe Biihlmann, “Calibration-free potentiometric sensing with solid-contact ion-selective electrodes”, TrAC Trends in Analytical Chemistry, Volume 140, July 2021, 116277, https: / / doi.Org / 10.1016 / j.trac.2021.116277.

[0033] In the presence of the analyte, the main electrode may develop a potential proportional to the analyte of interest in the sample. The potential may be provided to a measurement engine for further analysis, in particular for determining the concentration of the analyte therefrom. The measurement engine may comprise a processor configured for determining the concentration of the analyte from the potential using a pre-determined, e.g. determined in a calibration measurement, relationship between the potential and the analyte concentration. The relationship may be stored in a database of the measurement engine.

[0034] The term “counter electrode” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an additional electrode which is used for performing an electrochemical impedance spectroscopy measurement. The counter electrode may have a very high electrical conductance (therefore a very low ohmic resistance) in order to provide a high conductivity for impedance measurements. The counter electrode may be a low impedance counter electrode. The term “low impedance” counter electrode as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to low in comparison to impedance of standard electrodes. For example, the low impedance electrode may have an impedance of 1 mQ to 4 kQ. The impedance may depend on the size of the impedance electrode and composition of materials. The counter electrode may provide an impedance as low as possible, normally in a range between 1 mOhm (almost ideal conductor) and 10 Ohm. In some cases, the counter electrode may be made of pure carbon material, in particular the sensor is very thin and small. In this special case of needle type sensors used for continuous monitoring the impedance can reach up to 4 kOhm or even more. However, the higher the impedance the worse may be the functionality of the counter electrode. Common materials for a counter electrode may be platinum and glassy carbon which provide a very high chemical stability, a wide potential window and a very low impedance. In many applications instead of glassy carbon a carbon coated metal, which lowers the total impedance significantly, can be used. For example gold, palladium, or silver may be coated by carbon paste. Only the carbon paste may have a contact to the analyte, the metal provides the conductive path to the instrument and has no contact to the electrolyte or analytes. The method may comprise contacting the counter electrode with the sample.

[0035] The at least one biomedical potentiometric electrochemical sensor may comprise and / or correspond to a screen printed electrode and / or a needle type electrode.

[0036] The method comprises the method steps as given in the corresponding independent claim and as listed as follows. The method steps may be performed in the given order. One or more of the method steps may be performed in parallel and / or in a time overlapping fashion. Further, one or more of the method steps may be performed repeatedly. Further, additional method steps may be present which are not listed.

[0037] The method comprising the steps: connecting the main electrode with the reference electrode; determining a potential between the main electrode and the reference electrode by a high-impedance potentiometric measurement; connecting the main electrode with the counter electrode and applying the determined potential between the main electrode and the counter electrode; recording electrochemical impedance data by performing an electrochemical impedance spectroscopy measurement (EIS), wherein the electrochemical impedance spectroscopy measurement comprising applying an alternating voltage; de-connecting the main electrode from the counter electrode after applying the alternating voltage; and characterizing the biomedical potentiometric electrochemical sensor based on the recorded electrochemical impedance data. The method according to the present invention allows for impedance spectroscopy. This can allow for detecting and / or monitoring sensor shifts and effects, which lead to corrupt measurement results. The impedance results using specific frequencies or frequency spectra can be used to prevent false measurements and identify defective sensors. The term impedance spectroscopy is to be understood herein as encompassing both a single measurement using an AC voltage with one predefined frequency or several measurements using an AC voltage whose frequency is modified over time.

[0038] According to one embodiment, the method of performing the electrochemical impedance spectroscopy measurement comprises the steps:

[0039] Applying a sinusoidal voltage: recording a current response to the applied sinusoidal voltage; and specifically determining a phase shift and an attenuation between the applied sinusoidal voltage and the current response, specifically wherein the characterizing of the at least one biomedical potentiometric electrochemical sensor comprises evaluating and / or analyzing the determined phase shift, the attenuation between the applied sinusoidal voltage and the current response.

[0040] The primary parameters obtained from electrochemical impedance spectroscopy for characterizing an electrode are the phase shift and the attenuation. These parameters are key parameters for electrode characterization. This leads to a significantly more accurate determination of the electrode's condition.

[0041] According to one embodiment, the sinusoidal voltage has an amplitude between 1 mV and 100 mV, specifically between 5 mV and 30 mV, more specifically between 8 mV and 20 mV and even more specifically at 10 mV; and / or the sinusoidal voltage is applied over a time period of 0.05 s to 5 s, specifically 0.08 s to 3 s and more specifically 1 s to 2 s; and / or the sinusoidal voltage is at least one frequency in a frequency range between 1 Hz and 100 kHz, specifically between 500 Hz and 50 kHz, more specifically between 1 kHz and 40 kHz; and / or the sinusoidal voltage comprises 2 to 500 frequencies, specifically 2 to 100 frequencies, more specifically 4 to 16 frequencies. The duration of the measurement varies between the individual frequencies. Lower frequencies take longer to measure for the same number of periods. The time required for a measurement is directly dependent on the period duration of the signal, which is inversely proportional to the frequency. The period (T) is the time for one complete cycle and is calculated using the formula T=l / f. A low-frequency signal has a long period. For example, a 1 kHz signal has a period of 1 ms per cycle. A measurement over multiple cycles, e.g. 10 periods, has the advantage to ensure high accuracy and reproducibility of the data. A measurement over 10 periods would take 10^ 1 ms=10 ms in this case. To ensure a stable result with a good signal-to-noise ratio, the device must wait until several full cycles have been completed. A high-frequency signal has a very short period. For example, a 10 kHz signal has a period of 0.1 ms per cycle. A measurement over 10 periods would take 10x0.1 ms=l ms in this case.

[0042] Typically, the complete impedance measurement at 2 to 10 different discrete frequencies, preferably four different discrete frequencies, takes between 20 ms and 800 ms, preferably between 80 and 200 ms.

[0043] According to one embodiment, the electrochemical impedance spectroscopy measurement comprises applying an alternating voltage at one predefined frequency, wherein the characterizing of the at least one biomedical potentiometric electrochemical sensor comprises evaluating and / or analyzing the determined phase shift, the attenuation between the applied sinusoidal voltage and the current response exactly once at this predefined frequency.

[0044] Once the relevant information of the application of the sensor to be measured is known to be within a specific frequency range, the measurement can be limited to a specific frequency. Measuring at one predefined frequency has advantages, especially for biomedical or real-time applications. The measurement time is significantly reduced and through an increased efficiency, the method becomes much more practical for routine quality control or continuous monitoring in a device. Additionally, the duration of the exposure of the electrode to the measurement signal is minimized which leads to a preservation of the electrode. According to one embodiment, the electrochemical impedance spectroscopy measurement comprises applying an alternating voltage with an amplitude which is kept constant during the measurement, and modifying the frequency of the alternating voltage over time during the measurement. The characterizing of the at least one biomedical potentiometric electrochemical sensor may comprise evaluating and / or analyzing the determined phase shift, the attenuation between the applied sinusoidal voltage and the current response for a plurality of frequencies of the alternating voltage, preferably for 2 to 16 frequencies.

[0045] The alternating voltage can be applied between the main electrode and the reference electrode, alternatively, the alternating voltage can be applied between the main electrode and the counter electrode or between the reference electrode and the counter electrode. This can allow for detecting and / or monitoring sensor shifts and effects for each of the electrodes of a sensor. The frequency of the alternating voltage is changed from one value to the next during the measurement. The phase shift and attenuation are then measured at each frequency. The result of measuring at different frequencies is a more detailed impedance spectrum. This data allows for a more comprehensive diagnosis of the electrode condition. Different processes, such as charge transfer or diffusion, can be distinguished from one another because they become visible in different frequency ranges. This provides deeper insight into the possible causes of faults.

[0046] According to one embodiment, the de-connecting of the at least one main electrode from the counter electrode after applying the sinusoidal voltage is performed immediately after applying the sinusoidal voltage and / or in a ns to ps-time range after applying the sinusoidal voltage.

[0047] According to one embodiment, the at least one biomedical potentiometric electrochemical sensor has an inner resistance between 1 kQ and 100 MQ specifically between 50 kQ and 50 MO.

[0048] According to one embodiment, the method further comprises de-connecting the at least one main electrode from the reference electrode prior to the connecting of the main electrode with the counter electrode and re-connecting the main electrode with the reference electrode after the recording of the electrochemical impedance data. According to one embodiment, the at least one ion-selective membrane is selective for at least one of Na+, K+, Ca2+, C1-, Urea, pH, Li+, Mg2+, Ammonium.

[0049] The method may be performed at least partially while the at least one biomedical potentiometric electrochemical sensor is contacted with a fluid. The fluid may comprise at least one of: an aqueous solution; a buffer solution; a quality control sample; a calibrator sample; a stand-by solution for keeping the at least one biomedical potentiometric electrochemical sensor wetted; a sample fluid, specifically a bodily fluid, more specifically whole blood and / or a component of whole blood, specifically blood serum and / or blood plasma; cerebrospinal fluid (CSF); and / or interstitial fluid. The expression “at least partially while the at least one biomedical potentiometric electrochemical sensor is contacted with a fluid” as used herein is a broad expression and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The expression specifically may refer, without limitation, to a situation in which the biomedical potentiometric electrochemical sensor is in contact with the fluid during the complete duration of performing the method and to a situation in which the biomedical potentiometric electrochemical sensor in contact for a certain time period during performing the method only, e.g. only before characterizing step. For example, the method may comprise a step in which the sample is applied to the biomedical potentiometric electrochemical sensor and / or the biomedical potentiometric electrochemical sensor is contacted to the sample, e.g. by insertion.

[0050] The method may be performed in-vitro. The term “in-vitro” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to performing the method on a sample of the subject outside the subject’s body or another sample of fluid such as a quality control sample or a calibrator and the like. For example, the method may be performed in a random examination of a batch of cartridges, e.g. blood gas cartridges such as for pH, pCO2, electrolyte such as Na+, K+, Ca2+, C1-, Urea Ammonium, each one comprising the at least one biomedical potentiometric electrochemical sensor. The method may comprise testing at least one cartridge of the batch of cartridges or in-use of at least one cartridge comprising the at least one biomedical potentiometric electrochemical sensor.

[0051] The method may be performed in-vivo. The term “in-vivo” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to performing the method while the sensor is at least partially implanted into a bodily tissue of a subject. Specifically, the at least one biomedical potentiometric electrochemical sensor is implanted in a body and contacted with a bodily fluid, more specifically an interstitial fluid. For example, the biomedical potentiometric electrochemical sensor is an element of a continuous monitoring system configured for continuous monitoring of the analyte. The biomedical potentiometric electrochemical sensor may be fully implantable or partially implantable.

[0052] A system for performing the method according to the present invention for characterizing the at least one biomedical potentiometric electrochemical sensor, e.g. as further described in more detail below, may comprise at least one impedance analyzer, also denoted as measurement engine herein. The impedance analyzer may comprise at least one potentiometric measurement unit, at least one frequency response analyzer unit, at least one switch matrix, and electrode connectors for connecting the respective electrode and a corresponding switch of the switch matrix. For example, the system for performing the method according to the present invention for characterizing the at least one biomedical potentiometric electrochemical sensor may operate completely computer controlled, and / or the method of characterizing at least one biomedical potentiometric electrochemical sensor may be performed completely computer controlled.

[0053] The potentiometric measurement unit may have a very high input impedance.

