Electrolyte for Electrochemical Gas Sensor 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, an electrochemical gas sensor for blood gas monitoring, a method for detecting a target gas partial pressure, and the use of an electrolyte as described in the preamble of the independent claim.

Background Art

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

[0003] Gases, especially CO2 and O2, play important roles in the physiological functions of different functions of the living body. Therefore, techniques such as electrochemical-based gas detection are applied to medical device sensors that enable the monitoring of these respiratory gases, among which there are sensors for transcutaneously measuring blood gases, in which carbon dioxide and oxygen diffused from the blood to the skin surface are measured.

[0004] In these medical devices, the electrolyte defines the interface between the gas and the sensing electrode. Therefore, the electrolyte medium needs to meet specific criteria in order to enable stable measurements over a relatively long application time and provide an appropriate response time in a general clinical situation. The main 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 the non-toxicity of electrolyte components where unintended patient or biological contact can pose a significant risk.

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

[0006]

Number

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

[0008] Water, which is an important part of the electrolyte composition, on the one hand, participates in the CO2 hydrolysis reaction and, on the other hand, significantly affects the activity of ions and protons (H + ). Therefore, maintaining a certain water content in the electrolyte is an important factor in reducing measurement drift over time, which enables highly reliable and rapid detection. These sensors conventionally need to be frequently calibrated with dry gases of known composition, which makes it even more difficult to maintain a certain water content in the electrolyte, and thus this is particularly important in the field of medical sensors used for gas detection.

[0009] To minimize the evaporation of water, hygroscopic electrolytes that attract and retain water molecules via either absorption or adsorption from the ambient environment have been used. Additionally, gas-permeable membranes have been used to cover the electrolyte and further reduce evaporation.

[0010] Such a liquid electrolyte composition for an electrochemical gas sensor, wherein the electrolyte comprises a hygroscopic matrix of ethylene glycol and / or propylene glycol and an aqueous salt solution that enhances ionic conductivity, is known, for example, from European Patent Application Publication No. 3151000.

[0011] However, the electrolytes known from the prior art have certain drawbacks, which in turn affect the electrochemical sensors and clinical measurements in which the electrolytes are used. For example, electrolytes based on high vapor pressure compounds such as ethylene glycol or propylene glycol evaporate within a few days of measurement. Evaporation leads to two known drawbacks. First, it changes the relative composition of the electrolyte and thus the ionic activity, which results in drift and requires frequent calibration of the sensor. Second, advanced evaporation causes the previously dissolved salts to precipitate from the electrolyte, resulting in deposits on the electrode and the structural surface of the sensor. This phenomenon not only slows down the response of the sensor over time, but also, after reapplication of a new electrolyte, the precipitated salts redissolve, resulting in additional compositional changes associated with the problems of drift and inaccuracy. Overall, the associated problems due to electrolyte evaporation determine the frequent calibration and maintenance of the sensor. This maintenance leads to a laborious workload for clinicians in stressful patient monitoring situations and hinders the usefulness of the medical device. State-of-the-art products require electrolyte replacement from weekly to monthly, beyond which the sensor operates unstably.

[0012] To address the issue of evaporation 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, the reported hydrogels suffer from long response times over long-term applications, either due to the low ability of the hydrogel to retain water over longer measurement periods of several days and / or the high viscosity of the hydrogel resulting in low ionic conductivity. In contrast, solid electrolytes have no problem with evaporation but typically operate at temperatures above 80°C. These advancements avoid electrolyte evaporation, but their performance, i.e., response time, or their operating conditions such as the operating temperature of 80°C, hinder their implementation in transcutaneous blood gas monitoring, which is the main application focus of the present 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, the electrolyte formulation should enable easy application of the electrolyte onto the sensor. Here, two main important properties, namely viscosity and surface tension, play a major role. Viscosity affects the rheology of the electrolyte. Generally, an appropriate viscosity is required to apply a thin layer and hold the electrolyte on the sensor without dropping the electrolyte from the reaction chamber during application. On the other hand, the formulation needs to have a medium surface tension to cover different parts of the sensor with variable hydrophobic and hydrophilic properties. If there is a mismatch between the sensor surface characteristics and the electrolyte coating ability, bubbles may occur. Such bubbles lead to inaccurate measurements and drift over time due to the mismatch in their gas composition and partitioning with the electrolyte, as well as their movement in 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 that 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 / resistance to decomposition, compatibility with sensor components 8. Low toxicity

