Electrochemical measurement with additional reference measurement

Abstract

A method for measuring one or more potential differences indicative of one or more concentrations of one or more analyte ions in a sample (102), such as a liquid whole blood sample, is presented herein, the method comprising measuring, with a reference ion measurement device (104), a parameter indicative of a concentration of a reference ion in the sample, wherein the reference ion measurement device (104) is different from an electroanalytical measurement device, measuring one or more potential differences between each of one or more optionally solid state working electrodes directly or indirectly with an analyte ion measurement device (105), wherein each of the one or more optionally solid state working electrodes comprises an ion selective electrode selective for the analyte ion and an optionally solid state reference electrode selective for the reference ion, wherein the analyte ion measurement device is an electroanalytical device. An apparatus (100) and use of the apparatus are also presented herein.

Description

Technical Field

[0001] The present invention relates to a method for measuring parameters indicating the concentration of analyte ions in an indicator liquid, and more specifically, to a method for measuring one or more potential differences of one or more concentrations of one or more analyte ions in an indicator sample, such as a liquid whole blood sample, and also to a corresponding apparatus and the use of such an apparatus. Background Technology

[0002] For a variety of reasons, it is generally advantageous to be able to determine one or more potential differences that indicate one or more concentrations of one or more analyte ions in a sample, such as a liquid whole blood sample. However, doing so may involve expensive, complex and / or inaccurate equipment that may also require large sample volumes and may additionally have a limited lifespan and / or be easily damaged.

[0003] Therefore, there is a need for an improved method and apparatus for measuring one or more potential differences indicating the concentration of one or more analyte ions in a sample, such as a liquid whole blood sample, and in particular, there is a need for an improved method and apparatus that is more cost-effective, simpler, more accurate, capable of operating with smaller sample volumes, and also more durable and / or less prone to damage. Summary of the Invention

[0004] One object of the present invention is to provide an improved method and apparatus that overcomes at least some of the drawbacks of known methods and apparatus for measuring one or more potential differences indicating one or more concentrations of one or more analyte ions in a sample, such as a liquid whole blood sample. Additionally or alternatively, an object of the present invention is to provide alternatives to known methods and apparatus.

[0005] According to a first aspect, the present invention provides a method for measuring one or more potential differences indicating the concentration of one or more analyte ions in a sample, such as a liquid whole blood sample, and optionally further determining the concentration of one or more analyte ions, the method comprising,

[0006] -Optionally, the equipment according to the second aspect shall be provided.

[0007] - A parameter indicating the concentration of a reference ion in the sample is measured using a reference ion measuring device (104), which is different from an electroanalytical measuring device, and optionally further determines the concentration of the reference ion, and

[0008] - Measure one or more potential differences between the following, directly or indirectly, using an analyte ion measuring device, which indicate one or more concentrations of one or more analyte ions in the sample:

[0009] i. Each of one or more working electrodes, such as one or more solid-state working electrodes, each of the working electrodes comprising an ion-selective electrode having selectivity for analyte ions, and

[0010] ii. A reference electrode, such as a solid-state reference electrode, which is selective for reference ions.

[0011] The analyte ion measuring device is an electroanalytical device, such as a potential measuring device.

[0012] - and optionally, determine the concentration of the one or more analyte ions.

[0013] One advantage of the present invention may be that the reference ion measuring device makes it possible to eliminate the need for a reference electrode with a known or predictably varying potential, such as eliminating the need for a reference electrode with a stable potential, or eliminating the need for conditions on a reference electrode with a potential that are known or can be predicted. This may in turn result in one or more more cost-effective, simpler and / or more accurate methods that can be additionally more durable and / or less susceptible to damage, and / or allow operation with smaller sample volumes.

[0014] The key point of the invention can be viewed as realizing that providing a constant, known, or predictably varying potential can be advantageously replaced by the measurement of the concentration of a reference ion, which reduces the requirements for a reference electrode (e.g., by not requiring the electrode to maintain a constant potential) and / or the requirements for the measurement solution, such as liquid whole blood (e.g., by not requiring the parameters of the measurement solution, such as the concentration of the reference ion, to be known or predictable).

[0015] For example, instead of relying on a reference electrode with a nominally known potential, such as a standard hydrogen electrode (SHE), which utilizes an aqueous electrode, a solid-state ion-selective electrode, such as a pH-sensitive solid-state electrode (and additionally a reference measuring device for pH measurement), can be used as a reference. Aqueous reference electrodes can be circumstantial, expensive, space-consuming (e.g., due to the liquid-liquid interface and a separate electrolyte solution chamber), and may have a limited lifespan due to ion loss from the electrolyte chamber to the sample and / or rinse solution. Furthermore, ion loss itself can lead to contamination problems of the sample and / or rinse solution, which can introduce measurement errors and a loss of accuracy. Ion leakage from aqueous reference electrodes may require a large distance between the working and reference electrodes, which could in turn increase size and require a larger sample volume (where a large volume may be particularly detrimental for whole blood samples in some cases, such as for neonates and / or intensive care patients).

[0016] As another example, instead of relying on a reference electrode that varies with conditions, and further on knowing or predicting the measurement conditions, it is possible to use an ion-selective electrode, such as a pH-sensitive solid-state electrode, as a reference, and to measure the concentration of the reference ion, such as via a device for measuring pH. An advantage of measuring the concentration of the reference ion is that it improves the accuracy of determining the concentration of the analyte ion, where this improvement stems from the increased accuracy of the reference ion concentration due to the measurement being more precise than the assumption or prediction. Furthermore, an advantage of measuring the concentration of the reference ion can be seen as extending the applicability of the method to applications where conditions, such as the concentration of the reference ion, are unknown or unpredictable. For example, when relying on a known constant concentration of a particular reference ion or when the concentration of a particular reference ion behaves in a predictable manner, the selection of the reference ion is limited to reference ions (candidate ions) whose concentration is known and constant or behaves in a predictable manner. This can be disadvantageous for several reasons, including that no (reference) ion concentration is truly constant between individuals (e.g., for different people), and / or there may be no overlap between the applicable reference ion and the optimal ion-selective reference electrode (in other words, it may be necessary to use a suboptimal reference electrode because the concentration of the reference ion to which the optimal reference electrode is specific is not known and constant or predictable). Conversely, in embodiments according to the invention, the reference ion can be freely chosen, for example, according to the optimal reference (ion-specific) electrode. This may, in turn, benefit the accuracy of the reference ion measuring device, and thus potentially benefit the overall accuracy for determining the analyte ion concentration.

[0017] "Measuring one or more potential differences" should be understood as common in the art (where a potential difference is a difference in potentials), such as measuring one or more voltages, such as DC voltages. Such a potential difference can be measured, for example, by a potential determination method. It should be understood that in the case of multiple potential differences, each potential difference will be measured between a reference electrode and a (corresponding) working electrode.

[0018] "Indicating one or more concentrations of one or more analyte ions in a sample" should be understood as the method being arranged such that the measured potential difference each indicates the concentration of one ion or a group of ions in the sample.

[0019] "Indication concentration" can generally be understood as a concentration that can be determined. For example, a potential difference (which is not a concentration in itself) is measured and makes it possible to determine the concentration. Determining the concentration can be understood as qualitatively detecting the presence (yes / no) of an analyte, such as when the concentration exceeds the detection limit, and quantitatively determining the concentration, such as on sequential, interval, or ratio-type scales.

[0020] A "reference ion" is understood to be any ion that may naturally exist in whole blood, and in the sense that a (reference) electrode selectively used for a (reference) ion can be used as a reference electrode (such as a reference electrode in a potential measuring device). Reference ions can be, for example, hydrogen ions (H+), sodium ions (Na+), potassium ions (K+), calcium ions (Ca2+), chloride ions (Cl-), magnesium ions (Mg2+), or bicarbonate ions (HCO3-).