[0054] The potentiometric measurement unit may be configured for measuring an equilibrium potential, E equ, between two of the electrodes. The equilibrium potential may be the potential when the sum of all currents flowing from one electrode to the other is zero. The equilibrium potential may be a strictly thermodynamic parameter of an electrode where no electron transfer processes occur. The frequency response analyzer unit may be configured for measuring the impedance between two electrodes by adding the equilibrium potential E equ as a DC offset and applying a sinusoidal voltage. This DC offset may prevent a current flow between the two electrodes. The sinusoidal voltage of a very small amplitude, e.g. of 10 mVpp, may be modulated over the equilibrium potential and actively applied between two electrodes. The complete signal which is applied between two electrodes can be described as u(t) = E_equ + A • sin(cot + (pl) with A = const, and is the amplitude of the sinusoidal wave [V], < 10 mVpp, co = 2-7t-f is the angular frequency [Hz], (pl is the phase of the stimulation potential [degree], and E equ is the equilibrium potential [V],

[0055] The frequency response analyzer unit may be configured for measuring, in particular simultaneously, the, in particular very small, AC current between the two electrodes. The AC current between the two electrodes may also be a sine wave: i(t) = B-sin(cot + (p2) with i(t) is the sinusoidal wave of the AC current, measured by the frequency response analyzer unit as system response, B is the amplitude of the AC current [A], range 10 pA ... 100 nA, co = 2-7t-f is the Angular frequency [Hz], (p2 is the phase of the resulting current [degree].

[0056] The frequency response analyzer unit may be configured for calculating output parameters such as one or more of amplitude, phase shift, impedance, real part and imaginary part. The absolute value |Z| of the impedance Z may be calculated by the frequency response analyzer unit:

[0057] |Z| = A / B (corresponding to Ohm’s Law).

[0058] The phase shift A(p = |(p2 — (pl | may be measured between the stimulating potential u(t) and the resulting current i(t). The Real Part Re(Z) and the imaginary part Im(Z) of the impedance Z may be calculated as follows:

[0059] Re(Z) = |Z| • cos(A(p)

[0060] Im(Z) = |Z| • sin(A(p)

[0061] The impedance is defined from Euler’s formula:

[0062] Z = Re(Z) + j-Im(Z) = |Z| • [cos(A(p) + j-sin(A(p)] = |Z|-exp(j • Acp) The admitance Y is calculated from the impedance Z: Y = 1 / Z.

[0063] The switch matrix may be a fast switch matrix. The switch matrix comprises at least three independent switches, in particular fast switches denoted as FS1, FS2 and FS3. A first switch, e.g. FS1, of the switch matrix, may be configured for connecting the main electrode to the potentiometric measurement unit, e.g. by using a first position of the first switch, or to frequency response analyzer unit, e.g. using a second position of the first switch. A second switch, e.g. FS2, of the switch matrix, may be configured for connecting the reference electrode to the potentiometric measurement unit, e.g. by using a first position of the second switch, or to frequency response analyzer unit, e.g. using a second position of the second switch. A third switch, e.g. FS3, of the switch matrix, may be configured for connecting the counter electrode to the potentiometric measurement unit, e.g. by using a first position of the third switch, or to frequency response analyzer unit, e.g. using a second position of the third switch.

[0064] The term “connecting” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a process of generating and / or establishing an electrical connection. The connecting of the main electrode and the reference electrode may be performed using the first switch and the second switch of the switch matrix. The connecting of the main electrode and the counter electrode may be performed using the first switch and the third switch of the switch matrix. The connecting may be performed manually and / or automatically by a processor.

[0065] The term “de-connecting”, also denoted as disconnecting, as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to interrupting and / or terminating of the electrical connection. The de-connecting of the main electrode and the reference electrode may be performed using the first switch and the second switch of the switch matrix. The de-connecting of the main electrode and the counter electrode may be performed using the first switch and the third switch of the switch matrix. The de-connecting may be performed manually and / or automatically by a processor. For example, a workflow for measuring the analyte concentration and the impedance of the main electrode may comprise the following steps: configuring of the switch matrix for connecting the main electrode, the reference electrode and the counter electrode with the potentiometric measurement unit, wherein in particular the first switch is set to its first position and may connect the main electrode to the potentiometric measurement unit, the second switch is set to its first position and may connect the reference electrode to the potentiometric measurement unit and the third switch is set to its first position and may connect the counter electrode to the potentiometric measurement unit; measuring an equilibrium potential E equl between the main electrode and the reference electrode, wherein E equl may be used for the determination of the analyte concentration; measuring an equilibrium potential E_equ2 between the main electrode and the counter electrode, wherein E_equ2 may be used to prevent any current flow between the counter electrode and the main electrode; configuring of the switch matrix for connecting the main electrode and the counter electrode to the frequency response analyzer unit, wherein in particular the first switch is set to its second position and may connect the main electrode to the frequency response analyzer unit and the third switch is set to its second position and may connect the counter electrode to the frequency response analyzer unit; applying on the frequency response analyzer unit the equilibrium potential E_equ2 between the main electrode and the counter electrode and measuring the impedance of the main electrode; configuring of the switch matrix for connecting the main electrode to the potentiometric measurement unit, wherein in particular the first switch is set to its first position and may connect the main electrode to the potentiometric measurement unit, wherein the counter electrode can be stayed connected to the frequency response analyzer unit, thereby de-connecting the main electrode from the counter electrode after applying the alternating voltage.

[0066] The total time of the steps of configuring of the switch matrix for connecting the main electrode and the counter electrode to the frequency response analyzer unit, applying on the frequency response analyzer unit the equilibrium potential E_equ2 and deconnecting with the counter electrode should happen in a time as short as possible between 10 ms to max. 250 ms. This can allow keeping unnecessary electrochemical stress away from the main electrode.

[0067] For example, a workflow for measuring the analyte concentration and the impedance of the reference electrode may comprise the following steps: configuring of the switch matrix for connecting the main electrode, the reference electrode and the counter electrode with the potentiometric measurement unit, wherein in particular the first switch is set to its first position and may connect the main electrode to the potentiometric measurement unit, the second switch is set to its first position and may connect the reference electrode to the potentiometric measurement unit and the third switch is set to its first position and may connect the counter electrode to the potentiometric measurement unit; measuring an equilibrium potential E equl between the main electrode and the reference electrode, wherein E equl may be used for the determination of the analyte concentration; measuring an equilibrium potential E_equ3 between the reference electrode and the counter electrode, wherein E_equ3 may be used to prevent any current flow between the counter electrode and the reference electrode; configuring of the switch matrix for connecting the reference electrode and the counter electrode to the frequency response analyzer unit, wherein in particular the second switch is set to its second position and may connect the reference electrode to the frequency response analyzer unit and the third switch is set to its second position and may connect the counter electrode to the frequency response analyzer unit; applying on the frequency response analyzer unit the equilibrium potential E_equ3 between the reference electrode and the counter electrode and measuring the impedance of the reference electrode; configuring of the switch matrix for connecting the reference electrode to the potentiometric measurement unit, wherein in particular the second switch is set to its first position and may connect the reference electrode to the potentiometric measurement unit, wherein the counter electrode can be stayed connected to the frequency response analyzer unit, thereby de-connecting the reference electrode from the counter electrode after applying the alternating voltage.

[0068] The total time of the steps of configuring of the switch matrix for connecting the reference electrode and the counter electrode to the frequency response analyzer unit, applying on the frequency response analyzer unit the equilibrium potential E_equ3 and configuring of the switch matrix for connecting the reference electrode to the potentiometric measurement unit and deconnecting with the counter electrode should happen in a time as short as possible between 10 ms to max. 250 ms. The intention is to keep unnecessary electrochemical stress away from the reference electrode.

[0069] For example, a workflow for measuring the analyte concentration and the impedance between the main electrode and the reference electrode may comprise the following steps: configuring of the switch matrix for connecting the main electrode, the reference electrode and the counter electrode with the potentiometric measurement unit, wherein in particular the first switch is set to its first position and may connect the main electrode to the potentiometric measurement unit, the second switch is set to its first position and may connect the reference electrode to the potentiometric measurement unit and the third switch is set to its first position and may connect the counter electrode to the potentiometric measurement unit; measuring an equilibrium potential E equl between the main electrode and the reference electrode, wherein E equl may be used for the determination of the analyte concentration; configuring of the switch matrix for connecting the main electrode and the reference electrode to the frequency response analyzer unit, wherein in particular the first switch is set to its second position and may connect the main electrode to the frequency response analyzer unit and the second switch is set to its second position and may connect the reference electrode to the frequency response analyzer unit; applying on the frequency response analyzer unit the equilibrium potential E equl between the main electrode and the reference electrode and measuring the impedance between the main electrode and the reference electrode; configuring of the switch matrix for connecting the main electrode and the reference electrode to the potentiometric measurement unit, wherein in particular the first switch is set to its first position and may connect the main electrode to the potentiometric measurement unit and the second switch is set to its first position and may connect the reference electrode to the potentiometric measurement unit.

[0070] The total time of the steps of configuring of the switch matrix for connecting the main electrode and the reference electrode to the frequency response analyzer unit, applying on the frequency response analyzer unit the equilibrium potential E equl and configuring of the switch matrix for connecting the main electrode and the reference electrode to the potentiometric measurement unit should happen in a time as short as possible between 10 ms to max. 250 ms. The intention is to keep unnecessary electrochemical stress away from the main electrode and the reference electrode.

[0071] The term “impedance”, as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to the complex impedance Z which may be described as Z = Re(Z) + j Im(Z), wherein Re(Z) is the real part of the complex impedance and Im(Z) is the imaginary part of the complex impedance. The complex number is written as j. In polar form the complex impedance may be described as Z = |Z| e 10 , wherein 0 is the phase difference between voltage and current. The admittance Y may be defined as Y = — . The impedance data may relate to or may comprise data indicative of impedance. The impedance data may comprise at least one voltage value and / or at least one current value.

[0072] The term “impedance analyzer”, as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a device configured for determining information indicative for impedance. The impedance analyzer may be configured for one or more of determining a potential between two electrodes, connecting and / or de-connecting an electrode, applying at least one voltage, recording electrochemical impedance data and evaluating the recorded electrochemical impedance data.

[0073] The impedance analyzer may comprise at least one voltage generator device. The term “voltage generator device” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a device or unit, for example a voltage source, being configured to generate a voltage signal. The voltage generator device may comprise at least one voltage source. The voltage generator device may comprise at least one function generator selected from the group consisting of: at least one square wave generator and at least one sine wave generator.

[0074] The impedance analyzer may comprise and / or may correspond to potentiostat such as a multichannel potentiostat. The impedance analyzer may comprise the named electrodes. The impedance analyzer may comprise at least one electric circuit configured for one or more of connecting the electrodes, de-connecting the electrodes, applying a voltage, recording impedance data. The electric circuit may comprise at least one operational amplifier. The impedance analyzer may comprise at least one measurement channel configured for performing an impedance measurement. The impedance analyzer may comprise a plurality of measurement channels, e.g. the impedance analyzer may be and / or may comprise a multi-channel potentiostat. The multi-channel potentiostat may comprise a plurality of measurement channels configured for performing a plurality of measurements in parallel.

