Electrolytes for electrochemical gas sensors and blood gas monitoring

Abstract

An electrolyte composition for use in an electrochemical sensor, the electrolyte composition comprising at least one hygroscopic compound containing at least two moieties (HB) having a hydrogen bonding ability, and at least one hydrophilic evaporation-inhibiting compound having a carbon-to-HB ratio of 2 or more and a molecular weight MW exceeding 100 g / mol, the evaporation-inhibiting compound having a lower viscosity and a lower surface tension than the hygroscopic compound.

Description

[Technical Field]

[0001] The present invention relates to an electrolyte for an electrochemical gas sensor as described in the preamble of an independent claim, an electrochemical gas sensor for blood gas monitoring, a method for detecting the partial pressure of a target gas, and the use of the electrolyte. [Background technology]

[0002] Electrochemical sensors enable the measurement of an analyte using two or more electrodes connected by an electrolyte, where at least one of the electrodes represents an indicator electrode, where the analyte to be determined undergoes a chemical change, generating a potential shift on the electrode. Electrochemical sensors have proven particularly well-suited for measuring gaseous analytes.

[0003] Gases, particularly CO2 and O2, play crucial roles in the physiological functions of various biological processes. Therefore, electrochemical-based gas detection technologies are being applied to medical device sensors that enable the monitoring of these respiratory gases. These include sensors for transcutaneous measurement of blood gases, which measure carbon dioxide and oxygen diffused from the blood onto the skin surface.

[0004] In these medical devices, the electrolyte defines the interface between the gas and the sensing electrode. Therefore, the electrolyte medium must meet certain criteria to enable stable measurements over relatively long application times and provide adequate response times under typical clinical conditions. Key criteria include the stability of the electrolyte composition, the appropriate solubility of each target gas in the electrolyte, temperature stability, chemical inertness, appropriate ionic conductivity, appropriate surface tension, and non-toxicity of the electrolyte components, as unintended contact with a patient or living organism could pose a significant risk.

[0005] For blood gas monitoring, measurement of carbon dioxide or its partial pressure (pCO2) can be performed by using a potentiometric sensor equipped with at least one indicator electrode and at least one reference electrode. For Stow-Severinghaus type electrodes, measurement of CO2 partial pressure is based on pH measurement. This generally requires a reaction chamber spatially separated from the analytical medium by a gas-permeable, mostly ion-impermeable membrane. Within this reaction chamber, the pH value is measured in an electrolyte containing a mild buffer solution with sodium bicarbonate. Carbon dioxide diffuses through the membrane into the electrolyte, where it is partially converted to carbonic acid following the reaction.

[0006]

number

[0007] Given a given temperature, initial pH, and electrolyte composition in the reaction chamber, the pH value of the reaction chamber depends on the CO2 partial pressure of the sample.

[0008] Water, a crucial component of electrolyte composition, is involved in the CO2 hydrolysis reaction on the one hand, and in the ion and proton (H) reaction on the other hand. + This significantly affects the activity of the electrolyte. Therefore, maintaining a constant water content in the electrolyte is a crucial factor in reducing measurement drift over time, enabling reliable and rapid detection. This is particularly important in the field of medical sensors used for gas detection, as these sensors conventionally require frequent calibration with dry gases of known composition, making it even more difficult to maintain a constant water content in the electrolyte.

[0009] To minimize water evaporation, hygroscopic electrolytes have been used that attract and retain water molecules either through absorption or adsorption from the surrounding environment. Furthermore, gas-permeable membranes have been used to encase the electrolyte and further reduce evaporation.

[0010] Such liquid electrolyte compositions for electrochemical gas sensors, in which the electrolyte comprises a hygroscopic matrix of ethylene glycol and / or propylene glycol and a saline aqueous solution to enhance ionic conductivity, are known, for example, from European Patent Application Publication No. 3151000.

[0011] However, electrolytes known from conventional technology have certain drawbacks, which consequently affect the electrochemical sensors and clinical measurements in which they are used. For example, electrolytes based on high vapor pressure compounds such as ethylene glycol or propylene glycol evaporate within days of measurement. Evaporation leads to two known drawbacks. First, it alters the relative composition of the electrolyte, and therefore its ionic activity, resulting in drift and requiring frequent calibration of the sensor. Second, due to the progressed evaporation, previously dissolved salts precipitate from the electrolyte, resulting in deposits on the structural surfaces of the electrode and sensor. This phenomenon not only slows the sensor's response over time, but also leads to additional compositional changes, with the precipitated salts redissolving after reapplication of new electrolyte, resulting in associated drift and inaccuracy issues. Overall, the associated problems caused by electrolyte evaporation necessitate frequent sensor calibration and maintenance. This maintenance leads to a burdensome workload for clinicians in stressful patient monitoring situations, hindering the usefulness of medical devices. Modern technology products require weekly to monthly electrolyte replacement; beyond this, the sensor operates unstably.

[0012] To address the evaporation problem in the general field of electrochemical sensor research, electrolytes based on hydrogels and solid compounds have been proposed (M. Tierney et al., Anal. Chem 1993, 65, 23, 3435-3440; U. Guth et al., J. Solid State Electrochem. 2009, 13, 27-39). However, reported hydrogels suffer from long response times over long-term applications, due to either the hydrogel's poor ability to retain water over longer measurement periods of several days, or / or the high viscosity of the hydrogel resulting in low ionic conductivity. In contrast, solid electrolytes do not have evaporation problems, but typically operate at temperatures above 80°C. While these advances avoid electrolyte evaporation, their performance, i.e., response time, or their operating conditions, such as the 80°C operating temperature, hinders their implementation in transcutaneous blood gas monitoring, which is the main application of this invention. In transcutaneous monitoring, the sensor remains in contact with the skin and needs to be fast enough to reflect physiological changes.