[0021] "Reference ion measuring device" is understood as any device capable of determining parameters indicating the concentration of a reference ion (wherein a reference ion can typically be understood as a single, specific reference ion or a group of reference ions), such as a device arranged to optically probe a sample (such as a whole blood sample) and determine its optical parameters indicating the concentration of a reference ion.

[0022] The reference ion measuring device can be selective for a single ion or a group of ions.

[0023] The reference ion measuring device is (cross-)selective to some extent to one or more interfering ions. However, the reference ion measuring device can be understood as being more selective to one ion or group of ions than another ion or group of ions (e.g., a selectivity coefficient for interfering ions less than 1.0, less than 0.9, less than 0.5, less than 0.1, less than 0.07, less than 0.05, less than 0.03, less than 0.02, less than 0.01).

[0024] It is generally advantageous for cross-selectivity to be negligible or zero, for example, because it eliminates the need to take cross-selectivity into account. It is still advantageous if cross-selectivity is non-zero, such as non-negligible, or if it is below a certain threshold, such as a selectivity coefficient for interfering ions less than 1.0, less than 0.9, less than 0.5, less than 0.1, less than 0.07, less than 0.05, less than 0.03, less than 0.02, or less than 0.01, because if cross-selectivity is sufficiently low (e.g., a selectivity coefficient for interfering ions less than 1.0), it is still possible to make corrections and take cross-selectivity into account, and the measurement can still be utilized.

[0025] According to one embodiment, the reference ion is a single specific ion or a group of ions, and there is no actual cross-selectivity in the reference ion measuring device or reference electrode.

[0026] According to another embodiment, the reference ion is a single specific ion or a group of ions, and there is cross-selectivity in the reference ion measuring device and / or reference electrode, and each cross-selectivity is accounted for, for example, by measuring and / or estimating the concentration of each of one or more interference types and taking into account these one or more concentrations.

[0027] "Electroanalytical measuring apparatus" is understood to be common in the art, such as apparatus for electroanalytical methods, such as methods for chemical analysis, such as methods capable of determining parameters indicating the concentration of reference ions and / or analyte ions in a liquid sample by electrolysis, wherein "electrolysis method" is understood to be common in the art, such as methods that produce a chemical change by applying an electric potential and / or passing an electric current through an electrolyte. More specifically, it should be understood that electroanalytical methods determine parameters indicating the concentration of analyte ions and / or reference ions by measuring the electric potential (volts) and / or current (amperes) in an electrochemical cell containing analyte ions and / or reference ions. Electroanalytical methods use conductive probes, called electrodes, to make electrical contact with the analyte solution. The electrodes are used with electrical or electronic equipment to which they are connected to measure parameters of the solution. The measured parameters relate to the identity and / or quantity of the analyte ions or reference ions in the solution. Electrical analysis methods include potential analysis, current analysis, conductivity analysis, electrogravimetric analysis, voltammetry (and polarography) and coulometric analysis.

[0028] "The reference ion measuring device is different from the electroanalytical measuring device" is understood to mean that the reference ion measuring device exists and is used in the method, but belongs to a different group of measuring devices than the electroanalytical measuring device group. One advantage of this is that while electroanalytical measuring devices typically require a reference electrode, this requirement can be waived for measuring devices that are different from electroanalytical measuring devices. Furthermore, once the parameters for the concentration of the reference ion in the indicator sample are determined, it is possible to benefit from the advantages of electroanalytical methods (such as potentiometric methods) for determining parameters (i.e., potential difference) for the purpose of determining one or more concentrations of one or more analyte ions in the indicator sample, without requiring a reference electrode with a predetermined and known potential.

[0029] In some embodiments, the reference ion measuring device is selected from a group of measuring devices that depend on measuring optical parameters (such as emitted light and / or optical properties of the sample detected by light, such as fluorescence, chemiluminescence, refractive index, or absorption), mass parameters (e.g., using a quartz crystal microbalance (QCM)), magnetic field parameters (e.g., using a Hall sensor combined with labeled magnetic nanoparticles), stress parameters (e.g., using a micro cantilever), or dissipation parameters (e.g., using a quartz crystal microbalance (QCM-D) with a dissipation mode).

[0030] For example, a reference ion device can be a means for determining the concentration of a reference ion in a sample (such as a whole blood sample) via optical detection of the sample (such as an optical pH sensor). "Optical detection" is understood to be common in the art, such as involving illuminating at least a portion of a sample with light and receiving at least a portion (emitted) light therefrom, wherein the received light enables the derivation of information (such as concentration) about an analyte (such as a reference ion) therein. In another example, a reference ion measuring device can be a means based on measurements of mechanical properties (such as dissipation) and / or mass, such as measuring mass and / or dissipation using a quartz crystal microbalance sensor (QCM-D) with dissipation measurement capability, or measuring mass (in dynamic mode) and / or stress (in static mode) using a microcantilever, or a means based on measurements of magnetic parameters, such as measuring the magnetic field of a labeled magnetic particle using a Hall sensor. It covers parameters that can be measured directly or indirectly to indicate the concentration of reference ions because it covers measurement effects (such as conformational changes in macromolecules caused by reference ions, or adsorption or desorption rates of relatively heavy molecules affected by reference ions from the surface) and from which indirect measurements of the concentration of reference ions can be derived.

[0031] Generally, when referring to “optical” or “optical” in this application, it can usually be understood as referring to electromagnetic radiation, such as light (one or more) with wavelengths in the range of 380 nm to 750 nm.

[0032] In some embodiments, the reference ion measuring device is a setup that relies on a measurement principle different from that of electroanalytical techniques. Such different measurement principles depend on an effect (e.g., a change in optical properties, mechanical properties, or mass) other than that measurable by electroanalytical techniques (e.g., potentiometry, coulometrics, voltammetry). One advantage of this is that it reduces or eliminates the risk of sample damage, such as the risk of extracting ions from red blood cells, which could be the risk associated with, for example, chronopotentialography. Another advantage is that it does not require a reference electrode with a known potential.

[0033] "Measuring the parameter indicating the concentration of a reference ion in a sample using a reference ion measuring device" is understood to determine a parameter by means of a reference ion measuring device that can determine the concentration of a reference ion in the sample, such as the intensity of (emitted) light within a specific wavelength.

[0034] "Directly or indirectly measuring one or more potential differences" can be understood as each potential difference being directly determined between two points, such as directly between the working electrode and the reference electrode, such as via a (optionally high-impedance) voltmeter directly between the working electrode and the reference electrode, or indirectly, such as measuring each potential difference between the working electrode and the reference electrode relative to a third electrode, the potential difference between the working electrode and the reference electrode being subsequently determined, and thus (only) indirectly measured.

[0035] "Working electrode" is understood to be common in the art, such as an electrode in which analyte ions can react and in which the reaction can be measured.

[0036] Ion-selective electrodes (ISEs) are understood to be common in the art. An ISE can be selective for a single ion or a group of ions. More specifically, an ISE is an electrochemical sensor or electrode that allows for the potential determination of the activity of a particular ion in the presence of other ions. An ISE may include an ion-selective membrane that allows only selected ions to pass through (possibly with some cross-selectivity considered below) to a conductive internal electrode. An ISE may include an electrode that has some degree of (cross-)selectivity to one or more interfering ions. However, an ISE can be understood as being more selective for one ion or group of ions than another ion or group of ions (e.g., a selectivity coefficient for interfering ions less than 1.0, less than 0.9, less than 0.5, less than 0.1, less than 0.07, less than 0.05, less than 0.03, less than 0.02, less than 0.01).

[0037] The “membrane” may be entirely or partially solid, but may also contain plasticizers (such as those in which the remainder is partially or entirely liquid), such as containing at least 20 volume / volume percentage (v / v%) of solid material, such as containing at least 40 v / v% of solid material, such as containing at least 60 v / v% of solid material, such as containing at least 80 v / v% of solid material, such as containing at least 90 v / v% of solid material, such as containing at least 95 v / v% of solid material, such as containing at least 99 v / v% of solid material, such as being entirely solid.