[0075] The impedance analyzer may comprise at least one measurement engine. The measurement engine may be configured for characterizing the biomedical potentiometric electrochemical sensor based on the recorded electrochemical impedance data. The measurement engine may comprise a processor. The term “processor” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary logic circuitry configured for performing basic operations of a computer or system, and / or, generally, to a device which is configured for performing calculations or logic operations. In particular, the processor may be configured for processing basic instructions that drive the computer or system. As an example, the processor may comprise at least one arithmetic logic unit (ALU), at least one floating-point unit (FPU), such as a math co-processor or a numeric co-processor, a plurality of registers, specifically registers configured for supplying operands to the ALU and storing results of operations, and a memory, such as an LI and L2 cache memory. In particular, the processor may be a multi-core processor. Specifically, the processor may be or may comprise a central processing unit (CPU). Additionally or alternatively, the processor may be or may comprise a microprocessor, thus specifically the processor’s elements may be contained in one single integrated circuitry (IC) chip. Additionally or alternatively, the processor may be or may comprise one or more application-specific integrated circuits (ASICs) and / or one or more field-programmable gate arrays (FPGAs) and / or one or more tensor processing unit (TPU) and / or one or more chip, such as a dedicated machine learning optimized chip, or the like. The processor specifically may be configured, such as by software programming, for performing one or more evaluation operations.

[0076] Moreover, the measurement engine may be configured for evaluating a potential between the main electrode and the reference electrode for determining the concentration of the analyte therefrom.

[0077] The determination of a potential between the main electrode and the reference electrode is performed by a high-impedance potentiometric measurement. The term “high-impedance potentiometric measurement”, as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a potentiometric measurement with an impedance input of the measurement engine taking into account inner resistance of the biomedical potentiometric electrochemical sensor. The potentiometric measurement may be a high-impedance measurement (or current less) since otherwise the half-cells of an electrochemical cell formed by the main electrode and the reference electrode would discharge. The biomedical potentiometric electrochemical sensor may have an impedance between 1 kQ and 500 MO specifically between 10 kQ and 100 MO. The inner resistance may be ohmic corresponding to the real part of the impedance. Using the impedance can allow for including the inner resistance automatically. The frequency dependence may be described, too. After measuring the potential of the biomedical potentiometric electrochemical sensor in the sample this value may be saved in a database, e.g. of the measurement engine. As a result, the measurement engine can automatically take the measured potential as an offset polarization voltage for the electrochemical impedance spectroscopy. The potential may be used as an offset, in particular as a DC offset. The offset can allow performing an EIS measurement of the high impedance biomedical potentiometric electrochemical sensor. Thus, the present invention proposes polarizing of the biomedical potentiometric electrochemical sensor during the EIS measurement. Surprisingly, this can allow performing EIS at high impedance systems. For example, the determined potential (absolute vs. reference electrode) may be between -300 and 300 mV. The offset may be in the same range.

[0078] The term “database” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary collection of information, such as information stored in at least one data storage device. The database may comprise the at least one data storage device with the information stored therein. The database may contain an arbitrary collection of information. The database may be or may comprise at least one database selected from the group consisting of: at least one server, at least one server system comprising a plurality of servers, at least one cloud server or cloud computing infrastructure. The database may comprise at least one storage unit configured to store data.

[0079] The method comprises performing an electrochemical impedance spectroscopy measurement. The term “electrochemical impedance spectroscopy” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to measuring impedance, i.e. an alternating current resistance, as a function of the frequency of an alternating voltage, e.g. a sinusoidal voltage. Generally, impedance measurements have to be performed at low resistance because currents are measured. However, as outlined above, the biomedical potentiometric electrochemical sensor may be a high impedance sensor such that it would discharge, short-circuit-like, during a measurement at low resistance since its sensor potential collapses. The present invention proposes to prevent this by actively applying the potential determined shortly before which corresponds to a rest potential (current = zero) between main electrode and reference electrode.

[0080] The EIS measurement may be performed between the main electrode and the counter electrode. The term “electrochemical impedance data”, also demoted as impedance data”, as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to data relating to and / or indicative to impedance. The electrochemical impedance data may comprise a current response to the applied alternating voltage. From the known or measured applied alternating voltage and the measured current response a phase shift and an attenuation between the applied sinusoidal voltage and the current response can be determined. The term “recording” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to detecting and / or measuring and / or storing of data.

[0081] The performing of the electrochemical impedance spectroscopy measurement may comprise: applying a sinusoidal voltage; recording a current response to the applied sinusoidal voltage; and specifically determining a phase shift and an attenuation between the applied sinusoidal voltage and the current response, specifically wherein the characterizing of the at least one biomedical potentiometric electrochemical sensor comprises evaluating and / or analyzing the determined phase shift, the attenuation between the applied sinusoidal voltage and the current response.

[0082] The sinusoidal voltage may have an amplitude between 1 mV and 100 mV, specifically between 5 mV and 30 mV, more specifically between 8 mV and 20 mV and even more specifically at 10 mV. The sinusoidal voltage may be applied over a time period of 0.05 s to 5 s, specifically 0.08 s to 3 s and more specifically 1 s to 2 s. The sinusoidal voltage may have at least one frequency in a frequency range between 1 Hz and 100 kHz, specifically between 500 Hz and 50 kHz, more specifically between 1 kHz and 40 kHz. The sinusoidal voltage may comprise 2 to 500 frequencies, specifically 2 to 100 frequencies, more specifically 4 to 16 frequencies.

[0083] After applying the alternating voltage, the main electrode is disconnected from the counter electrode. The de-connecting of the at least one main electrode from the counter electrode after applying the sinusoidal voltage may be performed immediately after applying the sinusoidal voltage and / or in a ns to ps-time range after applying the sinusoidal voltage. The de-connecting from the counter electrode may allow preventing the sensor from unnecessary currents. The de-connecting may be performed directly after the measurement, e.g. after ms to ps after the measurement.

[0084] The method may comprise performing EIS by using a three-electrode measurement or a two-electrode measurement. For the two-electrode measurement, the method may comprise de-connecting the main electrode from the reference electrode prior to the connecting of the at least one main electrode with the counter electrode and re-connecting the at least one main electrode with the reference electrode after the recording of the electrochemical impedance data.

[0085] For example, the three-electrode measurement may be performed as follows. Impedance may be measured by switching on the counter electrode, in particular for draining off a measurement current. The potential may be held potentiostatic between reference electrode and main electrode by applying the determined DC offset. In addition, a sinusoidal voltage, e.g. in a range from 1 to 10 mV, may be modulated onto the DC offset and the DC offset and the sinusoidal voltage may be applied between the main electrode and the counter electrode. This can allow maintaining all potentials (sinusoidal and DC offset) correctly. This DC offset and the sinusoidal voltage between the main electrode and the counter electrode may result in a current flow between the main electrode and the counter electrode with regard to the AC part of the sinusoidal voltage (the DC offset is the rest potential with current = zero). This technique can allow measuring impedance without sensor discharge.

[0086] For example, the two-electrode measurement may be performed as follows. The reference electrode may be de-connected from the main electrode. The DC offset is applied between the main electrode and the counter electrode. A sinusoidal voltage, e.g. in a range from 1 to 10 mV, may be modulated onto the DC offset and an AC response current is measured between the main electrode and the counter electrode. Afterwards the counter electrode is de-connected from the main electrode and the reference electrode is re-connected.

[0087] The EIS measurement may consist in one single measurement where one sinusoidal voltage with an amplitude in a range from 1 to lOOmV and a predefined frequency is applied, namely modulated onto the DC offset, the current response is recorded, and a phase shift and an attenuation between the applied sinusoidal voltage and the current response is determined. Such a single measurement with one pre-defined frequency for the AC voltage may be sufficient to characterize the biomedical potentiometric electrochemical sensor if the sensor properties are well understood. Alternatively, a sinusoidal voltage with different frequencies may be applied, and the current response recorded for each frequency.

[0088] The biomedical potentiometric electrochemical sensor is characterized based on the recorded electrochemical impedance data. For example, the recorded electrochemical impedance data and / or phase shift and attenuation derived from the recorded electrochemical impedance data may be compared to at least one reference value, e.g. which is stored in the database of the measurement engine. The comparison may comprise determining a difference from the reference value. In case the difference from the reference value is within pre-defined tolerances, the biomedical potentiometric electrochemical sensor is characterized as good or non-aged. Otherwise, the biomedical potentiometric electrochemical sensor may be characterized as bad or aged.

[0089] The method may further comprise based on a result of characterizing the at least one biomedical potentiometric electrochemical sensor performing at least one failsafe action comprising at least one of: applying at least one correction to a measurement value comprised by the recorded electrochemical impedance data; issuing at least one indication, specifically a warning; dismissing a measurement value comprised by the recorded electrochemical impedance data; de-connecting the at least one biomedical potentiometric electrochemical sensor from a connected component; dismissing the at least one biomedical potentiometric electrochemical sensor, a cartridge comprising the at least one biomedical potentiometric electrochemical sensor and / or an entire batch of cartridges comprising the characterized at least one biomedical potentiometric electrochemical sensor. The failsafe action may be performed by using at least one user interface. The term "user interface" as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term may refer, without limitation, to an element or device which is configured for interacting with its environment, such as for the purpose of unidirectionally or bidirectionally exchanging information, such as for exchange of one or more of data or commands. For example, the user interface may be configured to share information with a user and to receive information by the user. The user interface may be a feature to interact visually with a user, such as a display, or a feature to interact acoustically with the user. The user interface, as an example, may comprise one or more of: a graphical user interface; a data interface, such as a wireless and / or a wire-bound data interface.

[0090] The method may be performed by the manufacturer and / or during operation of the biomedical potentiometric electrochemical sensor, e.g. in-line or in-use. For example, the method may be performed repeatedly, e.g. at pre-defined times or continuously. The method may comprise using a multichannel potentiostat configured for measuring potential between the main and reference electrode and performing the EIS measurement. The method may be performed automatically. The term “automatically” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a process which is performed completely by means of at least one computer and / or computer network and / or machine, in particular without manual action and / or interaction with a user. The proposed method can be integrated directly in the measurement engine and / or can be used during sensor manufacturing processes. This is aggravated by the fact that potentiometric sensors may not be polarized to a divergent voltage to prevent destruction of the sensor. The solution for this issue may be to perform the sensor characterization on the fly directly after the proper sample measurement. After measuring the voltage of the sensor in the fluidic this value can be saved in the measurement engine. As a result, the measurement engine can automatically take the measured voltage as an offset polarization voltage for the impedance spectroscopy. This can enable the characterization of potentiometric sensors during a measurement without destroying it. In a further aspect, a system for or characterizing at least one biomedical potentiometric electrochemical sensor is disclosed. The term "system" as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary set of interacting or interdependent components forming a whole. Specifically, the components may interact with each other in order to fulfill at least one common function. The at least two components may be handled independently or may be coupled or connectable.

[0091] The system may be configured for performing a method of characterizing at least one biomedical potentiometric electrochemical sensor according to the present invention such as disclosed above or as disclosed in further detail below. For definitions of the features and for optional details, reference may be made to one or more of the embodiments of the method as disclosed above or as disclosed in further detail below.

[0092] The system comprises: the at least one biomedical potentiometric electrochemical sensor comprising at least one main electrode with at least one ion-selective membrane; a reference electrode connectable with the at least one main electrode; a counter electrode connectable with and de-connectable from the at least one main electrode; and an impedance analyzer configured to perform at least the following main steps: determining a potential between the at least one main electrode and the reference electrode by a high-impedance potentiometric measurement; connecting the at least one main electrode with a counter electrode and applying the determined potential between the at least one main electrode and the counter electrode; recording electrochemical impedance data by performing an electrochemical impedance spectroscopy measurement (EIS), wherein the electrochemical impedance spectroscopy measurement comprising applying an alternating voltage; de-connecting the at least one main electrode from the counter electrode after applying the alternating voltage.

[0093] The impedance analyzer may comprise and / or may correspond to a multichannel potentiostat.