[0013] From a processing and manufacturing perspective, electrolyte formulations should allow for easy application of the electrolyte to the sensor. Two key properties, viscosity and surface tension, play a major role here. Viscosity affects the rheology of the electrolyte. Generally, moderate viscosity is required to coat a thin layer and retain the electrolyte on the sensor without it falling out of the reaction chamber during application. On the other hand, the formulation needs to have moderate surface tension to cover different parts of the sensor with variable hydrophobicity and hydrophilicity. A mismatch between the sensor surface properties and the electrolyte coating capability can lead to bubble formation. Such bubbles result in inaccurate measurements and drift over time due to mismatches in their gas composition and distribution with the electrolyte, as well as their migration within the electrolyte over time.

[0014] Overall, the clinical utility and manufacturability of an electrochemical sensor are determined by the specific molecular properties of the electrolyte, which serves as the heart of the electrochemical sensor. The properties ideally include, but are not limited to, the following: 1. Low vapor pressure 2. High density of hydrogen bonds 3. High ion mobility and sensitivity 4. Increased hygroscopicity 5. Medium viscosity 6. Adjustable surface tension 7. Chemical stability under clinical conditions, i.e., oxidation / decomposition resistance, compatibility with sensor components 8. Low toxicity

Summary of the Invention

Problems to be Solved by the Invention

[0015] Therefore, an object of the present invention is to improve these and other drawbacks of the prior art, and in particular, to provide an electrolyte composition and an electrochemical gas sensor having improved clinical utility, thereby enabling reliable and stable measurement of target gases, rapid clinically acceptable response times (typically meaning seconds to minutes in the context of respiratory gas monitoring), and an extended interval between electrolyte changes, maintenance, and calibration. A further object of the present invention is to provide a method for detecting a gas and to propose the use of an electrolyte that is safe and easy to use for the detection of at least one target gas, particularly carbon dioxide and / or oxygen.

Means for Solving the Problems

[0016] This object is achieved by an electrolyte composition, an electrochemical gas sensor for CO2 detection, optionally combined with an optical sensor for O2 measurement, a method for detecting a target gas, and the use of an electrolyte according to the independent claims. Advantageous embodiments are the subject matter of the dependent claims.

[0017] According to the present invention, an electrolyte composition for use in an electrochemical sensor comprises at least one hygroscopic compound having at least two hydrogen bonding capable moieties (HB), and at least one hydrophilic evaporation inhibiting compound having a carbon to HB ratio of 2 or more and a molecular weight MW exceeding 100 g / mol. The evaporation inhibiting compound has a lower viscosity and a lower surface tension than the hygroscopic compound.

[0018] Surprisingly, such electrolyte compositions are characterized by a gas solubility sufficient to enable gas sensing, a negligible vapor pressure to keep the electrolyte composition constant over a long measurement period, and thus a gas solubility sufficient to minimize measurement drift, have a hygroscopicity sufficient to retain water over several days of measurement, and have been found to calibrate electrochemical sensors using both wet and dry gases. Such electrolytes meet the requirements for the clinical evaluation of blood gases based on electrochemical gas sensing.

[0019] The electrolyte composition according to the present invention is particularly suitable for use in sensors for the transcutaneous measurement of blood gases because these sensors are exposed to frequent changes between wet and dry environments. The wet environment is caused or provided, for example, by patient sweat, application of sealant fluid or gel, and wet monitoring conditions such as incubators, while the dry environment exists, for example, during sensor calibration, storage or transport.

[0020] Preferably, at least one hygroscopic compound of the electrolyte composition disclosed herein is characterized by a carbon to HB ratio of 2 or less, more preferably 1.5 or less, even more preferably 1.34 or less, and most preferably 1.0.

[0021] By using compounds with these characteristics, the hygroscopicity of the electrolyte composition can be further enhanced, allowing it to retain moisture for a longer period. Furthermore, a larger number of HB moieties, i.e., a lower carbon-to-HB ratio, enables proton transport of gases with electrochemical measurement principles based on proton transport and hydrogen bonding, similar to the measurement of CO2, and thus allows for faster measurements. Hydrogen bonding contributes to proton mobility and therefore has a positive effect on the response time of the electrochemical sensor, as will be explained in more detail below.

[0022] Preferably, at least one hydrophilic evaporation inhibitor compound in the electrolyte composition disclosed herein, having a carbon-to-HB ratio of 2 or more, has a molecular weight greater than 400 g / mol.

[0023] The larger the molecular weight, the lower the volatility of the compound, which contributes to the stability of the electrolyte composition. Optionally, the hygroscopic compound of the electrolyte composition disclosed herein is 10 at 25°C. -7 cm 2 More than / s, preferably 10 -6 cm 2 It has a proton diffusion coefficient greater than / s.

[0024] Higher proton mobility has a positive effect on the response time of electrochemical sensors, as will be explained in more detail below.

[0025] In the context of this specification, the moieties having hydrogen bonding capability (HB) may be hydrogen bond donors (HBD) and / or hydrogen bond acceptors (HBA). Preferably, the moieties having hydrogen bonding capability are at least hydrogen bond acceptors (HBA). The moieties having hydrogen bonding capability are parts of the compounds constituting the electrolyte, i.e., covalently bonded to the rest of each molecule. Each compound may have different, i.e., mixed or identical moieties having hydrogen bonding capability. Each moiety may form at least one hydrogen bond with the same or different type or water moiety. Hydrogen bonds may be intermolecular or intramolecular, but the positive effect of hydrogen bonding on the electrolyte properties described herein is particularly due to intermolecular hydrogen bonding.