[0038] "Reference electrode" is understood to be common in the art, such as an electrode that can be used as a reference point for measuring the potential difference relative to each of one or more working electrodes.

[0039] The reference electrode may exhibit some degree of (cross) selectivity to one or more interfering ions. However, the reference electrode can be understood as being more selective to one ion or group of ions than another ion or group of ions (e.g., a selectivity coefficient for interfering ions less than 1.0, less than 0.9, less than 0.5, less than 0.1, less than 0.07, less than 0.05, less than 0.03, less than 0.02, less than 0.01).

[0040] "Analyt ions" can be understood as ions whose concentrations are of interest and / or to be determined.

[0041] According to some embodiments, a method is proposed in which each of one or more working electrodes is a solid-state (ion-selective, working) electrode, and / or where a reference electrode is a solid-state (ion-selective, reference) electrode. More specifically, a solid-state ion-selective electrode is understood as an ion-selective electrode comprising an ion-selective membrane and a conductive internal electrode, wherein a small amount or no liquid is present between the membrane and the conductive internal electrode, such as between the side of the membrane facing the conductive internal electrode and the side of the conductive internal electrode facing the membrane. "Small amount" of liquid can be understood as a liquid volume less than 10 times the membrane volume, such as less than 5 times the membrane volume, such as less than 2 times the membrane volume, such as less than the membrane volume, such as less than 0.5 times the membrane volume, such as less than 0.1 times the membrane volume, such as less than 0.01 times the membrane volume. Additionally or alternatively, it is understood that the percentage of the distance from the conductive internal electrode to the opposite side of the membrane when the conductive internal electrode is in contact with or close to the membrane is given by a value such as less than 90%, less than 75%, less than 50%, less than 25%, less than 10%, less than 5%, less than 2%, less than 1%, or less than 0.1%. Additionally or alternatively, it is understood that the conductive internal electrode is arranged to be close to or near the sample, and the distance between the conductive internal electrode and the sample is such as less than 1 mm, less than 0.75 mm, less than 0.5 mm, less than 0.25 mm, less than 0.1 mm, less than 0.03 mm, less than 0.01 mm, or less than 0.003 mm.

[0042] A “conductive internal electrode” can be understood as a solid sub-part on which electrochemical reactions occur, and which is conductive and coupled to an analytical device, such as a (high impedance) voltmeter. Therefore, it can be understood that the (electro)conductive internal electrode forms part of a solid electrode. The conductive electrode can comprise one or more different materials, which can include non-solid substances, such as liquids, and / or substances readily absorbing liquids, such as where the conductive internal electrode forms a matrix comprising solid materials. The conductive internal electrode is completely or partially solid (such as where the remaining portion is partially or completely liquid), such as comprising at least 50 v / v% solid material, such as comprising at least 60 v / v% solid material, such as comprising at least 70 v / v% solid material, such as comprising at least 80 v / v% solid material, such as comprising at least 90 v / v% solid material, such as comprising at least 95 v / v% solid material, such as comprising at least 99 v / v% solid material, such as being completely solid.

[0043] According to one embodiment, a method is proposed in which each of one or more working electrodes is a solid-state electrode, and wherein a reference electrode is a solid-state reference electrode. The advantage of this approach may be overcoming the disadvantages associated with non-solid (aqueous or liquid-liquid) electrodes, such as those related to large size, high cost, electrolyte contamination or consumption, fragility, and / or erroneous measurements, for example due to electrolyte leakage (from aqueous liquid-liquid electrodes) and its impact on measurements (at the working electrode).

[0044] According to one embodiment, a method is proposed that includes determining one or more concentrations of one or more analyte ions in a sample based on:

[0045] i. The concentration of the reference ion, and

[0046] ii. One or more potential differences.

[0047] One advantage of this approach is that one or more concentrations of one or more analyte ions can be determined, and / or, because the concentration of a reference ion (determined using a reference ion measuring device) is taken into account, such as depending not only on the assumed and possibly sought (e.g., by adding a certain amount of reference ion) concentration of the reference ion, the determination can be made with high (or even higher) accuracy. The concentration of the analyte ion can be determined by calculating the concentration (e.g., by utilizing the Nernst equation).

[0048] To determine the concentration of one or more analyte ions in a sample, the following framework can be relied upon.

[0049] The Nernst equation gives the relationship between potential and analyte ion concentration:

[0050] E = E0 + N_fac * log 10 (X), where N_fac is the slope (Nernst factor) of the half-cell, for example, where X = cH + ,cK + ,cNa + ,cCa ++ or cCl - (Where "c" represents "concentration"). In the following text, "+" and "-" may be omitted; for example, cK represents cK. + , which is the concentration of potassium ions; in the case of an element, such as K, without the prefix c, it is simply the parameter K(potassium). E0 is eliminated by the difference between samples.

[0051] Taking pH as an example: ΔE(pH)=N_fac(pH)*log 10 (cH1 / cH2), where sample 1 has cH1 = cH (i.e., hydrogen ion H+). +(concentration), and the concentration of sample 2 is cH2=cH.

[0052] The same applies to electrolytes; for example, for cK: ΔE(cK) = N_fac(cK) * log 10 (cK1 / cK2)

[0053] An equation can be established for N_fac(pH) = Nernst factor for parameter pH, and similarly for N_fac(X): Nernst factor for parameter X, where X represents the electrolyte. These equations are used to calculate the correction potential by calculating the concentration of the analyte in the sample (see below).

[0054] Derivation of the N_fac(X) equation: Between sample 1 and sample 2, with pH as a reference:

[0055]

[0056] The value of N_fac(pH) can be estimated, for example, to be 57 mV (e.g., based on existing knowledge about the slope of the half-cell of the electrode). A set of optional optimal calibration solutions (“optimal”), such as solutions with the same or nearly the same pH value, can be used to obtain N_fac(pH) by the following formula:

[0057]

[0058] “Optimal” can refer to the set of alternative optimal solutions N_fac(X), such as two solutions with nearly identical pH values, where for n_Fac(pH), the average of the two values ​​is calculated and used for further calculations.

[0059] Since the pH value of the (unknown) sample is unknown and may differ from that of the calibration solution, this pH difference must be calculated as a voltage (mV value) by subtracting this voltage from the different electrolyte concentrations. For example, the applicable formula for calculating the correction potential Pot.corr is:

[0060] Pot.corr = ΔpH * N_fac(pH)

[0061] A new potential can be calculated for an example, where "cal1" is the calibration liquid and "sample" is the unknown sample whose analyte ion concentrations will be determined:

[0062] E(new)=ΔE((cal1-sample)X)pH-Pot.corr.

[0063] Electrolyte concentration (mM) can be calculated as follows:

[0064]

[0065] According to one embodiment, a method is proposed in which one or more potential differences depend on the concentration of a reference ion in the sample. Therefore, it can be understood that one or more potential differences can depend on the ion concentration in the sample, such as by eliminating the need for a reference electrode with a known or predictably varying potential. One advantage is that this need can be eliminated.

[0066] According to one embodiment, a method is proposed in which the determination of one or more concentrations of one or more analyte ions in a sample is based on an expression reflecting and / or incorporating the dependence of one or more potential differences on the concentration of a reference ion in the sample. For example, the reference ion concentration may affect one or more potential differences described in the equation above, and this same dependence of one or more potential differences may be incorporated into the expression for the electrolyte concentration (see, for example, the last equation above, denoted as “cXsample”). In other words, the reference ion concentration is allowed to affect one or more potential differences in some way (such as with a logarithmic term), but in the expression used to determine one or more concentrations of one or more analyte ions, this dependence is at least partially, such as partially or completely, considered in the same way, such as reducing, minimizing, or eliminating the effect of the reference ion concentration on the (determined) concentration of one or more analyte ions in the sample. “Reflecting and / or incorporating” can be understood as the same or similar terms (which may be negation or inverse terms used to negate an effect) being included in the expression, as in the expression expressing the effect of the reference ion concentration on one or more potential differences.