[0094] The impedance analyzer may be configured for performing the main steps at least partially in an automated manner.

[0095] The system may comprise at least one cartridge which comprises a microfluidic channel in which the at least one biomedical potentiometric electrochemical sensor can be contacted with a fluid. Specifically, the microfluidic channel is configured to guide the fluid with a volume of 5000pL to IpL, specifically 300pL to lOpL, more specifically 210pL to 25pL or 200pL to lOpL; and / or the microfluidic channel is configured to guide the fluid comprising at least one of: an aqueous solution; a quality control sample; a stand-by solution for keeping the at least one biomedical potentiometric electrochemical sensor wetted; a sample fluid, specifically a bodily fluid, more specifically whole blood and / or a component of whole blood, specifically blood serum and / or blood plasma.

[0096] The at least one main electrode may comprise a contact area of 0.1 mm2to 2 cm2.

[0097] The at least one main electrode may comprise and / or may be coated with at least one of the following components: gold, platinum, carbon, carbon paste.

[0098] The at least one ion-selective membrane may have a capacity in the range of 10 pF to 100 pF.

[0099] The at least one biomedical potentiometric electrochemical sensor may comprise and / or correspond to a screen printed electrode and / or a needle type electrode.

[0100] The system further may comprise a processor configured for characterizing the at least one biomedical potentiometric electrochemical sensor based on the recorded electrochemical impedance data. The system may comprise and / or may correspond to at least one of: a blood gas analyzer cartridge, specifically for determining at least one of: pH, pCO2; electrolyte such as Na+, K+, Ca2+, C1-, Urea Ammonium, Li+, Mg2+; a continuous monitoring system, specifically being at least partially implantable; a handheld device; a laboratory analyzer.

[0101] As further used herein, the term "continuous monitoring system" is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to a system configured for continuously acquiring data and / or deriving desired information therefrom. The term "at least partially implantable" as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to embodiments in which a part or component of the system is configured to be insertable into an arbitrary body tissue, wherein other parts may remain outside the body tissue, e.g. an electrode.

[0102] The term "handheld device" as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to an arbitrary, portable device. The handheld device specifically may be configured, by its dimensions and / or its weight, for being carried by a user with a single hand. Thus, as an example, a volume of the handheld device may not exceed 0.001 m3, and / or the weight of the handheld diagnostic device may not exceed 1 kg.

[0103] The term “laboratory analyzer” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. The term specifically may refer, without limitation, to any device configured for performing sample analysis steps. For example, the laboratory analyzer may be a clinical diagnostic analyzer. For example, the laboratory analyzer may be or may comprise at least one ion-selective electrodes (ISE) unit of a cobas® analyzer. The laboratory analyzer may be part of an in-vitro diagnostics (IVD) laboratory. The term “IVD laboratory” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art and is not to be limited to a special or customized meaning. According to some embodiments, the IVD laboratory may be a laboratory designed for performing at least one test on a sample, e.g. a biological sample that has been taken off the human body or animal body. For example, the test on the sample may comprise applying at least one reagent to the sample and monitoring a detectable reaction. According to some embodiments, the IVD laboratory may be a clinical laboratory. According to some embodiments, the IVD laboratory may be a medical laboratory. According to some embodiments, the IVD laboratory may be a forensic laboratory or a blood bank.

[0104] Further disclosed and proposed herein is a computer program including computer-executable instructions for performing the method according to the present invention in one or more of the embodiments enclosed herein when the instructions are executed on a computer or computer network. Specifically, the computer program may be stored on a computer-readable data carrier and / or on a computer-readable storage medium.

[0105] As used herein, the terms “computer-readable data carrier” and “computer-readable storage medium” specifically may refer to non-transitory data storage means, such as a hardware storage medium having stored thereon computer-executable instructions. The computer-readable data carrier or storage medium specifically may be or may comprise a storage medium such as a random-access memory (RAM) and / or a read-only memory (ROM).

[0106] Thus, specifically, one, more than one or even all of method steps connecting the main electrode with the reference electrode; determining a potential between the main electrode and the reference electrode by a high-impedance potentiometric measurement; connecting the one main electrode with the counter electrode and applying the determined potential between the main electrode and the counter electrode; recording electrochemical impedance data by performing an electrochemical impedance spectroscopy measurement (EIS), wherein the electrochemical impedance spectroscopy measurement comprising applying an alternating voltage; de-connecting the main electrode from the counter electrode after applying the alternating voltage; and characterizing the biomedical potentiometric electrochemical sensor based on the recorded electrochemical impedance data, as indicated above may be performed by using a computer or a computer network, preferably by using a computer program.

[0107] Further disclosed and proposed herein is a computer program product having program code means, in order to perform the method according to the present invention in one or more of the embodiments enclosed herein when the program is executed on a computer or computer network. Specifically, the program code means may be stored on a computer-readable data carrier and / or on a computer-readable storage medium.

[0108] Further disclosed and proposed herein is a data carrier having a data structure stored thereon, which, after loading into a computer or computer network, such as into a working memory or main memory of the computer or computer network, may execute the method according to one or more of the embodiments disclosed herein.

[0109] Further disclosed and proposed herein is a non-transient computer-readable medium including instructions that, when executed by one or more processors, cause the one or more processors to perform the method according to the present invention.

[0110] Further disclosed and proposed herein is a computer program product with program code means stored on a machine-readable carrier, in order to perform the method according to one or more of the embodiments disclosed herein, when the program is executed on a computer or computer network. As used herein, a computer program product refers to the program as a tradable product. The product may generally exist in an arbitrary format, such as in a paper format, or on a computer-readable data carrier and / or on a computer-readable storage medium. Specifically, the computer program product may be distributed over a data network. Finally, disclosed and proposed herein is a modulated data signal which contains instructions readable by a computer system or computer network, for performing the method according to one or more of the embodiments disclosed herein.

[0111] Referring to the computer-implemented aspects of the invention, one or more of the method steps or even all of the method steps of the method according to one or more of the embodiments disclosed herein may be performed by using a computer or computer network. Thus, generally, any of the method steps including provision and / or manipulation of data may be performed by using a computer or computer network. Generally, these method steps may include any of the method steps, typically except for method steps requiring manual work, such as providing the samples and / or certain aspects of performing the actual measurements.

[0112] Specifically, further disclosed herein are: a computer or computer network comprising at least one processor, wherein the processor is adapted to perform the method according to one of the embodiments described in this description, a computer loadable data structure that is adapted to perform the method according to one of the embodiments described in this description while the data structure is being executed on a computer, a computer program, wherein the computer program is adapted to perform the method according to one of the embodiments described in this description while the program is being executed on a computer, a computer program comprising program means for performing the method according to one of the embodiments described in this description while the computer program is being executed on a computer or on a computer network, a computer program comprising program means according to the preceding embodiment, wherein the program means are stored on a storage medium readable to a computer, a storage medium, wherein a data structure is stored on the storage medium and wherein the data structure is adapted to perform the method according to one of the embodiments described in this description after having been loaded into a main and / or working storage of a computer or of a computer network, and a computer program product having program code means, wherein the program code means can be stored or are stored on a storage medium, for performing the method according to one of the embodiments described in this description, if the program code means are executed on a computer or on a computer network.

[0113] Summarizing and without excluding further possible embodiments, the following embodiments may be envisaged:

[0114] Embodiment 1. A method of characterizing at least one biomedical potentiometric electrochemical sensor, wherein the biomedical potentiometric electrochemical sensor comprises at least one main electrode with at least one ion-selective membrane, at least one reference electrode, and at least one counter electrode, wherein the method comprises: connecting the main electrode with the reference electrode; determining a potential between the main electrode and the reference electrode by a high-impedance potentiometric measurement; connecting the one main electrode with the counter electrode and applying the determined potential between the main electrode and the counter electrode; recording electrochemical impedance data by performing an electrochemical impedance spectroscopy measurement (EIS), wherein the electrochemical impedance spectroscopy measurement comprising applying an alternating voltage; de-connecting the main electrode from the counter electrode after applying the alternating voltage; and characterizing the biomedical potentiometric electrochemical sensor based on the recorded electrochemical impedance data.

[0115] Embodiment 2. The method of embodiment 1, wherein the performing of the electrochemical impedance spectroscopy measurement comprises: applying a sinusoidal voltage; recording a current response to the applied sinusoidal voltage; and specifically determining a phase shift and an attenuation between the applied sinusoidal voltage and the current response, specifically wherein the characterizing of the at least one biomedical potentiometric electrochemical sensor comprises evaluating and / or analyzing the determined phase shift, the attenuation between the applied sinusoidal voltage and the current response.

[0116] Embodiment 3. The method according to embodiment 2, wherein the sinusoidal voltage has an amplitude between 1 mV and 100 mV, specifically between 5 mV and 30 mV, more specifically between 8 mV and 20 mV and even more specifically at 10 mV; and / or the sinusoidal voltage is applied over a time period of 0.05 s to 5 s, specifically 0.08 s to 3 s and more specifically 1 s to 2 s; and / or the sinusoidal voltage is at least one frequency in a frequency range between 1 Hz and 100 kHz, specifically between 500 Hz and 50 kHz, more specifically between 1 kHz and 40 kHz; and / or the sinusoidal voltage comprises 2 to 500 frequencies, specifically 2 to 100 frequencies, more specifically 4 to 16 frequencies.

[0117] Embodiment 4. The method according to any one of the preceding embodiments, wherein the counter electrode is a low impedance counter electrode.

[0118] Embodiment 5. The method according to any one of the preceding embodiments, wherein the de-connecting of the at least one main electrode from the counter electrode after applying the sinusoidal voltage is performed immediately after applying the sinusoidal voltage and / or in a ns to ps-time range after applying the sinusoidal voltage. Embodiment 6. The method of any one of the preceding embodiments, wherein the at least one biomedical potentiometric electrochemical sensor has an inner resistance between 1 kQand 100 MQ specifically between 50 kQ and 50 MO.

[0119] Embodiment 7. The method according to any one of the preceding embodiments, further comprising de-connecting the at least one main electrode from the reference electrode prior to the connecting of the main electrode with the counter electrode and re-connecting the main electrode with the reference electrode after the recording of the electrochemical impedance data.

[0120] Embodiment 8. The method according to any one of the preceding embodiments, wherein the at least one ion-selective membrane is selective for at least one of Na+, K+, Ca2+, C1-, Urea, pH, Li+, Mg2+, Ammonium.

[0121] Embodiment 9. The method according to any one of the preceding embodiments, wherein the method is performed at least partially while the at least one biomedical potentiometric electrochemical sensor is contacted with a fluid, wherein the fluid comprises at least one of: an aqueous solution; a buffer solution; a quality control sample; a calibrator sample; a stand-by solution for keeping the at least one biomedical potentiometric electrochemical sensor wetted; a sample fluid, specifically a bodily fluid, more specifically whole blood and / or a component of whole blood, specifically blood serum and / or blood plasma; and / or cerebrospinal fluid (CSF); and / or interstitial fluid, and / or wherein the method is performed in-vitro, specifically in a random examination of a batch of cartridges each one comprising the at least one biomedical potentiometric electrochemical sensor by testing at least one cartridge of the batch of cartridges or in-use of at least one cartridge comprising the at least one biomedical potentiometric electrochemical sensor; or wherein the method is performed in-vivo, specifically wherein the at least one biomedical potentiometric electrochemical sensor is implanted in a body and contacted with a bodily fluid, more specifically an interstitial fluid.