Summary of the Invention

Problems to be Solved by the Invention

[0015] Accordingly, it is an object of the present invention 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, a rapid clinically acceptable response time (which typically means from a few seconds to a few 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, in particular 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 an electrolyte composition features a gas solubility sufficient to enable gas sensing, a negligible vapor pressure to keep the composition of the electrolyte constant over a long measurement period, and thus a gas solubility sufficient to minimize measurement drift, has a hygroscopicity sufficient to retain water over several days of measurement, and has been found to calibrate an electrochemical sensor using both wet and dry gases. Such an electrolyte meets 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. A wet environment is caused or provided, for example, by a patient's sweat, the application of a sealing liquid or gel, and a wet monitoring state such as an incubator, while a dry environment exists, for example, during sensor calibration, storage or transportation.

[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 the compounds having these characteristics, the hygroscopicity of the electrolyte composition can be further enhanced, and moisture can be retained for a longer time. Further, when the number of HB moieties is large, i.e., the carbon-to-HB ratio is low, as in the case of CO2 measurement, proton transport of gases having an electrochemical measurement principle based on proton transport and hydrogen bonding, and thus even faster measurement becomes possible. Hydrogen bonding contributes to proton mobility and thus 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-inhibiting compound of the electrolyte compositions disclosed herein having a carbon-to-HB ratio of 2 or more has a molecular weight exceeding 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 has a proton diffusion coefficient exceeding 10 -7 cm 2 / s, preferably exceeding 10 -6 cm 2 / s.

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

[0025] In the context of this specification, a moiety having hydrogen bonding capability (HB) can be a hydrogen bond donor (HBD) and / or a hydrogen bond acceptor (HBA). Preferably, the moiety having hydrogen bonding capability is at least a hydrogen bond acceptor (HBA). The moiety having hydrogen bonding capability is part of a compound that constitutes an electrolyte, i.e., it is covalently connected to the rest of each molecule. Each compound can have different, i.e., mixed or identical, moieties having hydrogen bonding capability. Each moiety can form at least one hydrogen bond with the same or different types or parts of water. The hydrogen bond can be intermolecular or intramolecular, but the positive effect of the hydrogen bond on the electrolyte properties described herein is particularly due to intermolecular hydrogen bonds.

[0026] There are two general mechanisms involved in proton mobility in proton-conducting electrolytes: the vehicle mechanism (which depends on the physical transport of a vehicle to move protons) and the Grotthuss mechanism (A. Hassanali et al., PNAS 2013, 110(34), 13723 - 13728) which involves the handoff of a proton from one hydrogen-bonding site to another. The Grotthuss mechanism depends on the site-to-site hopping mechanism of protons (H + ), while the vehicle mechanism depends on the physical diffusion rate of the vehicle, i.e., H3O + . The vehicle is a mere molecule that can form a bond with a free proton and diffuse freely. Previous studies have demonstrated that protons can jump over hydrogen bonds and thus that hydrogen bonds enhance 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 a preferred embodiment of the electrolyte disclosed herein, the moiety having a hydrogen bonding ability 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 moiety having a hydrogen bonding ability 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, it is preferred that the hygroscopic compound is present in the electrolyte in an amount 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, both characterized by a carbon-to-HB ratio of 2 or less and concomitantly low vapor pressure, enables the long-term retention of humidity in the electrolyte composition. Furthermore, the high hydrogen bonding density enables the rapid transport of protons and thus the rapid detection of gases such as CO2. Additionally, these compounds are non-toxic and most are chemically inert.

[0030] In a preferred embodiment of the electrolyte disclosed herein, the evaporation-inhibiting 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 their copolymers, graft copolymers and / or short-chain (oligomeric) 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 strongly hygroscopic compounds such as glycerol, these compounds have lower viscosities, surface tensions, and hydrophilicities. As a result, the formation of a bubble - free layer on the sensor structure, which is characterized by relative hydrophobicity, is significantly 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 both water and many organic solvents. Furthermore, even short - chain PEGs are viscous liquids with low vapor pressures. For the important detection of oxygen, PEG has a higher O2 solubility compared to strongly hygroscopic compounds such as glycerol. Thus, the use of PEG enables a clinically acceptable response time in the detection of O2 when optical - based oxygen detection is embedded in an electrolyte.