[0067] According to one embodiment, a method is proposed in which the sample is a liquid whole blood sample. One advantage of using a whole blood sample is that it may not require separating the components of the (raw) whole blood sample, such as providing plasma or serum. The term "whole blood" is understood to refer in the art to blood without the removal of naturally present portions, such as unprocessed blood from (and optionally derived from) humans or animals. More specifically, whole blood can refer to blood composed of plasma and cellular components. Plasma comprises approximately 50%-60% of the volume, and the cellular component comprises approximately 40%-50% of the volume. The cellular components are red blood cells (erythrocytes), white blood cells (leukocytes), and platelets (platelets). Preferably, the term "whole blood" refers to the whole blood of a human subject, but it can also refer to the whole blood of an animal. The term "blood plasma" or "plasma" refers to the liquid portion of blood and lymph, which comprises approximately half the volume of blood (e.g., approximately 50%-60% of the volume). Plasma lacks cells. It contains all clotting factors, especially fibrinogen, and is approximately 90%-95% water by volume. Plasma components include electrolytes, lipid metabolites such as markers for infection or tumors, enzymes, substrates, proteins, and other molecular components.

[0068] According to one embodiment, a method is proposed that includes aspirating a sample, such as aspirating the sample at the sample inlet of a device (such as the device according to the second aspect), thereby creating an aspirated portion of the sample. One advantage of doing so may be that this allows for the aspiration of a controlled portion of the sample, such as for aspiration and analysis. In another embodiment, both the measurement using a reference ion measuring device and the measurement using an analyte ion measuring device are performed on the aspirated portion of the sample. One advantage of doing so may be that the (identical) aspirated portion of the sample undergoes both types of analysis, and therefore the risk of differences between (sub)sample portions can be reduced or eliminated.

[0069] According to one embodiment, a method is proposed in which the reference ion measuring device is based on a measurement principle that depends on the concentration of the reference ion (such as a pH-sensitive luminescent indicator), such as the reference ion sensitive indicator (which modifies one or more optical properties, such as absorption (e.g., in wavelength ranges of] 400; 1200 [nm, such as in wavelength ranges of] 500; 1000 [nm, such as in wavelength ranges of] 600; 1000 [nm, such as in wavelength ranges of] 700; 900 [nm)), and wherein the measurement principle of the analyte ion measuring device is a potential measurement principle. One advantage of doing so is that the disadvantages associated with potential measurement principles, such as the need for certain electrodes and / or conditions, can be completely or partially overcome, for example, by using an optically based measurement principle, which can, for example, eliminate the need to establish a known potential via an aqueous liquid-liquid reference electrode.

[0070] The "measurement principle" can be understood as the principle of measuring concentration based on the measurement of a certain parameter (such as (electric) voltage or (light) absorptivity or luminescence intensity).

[0071] According to one embodiment, a method is proposed in which measuring one or more potential differences includes specifically measuring, such as directly measuring one or more potential differences between solid-state electrodes, such as one or more potential differences between a solid-state working electrode and a solid-state reference electrode. One advantage of doing so may be that it involves only solid-state electrodes, such as excluding aqueous liquid-liquid electrodes (and associated disadvantages). "Specifically" between solid-state electrodes is understood to mean measuring only the potential difference between solid-state electrodes; however, the potential difference between the solid-state working electrode and the solid-state reference electrode can be measured separately as the sum or difference of the potential difference between the solid-state working electrode and a third solid-state electrode, and the potential difference between the solid-state reference electrode and the third solid-state electrode. "Directly" is understood to mean that the potential difference between the solid-state working electrode and the solid-state reference electrode is directly measured, such as by inserting a (high-impedance) voltmeter between the solid-state working electrode and the solid-state reference electrode.

[0072] According to one embodiment, a method is proposed in which measuring the concentration of a reference ion in a sample using a reference ion measuring device includes optical measurements. "Optical measurements" are understood to be any measurement that measures any of the optical parameters, such as absorptivity, reflectivity, fluorescence, refractive index, luminous flux, absorption, and wavelength. An advantage of optical measurements may be that they can be performed without damaging red blood cells. Another advantage may be that they are independent of electroanalytical techniques and thus provide an alternative to electroanalytical techniques. Yet another advantage may be that they do not require a known potential, such as a known potential provided by an aqueous liquid-liquid reference electrode.

[0073] According to one embodiment, a method is proposed in which the reference ion is a hydrogen ion, such as H+. + Sodium ions, such as Na + or potassium ions, such as K + The advantages of using hydrogen ions as a reference ion may be that it can be assumed to be present in many samples, such as, in particular, whole blood samples. The advantages of using sodium ions as a reference ion may be that: it can exist at relatively high concentrations (e.g., as the main ionic component in human plasma, such as the highest concentration of ionic component in human plasma); it can be measured optically, such as using (optionally readily available) sodium ion-sensitive fluorophores; sodium ion concentration is related to ionic strength (and using sodium ions as a reference ion will therefore include and exclude the influence of ionic strength); and / or its concentration can be relatively stable (e.g., absolute and / or relative fluctuations can be relatively small), for example, in human plasma. The advantages of using potassium ions as a reference ion may be that it can exist at relatively high concentrations (e.g., as the main ionic component in human plasma, such as the highest concentration of ionic component in human plasma).

[0074] According to one embodiment, a method is proposed in which optical measurements include measuring a pH-dependent optical parameter P. o (such as absorptivity, reflectivity, fluorescence, refractive index, or color), and the variation of optical parameters dP within them. o As pH changes, dpH, dP o / dpH has local and / or global maximum values ​​in the following areas: within the pH range [7; 8], such as within the pH range [7.2, 7.6], such as equal to or approximately equal to 7.4. One advantage of doing so is that the maximum sensitivity may therefore be expected over the range of whole (human) blood pH values. Thus, the accuracy of determining pH (or hydrogen ion concentration) and the accuracy of determining the concentration of one or more analytes are increased.

[0075] According to one embodiment, a method is proposed in which the reference ion is an ion naturally present in (human) whole blood, such as any of the following ions:

[0076] - Hydrogen ions, such as H+ + ,

[0077] -Sodium ions, such as Na+ + ,

[0078] - Potassium ions, such as K + ,

[0079] - Calcium ions, such as Ca 2+ ,

[0080] -Chloride ions, such as Cl- - ,

[0081] -Magnesium ions, such as Mg 2+ ,or

[0082] -Bicarbonate ions, such as HCO3- - .

[0083] In this case, the reference ion can be measured directly on whole blood without the need to add ions as a reference ion.

[0084] According to a second aspect, an apparatus is provided for measuring one or more potential differences indicating the concentrations of one or more analyte ions in a sample, such as a liquid whole blood sample, the apparatus comprising:

[0085] - A reference ion measuring device, arranged for measuring parameters indicating the concentration of a reference ion, wherein the reference ion measuring device (104) is different from the electroanalytical measuring device, and

[0086] -Analytical ion measuring device, including:

[0087] i. One or more optionally solid-state working electrodes, each of which includes an ion-selective electrode that is selective for analyte ions, and

[0088] ii. A reference electrode, including optionally a solid-state ion-selective electrode that is selective for reference ions.

[0089] -The analyte ion measuring device is an electroanalytical device, such as a potential measuring device.

[0090] Furthermore, the analyte ion measuring device is arranged to directly or indirectly measure one or more potential differences between the following:

[0091] i. Each of one or more working electrodes, and

[0092] ii. Reference electrode.

[0093] In the embodiments, each of one or more working electrodes is a solid-state electrode and / or the reference electrode is a solid-state reference electrode.

[0094] The analyte ion measuring device and the reference ion measuring device may be rigidly connected and / or the device may include a housing, such as a single housing, such as a single housing surrounding and enclosing the analyte ion measuring device and the reference ion measuring device.

[0095] The analyte ion measuring device and the reference ion measuring device can be arranged to detect samples in the same measuring chamber within the device. This can be advantageous for minimizing the required sample volume, as the sample only needs to fill a single measuring chamber. Furthermore, processing, rinsing, cleaning, etc., can be simplified because the sample does not need to be directed to different measuring chambers.