[0122] Embodiment 10. The method of any one of the preceding embodiments, further comprising based on a result of characterizing the at least one biomedical potentiometric electrochemical sensor performing at least one failsafe action comprising at least one of: applying at least one correction to a measurement value comprised by the recorded electrochemical impedance data; issuing at least one indication, specifically a warning; dismissing a measurement value comprised by the recorded electrochemical impedance data; de-connecting the at least one biomedical potentiometric electrochemical sensor from a connected component; dismissing the at least one biomedical potentiometric electrochemical sensor, a cartridge comprising the at least one biomedical potentiometric electrochemical sensor and / or an entire batch of cartridges comprising the characterized at least one biomedical potentiometric electrochemical sensor.

[0123] Embodiment 11. A system for characterizing at least one biomedical potentiometric electrochemical sensor, the system comprises: the at least one biomedical potentiometric electrochemical sensor comprising at least one main electrode with at least one ion-selective membrane; a reference electrode connectable with the at least one main electrode; a counter electrode connectable with and de-connectable from the at least one main electrode; and an impedance analyzer configured to perform at least the following main steps: determining a potential between the at least one main electrode and the reference electrode by a high-impedance potentiometric measurement; connecting the at least one main electrode with a counter electrode and applying the determined potential between the at least one main electrode and the counter electrode; recording electrochemical impedance data by performing an electrochemical impedance spectroscopy measurement (EIS), wherein the electrochemical impedance spectroscopy measurement comprising applying an alternating voltage; de-connecting the at least one main electrode from the counter electrode after applying the alternating voltage.

[0124] Embodiment 12. The system of embodiment 11, wherein the impedance analyzer comprises and / or corresponds to a multichannel potentiostat; wherein the impedance analyzer is configured for performing the main steps at least partially in an automated manner.

[0125] Embodiment 13. The system of embodiment 11 or 12, comprising at least one cartridge which comprises a microfluidic channel in which the at least one biomedical potentiometric electrochemical sensor can be contacted with a fluid, specifically wherein the microfluidic channel is configured to guide the fluid with a volume of 5000pL to IpL, specifically 300pL to lOpL, more specifically 210pL to 25pL or 200 pL to lOpL; and / or wherein the microfluidic channel is configured to guide the fluid comprising at least one of an aqueous solution; a quality control sample; a stand-by solution for keeping the at least one biomedical potentiometric electrochemical sensor wetted; a sample fluid, specifically a bodily fluid, more specifically whole blood and / or a component of whole blood, specifically blood serum and / or blood plasma.

[0126] Embodiment 14. The system of any one of embodiments 11 to 13, wherein the at least one main electrode comprises a contact area of 0.1 mm2to 2 cm2; and / or wherein the at least one main electrode comprises and / or is coated with at least one of the following components: gold, platinum, carbon, carbon paste; and / or wherein the at least one ion-selective membrane has a capacity in the range of 10 pF to 100 pF; and / or wherein the at least one biomedical potentiometric electrochemical sensor comprises and / or corresponds to a screen printed electrode and / or a needle type electrode.

[0127] Embodiment 15. The system of any one of embodiments 11 to 14, further comprising a processor configured for characterizing the at least one biomedical potentiometric electrochemical sensor based on the recorded electrochemical impedance data.

[0128] Embodiment 16. The system of any one of embodiments 11 to 15 comprising and / or corresponding to at least one of: a blood gas analyzer cartridge, specifically for determining at least one of: pH, pCO2; electrolyte such as Na+, K+, Ca2+, C1-, Urea Ammonium, Li+, Mg2+; a continuous monitoring system, specifically being at least partially implantable; a handheld device; a laboratory analyzer.

[0129] Short description of the Figures

[0130] Further optional features and embodiments will be disclosed in more detail in the subsequent description of embodiments, preferably in conjunction with the dependent claims. Therein, the respective optional features may be realized in an isolated fashion as well as in any arbitrary feasible combination, as the skilled person will realize. The scope of the invention is not restricted by the preferred embodiments. The embodiments are schematically depicted in the Figures. Therein, identical reference numbers in these Figures refer to identical or functionally comparable elements.

[0131] In the Figures:

[0132] Figure 1 shows an embodiment of a method of characterizing at least one biomedical potentiometric electrochemical sensor; and Figure 2 shows an exemplary embodiment of a system for characterizing at least one biomedical potentiometric electrochemical sensor.

[0133] Detailed description of the embodiments

[0134] Figure 1 shows an embodiment of a method of characterizing at least one biomedical potentiometric electrochemical sensor 110. The characterizing may comprise classifying the biomedical potentiometric electrochemical sensor 110 as “good” in case the sensor generates reliable measurement results and as “bad” for non-reliable measurement results. The quality may relate to sensor aging, wherein an aged sensor may be characterized as bad and a non-aged sensor is characterized as good. The characterizing may comprise quantitatively determining an age of the biomedical potentiometric electrochemical sensor 110 and / or remaining sensor lifetime. The characterizing may further comprise determining structural and material changes of the biomedical potentiometric electrochemical sensor 110. Using electrochemical impedance data can allow determining and / or predicting sensor age and / or sensor aging. Real part and / or imaginary part of impedance change, e.g. in case used membranes become leaky, if electrolyte leaks, if water penetrates into the reference electrolyte, if membranes are clogged.

[0135] The biomedical potentiometric electrochemical sensor 110 may be configured for qualitatively or quantitatively determining the presence and / or the concentration of at least one analyte in a sample. For example, the sample may be a fluid, wherein the fluid comprises at least one of: an aqueous solution; a buffer solution; a quality control sample; a calibrator sample; a stand-by solution for keeping the at least one biomedical potentiometric electrochemical sensor wetted; a sample fluid, specifically a bodily fluid, more specifically whole blood and / or a component of whole blood, specifically blood serum and / or blood plasma; and / or cerebrospinal fluid (CSF); and / or interstitial fluid. For example, the analyte may be a blood gas parameter. As an example, the analyte may be at least one analyte selected from the group consisting of: pH; pCO2; an electrolyte such as Na+, K+, Ca2+, C1-, Urea Ammonium, Li+, Mg2+. However, other analytes may be possible. As shown in Figure 2, the biomedical potentiometric electrochemical sensor 110 comprises at least one main electrode 112 with at least one ion-selective membrane, at least one reference electrode 114, and at least one counter electrode 116, in particular at least one low impedance counter electrode.

[0136] The main electrode 112 may be configured for performing at least one electrochemical detection reaction for detecting the at least one analyte. The main electrode 112 may be contactable with an electrolyte, in particular with a bodily fluid. The at least one main electrode 112 may comprise and / or may be coated with at least one of the following components: gold, platinum, carbon, carbon paste. The main electrode 112 may comprise a contact area of 0.1 mm2to 2 cm2. The contact area may be configured for contacting the bodily fluid.

[0137] The main electrode 112 may be an ion-selective electrode (ISE). The main electrode 112 comprise the ion-selective membrane. The membrane may be configured for allowing only the specific ion to pass through. For example, the at least one ion-selective membrane may be selective for at least one of Na+, K+, Ca2+, C1-, Urea, pH, Li+, Mg2+, Ammonium. For example, the membrane may be selective for a particular ion, such as hydrogen ions (pH) or sodium ions (Na+). The ions having passed the membrane may generate a measurable potential change that is proportional to the ion concentration. Depending on the application, the membrane may comprise different materials. The membrane may comprise at least one polymer or a glass. For example, the polymer may be or may comprise poly(3,4-ethylenedi oxythiophene) (PEDOT), polypyrrole, and poly (3 -octylthiophene) (POT), Poly(vinyl chloride) (PVC), polyurethane derivatives, poly(ethylene oxide) derivatives, carboxylated PVC, hydroxylated PVC, silicone-rubber, sol-gel glass, poly(2-methoxyethylacrylate), heparin-attached cellulose triacetate membrane, NO-releasing polymer films, polymers containing phospholipid polar group, 2-methacryloyloxyethyl phosphorylcholine (MPC), PVC membranes coated by biocompatible copolymers of MPC and an alkyl methacrylate. For example, the membrane may comprise at least one material as described in Setsuko Yajima, Yuri Sonoyama, Ken Suzuki, Keiichi Kimura’Ton-sensor property and blood compatibility of neutral-carrier-type poly(vinyl chloride) membranes coated by phosphorylcholine polymers”, Analytica Chimica Acta, Volume 463, Issue 1, 16 July 2002, Pages 31-37, https: / / doi.org / 10.1016 / 80003-2670(02)00341-0. The at least one ion-selective membrane may have a capacity in the range of 10 pF to 100 pF. The membrane may have even more functionalities, such as providing biocompatibility.

[0138] For example, the biomedical potentiometric electrochemical sensor 110 may be a pH sensor. The main electrode 112 may be embodied as a glass pH electrode. The pH electrode may comprise a glass shaft. Inside the glass shaft an electrical conductor may be arranged. The electrical conductor is connected via a cable to a measurement engine. The membrane, in this case a glass membrane, may be embodied as a, e.g. hemispherically shaped, electrode tip. The electrode tip may be in contact with the sample. The glass of the membrane may be made from hydrogen ion sensitive glass. The membrane may be fused to the shaft. The pH electrode may be partly filled with a buffer solution. The buffer solution may have a pH value of 7. Depending on the sample, H+ ions may diffuse either into or out of the electrode tip leading to a measurable potential change.

[0139] The reference electrode 114 may be configured to provide an electrochemical reference potential which, at least widely, is in-dependent of the presence or absence or concentration of the analyte. The reference electrode 114 may be configured for being or providing a reference for measuring a potential of the main electrode 112. The reference electrode 114 may comprise a housing, e.g. a glass shaft, in which an internal electrode is arranged. The housing and internal electrode may be similar to the design of the main electrode 112. The internal electrode may be immersed into a defined electrolyte. The electrolyte may be in contact with the sample via a liquid junction e.g. via a porous ceramic diaphragm. The liquid junction may allow diffusing of electrolyte out of the housing into the sample, thereby generating an electrical path between the inside of the reference electrode 114 and the main electrode 112. The main electrode 112 and the reference electrode 114 may be designed as separate elements having two separate housings or as combined element wherein the main electrode and the reference electrode are installed in the same housing. The reference electrode may consist of a metal and a poorly soluble salt of the same metal. The reference electrode may be a so-called reference electrode of second order. For example, the reference electrode may be at least one electrode selected from group consisting of: a Hydrogen (H2 / H+) electrode, Silver / Silver Chloride (Ag / AgCl) electrode, Silver / Silver Sulfate (Ag / Ag2SO4) electrode, Calomel (Hg / Hg2C12) electrode, Mercury / Mercurous Sulfate (Hg / Hg2SO4) electrode, Mercury / Mercury Oxide (Hg / HgO) electrode. Other embodiments may be possible. For example, calibration-free potentiometric sensors with solid-contact can be used as reference electrode(s) or as ion-selective electrode(s). For example, the ion-selective electrode may be designed as described in Celeste R. Rousseau, Philippe Biihlmann, “Calibration-free potentiometric sensing with solid-contact ion-selective electrodes”, TrAC Trends in Analytical Chemistry, Volume 140, July 2021, 116277, https: / / d0i.0rg / l 0.1016 / j .trac.2021.116277.

[0140] In the presence of the analyte, the main electrode 112 may develop a potential proportional to the analyte of interest in the sample. The potential may be provided to a measurement engine 118 for further analysis, in particular for determining the concentration of the analyte therefrom. The measurement engine 118 may comprise a processor configured for determining the concentration of the analyte from the potential using a pre-determined, e.g. determined in a calibration measurement, relationship between the potential and the analyte concentration. The relationship may be stored in a database of the measurement engine 118.