[0033] Preferably, the evaporation - inhibiting compound 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 the evaporation - inhibiting compound become particularly apparent. In a preferred embodiment, the electrolyte further comprises a surfactant.

[0035] By using a surfactant in the electrolyte composition, the surface tension of the electrolyte composition can be adjusted. Thereby, the coating property with a hydrophilic electrolyte composition on a superhydrophobic surface such as a film made of polytetrafluoroethylene (PTFE) can be improved. For example, the use of a surfactant may assist in generating a coating that does not contain air during coating, which is very important for the measurement accuracy of an unknown gas composition using an electrochemical sensor, as will be described in more detail later.

[0036] Preferably, the surfactant in the electrolyte composition disclosed herein is a nonionic and nonmetallic surfactant. This has the advantage that undesirable interactions with the measurement principle are avoided.

[0037] Different compounds are suitable for being regarded as surfactants either alone or in a mixture. In a preferred embodiment, the surfactant used in the electrolyte composition disclosed herein is selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polysaccharides, and long-chain (high molecular weight) copolymers, graft copolymers, and / or block copolymers thereof. It is particularly advantageous when the surfactant is selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polysaccharides, and copolymers, graft copolymers, and / or block copolymers thereof.

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

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

[0040] Another property of the electrolyte that should be considered in terms of the coating property of the substrate such as the surface of the sensor is the viscosity of the electrolyte composition. For example, since the thickness of the electrolyte defines the time required for ions and gas to diffuse and equilibrate, the viscosity of the electrolyte affects the achievable final thickness of the electrolyte coating after coating, and thus the sensor response time. The thickness of the electrolyte may also be defined by a porous spacer material that swells 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 a preferred embodiment, the electrolyte composition disclosed herein further comprises a thickening agent. By using a thickening agent in the electrolyte composition, the viscosity of the electrolyte can be adjusted by changing the concentration or molecular weight of each thickening agent. Thereby, for example, it is possible to prevent the electrolyte from leaking outside the sensor or through the membrane.

[0042] Preferably, the thickening agent in the electrolyte composition disclosed herein is a nonionic and nonmetallic thickening agent.

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

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

[0045] In a preferred embodiment, 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.

[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 thickener is preferably 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 a preferred embodiment, the electrolyte composition disclosed herein further comprises an aqueous solution of at least one inorganic bicarbonate-based pH buffer having a buffering range of particularly pH 7 to 9.

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

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

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

[0053] Chloride acts as a conductive salt component of the liquid electrolyte, provides stability to the silver chloride electrode, and increases the ionic strength, which is beneficial for a faster system response time.

[0054] Preferably, the concentration of the chloride salt in the buffered aqueous solution is less than 1 mol / L. In a preferred embodiment of the electrolyte composition 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 value of the electrolyte in the 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. In particular, NaCl and / or KCl are preferred alkali metal chlorides because they provide the advantage of providing a stable potential to the reference electrode.

[0056] In a preferred embodiment, the evaporation-inhibiting compound of the electrolyte composition disclosed herein has 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 the detection of oxygen. In addition or alternatively, all compounds in the electrolyte composition disclosed herein, except water, have a vapor pressure of less than 0.1 mmHg at 25 °C.

[0058] The use of compounds satisfying this property is particularly suitable for use in the electrolytes according to the invention, as it enables particularly stable detection measurements with little drift.

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

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

[0061] In a preferred embodiment, the electrolyte comprises less than 90% of the hygroscopic compound, preferably glycerol, more than 10% of the hydrophilic evaporation-inhibiting compound, preferably polyethylene glycol, less than 10% of an aqueous solution of NaHCO3 and KCl, and less than 5% of the surfactant, preferably polyvinylpyrrolidone, based on the total weight of the electrolyte. 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 an electrolyte composition is particularly suitable for measuring CO2 according to the principle of the Stoewe-Severinghaus house.