[0096] According to one embodiment, an apparatus is provided in which a reference ion measuring device includes an optical sensor, such as an optical sensor for measuring a parameter indicating a reference ion concentration, wherein the optical sensor is arranged to perform a measurement, the optical measurement including measuring a pH-dependent optical parameter P. o (such as absorptivity, reflectivity, fluorescence, refractive index, or color), and the variation of optical parameters dP within them. o As pH changes, dpH, dP o / dpH has local and / or global maximum values ​​in the following: within the pH range [7; 8], such as within the pH range [7.2, 7.6], such as equal to or approximately equal to 7.4. For example, the optical sensor can be an optical pH sensor, such as one based on a reference ion sensitive indicator (which changes one or more optical properties depending on the concentration of the reference ion, such as absorption (e.g., in the wavelength range] 400; 1200 [nm, such as in the wavelength range] 500; 1100 [nm, such as in the wavelength range] 600; 1000 [nm, such as in the wavelength range] 700; 900 [nm]), such as a pH-sensitive luminescent indicator.

[0097] The reference ion-sensitive indicator may have maximum or minimum optical properties, such as maximum absorption in wavelength regions greater than 400 nm, 500 nm, 600 nm, 700 nm, and / or less than 1200 nm, 1100 nm, 1000 nm, or 900 nm, such as in the wavelength ranges of 400; 1200 nm, 500; 1100 nm, 600; 1000 nm, and 700; 900 nm, with maximum absorption in such wavelength ranges. The advantages of a reference ion-sensitive indicator with minimal optical properties may be: minimal hemoglobin absorption in the 600-1000 nm range and / or limited interference with other sensors (due to the wavelength being long enough in this region to not interact with / weaken entities (e.g., ion carriers) present in other sensors in the device), and / or limited scattering of lipid particles (due to the wavelength being long enough in this region to be less easily scattered by relatively small lipid particles in a sample, such as a biological sample, such as a whole blood sample).

[0098] According to one embodiment, a device is provided in which the reference ion is any one of the following ions:

[0099] - Hydrogen ions, such as H+ + ,

[0100] -Sodium ions, such as Na+ + ,

[0101] - Potassium ions, such as K + ,

[0102] - Calcium ions, such as Ca 2+ ,

[0103] -Chloride ions, such as Cl- - ,

[0104] -Magnesium ions, such as Mg 2+ ,or

[0105] -Bicarbonate ions, such as HCO3- - .

[0106] Each listed reference ion is a naturally occurring ion in (human) whole blood. In this case, the reference ion can be measured directly from the whole blood without the need to add ions to serve as a reference ion.

[0107] According to one embodiment, a device is provided, further comprising:

[0108] - A data processing device, including a processor configured to:

[0109] i. Determine the concentration of one or more analyte ions in the sample based on the following:

[0110] 1. The concentration of the reference ion, and

[0111] 2. One or more potential differences.

[0112] By implementing data processing equipment, the concentrations of one or more analyte ions can be determined in a faster, more automated, and / or more reliable manner.

[0113] According to one embodiment, an apparatus is provided, further comprising:

[0114] - Sample processing system, including:

[0115] o Sample inlet, such as the sample inlet including a suction system,

[0116] a measurement chamber (such as the volume of a sample processing system in which a sample is placed while measurements of parameters indicating the concentration of a reference ion and / or one or more potential differences are performed), such as in which a reference ion measuring device (104) and an analyte ion measuring device (105) are arranged to measure the sample while it is in the measurement chamber.

[0117] One or more fluid channels, such as microfluidic channels, fluid connections between the sample inlet and the measurement chamber.

[0118] One advantage may be that sample handling is performed in a more hygienic, safe, automated, reliable, and / or repeatable manner. A “sample handling system” can generally be understood as a system capable of receiving and processing samples, such as bringing samples from a sample inlet to a measurement chamber via one or more fluid channels.

[0119] According to one embodiment, an apparatus is provided in which the sample processing system further includes:

[0120] - One or more valves, such as valves capable of delivering samples in segments (such as in the form of sample plugs) through a sample processing system, said valves optionally being controlled by a data processing device (such as a data processing apparatus).

[0121] One advantage may be that the valve can enable segmented delivery, such as in which the sample passes through at least a portion of the sample handling system (e.g., from the sample inlet to the measurement chamber) in the form of an embolus, and / or without mixing with the liquid before and / or after the sample.

[0122] According to one embodiment, a device is proposed in which the concentration accuracy of an analyte ion, as a monovalent ion, is less than 20%, such as less than 15%, such as less than 10%, such as less than 7%, such as less than 5.4%, such as less than 5%, such as less than 3.5%, such as less than 2.7%. The advantage of this low accuracy (where “low” accuracy is understood as a small deviation from the true value) is that it enables more precise concentration estimation, which may in turn enable improved diagnosis, improved assessment of treatment efficacy, or improved estimation of the physiological and / or nutritional status of subjects (such as patients or individuals from whom blood samples are drawn). “Accuracy” is understood in the art as the error between actual (“true”) values ​​(such as the true concentration of the analyte ion in this context) and measured values ​​(such as the concentration of the analyte ion at the device output and / or determined by the device in this context).

[0123] According to one embodiment, an apparatus is proposed, wherein the apparatus, such as the entire apparatus, enables the determination of one or more concentrations of one or more analyte ions in a sample based on one or more potential differences with an accuracy relative to one or more true concentrations, such accuracy being less than 20%, such as less than 15%, such as less than 10%, such as less than 7%, such as less than 5.4%, such as less than 5%, such as less than 3.5%, such as less than 2.7%. It should be understood that the apparatus, such as the entire apparatus, i.e., determining the analyte ion concentration based, for example, on a parameter indicating a reference ion concentration and a potential difference indicating an analyte ion concentration, achieves low accuracy in determining the analyte ion concentration. Furthermore, it should be understood that the accuracy is determined relative to the true value of the concentration.

[0124] According to one embodiment, a device is proposed in which the accuracy of the reference potential determined by the (optionally solid-state) reference electrode for monovalent analyte ions (i.e., the total accuracy of the reference ion measuring device and the reference electrode, i.e., selective for the reference ion considering cumulative error) is less than 10%, such as less than 7.5%, such as less than 5%, such as less than 3.5%, such as less than 2.7%, such as less than 2.5%, such as less than 1.75%, such as less than 1.35%. The advantage of this low accuracy of the reference potential (i.e., the reference ion measuring device and the reference electrode) (where “low” accuracy is understood as a smaller deviation from the true value) is that it provides a more accurate estimate of the reference potential, which may in turn enable improved accuracy regarding the concentration of the analyte ion, which may in turn enable improved diagnosis, improved assessment of treatment efficacy, or improved estimation of the physiological and / or nutritional status of subjects (such as patients or individuals from whom blood samples are drawn). "Accuracy" is understood in the art as, in this context, the error that will exist between the actual ("true") value of the reference potential (such as the "true" potential difference between the potential in the body portion of the sample and the potential in the conductive inner electrode within the reference electrode) and the reference potential determined based on the concentration of the reference ions, derived from a parameter indicating the concentration of the reference ions determined by the reference ion measuring device, and the potential at the reference electrode (such as the potential difference between the working electrode and the reference electrode, subtracted to obtain the potential difference between the potential in the body portion of the sample and the potential in the conductive inner electrode within the reference electrode).

[0125] According to one embodiment, a device is proposed, wherein

[0126] - For analyte ions that are monovalent ions, the analyte ion concentration accuracy is less than 20%, such as less than 15%, such as less than 10%, such as less than 7%, such as less than 5.4%, such as less than 5%, such as less than 3.5%, such as less than 2.7%, and

[0127] - The fraction of analyte ion concentration accuracy derived from the reference ion measuring device and reference electrode is less than 50%, such as less than 40%, such as less than 30%, such as less than 20%, such as less than 10%.