[0026] There are two common mechanisms involved in proton mobility in proton-conducting electrolytes: the vehicle mechanism (which relies on the physical transport of a vehicle to move protons) and the Grottus mechanism (A. Hassanali et al., PNAS 2013, 110(34), 13723-13728), which involves the handoff of protons from one hydrogen bonding site to another. + ) depends on the inter-site hopping mechanism, while the vehicle mechanism depends on the physical diffusion rate of the vehicle, i.e., H3O + It depends on the vehicle. The vehicle is simply a molecule that can form bonds with free protons and diffuse freely. Previous studies have demonstrated that protons can jump over hydrogen bonds, and therefore hydrogen bonds increase proton mobility based on the Grotthuss mechanism (Ghosh et al. Chem.Mater 2005,17(3),661-669, M.McDonnell et al.,J.Phys.Chem.B 2016,120,5223-5242).

[0027] In preferred embodiments of the electrolytes disclosed herein, the hydrogen-bonding moiety is at least one of a hydroxyl group, a carboxyl group, an amine group, an imine group, and / or an amide group. It is particularly advantageous when the hydrogen-bonding moiety is selected from a hydroxyl moiety, a carboxyl moiety, or an amine moiety.

[0028] Furthermore, the hygroscopic compound is preferably selected from the group consisting of polyhydric alcohols, glycerol, triglycerol, polyglycerol, diethylene glycol, triethylene glycol, triethanolamine, diethanolamine, and / or propylene glycol. More preferably, the hygroscopic compound is selected from polyhydric alcohols, glycerol, triglycerol, diethylene glycol, triethylene glycol, and / or diethanolamine. Most preferably, the hygroscopic compound is glycerol and / or diethylene glycol. Additionally or alternatively, the hygroscopic compound is preferably present in the electrolyte in an amount of less than 90% based on the total weight of the electrolyte.

[0029] The use of superhydrophilic and hygroscopic compounds such as glycerol and diethylene glycol, which are characterized by a carbon-to-HB ratio of 2 or less and consequently low vapor pressure, enables the long-term retention of humidity in electrolyte compositions. Furthermore, the high hydrogen bond density allows for rapid proton transport and therefore rapid detection of gases such as CO2. Moreover, these compounds are non-toxic and largely chemically inert.

[0030] In preferred embodiments of the electrolytes disclosed herein, the evaporation inhibitory compound is selected from the group consisting of polyethylene glycol, polyglycerol, polyoxazoline, polyhydroxy-functional acrylate, particularly poly(2-hydroxyethyl methacrylate), polyethylene oxide, hydrophilic polycarbonate, and short chains (oligomers) of their copolymers, graft copolymers, and / or block copolymers.

[0031] Hydrophilic polycarbonates containing hydroxyl groups in the polymer side chains can be prepared as described by Engler et al. (Macromolecules 2015, 48(6), 1673-1678).

[0032] The use of these evaporation-inhibiting compounds has the advantage that, compared to highly hygroscopic compounds such as glycerol, these compounds have lower viscosity, surface tension, and hydrophilicity. As a result, the formation of a bubble-free layer on the sensor structure, characterized by relative hydrophobicity, is greatly promoted. In particular, the use of polyethylene glycol (PEG) is preferred according to the present invention because its end groups can form hydrogen bonds and thus contribute to proton transport, while its main chain is amphiphilic and soluble in water and many organic solvents. Furthermore, even short-chain PEG is a viscous liquid with a low vapor pressure. For critical oxygen detection, PEG has higher O2 solubility compared to highly hygroscopic compounds such as glycerol. Therefore, the use of PEG allows for a clinically acceptable response time in O2 detection when optical-based oxygen detection is embedded in an electrolyte.

[0033] Preferably, the evaporation inhibitor is present in the electrolyte in an amount of at least 10% based on the total weight of the electrolyte.

[0034] At this concentration in the electrolyte, the advantageous properties of evaporation-inhibiting compounds become particularly apparent. In a preferred embodiment, the electrolyte further comprises a surfactant.

[0035] By using surfactants in the electrolyte composition, the surface tension of the electrolyte composition can be adjusted. This improves the coating properties of superhydrophobic surfaces, such as films made from polytetrafluoroethylene (PTFE), with hydrophilic electrolyte compositions. For example, the use of surfactants can help create air-free coatings, which is crucial for the accuracy of measuring unknown gas compositions using electrochemical sensors, as will be explained in more detail later.

[0036] Preferably, the surfactants in the electrolyte compositions disclosed herein are nonionic and nonmetallic surfactants. This has the advantage of avoiding undesirable interactions with the measurement principle.

[0037] Different compounds are suitable to be considered surfactants, either individually or in mixtures. In preferred embodiments, the surfactants used in the electrolyte compositions disclosed herein are selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polysaccharides, and their copolymers, graft copolymers, and / or block copolymers (long chains). It is particularly advantageous when the surfactant is selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polysaccharides, and their copolymers, graft copolymers, and / or block copolymers.

[0038] These surfactants have the advantage of not adversely affecting the measurement principle and being readily available commercially.

[0039] The surfactant is present in the electrolyte in an amount of less than 5%, more preferably less than 2%, based on the total weight of the electrolyte. Within these preferred concentration ranges, the optimal effectiveness of the surfactant used was found.