[0063] In another preferred embodiment, the electrolyte comprises less than 35% of the hygroscopic compound, preferably glycerol, more than 60% of the hydrophilic evaporation-inhibiting compound, preferably polyethylene glycol, less than 10% of an aqueous solution of NaHCO3 and KCl, and less than 2% of the surfactant, preferably polyvinylpyrrolidone, based on the total weight of the electrolyte. 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 an electrolyte composition provides sufficient gas solubility to measure oxygen (O2) gas by an optical method when the optical sensing element is covered with a thin layer of the electrolyte.

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

[0066] According to the present invention, the electrochemical sensor comprises a measurement chamber comprising an electrolyte and a working electrode and a reference electrode in contact with the electrolyte. The measurement chamber is 0.01 to 4 mm 3It can have a cylindrical shape having a volume. The sensor may optionally further comprise an optical module coated 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 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 bonding 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 comprises 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 two or more and a molecular weight MW greater than 100 g / mol. The evaporation inhibiting compound has a lower viscosity and 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 sensors disclosed herein are configured for multiple measurements, have a fast response time for determining an analyte, require little maintenance, and show only slight drift even after long-term measurements including changes from wet gas exposure to dry gas exposure. Thus, the electrochemical sensors disclosed herein are suitable for applications where a single sensor measures a large number of samples or continuous monitoring of the presence and / or amount of an analyte is 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 preferably has a proton diffusion coefficient of more than 10 -6 cm 2 / s at 25°C.

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

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

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

[0072] The indicator electrode and the reference electrode of the electrochemical sensor disclosed herein can be made of any material suitable for the purpose of potential difference measurement. The reference electrode can be present with or without a liquid junction and is preferably formed from Ag / AgCl. Ag or Ag / AgCl is suitable as a (pseudo) reference electrode for a sensor for potentiometric quantification of carbon dioxide using a pH electrode according to the Severinghaus principle.

[0073] The gas-permeable membrane allows the gaseous analyte to permeate the electrochemical sensor, but in particular is intended to prevent the ingress of ions and / or non-volatile components of the (aqueous) measurement medium in the electrolyte. The transcutaneous blood gas sensor typically locally heats the skin to 38-43 °C in order to induce vasodilation and maximize the correlation between the arterial pCO2 and pCO2 measured on the skin, so the gas-permeable membrane must also ensure heat transport to the tissue. Thus, the gas-permeable membrane can be made of any material suitable for such purposes. By way of example, the gas-permeable membrane comprises at least one polymeric material, and siloxanes, copolymers of polytetrafluoroethylene and / or tetrafluoroethylene have proven to be particularly advantageous membrane materials for this purpose. The gas-permeable membrane can be installed replaceably or permanently on the electrolyte.

[0074] The gas-permeable membrane used in the electrochemical sensor according to the 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 response time of the sensor and the robustness of the membrane itself, whereby the response time decreases as the thickness of the membrane increases.

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

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

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

[0079] This object is further achieved by using the electrolyte described herein in the electrochemical sensor 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 for illustrative purposes without limiting the present invention. Unless otherwise indicated, all amounts 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 depends on potentiometric measurement.

[0082] [Table 1]

[0083] Electrolyte composition for detecting CO2 and O2 The electrolyte composition is suitable for detecting O2 by an optical method. 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 more detail with reference to the drawings in which like reference numerals are used for like and corresponding parts of the accompanying drawings.

Brief Description of the Drawings

[0086]

Fig. 1a

Fig. 1b

Fig. 1c

Fig. 2

Fig. 3

Fig. 4

Fig. 5

Fig. 6

Fig. 7

Fig. 8

Mode for Carrying Out the Invention

[0087] Figure 1a shows the measurement side of the electrochemical sensor 1 for transcutaneous tc measurement of blood gases (the membrane ring is not 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 (indicator electrode) 5, and the partial pressure of oxygen PO2 is determined by the tcPO2 optical module 2, the pulse oximetry light-emitting diode 3, and the pulse oximetry photodiode 4 (optode). In the embodiment shown in Figure 1a, the electrolyte covers the entire surface of the modules 2, 3, 4, and 5, as can be better understood from Figure 1b as 22. The sensor housing of the electrochemical sensor 1 is configured as a coupling element, and the coupling element can engage with a coupling receptacle 10, that is, means for attaching the electrochemical sensor 1 to a living body, as will be described in more detail in Figures 1b and 1c.