[0128] Such as analyte ion concentration accuracy being less than 10%, and the fraction of analyte ion concentration accuracy derived from the reference ion measuring device and reference electrode being less than 30%, such as less than 25%, such as less than 20%. One advantage of doing so may be that an analyte ion concentration accuracy of less than 10% is sufficient for most purposes, and the relatively low fraction derived from the reference ion measuring device and reference electrode leaves room for actual accuracy (or lack thereof) derived from other sources (such as from ion-selective working electrodes).

[0129] The advantage of this low precision (where “low” precision is understood as a smaller deviation from the true value) is that it provides a more accurate estimate of the concentration, which may in turn enable improvements in diagnosis, assessment of treatment efficacy, or estimation of the physiological and / or nutritional status of subjects (such as patients or individuals from whom blood samples are drawn). “Precision” is understood in the art to be the error that will exist between actual (“true”) values ​​(such as the concentration of analyte ions) and indicated values ​​(such as the concentration of analyte ions at the device output and / or determined by the device).

[0130] According to one embodiment, a device is proposed in which the following distances (such as center-to-center distances) are provided:

[0131] - Each of one or more working electrodes, and

[0132] -Reference electrode,

[0133] Equal to or less than 10 mm, such as equal to or less than 5 mm, such as equal to or less than 3 mm, such as equal to or less than 1 mm, such as equal to or less than 1 mm. One advantage may be that (only) a relatively small sample volume is required. Another advantage may be that less (idle) time must pass between measurements of different samples, for example, in the case of a sample chamber, the sample chamber can be flushed more quickly (e.g., due to the smaller sample chamber volume).

[0134] According to one embodiment, an apparatus is provided in which the slope of the reference ion half-cell is at least 10% relative to the theoretical slope of the reference ion according to the Nernst equation, such as at least 25%, such as at least 50%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 97%. An advantage of having a relatively large slope may be that a normal, well-functioning, readily available ISE (which itself can be used as a working electrode) can be used as the reference electrode (because the reference ion measurement device makes it possible to consider the slope / sensitivity). The slope of the reference ion half-cell is understood as a proportionality constant between the measured potential and the logarithm of the reference ion concentration, such as where the measured electrode potential E is related to the activity of the ion species by the Nernst equation:

[0135] E = E0 + 2.3xRT / (nF)log A

[0136] Where E0 = constant for a given cell, R = gas constant, T = Kelvin temperature, n = ionic charge, F = Faraday constant, A is activity, and x is a factor that takes into account the possibility that the slope factor may deviate from the factor given by the expression RT / nF, which can be called the ideal slope factor. For example, when measuring potassium ions (i.e., n = +1), the slope factor is 59.16 mV at 298 K (25 °C), and 61.54 mV at 3725 °C. For example, for x = 0.1, the slope of the reference ion half-cell is 10% relative to the theoretical (ideal) slope of the reference ion according to the Nernst equation.

[0137] According to the third aspect, the use of the device according to the second aspect is proposed, wherein the device is used for measuring one or more potential differences indicating one or more concentrations of one or more analyte ions in a sample, such as a liquid whole blood sample, such as for determining one or more concentrations of one or more analyte ions in the sample, such as based on the concentration of a reference ion and one or more potential differences.

[0138] In the context of point-of-care measurement systems (also known in the art as “bedsite” systems) and similar laboratory environments, blood gas analysis is typically performed by users, such as nurses, who may not be trained in using, for example, blood gas analyzers.

[0139] According to a fourth aspect (or an embodiment of the third aspect) of the invention, the apparatus according to a second aspect of the invention is proposed for use in field-on-the-fly (POC) analysis, such as determining the concentration of one or more analytes in a sample (such as a liquid whole blood sample).

[0140] In this field, POC measurements are also referred to as “bedside” measurements. In this context, the term “field testing” should be understood as a measurement performed very close to the patient, i.e., not in a laboratory. Thus, according to this embodiment, the user of the device (such as a blood gas analyzer) performs measurements of whole blood samples in a handheld blood sample container near the patient, for example, in a ward or room housing the patient's bed or in a nearby room within the same hospital department. In such use, the user's skill level often varies between novices and experienced users; therefore, in this environment, the ability of the blood gas analyzer to automatically output instructions based on sensor input that match the skill level of each individual user is particularly beneficial.

[0141] The first, second, third, and fourth aspects of the present invention can each be combined with any other aspect. These and other aspects of the invention will become clear and explained with reference to the embodiments described below. Attached Figure Description

[0142] The methods, apparatus, and uses according to the invention will now be described in more detail with reference to the accompanying drawings. The drawings illustrate one mode of carrying out the invention and should not be construed as limiting oneself to other possible embodiments within the scope of the appended claims.

[0143] Preferred embodiments of the present invention will be described in more detail, and more specifically, in conjunction with the accompanying drawings:

[0144] Figure 1 This is a schematic diagram of device 100.

[0145] Figure 2 Method 200 is shown.

[0146] Figure 3 Examples of electrochemical measuring device 305 and reference ion measuring device 304 are shown.

[0147] Figure 4 An enlarged view of the conductive internal electrode 366 and the film 368 is shown.

[0148] Figure 5 An overview of the total (deviation / error) in the graphs for each system (systems 1-10, each consisting of NPT7 instruments 104, 304 and ABL725) and four different measurements ("#m.1", "#m.2", etc.) is shown. Detailed Implementation

[0149] Figure 1 This is a schematic diagram of an apparatus 100 for measuring one or more potential differences indicating the concentration of one or more analyte ions in a sample 102, such as a liquid whole blood sample, comprising:

[0150] - Reference ion measuring devices 104 and 304 are arranged to measure parameters indicating the concentration of reference ions 234, wherein the reference ion measuring device differs from electroanalytical measuring devices, such as optical sensors, and

[0151] -Analytical ion measuring devices 105 and 305 include:

[0152] i. One or more optionally solid-state working electrodes 352, each of the optionally solid-state working electrodes 352 comprising an ion-selective electrode that is selective for analyte ions.

[0153] ii. Reference electrode 350, comprising an optionally solid-state ion-selective electrode selective for reference ions.

[0154] The analyte ion measuring device is an electroanalytical device, such as a potential measuring device.

[0155] Furthermore, the electrochemical measuring devices 105 and 305 are arranged to directly or indirectly measure one or more potential differences between 236 and below:

[0156] iii. Each of one or more working electrodes 352, and

[0157] iv. Reference electrode 350.

[0158] Reference ion measuring devices 104, 304 and electrochemical measuring devices 105, 305 are described as being contained in or within separate measuring chambers; however, in alternative embodiments, they may all be in the same measuring chamber 354 to detect the sample.

[0159] The reference ion measuring devices 104 and 304 in the illustrative examples include optical devices, such as optical pH sensors, and also include...

[0160] - The data processing device 106, including the processor, is configured as follows:

[0161] i. Determine the concentration of one or more analyte ions in the 238 samples based on the following:

[0162] 1. The concentration of reference ions,

[0163] 2. One or more potential differences.

[0164] Figure 1 The device shown in the schematic diagram also illustrates a sample processing system, including:

[0165] Sample inlet 112,

[0166] Measurement Room 354

[0167] ο One or more fluid channels 114, such as microfluidic channels, fluid-connected sample inlets and(one or more) measurement chambers.

[0168] The described device also includes a digital storage device 116 (e.g., for storing data related to the control and / or calculation of the data processing device) and a user interface 118, wherein the user interface includes an output unit 120 and an input unit 122 (such as a keyboard, for example for providing information about the identity of the sample 102 to the device). The output unit 120 is arranged to visually output information related to operating the device and / or information representing one or more concentrations of one or more analyte ions in the sample 102 (in the illustrated embodiment, the output unit is a display unit). Thin arrows indicate information flows, such as parameters indicating reference ion concentrations flowing from reference ion measuring devices 104, 304 to the data processing device 106 and one or more potential differences flowing from electrochemical measuring devices 105, 305 to the data processing device 106, one or more concentrations of one or more analyte ions in the sample flowing from the data processing device 106 to the user interface 118 (more specifically, the output unit 120), and user input flowing from the input unit 122 to the data processing device 106.