[0141] The counter electrode 116 may be an additional electrode which can be used for performing an electrochemical impedance spectroscopy measurement. The counter electrode 116 may be a low impedance counter electrode. For example, the low impedance electrode may have an impedance of 1 mQ to 4 kQ. The impedance may depend on the size of the impedance electrode and composition of materials. The counter electrode may provide an impedance as low as possible, normally in a range between 1 mOhm (almost ideal conductor) and 10 Ohm. In some cases, the counter electrode may be made of pure carbon material, in particular the sensor is very thin and small. In this special case of needle type sensors used for continuous monitoring the impedance can reach up to 4 kOhm or even more. However, the higher the impedance the worse may be the functionality of the counter electrode. Common materials for a counter electrode may be platinum and glassy carbon which provide a very high chemical stability, a wide potential window and a very low impedance. In many applications instead of glassy carbon a carbon coated metal, which lowers the total impedance significantly, can be used. For example gold, palladium, or silver may be coated by carbon paste. Only the carbon paste may have a contact to the analyte, the metal provides the conductive path to the instrument and has no contact to the electrolyte or analytes.

[0142] The at least one biomedical potentiometric electrochemical sensor 110 may comprise and / or correspond to a screen printed electrode and / or a needle type electrode.

[0143] In the embodiment of Figure 1, the method comprises the following method steps (120) connecting the main electrode 112 with the reference electrode 114;

[0144] (122) determining a potential between the main electrode 112 and the reference electrode 114 by a high-impedance potentiometric measurement;

[0145] (124) connecting the main electrode 112 with the counter electrode 116 and applying the determined potential between the main electrode 112 and the counter electrode 116;

[0146] (126) recording electrochemical impedance data by performing an electrochemical impedance spectroscopy measurement (EIS), wherein the electrochemical impedance spectroscopy measurement comprising applying an alternating voltage;

[0147] (128) de-connecting the main electrode from the counter electrode 116 after applying the alternating voltage; and

[0148] (130) characterizing the biomedical potentiometric electrochemical sensor 110 based on the recorded electrochemical impedance data.

[0149] The method according to the present invention allows for impedance spectroscopy. This can allow for detecting and / or monitoring sensor shifts and effects, which lead to corrupt measurement results. The impedance results using specific frequencies or frequency spectra can be used to prevent false measurements and identify defective sensors.

[0150] The method may be performed at least partially while the at least one biomedical potentiometric electrochemical sensor 110 is contacted with a fluid. The fluid may comprise at least one of: an aqueous solution; a buffer solution; a quality control sample; a calibrator sample; a stand-by solution for keeping the at least one biomedical potentiometric electrochemical sensor wetted; a sample fluid, specifically a bodily fluid, more specifically whole blood and / or a component of whole blood, specifically blood serum and / or blood plasma; cerebrospinal fluid (CSF); and / or interstitial fluid. The method may be performed in-vitro. Alternatively, the method may be performed in-vivo.

[0151] Figure 2 shows an exemplary embodiment of a system 134 for characterizing at least one biomedical potentiometric electrochemical sensor 110. The system 134 may be configured for performing a method of characterizing at least one biomedical potentiometric electrochemical sensor 110 according to the present invention such as described with respect to Figure 1.

[0152] The system 134 comprises the at least one biomedical potentiometric electrochemical sensor 110 comprising at least one main electrode 112 with at least one ion-selective membrane, a reference electrode 114 connectable with the at least one main electrode 112 and a counter electrode 116 connectable with and de-conectable from the at least one main electrode 112.

[0153] The determination 122 of a potential between the main electrode 112 and the reference electrode 114 is performed by a high-impedance potentiometric measurement. The potentiometric measurement may be a high-impedance measurement (or current less) since otherwise the half-cells of an electrochemical cell formed by the main electrode and the reference electrode would discharge. The biomedical potentiometric electrochemical sensor 110 may have an inner resistance between 1 kQand 100 MQ specifically between 50 kQ and 50 MQ. After measuring the potential of the biomedical potentiometric electrochemical sensor 110 in the sample this value may be saved in a database, e.g. of the measurement engine. As a result, the measurement engine can automatically take the measured potential as an offset polarization voltage for the electrochemical impedance spectroscopy. The potential may be used as an offset, in particular as a DC offset. The offset can allow performing an EIS measurement of the high impedance biomedical potentiometric electrochemical sensor. Thus, the present invention proposes polarizing of the biomedical potentiometric electrochemical sensor during the EIS measurement. Surprisingly, this can allow performing EIS at high impedance systems. For example, the determined potential (absolute vs. reference electrode) may be between -300 and 300 mV. The offset may be in the same range. The EIS may comprise measuring impedance, i.e. an alternating current resistance, as a function of the frequency of an alternating voltage, e.g. a sinusoidal voltage. Generally, impedance measurements have to be performed at low resistance because currents are measured. However, as outlined above, the biomedical potentiometric electrochemical sensor 110 may be a high impedance sensor such that it would discharge, short-circuit-like, during a measurement at low resistance since its sensor potential collapses. The present invention proposes to prevent this by actively applying the potential determined shortly before which corresponds to a rest potential (current = zero) between main electrode and reference electrode.

[0154] The EIS measurement may be performed between the main electrode 112 and the counter electrode 116. The electrochemical impedance data may comprise a current response to the applied alternating voltage. From the known or measured applied alternating voltage and the measured current response a phase shift and an attenuation between the applied sinusoidal voltage and the current response can be determined.

[0155] The performing 126 of the electrochemical impedance spectroscopy measurement may comprise: applying a sinusoidal voltage; recording a current response to the applied sinusoidal voltage; and specifically determining a phase shift and an attenuation between the applied sinusoidal voltage and the current response, specifically wherein the characterizing of the at least one biomedical potentiometric electrochemical sensor 110 comprises evaluating and / or analyzing the determined phase shift, the attenuation between the applied sinusoidal voltage and the current response.

[0156] The sinusoidal voltage may have an amplitude between 1 mV and 100 mV, specifically between 5 mV and 30 mV, more specifically between 8 mV and 20 mV and even more specifically at 10 mV. The sinusoidal voltage may be applied over a time period of 0.05 s to 5 s, specifically 0.08 s to 3 s and more specifically 1 s to 2 s. The sinusoidal voltage may have at least one frequency in a frequency range between 1 Hz and 100 kHz, specifically between 500 Hz and 50 kHz, more specifically between 1 kHz and 40 kHz. The sinusoidal voltage may comprise 2 to 500 frequencies, specifically 2 to 100 frequencies, more specifically 4 to 16 frequencies.

[0157] The method may comprise performing EIS by using a three-electrode measurement or a two-electrode measurement. For the two-electrode measurement, the method may comprise de-connecting the main electrode 112 from the reference electrode 114 prior to the connecting of the at least one main electrode 112 with the counter electrode 116 and re-connecting the at least one main electrode 112 with the reference electrode 114 after the recording of the electrochemical impedance data.

[0158] For example, the three-electrode measurement may be performed as follows. Impedance may be measured by switching on the counter electrode 116, in particular for draining off a measurement current. The potential may held potentiostatic between reference electrode 114 and main electrode 112 by applying the determined DC offset. In addition, a sinusoidal voltage, e.g. in a range from 1 to 10 mV, may be modulated onto the DC offset and the DC offset and the sinusoidal voltage may be applied between the main electrode 112 and the counter electrode 116. This can allow maintaining all potentials (sinusoidal and DC offset) correctly. This DC offset and the sinusoidal voltage between the main electrode 112 and the counter electrode 116 may result in a current flow between the main electrode and the counter electrode 116 with regard to the AC part of the sinusoidal voltage (the DC offset is the rest potential with current = zero). This technique can allow measuring impedance without sensor discharge. More than one frequency can be applied for the AC voltage which is modulated onto the DC offset, for example 2 to 10, preferably 4 frequencies. The amplitude of the AC voltage which is applied for the impedance measurement is kept constant, and for each different frequency which is used, the current, phase shift and attenuation are measured. The total duration of the impedance measurement does not exceed 800 ms.

[0159] For example, the two-electrode measurement may be performed as follows. The reference electrode 114 may be de-connected from the main electrode 112. The DC offset is applied between the main electrode 112 and the counter electrode 116. A sinusoidal voltage, e.g. in a range from 1 to 10 mV, may be modulated onto the DC offset and an AC response current is measured between the main electrode 112 and the counter electrode 116. Afterwards the counter electrode 116 is de-connected from the main electrode 112 and the reference electrode 114 is re-connected.

[0160] The biomedical potentiometric electrochemical sensor 110 is characterized 130 based on the recorded electrochemical impedance data. For example, the recorded electrochemical impedance data and / or phase shift and attenuation derived from the recorded electrochemical impedance data may be compared to at least one reference value, e.g. which is stored in the database of the measurement engine. The comparison may comprise determining a difference from the reference value. In case the difference from the reference value is within pre-defined tolerances, the biomedical potentiometric electrochemical sensor 110 is characterized as good or non-aged. Otherwise, the biomedical potentiometric electrochemical sensor 110 may be characterized as bad or aged.

[0161] The method may further comprise based on a result of characterizing the at least one biomedical potentiometric electrochemical sensor 110 performing at least one failsafe action comprising at least one of: applying at least one correction to a measurement value comprised by the recorded electrochemical impedance data; issuing at least one indication, specifically a warning; dismissing a measurement value comprised by the recorded electrochemical impedance data; de-connecting the at least one biomedical potentiometric electrochemical sensor from a connected component; dismissing the at least one biomedical potentiometric electrochemical sensor, a cartridge comprising the at least one biomedical potentiometric electrochemical sensor and / or an entire batch of cartridges comprising the characterized at least one biomedical potentiometric electrochemical sensor. The failsafe action may be performed by using at least one user interface.

[0162] The method may be performed by the manufacturer and / or during operation of the biomedical potentiometric electrochemical sensor, e.g. in-line or in-use. For example, the method may be performed repeatedly, e.g. at pre-defined times or continuously. The method may comprise using a multichannel potentiostat configured for measuring potential between the main and reference electrode and performing the EIS measurement. The method may be performed automatically. As shown in Figure 2, the system 134 for performing the method according to the present invention for characterizing the at least one biomedical potentiometric electrochemical sensor 110 may comprise at least one impedance analyzer 136. The method steps may be performed at least partially and / or automatically by the impedance analyzer 136. The impedance analyzer 136 may be configured for determining information indicative for impedance. The impedance analyzer 136 may be configured for one or more of determining a potential between two electrodes, connecting and / or de-connecting an electrode, applying at least one voltage, recording electrochemical impedance data and evaluating the recorded electrochemical impedance data.

[0163] The impedance analyzer 136 may comprise at least one potentiometric measurement unit 138, at least one frequency response analyzer unit 140, at least one switch matrix 142, and electrode connectors for connecting the respective electrode and a corresponding switch of the switch matrix. For example, the system for performing the method according to the present invention for characterizing the at least one biomedical potentiometric electrochemical sensor may operate completely computer controlled, and / or the method of characterizing at least one biomedical potentiometric electrochemical sensor 110 may be performed completely computer controlled.

[0164] The potentiometric measurement unit 138 may have a very high input impedance.

[0165] The potentiometric measurement unit 138 may be configured for measuring an equilibrium potential, E equ, between two of the electrodes. The equilibrium potential may be the potential when the sum of all currents flowing from one electrode to the other is zero. The equilibrium potential may be a strictly thermodynamic parameter of an electrode where no electron transfer processes occur.