[0040] Another characteristic of electrolytes that should be considered when determining the coverage of substrates such as the sensor surface is the viscosity of the electrolyte composition. For example, the viscosity of the electrolyte affects the achievable final thickness of the electrolyte coating after application, and therefore the sensor response time, since the thickness of the electrolyte determines the time required for ions and gases to diffuse and equilibrate. The thickness of the electrolyte may also be defined by a porous spacer material that expands on the pH sensor and contains the electrolyte. In this case, the viscosity affects the penetration of the electrolyte into the pores of the spacer and the uniform wettability of the pores.

[0041] In preferred embodiments, the electrolyte composition disclosed herein further comprises a thickener. By using thickeners in the electrolyte composition, the viscosity of the electrolyte can be adjusted by changing the concentration or molecular weight of each thickener. This prevents, for example, the electrolyte from leaking outside the sensor or through the membrane.

[0042] Preferably, the thickeners in the electrolyte compositions disclosed herein are nonionic and nonmetallic thickeners.

[0043] Nonionic and nonmetallic thickeners have the advantage of not adversely affecting the measurement principle and being readily available commercially.

[0044] Of course, according to the present invention, it is also conceivable to use two or more surfactants and / or thickeners in the electrolyte composition disclosed herein.

[0045] In preferred embodiments, the thickener is selected from the group consisting of polyvinylpyrrolidone (PVP), polyethylene derivatives, polyvinyl alcohol, poly-(2-vinylpyridine), polyethylene oxide, polyethylene glycol monomethyl ether, polyvinyl methyl ether, polysaccharides, polycarbonates, and combinations thereof.

[0046] Preferably, the thickener in the electrolyte composition disclosed herein is selected from the group consisting of polyvinylpyrrolidone (PVP), polyethylene derivatives, polysaccharides, and combinations thereof.

[0047] Preferred polysaccharides in the present invention include cellulose, starch, dextran, cellulose derivatives, starch derivatives, and dextrose.

[0048] The thickening agent is present in the electrolyte in an amount of less than 5%, more preferably less than 2%, based on the total weight of the electrolyte.

[0049] In preferred embodiments, the electrolyte compositions disclosed herein further include an aqueous solution of at least one inorganic bicarbonate-based pH buffer having a buffer range of pH 7 to 9.

[0050] Such pH buffer systems that can be used in liquid electrolyte solutions include any bicarbonate buffer systems known in the art that help to semi-stabilize the pH value in aqueous media.

[0051] Depending on the electrode material used in the electrochemical sensor, for example, when using Ag / AgCl as a (pseudo) reference electrode, it may be advantageous to add the chloride to the buffer solution in direct contact with the electrolyte.

[0052] Optionally, the aqueous solution further contains at least one chloride salt, the concentration of said chloride salt in the buffer solution is less than 3 mol / L.

[0053] Chlorides act as conductive salt components in liquid electrolytes, providing stability to silver chloride electrodes and increasing ionic strength, which is beneficial for faster system response times.

[0054] Preferably, the concentration of chloride salt in the buffer solution is less than 1 mol / L. In preferred embodiments of the electrolyte compositions disclosed herein, the bicarbonate-based pH buffer is selected from the group consisting of sodium bicarbonate buffer and / or potassium bicarbonate buffer. Alternatively or additionally, the chloride salt is selected from the group consisting of LiCl, NaCl and / or KCl.

[0055] These buffer systems have the advantage of buffering the pH of the electrolyte within a preferred range of pH 7-9 when CO2 is added to the system, enabling stable detection of this gas. Preferred chlorides have the advantage of being water-soluble and readily available at very low cost. NaCl and / or KCl are particularly preferred alkali metal chlorides because they offer the advantage of providing a stable potential to the reference electrode.

[0056] In preferred embodiments, the evaporation-inhibiting compounds of the electrolyte compositions disclosed herein have an oxygen solubility greater than 0.01 mg / L and less than 10 mg / L at 25°C and 1 bar, i.e., atmospheric pressure.

[0057] Such electrolyte compositions are particularly well-suited for detecting oxygen. In addition, or alternatively, all compounds in the electrolyte compositions disclosed herein, with the exception of water, have a vapor pressure of less than 0.1 mmHg at 25°C.

[0058] The use of compounds that satisfy these characteristics is particularly suitable for use in electrolytes according to the present invention, as it enables particularly stable detection and measurement with minimal drift.

[0059] In the context of this specification, the values ​​given for vapor pressure refer to values ​​obtained by pressure measurements.

[0060] Other suitable additives that can be added to the electrolyte composition include antifoaming agents. By adding a small amount of at least one antifoaming agent, surface wetting by the electrolyte can be improved.

[0061] In a preferred embodiment, the electrolyte comprises (based on the total weight of each electrolyte) less than 90% of the hygroscopic compound, preferably glycerol; more than 10% of the hydrophilic evaporation inhibitory compound, preferably polyethylene glycol; less than 10% of an aqueous solution of NaHCO3 and KCl; and less than 5% of the surfactant, preferably polyvinylpyrrolidone. In this embodiment, the concentration of NaHCO3 in the aqueous solution is less than 0.1 mol / L, and the concentration of KCl in the aqueous solution is less than 0.2 mol / L.

[0062] Such electrolyte compositions are particularly suitable for measuring CO2 according to the Stow-Sevelinghaus principle.

[0063] In another preferred embodiment, the electrolyte comprises (based on the total weight of each electrolyte) less than 35% of the hygroscopic compound, preferably glycerol, more than 60% of the hydrophilic evaporation inhibitory compound, preferably polyethylene glycol, less than 10% of an aqueous solution of NaHCO3 and KCl, and less than 2% of the surfactant, preferably polyvinylpyrrolidone. In this embodiment, the concentration of NaHCO3 in the aqueous solution is less than 0.1 mol / L, and the concentration of KCl in the aqueous solution is less than 0.2 mol / L.