[0169] Figure 2 Method 200 (starting at box 230, ending at box 240) is illustrated, which measures one or more potential differences indicating one or more concentrations of one or more analyte ions in a sample 102, optionally a liquid whole blood sample, and optionally also determines one or more concentrations of one or more analyte ions, the method comprising,

[0170] - Optionally, sample 102 can be provided to 232 as... Figure 1 The sample inlet 112 of the device 100 according to the second aspect of the present invention.

[0171] - The parameter concentration of reference ions in indicator sample 102 is measured using reference ion measuring devices 104 and 304, wherein reference ion measuring device 104 is different from the electroanalytical measuring device, and optionally the reference ion concentration is further determined.

[0172] - Measure one or more potential differences between the following items directly or indirectly using an analyte ion measuring device:

[0173] iii. Each of one or more working electrodes 352, such as one or more solid-state working electrodes, each of said working electrodes comprising an ion-selective electrode having selectivity for analyte ions, and

[0174] iv. A reference electrode 350, such as a solid-state reference electrode, is selective for reference ions, wherein the analyte ion measuring device is an electroanalytical device, such as a potential measuring device, and

[0175] - Optionally, determine one or more concentrations of one or more analyte ions from 238 analyte groups.

[0176] Figure 3 Examples of electrochemical measuring devices 105, 305 and reference ion measuring devices 104, 304 are shown. More specifically, the figure shows electrochemical measuring devices 105, 305, which include a reference electrode 350 and a working electrode 352 partially located within a measuring chamber 354, a (high impedance) voltmeter 356 electrically connected between the reference electrode 350 and the working electrode 352, and an (inlet) fluid channel 314 arranged to allow the introduction of a sample into the measuring chamber 354. Parts of the reference electrode 350 and the working electrode 352 are similar, but for simplicity, only the reference electrode 350 is explained: a housing 360 includes an insulating encapsulating material 362 that surrounds a conductor 364 electrically connected to a conductive internal electrode 366, which is positioned on the opposite side of a membrane 368 relative to the interior of the measuring chamber 354 (where a sample may be present during use). A center-to-center distance 370 between the reference electrode 350 and the working electrode 352 is also shown.

[0177] Figure 3 Reference ion measuring devices 104 and 304 in the form of optical pH sensors are also shown, part of which is located within a measuring chamber 354 and includes an optical analysis unit 358 which may include one or more light sources and one or more photodetectors and optionally one or more filters.

[0178] Figure 4 An enlarged view of the conductive internal electrode 366 and the membrane 368 (e.g., working electrode 352 or reference electrode 350) is shown. The figure also shows that a gap 472 may exist between the conductive internal electrode 366 and the membrane 368. Furthermore, the figure indicates the distance 474 from the conductive internal electrode 366 to the opposite side of the membrane 368, which is also the distance between the conductive internal electrode 366 and the sample 102 (or the measurement chamber 354 of the sample 102 that may be present during use). Additionally, the figure shows the distance 476 from the conductive internal electrode 366 to the membrane 368.

[0179] Example

[0180] Human (non-smoker) blood sample 102 was adjusted to a total hemoglobin concentration of 15 g / dL and a pH of approximately 7.6 using a gas (SAT100) that ensures oxygen saturation, with the pH controlled by the CO2 level in the gas.

[0181] pH measurements of blood sample 102 were performed on five ABL725 (radiometer, Copenhagen, Denmark) electroanalytical blood gas analyzers. Measurements were repeated four times on each ABL725 electroanalytical blood gas analyzer. Results are shown in Table I (where n in "ABL725-n" represents the instrument number n).

[0182] 1 7.663 7.668 7.663 7.67 7.663 2 7.657 7.662 7.659 7.666 7.66 3 7.653 7.658 7.656 7.662 7.655 4 7.649 7.654 7.652 7.658 7.651

[0183] Table I

[0184] pH measurements of blood sample 102 were performed separately using 10NPT7 (radiometer, Copenhagen, Denmark) optical blood gas analyzers 104 and 304. Measurements were repeated four times on each NPT7 optical blood gas analyzer. The results are shown in Tables II and III (where "#m." indicates the measurement number and "n" in "NPT-n" indicates the instrument number), where each entry in Table II represents a discrete NPT7 measurement, and each entry in Table III represents the deviation or error from the mean, which was determined by five ABL725 measurements in the same round to remove interference from drift in sample 102 (through CO2 degassing and subsequent pH changes).

[0185]

[0186] Table II

[0187]

[0188] Table III

[0189] To evaluate the impact of replacing the full electrical analysis method and apparatus with the device 100 and method 200 according to embodiments of the present invention on accuracy, 40 sums or errors are formed, wherein each sum is the sum of errors from NPT7 measurements and errors from ABL725 measurements (where the ABL725 dataset is copied to match the NPT7 dataset of double size).

[0190] Assuming (for this purpose or to provide a conservative estimate) that the fully electroanalytical method and apparatus will rely on an ideal reference electrode 352, the impact on accuracy introduced by embodiments of the present invention can be estimated as the sum of the error on the optical pH measurement 234 of the NPT7 instruments 104, 304 (corresponding to the error introduced by the reference ion measurement device) and the error introduced by the solid-state ion-selective pH electrode of the ABL725 instrument (corresponding to the error introduced by the reference electrode of the analyte ion measurement device). Note that, depending on the sign of these errors, they may be additive or (completely or partially) cancel each other out.

[0191] Figure 5The graph shows an overview of systems 1-10 (each formed by NPT7 instruments 104, 304, and ABL725) and the sums of four different measurements ("#m.1", "#m.2", etc.) for each system. For each system, it can be seen that all errors are below 1.60 mV, with errors typically on the order of 1.0 mV, and the average absolute value is 0.888 mV. For a Nernst factor of 60 mV, this would correspond to an effect on the accuracy of analyte ion measurements of 100%*(10) for monovalent ions. (0.888mV / 60mV) -1) = 3.47%, and for divalent ions it is 6.93%. With the average value of the calibration system, these values ​​can be reduced to 2.7% and 5.4% for monovalent and divalent ions, respectively. Assuming the analyte ion-selective working electrode introduces an error of the same or smaller order of magnitude, the accuracy of the apparatus according to the method of the present invention can be estimated at 2.7-5.4% for monovalent analyte ions and 5.4-10.8% for divalent analyte ions.

[0192] Although the invention has been described in conjunction with specific embodiments, it should not be construed as limiting itself in any way to the presented examples. The scope of the invention is set forth by the appended claims. In the context of the claims, the term "comprising" does not exclude other possible elements or steps. Furthermore, references to words such as "a" or "an" should not be construed as excluding multiples. The use of reference numerals in the claims relating to elements shown in the figures should also not be construed as limiting the scope of the invention. Moreover, the various features mentioned in different claims may be advantageously combined, and the mention of these features in different claims does not preclude the possibility or disadvantage of combining features.

Claims

1. A method for measuring one or more potential differences of one or more concentrations of one or more analyte ions in an indicator sample, the method comprising, - A parameter indicating the concentration of a reference ion in a sample is measured using a reference ion measuring device (104), wherein the reference ion measuring device (104) is different from an electroanalytical measuring device, and - Measure one or more potential differences between the following, directly or indirectly, using an analyte ion measuring device, wherein the one or more potential differences indicate one or more concentrations of one or more analyte ions in the sample: i. Each of one or more working electrodes, each of the working electrodes comprising an ion-selective electrode having selectivity for analyte ions, and ii. A reference electrode, said reference electrode being selective for reference ions. The analyte ion measuring device is an electroanalytical device, and the reference ion measuring device measures the concentration of the reference ion in the sample including optical measurements, wherein the optical measurements include measuring a pH-dependent optical parameter P. o And the change of optical parameters dP o As pH changes, dpH, dP o / dpH has local and / or global maximum values ​​in the following pH ranges: [7; 8].