[0166] The frequency response analyzer unit 140 may be configured for measuring the impedance between two electrodes by adding the equilibrium potential E equ as a DC offset and applying a sinusoidal voltage. This DC offset may prevent a current flow between the two electrodes. The sinusoidal voltage of a very small amplitude, e.g. of 10 mVpp, may be modulated over the equilibrium potential and actively applied between two electrodes. The complete signal which is applied between two electrodes can be described as u(t) = E_equ + A • sin(cot + (pl) with A = const, and is the amplitude of the sinusoidal wave [V], < 10 mVpp, co = 2-7t-f is the angular frequency [Hz], (pl is the phase of the stimulation potential [degree], and E equ is the equilibrium potential [V],

[0167] The frequency response analyzer unit 140 may be configured for measuring, in particular simultaneously, the, in particular very small, AC current between the two electrodes. The AC current between the two electrodes may also be a sine wave: i(t) = B-sin(cot + (p2) with i(t) is the sinusoidal wave of the AC current, measured by the frequency response analyzer unit as system response, B is the amplitude of the AC current [A], range 10 pA ... 100 nA, co = 2-7t-f is the Angular frequency [Hz], (p2 is the phase of the resulting current [degree].

[0168] The frequency response analyzer unit 140 may be configured for calculating output parameters such as one or more of amplitude, phase shift, impedance, real part and imaginary part. The absolute value |Z| of the impedance Z may be calculated by the frequency response analyzer unit:

[0169] |Z| = A / B (corresponding to Ohm’s Law).

[0170] The phase shift A(p = |(p2 — (pl | may be measured between the stimulating potential u(t) and the resulting current i(t). The Real Part Re(Z) and the imaginary part Im(Z) of the impedance Z may be calculated as follows:

[0171] Re(Z) = |Z| • cos(A(p)

[0172] Im(Z) = |Z| • sin(A(p)

[0173] The impedance is defined from Euler’s formula:

[0174] Z = Re(Z) + j-Im(Z) = |Z| • [cos(A(p) + j-sin(A(p)] = |Z|-exp(j • A(p)

[0175] The admittance Y is calculated from the impedance Z: Y = 1 / Z.

[0176] The switch matrix 142 may be a fast switch matrix. The switch matrix 142 comprises at least three independent switches, in particular fast switches denoted as FS1, FS2 and FS3. A first switch FS1 of the switch matrix 142 may be configured for connecting the main electrode 112 to the potentiometric measurement unit 138, e.g. by using a first position 1 of the first switch FS1, or to frequency response analyzer unit 140, e.g. using a second position 2 of the first switch FS1. A second switch FS2 of the switch matrix 142, may be configured for connecting the reference electrode 114 to the potentiometric measurement unit 138, e.g. by using a first position 3 of the second switch FS2, or to frequency response analyzer unit 140, e.g. using a second position 4 of the second switch FS2. A third switch FS3 of the switch matrix 142 may be configured for connecting the counter electrode 116 to the potentiometric measurement unit 138, e.g. by using a first position 5 of the third switch FS3, or to frequency response analyzer unit 140, e.g. using a second position 6 of the third switch FS3.

[0177] The connecting of the main electrode 112 and the reference electrode 114 may be performed using the first switch FS1 and the second switch FS2 of the switch matrix 142. The connecting of the main electrode 112 and the counter electrode 116 may be performed using the first switch FS1 and the third switch FS3 of the switch matrix 142. The connecting may be performed manually and / or automatically by a processor.

[0178] The de-connecting of the main electrode 112 and the reference electrode 114 may be performed using the first switch FS1 and the second switch FS2 of the switch matrix 142. The de-connecting of the main electrode 112 and the counter electrode 116 may be performed using the first switch FS1 and the third switch FS3 of the switch matrix 142. The de-connecting may be performed manually and / or automatically by a processor.

[0179] For example, a workflow for measuring the analyte concentration and the impedance of the main electrode 112 may comprise the following steps: configuring of the switch matrix 142 for connecting the main electrode 112 with the reference electrode 114 and the counter electrode 116, wherein in particular the first switch FS1 is set to its first position 1 and may connect the main electrode 112 to the potentiometric measurement unit 138, the second switch FS2 is set to its first position 3 and may connect the reference electrode 114 to the potentiometric measurement unit 138 and the third switch FS3 is set to its first position 5 and may connect the counter electrode 116 to the potentiometric measurement unit 138; measuring an equilibrium potential E equl between the main electrode 223 and the reference electrode 114, wherein E equl may be used for the determination of the analyte concentration; measuring an equilibrium potential E_equ2 between the main electrode 112 and the counter electrode 116, wherein E_equ2 may be used to prevent any current flow between the counter electrode 116 and the main electrode 112; configuring of the switch matrix 142 for connecting the main electrode 112 and the counter electrode 116 to the frequency response analyzer unit 140, wherein in particular the first switch FS1 is set to its second position 2 and may connect the main electrode 112 to the frequency response analyzer unit 140 and the third switch FS3 is set to its second position 6 and may connect the counter electrode 116 to the frequency response analyzer unit 140; applying on the frequency response analyzer unit 140 the equilibrium potential E_equ2 between the main electrode 112 and the counter electrode 116 and measuring the impedance of the main electrode 112; configuring of the switch matrix 142 for connecting the main electrode 112 to the potentiometric measurement unit 138, wherein in particular the first switch FS1 is set to its first position 1 and may connect the main electrode 112 to the potentiometric measurement unit 138, wherein the counter electrode 116 can be stayed connected to the frequency response analyzer unit 140, thereby de-connecting the main electrode 112 from the counter electrode 116 after applying the alternating voltage.

[0180] The total time of the steps of configuring of the switch matrix 142 for connecting the main electrode 112 and the counter electrode 116 to the frequency response analyzer unit 140, applying on the frequency response analyzer unit 140 the equilibrium potential E_equ2 and deconnecting with the counter electrode 116 should happen in a time as short as possible between 10 ms to max. 250 ms. This can allow keeping unnecessary electrochemical stress away from the main electrode 112.

[0181] For example, a workflow for measuring the analyte concentration and the impedance of the reference electrode 114 may comprise the following steps: configuring of the switch matrix 142 for connecting the main electrode 112, the reference electrode 114 and the counter electrode 116 with the potentiometric measurement unit 138, wherein in particular the first switch FS1 is set to its first position 1 and may connect the main electrode 112 to the potentiometric measurement unit 138, the second switch FS2 is set to its first position 3 and may connect the reference electrode 114 to the potentiometric measurement unit 138 and the third switch FS3 is set to its first position 5 and may connect the counter electrode 116 to the potentiometric measurement unit 138; measuring an equilibrium potential E equl between the main electrode 112 and the reference electrode 114, wherein E equl may be used for the determination of the analyte concentration; measuring an equilibrium potential E_equ3 between the reference electrode 114 and the counter electrode 116, wherein E_equ3 may be used to prevent any current flow between the counter electrode 116 and the reference electrode 114; configuring of the switch matrix 142 for connecting the reference electrode 114 and the counter electrode 116 to the frequency response analyzer unit 140, wherein in particular the second switch FS2 is set to its second position 4 and may connect the reference electrode 114 to the frequency response analyzer unit 140 and the third switch FS3 is set to its second position 6 and may connect the counter electrode 116 to the frequency response analyzer unit 140; applying on the frequency response analyzer unit 140 the equilibrium potential E_equ3 between the reference electrode 114 and the counter electrode 116 and measuring the impedance of the reference electrode 114; configuring of the switch matrix 142 for connecting the reference electrode 114 to the potentiometric measurement unit 138, wherein in particular the second switch FS2 is set to its first position 3 and may connect the reference electrode 114 to the potentiometric measurement unit 138, wherein the counter electrode 116 can be stayed connected to the frequency response analyzer unit 140, thereby de-connecting the reference electrode 114 from the counter electrode 116 after applying the alternating voltage.

[0182] The total time of the steps of configuring of the switch matrix 142 for connecting the reference electrode 114 and the counter electrode 116 to the frequency response analyzer unit 140, applying on the frequency response analyzer unit 140 the equilibrium potential E_equ3 and configuring of the switch matrix 142 for connecting the reference electrode 114 to the potentiometric measurement unit 138 and deconnecting with the counter electrode 116 114 should happen in a time as short as possible between 10 ms to max. 250 ms. The intention is to keep unnecessary electrochemical stress away from the reference electrode.

[0183] For example, a workflow for measuring the analyte concentration and the impedance between the main electrode 112 and the reference electrode 114 may comprise the following steps: configuring of the switch matrix 142 for connecting the main electrode 112, the reference electrode 114 and the counter electrode 116 with the potentiometric measurement unit 138, wherein in particular the first switch FS1 is set to its first position 1 and may connect the main electrode 112 to the potentiometric measurement unit 138, the second switch FS2 is set to its first position 3 and may connect the reference electrodell4 to the potentiometric measurement unit 138 and the third switch FS3 is set to its first position 5 and may connect the counter electrode 116 to the potentiometric measurement unit 138; measuring an equilibrium potential E equl between the main electrode 112 and the reference electrode 114, wherein E equl may be used for the determination of the analyte concentration; configuring of the switch matrix 142 for connecting the main electrode 112 and the reference electrode 114 to the frequency response analyzer unit 140, wherein in particular the first switch FS1 is set to its second position 2 and may connect the main electrode 112 to the frequency response analyzer unit 140 and the second switch FS2 is set to its second position 4 and may connect the reference electrode 114 to the frequency response analyzer unit 140; applying on the frequency response analyzer unit 140 the equilibrium potential E equl between the main electrode 112 and the reference electrode 114 and measuring the impedance between the main electrode 112 and the reference electrode 114; configuring of the switch matrix 142 for connecting the main electrode 112 and the reference electrode 114 to the potentiometric measurement unit 138, wherein in particular the first switch FS1 is set to its first position 1 and may connect the main electrode 112 to the potentiometric measurement unit 138 and the second switch FS2 is set to its first position 3 and may connect the reference electrode 114 to the potentiometric measurement unit 138. The total time of the steps of configuring of the switch matrix for connecting the main electrode and the reference electrode to the frequency response analyzer unit, applying on the frequency response analyzer unit the equilibrium potential E equl and configuring of the switch matrix for connecting the main electrode 112 and the reference electrode 114 to the potentiometric measurement unit 138 should happen in a time as short as possible between 10 ms to max. 250 ms. The intention is to keep unnecessary electrochemical stress away from the main electrode and the reference electrode.

[0184] The main electrode 112 and the reference electrode 114 may be used for performing detecting the at least one analyte of interest, in particular for measuring the concentration of the at least one analyte of interest. The main electrode 112 may be contactable with a sample 146, e.g. an electrolyte solution suspected to comprise the analyte of interest. The sample 146 may be hold by a vessel, e.g. a disposable vessel 148. The method may comprise contacting the main electrode 112, the reference electrode 114 and the counter electrode 116 with the sample 146.

[0185] The disposable vessel 148 may comprise a microfluidic channel in which the at least one biomedical potentiometric electrochemical sensor can be contacted with a fluid. Specifically, the microfluidic channel is configured to guide the fluid with a volume of 5000pL to IpL, specifically 300pL to lOpL, more specifically 210pL to 25pL or 200pL to lOpL; and / or the microfluidic channel is configured to guide the fluid comprising at least one of: an aqueous solution; a quality control sample; a stand-by solution for keeping the at least one biomedical potentiometric electrochemical sensor wetted; a sample fluid, specifically a bodily fluid, more specifically whole blood and / or a component of whole blood, specifically blood serum and / or blood plasma.