[0064] Such electrolyte compositions provide sufficient gas solubility to measure oxygen (O2) gas by optical means when an optical sensing element is covered with a thin layer of the electrolyte.

[0065] This objective is further achieved by an electrochemical sensor for detecting at least one target gas, particularly carbon dioxide and / or oxygen.

[0066] According to the present invention, the electrochemical sensor comprises a measuring chamber having an electrolyte and an indicator electrode and a reference electrode in contact with the electrolyte. The measuring chamber has a range of 0.01 to 4 mm 3It can have a cylindrical shape having a volume. The sensor may optionally further comprise an optical module covered with a fluorescent indicator for reactive oxygen detection. The electrochemical sensor further comprises a gas permeable membrane through which a sample gas containing the target gas can penetrate into the electrolyte. In other words, the gas permeable membrane is the contact surface between the measurement chamber and the environment. So that the sensor can be attached to a living body, the sensor also includes means for attaching the electrochemical sensor to the living body. Such means for attaching the electrochemical sensor to a living body include, for example, fasteners configured for shape fitting and / or frictional connection with a binding receptacle adhered, clamped and / or strapped to the skin of the living body. Additionally or alternatively, the electrochemical sensor itself can be adhered, clamped, and / or strapped to the skin of the living body. The electrolyte in the electrochemical sensor disclosed herein includes at least one hygroscopic compound containing at least two hydrogen-bonding capable moieties (HB), and at least one hydrophilic evaporation-inhibiting compound having a carbon-to-HB ratio of 2 or more and a molecular weight MW greater than 100 g / mol. The evaporation-inhibiting compound has a lower viscosity and a lower surface tension than the hygroscopic compound. The hygroscopic compound of the electrolyte composition disclosed herein may additionally or alternatively have a proton diffusivity greater than 10 -7 cm 2 / s.

[0067] The electrochemical sensor disclosed herein is configured for multiple measurements, has a fast response time for determining an analyte, requires little maintenance, and shows only slight drift even after long-term measurements including changes from wet gas exposure to dry gas exposure. Thus, the electrochemical sensor disclosed herein can measure multiple samples with one sensor, or continuous monitoring of the presence and / or amount of an analyte can be carried out, for example, but not limited to, transcutaneous measurement of blood gases, etc., for a longer period, for example, for more than one week, especially for more than one month.

[0068] Preferably, at least one hygroscopic compound of the electrolyte used in the electrochemical sensor disclosed herein has a carbon-to-HB ratio of 2 or less, more preferably 1.5 or less, even more preferably 1.34 or less, and most preferably 1.0. Optionally, the hygroscopic compound is preferably 10 at 25°C. -6 cm 2 It may have a proton diffusion coefficient greater than / s.

[0069] Preferably, at least one hydrophilic evaporation inhibitor compound used in the electrochemical sensor disclosed herein has a molecular weight MW greater than 400 g / mol.

[0070] Preferably, the electrolyte used in the electrochemical sensor is one embodiment of the electrolyte disclosed herein.

[0071] The use of the electrolytes disclosed herein in the electrochemical sensors disclosed herein has the advantages described above for the electrolyte composition.

[0072] The indicator and reference electrodes of the electrochemical sensors disclosed herein may be made of any material suitable for the purpose of potentiometric measurement. The reference electrode may be present with or without liquid bonding and is preferably formed from Ag / AgCl. Ag or Ag / AgCl are suitable as (pseudo) reference electrodes for sensors for the potentiometric determination of carbon dioxide using a pH electrode following the Severinghaus principle.

[0073] Gas-permeable membranes allow gaseous analytes to pass through an electrochemical sensor, but are particularly intended to prevent the intrusion of ions and / or non-volatile components of the (aqueous) measurement medium in the electrolyte. Since transcutaneous blood gas sensors locally heat the skin to typically 38–43°C to induce vasodilation and maximize the correlation between arterial pCO2 and pCO2 measured on the skin, the gas-permeable membrane must also ensure heat transport to the tissue. Therefore, gas-permeable membranes can be made from any material suitable for such purposes. As an example, a gas-permeable membrane comprises at least one polymer material, and copolymers of siloxane, polytetrafluoroethylene, and / or tetrafluoroethylene have proven to be particularly advantageous membrane materials for this purpose. Gas-permeable membranes can be replaced or permanently installed on the electrolyte.

[0074] The gas-permeable membrane used in the electrochemical sensor according to the present invention typically has a thickness of 5 μm to about 50 μm, preferably about 10 μm to about 25 μm.

[0075] The thickness of the gas-permeable membrane represents a trade-off between the sensor's response time and the membrane's own robustness, where response time decreases as the membrane thickness increases.

[0076] To determine a target gas, the electrochemical sensors disclosed herein can be designed in any way that allows contact between the electrochemical sensor and the measuring medium. For this purpose, the electrochemical sensors include means for attaching the electrochemical sensor to a living organism, as will be described in detail below based on exemplary embodiments.

[0077] In a further aspect of the present invention, the objective is achieved by a method for detecting the partial pressure of a target gas in a sample gas. According to the present invention, the method includes the steps of introducing a sample gas into an electrochemical sensor described herein and outputting an electrical signal from the electrochemical sensor representing the partial pressure of the target gas.

[0078] Depending on the presence and / or amount of the analyte, a measurable electrical signal is generated by the sensor. Preferably, this electrical signal, such as current, voltage, or resistance, is evaluated or read out using appropriate means. Preferably, the electrochemical sensor is a potentiometric sensor, such as the carbon dioxide sensor having a (Stow-)Sevelinghaus type electrode. Oxygen gas is preferably measured optically via a photodiode, detecting the current from the decay of fluorescence from an excitation pigment coated with an electrolyte.