2. The method according to claim 1, wherein the change in the optical parameter dP o As pH changes, dpH, dP o / dpH has local and / or global maximum values ​​in the pH range [7.2, 7.6].

3. The method according to claim 1, wherein the change in the optical parameter dP o As pH changes, dpH, dP o / dpH has local and / or global maximum values ​​at 7.

4.

4. The method according to claim 1, wherein the electrical analysis device is an electrical potential measuring device.

5. The method of claim 1, wherein each of the one or more working electrodes is a solid-state electrode, and / or wherein the reference electrode is a solid-state reference electrode.

6. The method of claim 1, further comprising determining the concentration of one or more analyte ions in the sample based on: i. The concentration of the reference ion, and ii. The one or more potential differences.

7. The method of claim 1, wherein the one or more potential differences depend on the concentration of the reference ion in the sample.

8. The method according to any one of claims 1-7, wherein determining the concentration of the one or more analyte ions in the sample is based on an expression reflecting and / or incorporating the dependence of the one or more potential differences on the concentration of the reference ion in the sample.

9. The method according to any one of claims 1-7, wherein the sample is a liquid whole blood sample.

10. The method according to any one of claims 1-7, comprising aspirating the sample, wherein aspirating the sample is performed at the sample inlet of the device to generate an aspirated portion of the sample, and wherein measurements using the reference ion measuring device and measurements using the analyte ion measuring device are performed on the aspirated portion of the sample.

11. The method according to any one of claims 1-7, wherein the reference ion is a hydrogen ion, a sodium ion, or a potassium ion.

12. An apparatus for measuring one or more potential differences of one or more concentrations of one or more analyte ions in an indicator sample, the apparatus comprising: - A reference ion measuring device, arranged to measure parameters indicating the concentration of a reference ion, wherein the reference ion measuring device is different from an electroanalytical measuring device, and -Analytical ion measuring device, including: i. One or more working electrodes, each of which includes an ion-selective electrode that is selective for analyte ions. ii. A reference electrode, comprising a working electrode selective for the reference ion. The analyte ion measuring device mentioned above is an electroanalytical device. Furthermore, the analyte ion measuring device is arranged to directly or indirectly measure one or more potential differences between the following: i. Each of the one or more working electrodes, and ii. The reference electrode, The reference ion measuring device includes an optical sensor, wherein the optical sensor measures an optical parameter P that is pH-dependent. o And the change of optical parameters dP o As pH changes, dpH, dP o / dpH has local and / or global maximum values ​​in the following pH ranges: [7; 8].

13. The apparatus of claim 12, wherein the change in optical parameters dP o As pH changes, dpH, dP o / dpH has local and / or global maximum values ​​in the pH range [7.2, 7.6].

14. The apparatus of claim 12, wherein the change in optical parameters dP o As pH changes, dpH, dP o / dpH has local and / or global maximum values ​​at 7.

4.

15. The apparatus of claim 12, wherein the sample is a liquid whole blood sample.

16. The apparatus of claim 12, wherein the electrical analysis apparatus is a potential measuring apparatus.

17. The apparatus according to any one of claims 12-16, further comprising: - A data processing device, including a processor, is configured as follows: i. Determine the concentration of one or more of the analyte ions in the sample based on the following: The concentration of the reference ion, and The one or more potential differences.

18. The apparatus according to any one of claims 12-16, further comprising: - Sample processing system, including: o Sample inlet, the sample inlet including the sample inlet of the suction system. A measurement chamber, wherein both the reference ion measuring device and the analyte ion measuring device are arranged for measuring the sample while the sample is in the measurement chamber. o One or more fluid channels, which are microfluidic channels, fluidly connecting the sample inlet and the measurement chamber.

19. The apparatus according to any one of claims 12-16, wherein the analyte ion concentration accuracy is less than 20% for the analyte ion as a monovalent ion.

20. The apparatus according to any one of claims 12-16, wherein the analyte ion concentration accuracy is less than 15% for the analyte ion as a monovalent ion.

21. The apparatus according to any one of claims 12-16, wherein the analyte ion concentration accuracy is less than 10% for the analyte ion as a monovalent ion.

22. The apparatus according to any one of claims 12-16, wherein the analyte ion concentration accuracy is less than 7% for the analyte ion as a monovalent ion.

23. The apparatus according to any one of claims 12-16, wherein the analyte ion concentration accuracy is less than 5.4% for the analyte ion as a monovalent ion.

24. The apparatus according to any one of claims 12-16, wherein the analyte ion concentration accuracy is less than 5% for the analyte ion as a monovalent ion.

25. The apparatus according to any one of claims 12-16, wherein the analyte ion concentration accuracy is less than 3.5% for the analyte ion as a monovalent ion.

26. The apparatus according to any one of claims 12-16, wherein the analyte ion concentration accuracy is less than 2.7% for the analyte ion as a monovalent ion.

27. The apparatus according to any one of claims 12-16, wherein the apparatus, or the entire apparatus, enables the determination of one or more concentrations of one or more analyte ions in a sample based on the one or more potential differences with an accuracy relative to one or more true concentrations, the accuracy being less than 20%.

28. The apparatus according to any one of claims 12-16, wherein the apparatus, or the entire apparatus, enables the determination of one or more concentrations of one or more analyte ions in a sample based on the one or more potential differences with an accuracy relative to one or more true concentrations, the accuracy being less than 15%.

29. The apparatus according to any one of claims 12-16, wherein the apparatus, or the entire apparatus, enables the determination of one or more concentrations of one or more analyte ions in a sample based on the one or more potential differences with an accuracy relative to one or more true concentrations, the accuracy being less than 10%.

30. The apparatus according to any one of claims 12-16, wherein the apparatus, or the entire apparatus, enables the determination of one or more concentrations of one or more analyte ions in a sample based on the one or more potential differences with an accuracy relative to one or more true concentrations, the accuracy being less than 7%.

31. The apparatus according to any one of claims 12-16, wherein the apparatus, or the entire apparatus, enables the determination of one or more concentrations of one or more analyte ions in a sample based on the one or more potential differences with an accuracy relative to one or more true concentrations, the accuracy being less than 5.4%.

32. The apparatus according to any one of claims 12-16, wherein the apparatus, or the entire apparatus, enables the determination of one or more concentrations of one or more analyte ions in a sample based on the one or more potential differences with an accuracy relative to one or more true concentrations, the accuracy being less than 5%.

33. The apparatus according to any one of claims 12-16, wherein the apparatus, or the entire apparatus, enables the determination of one or more concentrations of one or more analyte ions in a sample based on the one or more potential differences with an accuracy relative to one or more true concentrations, the accuracy being less than 3.5%.

34. The apparatus according to any one of claims 12-16, wherein the apparatus, or the entire apparatus, enables the determination of one or more concentrations of one or more analyte ions in a sample based on the one or more potential differences with an accuracy relative to one or more true concentrations, the accuracy being less than 2.7%.

35. The device according to any one of claims 12-16, wherein the distance between the following is equal to or less than 10 mm: - Each of the one or more working electrodes, and -The reference electrode.

36. The device according to any one of claims 12-16, wherein the distance between the following is equal to or less than 5 mm: - Each of the one or more working electrodes, and -The reference electrode.

37. The device according to any one of claims 12-16, wherein the distance between the following is equal to or less than 3 mm: - Each of the one or more working electrodes, and -The reference electrode.

38. The device according to any one of claims 12-16, wherein the distance between the following is equal to or less than 1 mm: - Each of the one or more working electrodes, and -The reference electrode.

39. The apparatus according to any one of claims 12-16, wherein the one or more working electrodes are one or more solid working electrodes.

40. Use of the apparatus according to any one of claims 12-39, wherein the apparatus is used to measure one or more potential differences indicating one or more concentrations of one or more analyte ions in a sample.

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