[0186] The impedance analyzer 136 may comprise at least one voltage generator device 132. The voltage generator device 132 may comprise at least one voltage source. The voltage generator device 132 may comprise at least one function generator selected from the group consisting of: at least one square wave generator and at least one sine wave generator. The impedance analyzer 136 may comprise and / or may correspond to potentiostat such as a multichannel potentiostat. The impedance analyzer 136 may comprise the named electrodes. The impedance analyzer 136 may comprise at least one electric circuit configured for one or more of connecting the electrodes, de-connecting the electrodes, applying a voltage, recording impedance data. The electric circuit may comprise at least one operational amplifier. The impedance analyzer 136 may comprise at least one measurement channel configured for performing an impedance measurement. The impedance analyzer 136 may comprise a plurality of measurement channels, e.g. the impedance analyzer 136 may be and / or may comprise a multi-channel potentiostat. The multi-channel potentiostat may comprise a plurality of measurement channels configured for performing a plurality of measurements in parallel. The impedance analyzer 136 may comprise the at least one measurement engine 118. The measurement engine 118 may be configured for characterizing the biomedical potentiometric electrochemical sensor 110 based on the recorded electrochemical impedance data. The measurement engine 118 may comprise a processor. The impedance analyzer 136 may comprise and / or may correspond to a multichannel potentiostat. The impedance analyzer 136 may be configured for performing the steps of the method according to the present invention at least partially in an automated manner.

[0187] The system 134 may comprise and / or may correspond to at least one of a blood gas analyzer cartridge, specifically for determining at least one of pH, pCO2; electrolyte such as Na+, K+, Ca2+, C1-, Urea Ammonium, Li+, Mg2+; a continuous monitoring system, specifically being at least partially implantable; a handheld device; a laboratory analyzer.

[0188] List of reference numbers

[0189] 110 biomedical potentiometric electrochemical sensor

[0190] 112 main electrode

[0191] 114 reference electrode

[0192] 116 counter electrode

[0193] 118 measurement engine

[0194] 120 connecting

[0195] 122 determining a potential

[0196] 124 connecting

[0197] 126 recording electrochemical impedance data

[0198] 128 de-connecting

[0199] 130 characterizing

[0200] 132 voltage generator device

[0201] 134 system

[0202] 136 impedance analyzer

[0203] 138 potentiometric measurement unit

[0204] 140 frequency response analyzer unit

[0205] 142 switch matrix

[0206] 144 electrode connectors

[0207] 146 sample

[0208] 148 disposable vessel

[0209] FS1 first switch

[0210] FS2 second switch

[0211] FS3 third switch

[0212] 1 first position of the first switch

[0213] 2 second position of the first switch

[0214] 3 first position of the second switch

[0215] 4 second position of the second switch

[0216] 5 first position of the third switch

[0217] 6 second position of the third switch

Claims

Roche Diagnostics GmbHClaims1. A method of characterizing at least one biomedical potentiometric electrochemical sensor (110), wherein the biomedical potentiometric electrochemical sensor (110) comprises at least one main electrode (112) with at least one ion-selective membrane, at least one reference electrode (114), and at least one counter electrode (116), wherein the method comprises:(120) connecting the main electrode (112) with the reference electrode (114);(122) determining a potential between the main electrode (112) and the reference electrode (114) by a high-impedance potentiometric measurement;(124) connecting the one main electrode (112) with the counter electrode (116) and applying the determined potential between the main electrode (112) and the counter electrode (116);(126) recording electrochemical impedance data by performing an electrochemical impedance spectroscopy measurement (EIS), wherein the electrochemical impedance spectroscopy measurement comprising applying an alternating voltage;(128) de-connecting the main electrode (112) from the counter electrode (116) after applying the alternating voltage; and(130) characterizing the biomedical potentiometric electrochemical sensor (110) based on the recorded electrochemical impedance data.

2. The method of claim 1, wherein the performing of the electrochemical impedance spectroscopy measurement comprises:applying a sinusoidal voltage; recording a current response to the applied sinusoidal voltage; and specifically determining a phase shift and an attenuation between the applied sinusoidal voltage and the current response, specifically wherein the characterizing of the at least one biomedical potentiometric electrochemical sensor (110) comprises evaluating and / or analyzing the determined phase shift, the attenuation between the applied sinusoidal voltage and the current response.

3. The method according to claim 2, wherein the sinusoidal voltage has an amplitude between 1 mV and 100 mV, specifically between 5 mV and 30 mV, more specifically between 8 mV and 20 mV and even more specifically at 10 mV; and / or the sinusoidal voltage is applied over a time period of 0.05 s to 5 s, specifically 0.08 s to 3 s and more specifically 1 s to 2 s; and / or the sinusoidal voltage is at least one frequency in a frequency range between 1 Hz and 100 kHz, specifically between 500 Hz and 50 kHz, more specifically between 1 kHz and 40 kHz; and / or the sinusoidal voltage comprises 2 to 500 frequencies, specifically 2 to 100 frequencies, more specifically 4 to 16 frequencies.

4. The method according to any of the proceeding claims, wherein the electrochemical impedance spectroscopy measurement comprises applying an alternating voltage at one predefined frequency, and wherein the characterizing of the at least one biomedical potentiometric electrochemical sensor (110) comprises evaluating and / or analyzing the determined phase shift, the attenuation between the applied sinusoidal voltage and the current response exactly once at this predefined frequency.

5. The method according to any of claims 1 to 3, wherein the electrochemical impedance spectroscopy measurement comprises applying an alternating voltage with an amplitude which is kept constant during the measurement, and modifying the frequency of the alternating voltage over time during the measurement, wherein the characterizing of the at least one biomedical potentiometric electrochemical sensor (110) comprises evaluating and / or analyzing the determined phase shift, the attenuation between the applied sinusoidal voltage and the current response for a plurality of frequencies of the alternating voltage, preferably for 2 to 16 frequencies.

6. The method according to any one of the preceding claims, wherein the counter electrode (116) is a low impedance counter electrode.

7. The method according to any one of the preceding claims, wherein the de-connecting (128) of the at least one main electrode (112) from the counter electrode (116) after applying the sinusoidal voltage is performed immediately after applying the sinusoidal voltage and / or in a ns to ps-time range after applying the sinusoidal voltage.

8. The method of any one of the preceding claims, wherein the at least one biomedical potentiometric electrochemical sensor (110) has an inner resistance between 1 kQ and 100 MQ specifically between 50 kQ and 50 MO.

9. The method according to any one of the preceding claims, further comprising de-connecting the at least one main electrode (112) from the reference electrode (114) prior to the connecting of the main electrode (112) with the counter electrode (116) andre-connecting the main electrode (112) with the reference electrode (114) after the recording of the electrochemical impedance data.

10. The method according to any one of the preceding claims, wherein the at least one ion-selective membrane is selective for at least one of Na+, K+, Ca2+, C1-, Urea, pH, Li+, Mg2+, Ammonium.

11. The method according to any one of the preceding claims, wherein the method is performed at least partially while the at least one biomedical potentiometric electrochemical sensor (110) is contacted with a fluid, wherein the fluid comprises at least one of: an aqueous solution; a buffer solution; a quality control sample; a calibrator sample; a stand-by solution for keeping the at least one biomedical potentiometric electrochemical sensor (110) wetted; a sample fluid, specifically a bodily fluid, more specifically whole blood and / or a component of whole blood, specifically blood serum and / or blood plasma; and / or cerebrospinal fluid (CSF); and / or interstitial fluid, and / or wherein the method is performed in-vitro, specifically in a random examination of a batch of cartridges each one comprising the at least one biomedical potentiometric electrochemical sensor (110) by testing at least one cartridge of the batch of cartridges or in-use of at least one cartridge comprising the at least one biomedical potentiometric electrochemical sensor (110); or wherein the method is performed in-vivo, specifically wherein the at least one biomedical potentiometric electrochemical sensor (110) is implanted in a body and contacted with a bodily fluid, more specifically an interstitial fluid.

12. The method of any one of the preceding claims, further comprising based on a result of characterizing the at least one biomedical potentiometric electrochemical sensor (110) performing at least one failsafe action comprising at least one of: applying at least one correction to a measurement value comprised by the recorded electrochemical impedance data; issuing at least one indication, specifically a warning; dismissing ameasurement value comprised by the recorded electrochemical impedance data; de-connecting the at least one biomedical potentiometric electrochemical sensor (110) from a connected component; dismissing the at least one biomedical potentiometric electrochemical sensor (110), a cartridge comprising the at least one biomedical potentiometric electrochemical sensor (110) and / or an entire batch of cartridges comprising the characterized at least one biomedical potentiometric electrochemical sensor (110).

13. A system (134) for characterizing at least one biomedical potentiometric electrochemical sensor (110), the system (134) comprises: the at least one biomedical potentiometric electrochemical sensor (110) comprising at least one main electrode (112) with at least one ion-selective membrane; a reference electrode (114) connectable with the at least one main electrode (112); a counter electrode (116) connectable with and de-conectable from the at least one main electrode (112); and an impedance analyzer (136) configured to perform at least the following main steps: determining a potential between the at least one main electrode (112) and the reference electrode (114) by a high-impedance potentiometric measurement; connecting the at least one main electrode (112) with a counter electrode (114) and applying the determined potential between the at least one main electrode (112) and the counter electrode (116); recording electrochemical impedance data by performing an electrochemical impedance spectroscopy measurement (EIS), wherein the electrochemical impedance spectroscopy measurement comprising applying an alternating voltage; de-connecting the at least one main electrode (112) from the counter electrode (116) after applying the alternating voltage; and(130) characterizing the biomedical potentiometric electrochemical sensor (110) based on the recorded electrochemical impedance data.

14. The system (134) of claim 13, wherein the impedance analyzer (136) comprises and / or corresponds to a multichannel potentiostat; wherein the impedance analyzer (136) is configured for performing the main steps at least partially in an automated manner.

15. The system of claim 13 or 14, comprising at least one cartridge which comprises a microfluidic channel in which the at least one biomedical potentiometric electrochemical sensor (110) can be contacted with a fluid, specifically wherein the microfluidic channel is configured to guide the fluid with a volume of 5000pL to IpL, specifically 300pL to lOpL, more specifically 210pL to 25 pL or 200pL to lOpL; and / or wherein the microfluidic channel is configured to guide the fluid comprising at least one of: an aqueous solution; a quality control sample; a stand-by solution for keeping the at least one biomedical potentiometric electrochemical sensor (110) wetted; a sample fluid, specifically a bodily fluid, more specifically whole blood and / or a component of whole blood, specifically blood serum and / or blood plasma.

16. The system (134) of any one of claims 13 to 15, wherein the at least one main electrode (112) comprises a contact area of 0.1 mm2to 2 cm2; and / or wherein the at least one main electrode (112) comprises and / or is coated with at least one of the following components: gold, platinum, carbon, carbon paste; and / or wherein the at least one ion-selective membrane has a capacity in the range of 10 pF to 100 pF; and / or wherein the at least one biomedical potentiometric electrochemical sensor comprises and / or corresponds to a screen printed electrode and / or a needle type electrode.

17. The system (134) of any one of claims 13 to 16 comprising and / or corresponding to at least one of: a blood gas analyzer cartridge, specifically for determining at least one of: pH, pCO2; electrolyte such as Na+, K+, Ca2+, C1-, Urea Ammonium, Li+, Mg2+; a continuous monitoring system, specifically being at least partially implantable; a handheld device; a laboratory analyzer.

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