[0079] This objective is further achieved by using the electrolyte described herein in an electrochemical sensor, in particular, described herein, for detecting at least one target gas. Preferably, the target gas is selected from oxygen and / or carbon dioxide.

[0080] The following examples are provided to illustrate the invention without limiting it. Unless otherwise indicated, all quantities are based on the total weight of each electrolyte formulation.

[0081] Electrolyte composition for detecting only CO2 The electrolyte composition for detecting CO2 by electrochemical detection relies on potentiometric measurement.

[0082] [Table 1]

[0083] Electrolyte composition for detecting CO2 and O2 The electrolyte composition is suitable for detecting O2 by optical methods. The same electrolyte is also suitable for simultaneously detecting CO2 and O2 via electrochemical and optical detection, respectively.

[0084] [Table 2]

[0085] The present invention will be described in further detail with reference to the accompanying drawings, in which the same reference numerals are used for similar parts and corresponding parts of the drawings. [Brief explanation of the drawing]

[0086] [Figure 1a] A top view of the measurement side of the sensor according to the present invention, configured for transcutaneous measurement. [Figure 1b] Cross-sectional view of the sensor from Figure 1a along line AA in Figure 1a. [Figure 1c] Cross-sectional view of the sensor in Figure 1a along line BB in Figure 1a (the membrane ring with membranes (6a and 6d) is not shown). [Figure 2] Perspective view of the multi-site binding receptacle for the sensor shown in Figure 1a. [Figure 3] Cross-sectional view of a mounting clip equipped with a coupling receptacle for an electrochemical sensor according to the present invention. [Figure 4] A plot showing the results of potential difference measurements obtained using the electrochemical sensor according to the present invention during long-term exposure to a humid gas with a constant CO2 partial pressure. [Figure 5] The response time of an electrolyte newly coated on an electrochemical sensor according to the present invention to a gas swing with a CO2 concentration of 5-10%. [Figure 6] Electrolyte stability: Response of the electrochemical sensor to gas swings at 5-10% CO2 concentration 8 months after the electrolyte was applied to the electrochemical sensor according to the present invention. [Figure 7] Nernst gradient for a Severinghaus electrode due to 8 months of application of the electrolyte according to the present invention. [Figure 8] a) Estimated arterial blood gas based on transcutaneous measurements of healthy adults using the sensor according to the present invention, 11 months after the electrolyte was applied to the sensor; b) Estimated arterial blood gas based on transcutaneous measurements of healthy adults using the sensor according to the present invention and the newly applied electrolyte according to the present invention. [Modes for carrying out the invention]

[0087] Figure 1a shows the measuring side of the electrochemical sensor 1 for transcutaneous tc measurement of blood gases (without the membrane ring attached). In the embodiment of the sensor 1 shown here, only the partial pressure of carbon dioxide PCO2 is measured by the tcPCO2 electrochemical module (indicating electrode) 5, and the partial pressure of oxygen PO2 is determined by the tcPO2 optical module 2, pulsed oximetry light-emitting diode 3, and pulsed oximetry photodiode 4 (optode). In the embodiment shown in Figure 1a, the electrolyte covers the entire surface of modules 2, 3, 4, and 5, as better understood as Figures 1b to 22. The sensor housing of the electrochemical sensor 1 is configured as a binding element, which can be engaged with a binding receptacle 10, i.e., a means for attaching the electrochemical sensor 1 to a living organism, as described in more detail in Figures 1b and 1c.

[0088] In the context of this application, the term “multi-site” refers to application sites of the binding receptacle located at different locations in the living body. For example, for CO2 measurement, the binding receptacle is attached to the chest, ventral, thigh, subclavian, forehead, earlobe, and cheek of the living body. Figure 1b shows a cross-sectional view of the sensor 1 from Figure 1a along line AA of Figure 1a through optodes 3 and 4. The membrane ring 6a is positioned only for orientation and is attachable to groove 6b. Means for attaching the electrochemical sensor 1 to the living body include the engagement groove 6b and a retaining element 7. Both 6b and 7 extend along the radial outer surface of the sensor 1.

[0089] Ideally, the electrolyte 22 covers the entire surface indicated by measurement d, and is itself covered by a film. Alternatively, the electrolyte 22 can cover the electrochemical module (see reference numeral 5 in Figure 1a) alone or in combination with other modules.

[0090] The membrane ring 6a is lockable within the groove 6b, and a pressure seal is mounted on the side 6c, with a diameter of approximately 10 mm and 100 mm. 2It is stretched over a cross-section d having an area less than . The membrane can be fixed temporarily or permanently. The membrane may consist of a single layer or multiple layers. The top layer of module 5 must be gas permeable and is free from organic CO2 permeable materials, porous metal compounds, or any combination of both in composite form. The outer layer of module 5 is free from materials of the class polymer, metallic, nonmetallic, organic, inorganic, or any combination thereof. To detect O2, the top layer of module 2 must be oxygen permeable.

[0091] To engage the sensor 1 with the coupling receptacle 10, the sensor 1 is inserted into the coupling receptacle 10 such that the engaging element 13 of the coupling receptacle 10 engages with the engaging groove 6b of the coupling element.

[0092] Once the binding element and binding receptacle 10 are engaged, the actual measurement module should be placed as flat as possible on the living skin and slightly pressed against it. As can be seen from the cross-sections shown in Figures 1b and 1c, the sensor 1 features a slightly convex bottom surface facing the living skin to ensure skin contact. In this example, the sensor 1 is inserted into the binding receptacle 10 to approximately height h. The diameter d of the engaging element is selected so that the sensor 1 can be accommodated within the binding receptacle 10 in an essentially precise fit, and the sensor 1 can still rotate within the binding receptacle 10 when connected. In this embodiment, the diameter d shown in Figure 1b is approximately 10 mm, and the insertion height h is approximately 4 mm.

[0093] Figure 1c shows a cross-sectional view of sensor 1 from Figure 1a along line BB in Figure 1a, passing through the tcPO2 optical module 2 and the tcPCO2 electrochemical module 5. The tcPCO2 electrochemical module 5 comprises a cation exchange glass membrane 8 having a diameter of approximately 3 mm to enable selective proton transport, and a glass wall 9 containing an inner standard electrolyte 21, with an inner working electrode (Ag / AgCl) 20 attached to a platinum electrode 19. The inner standard electrolyte 21 may be selected by those skilled in the art and is not necessarily the electrolyte described herein. Sensor 1 further comprises a reference electrode 24, which in the embodiment shown in the figure is designed as an Ag / AgCl electrode. The thickness of the electrolyte layer 22 is approximately 5 μm to 10 μm when newly coated on the cross-section d shown in Figure 1b, and approximately 0.4 mm 3 ~0.8mm 3 This corresponds to the volume of 100 mm². The exposed surface-to-volume ratio there is 100 mm². -1 ~200mm -1 Preferably 130 mm -1 ~170mm -1 This range is, most preferably 150 mm -1 The circumferential membrane engagement groove 6b and circumferential retaining element 7 shown in Figure 1b are also indicated.

[0094] Figure 2 shows a perspective view of a multi-site binding receptacle 10 for the sensor 1 of Figure 1a. In this embodiment, the binding receptacle 10 comprises an adhesive pad 11 that can be applied to the skin 100 of a living organism. The binding receptacle 10 further comprises several engaging elements 13, preferably eight engaging elements 13, which can be inserted into engaging grooves 6b of the binding element of the sensor 1. The engaging grooves 6b are preferably located in a region of the binding element that tapers toward the direction of the binding receptacle 10. The sensor 1 is further supported by retaining elements 14, which, in addition to the lateral engaging elements 13, restrict and support the mobility of the sensor 1. In this embodiment, both the engaging elements 13 and the retaining elements 14 are arranged in a circular shape. The inner diameter of the circle defined by these elements 13, 14 is approximately 14 mm, and the height of these elements 13, 14 is approximately 4 mm.

[0095] To measure on a living earlobe or skin flap, Figure 3 shows a cross-section of a mounting clip comprising a binding receptacle 10, the binding receptacle 10 characterized by an engaging element 13 and a retaining element 14, both of which are arranged in a circular shape. In this embodiment, the height h of the engaging element 13 and the retaining element 14 is approximately 4 mm. The inner diameter of the circle defined by these elements 13, 14 is approximately 14 mm. The mounting clip is configured to be attached to a living earlobe or skin flap, and for this purpose comprises a clamping opening 18 defined by the upper part 15 and lower part 16 of the binding receptacle 10, so that, for example, the living earlobe or skin flap can be inserted and clamped using a torsion spring 17 or another friction locking fastener.

[0096] This type of binding receptacle allows for secure and easy connection of the sensor to the patient's earlobe for reliable and accurate measurement of blood gases. It simplifies and reduces the workload required of the user and improves process reliability.

[0097] Figure 4 shows the generation of potentiometric measurements of humidified 10% CO2 gas performed using the sensor and the newly coated electrolyte according to the present invention for gas exposure over several days. As is evident from the recorded voltages, the drift of the CO2 measurement remained below 2% over 7 days. No drift correction algorithm was applied. Both the long-term stability of the measurements and the short-term drift behavior are excellent for clinical applications.

[0098] Figure 5 shows the response time of the CO2 sensor according to the present invention for dry gas exchange of a 5% to 10% CO2 composition using the newly coated electrolyte of the present invention. Response time (T 90 Response time is defined as the time required for the sensor to show a shift from 10% to 90% of the final stable value of CO2 partial pressure. The response time is consistent with the in vitro performance of commercially available products for monitoring physiological changes in clinical applications.

[0099] Figure 6 shows the progress of potentiometric measurements as the dry gas CO2 concentration shifts to 5-10% at ambient temperature. The data corresponds to electrolytes present on the sensor according to an embodiment of the present invention for eight months. During this time, the sensor performed transcutaneous gas measurements according to an embodiment of the present invention. Furthermore, the drift of the measured values ​​was less than 2%, indicating that aging had little effect on the sensitivity and low-drift behavior of the electrolyte according to the present invention, even with multiple measurements in a clinical setting without any maintenance.

[0100] Figure 7 shows the Nernst gradient of a sensor operating on the Sevelinghaus principle. The gradient is measured by shifting the CO2 concentration to 5-10% CO2 for 800 minutes under ambient conditions after the electrolyte has been present on the sensor for 8 months. By evaluating the difference of this gradient from the ideal theoretical Nernst value of 62.5 mV / decade at 42°C, significant changes in the electrolyte composition during aging can be identified. As shown in Figure 7, the gradient value remained within the range of 57 mV, reflecting the stability of the electrolyte composition over the 8-month measurement period.

[0101] Figure 8 demonstrates estimated arterial carbon dioxide blood gas from transcutaneous measurements of healthy adults performed with electrolytes and sensors of a preferred embodiment of the present invention, where (a) the electrolyte was present on the sensor for 11 months and (b) the electrolyte was newly applied. The initial increase in the measurement corresponds to the stabilization of the sensor to equilibrate with skin temperature and CO2 concentration. The data are derived from raw physical measurements and are not corrected by algorithmic correction. In Figure 8a, the electrolyte had an age of over 11 months from the application time on the sensor without maintenance in between. During this period, the sensor was under periodic dry calibration gas or set up on a healthy adult for multiple transcutaneous measurements. The measurement is within the expected range of 30–40 mmHg for healthy individuals without drift algorithm correction. Figure 8b demonstrates the results of the same type of measurement as 8a, but using a newly applied electrolyte. These two measurement values ​​do not reflect a significant change within acceptable performance of the physiological relevance of the electrolyte during the 11-month aging period. These facts demonstrate that the electrolyte according to the present invention remained clinically functional without any maintenance required, reflecting electrolyte stability for nearly one year.

[0102] Overall, the observed performance of the electrolyte according to the preferred embodiment of the present invention satisfies the characteristics required for long-term stable measurement without the need for maintenance, assuming that the other parts of the sensor also remain stable.

Claims

1. An electrolyte (22) composition for use in an electrochemical sensor, wherein the electrolyte (22) composition is A hygroscopic compound comprising at least two moieties (HB) having a hydrogen bonding ability ratio of -2 or less, - A hydrophilic evaporation inhibitory compound having a carbon-to-HB ratio of 2 or higher and a molecular weight MW greater than 100 g / mol, An electrolyte (22) composition wherein the hydrophilic evaporation-inhibiting compound has a lower viscosity and lower surface tension than the hygroscopic compound.

2. The electrolyte (22) composition according to claim 1, wherein each of the at least two portions having hydrogen bonding ability is selected from a hydroxyl group, a carboxyl group, an amine group, an imine group, and an amide group.

3. The electrolyte (22) composition according to claim 1 or 2, wherein the hydrophilic evaporation inhibitory compound is selected from the group consisting of polyethylene glycol, polyglycerol, polyoxazoline, polyhydroxy-functional acrylate, polyethylene oxide, hydrophilic polycarbonate, and / or short-chain oligomers of copolymers, graft copolymers, and block copolymers thereof.

4. The electrolyte (22) composition according to claim 1, wherein the electrolyte (22) composition further comprises a surfactant.

5. The electrolyte (22) composition according to claim 4, wherein the surfactant is selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polysaccharides, and copolymers, graft copolymers, and / or block copolymers thereof.

6. The electrolyte (22) composition according to claim 1, wherein the electrolyte (22) composition further comprises a thickening agent.

7. The electrolyte (22) composition according to claim 6, wherein the thickening agent is selected from the group consisting of polyvinylpyrrolidone (PVP), polyethylene derivatives, polyvinyl alcohol, poly-(2-vinylpyridine), polyethylene oxide, polyethylene glycol monomethyl ether, polyvinyl methyl ether, polysaccharides, polycarbonates, and combinations thereof.

8. The electrolyte (22) composition according to claim 1, wherein the electrolyte (22) composition further comprises an aqueous solution of at least one inorganic bicarbonate-based pH buffer.

9. The electrolyte (22) composition according to claim 8, wherein the bicarbonate-based pH buffer is selected from the group consisting of sodium bicarbonate buffer and / or potassium bicarbonate buffer.

10. The electrolyte (22) composition according to claim 1, wherein the hydrophilic evaporation-inhibiting compound has an oxygen solubility of more than 0.01 mg / L and less than 10 mg / L at 25°C and 1 bar, and / or all compounds except water have a vapor pressure of less than 0.1 mmHg at 25°C.

11. The electrolyte (22) composition is determined based on the total weight of each of the electrolyte (22) compositions. - The hygroscopic compound with less than 90%, - A hydrophilic evaporation inhibitory compound exceeding 10%, - Less than 10% NaHCO ３ and an aqueous solution of KCl, wherein the aqueous solution contains NaHCO ３ An aqueous solution in which the concentration of is less than 0.1 mol / L and the concentration of KCl in the aqueous solution is less than 0.2 mol / L, - Less than 5% of the aforementioned surfactant, The electrolyte (22) composition according to claim 4, comprising:

12. Each of the electrolyte (22) compositions is determined based on the total weight of the electrolyte (22) composition. - The hygroscopic compound in a concentration of less than 35%, - The hydrophilic evaporation inhibitory compound exceeding 60%, - Less than 2% of the aforementioned surfactant, The electrolyte (22) composition according to claim 11, comprising:

13. An electrochemical sensor (1) for detecting at least one target gas, wherein the electrochemical sensor is - A measurement chamber (23) comprising an electrolyte (22) composition, - An indicator electrode (5) and a reference electrode (24) that come into contact with the electrolyte (22) composition, - An arbitrary optical module (2) covered with a fluorescent indicator for reactive oxygen detection, - A gas-permeable membrane (6d) that allows the sample gas containing the target gas to permeate the electrolyte (22) composition, - The system comprises means for attaching the electrochemical sensor (1) to a living organism (100), The electrolyte (22) composition is A hygroscopic compound comprising at least two moieties (HB) having a hydrogen bonding ability ratio of -2 or less, - A hydrophilic evaporation inhibitory compound having a carbon-to-HB ratio of 2 or higher and a molecular weight MW greater than 100 g / mol, - An electrochemical sensor (1) wherein the hydrophilic evaporation-inhibiting compound has lower viscosity and lower surface tension than the hygroscopic compound.

14. A method for detecting the partial pressure of a target gas in a sample gas, wherein the method is - Introducing the sample gas into the electrochemical sensor (1) described in claim 13, - Outputting an electrical signal from the electrochemical sensor (1) that represents the partial pressure of the target gas, Methods that include...

15. Use of the electrolyte (22) composition according to claim 1 for an electrochemical sensor (1) for detecting at least one target gas.

Images