[0088] In the context of this application, the term "multi-site" refers to the application sites of coupling receptacles at different positions on a living body. As an example, for CO2 measurement, the coupling receptacle can be attached to the chest, ventral side, thigh, subclavian, forehead, earlobe, and cheek of a living body. Figure 1b shows a cross-sectional view of the sensor 1 from Figure 1a along line A-A through the optodes 3 and 4. The membrane ring 6a is given only for orientation of its position and can be attached to the groove 6b. The means for attaching the electrochemical sensor 1 to a living body includes the engagement groove 6b and the retaining element 7. Both 6b and 7 extend along the radially outer surface of the sensor 1.

[0089] Ideally, the electrolyte 22 covers the entire surface indicated by the measurement value d and is itself covered by a membrane. 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 can be locked in the groove 6b, implements a pressure seal on the side surface 6c, and has a diameter of approximately 10 mm and 100 mm 2It extends across a cross-section d having an area less than. The membrane can be temporarily or permanently fixed. The membrane can be composed of a single layer or multiple layers. The upper layer of module 5 must be gas permeable and is excluded from any combination of organic CO2 permeable materials, porous metal compounds, or both in composite form. The outer layer of module 5 is excluded from materials of the class of polymers, metals, non-metals, organics, inorganics, or any combination thereof. In order to detect O2, the upper layer of module 2 must be oxygen permeable.

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

[0092] Once the engagement element and coupling receptacle 10 are engaged, the actual measurement module should be placed as flat as possible on the skin of the living body and slightly pressed against it. As can be seen from the cross-sections shown in FIGS. 1b and 1c, sensor 1 features a slightly convex bottom surface facing the skin of the living body to ensure skin contact. In this example, sensor 1 is inserted into coupling receptacle 10 to approximately height h. The diameter d of the engagement element is selected such that sensor 1 can be accommodated within coupling receptacle 10 with an essentially accurate fit and still be able to rotate within coupling receptacle 10 when connected. In this embodiment, the diameter d shown in FIG. 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 B-B of Figure 1a through tcPO2 optical module 2 and tcPCO2 electrochemical module 5. The tcPCO2 electrochemical module 5 includes a cation exchange glass membrane 8 having a diameter of approximately 3 mm that allows for selective proton transport, and a glass wall 9 containing an inner reference electrolyte 21 with an inner working electrode (Ag / AgCl) 20 attached to a platinum electrode 19. The inner reference electrolyte 21 may be selected by those skilled in the art and does not necessarily have to be the electrolyte described herein. Sensor 1 further includes a reference electrode 24 designed as an Ag / AgCl electrode in the illustrated embodiment. The thickness of the electrolyte layer 22 is approximately 5 μm to 10 μm when newly applied on cross-section d shown in Figure 1b, corresponding to a volume of approximately 0.4 mm 3 ~0.8 mm 3 The exposed surface to volume ratio there is 100 mm -1 ~200 mm -1 , preferably in the range of 130 mm -1 ~170 mm -1 and most preferably 150 mm -1 . Also shown are the circumferential membrane engagement groove 6b and circumferential retaining element 7 described in Figure 1b.

[0094] Figure 2 shows a perspective view of a multi-site coupling receptacle 10 for sensor 1 of Figure 1a. In this embodiment, the coupling receptacle 10 includes an adhesive pad 11 that can be applied to the skin 100 of a living body. The coupling receptacle 10 further includes a number of engagement elements 13, preferably eight engagement elements 13, that can be inserted into the engagement groove 6b of the coupling element of sensor 1. The engagement groove 6b is preferably located in a region of the coupling element that tapers towards the coupling receptacle 10. Sensor 1 is further supported by a retaining element 14 that, in addition to the lateral engagement elements 13, restricts and supports the mobility of sensor 1. In this embodiment, both the engagement elements 13 and the retaining element 14 are arranged circularly. 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] For measuring on the auricle or skin flap of a living body, FIG. 3 shows a cross-section of a mounting clip having a coupling receptacle 10, the coupling receptacle 10 being characterized by an engagement element 13 and a holding element 14, both of which are arranged circularly. In this embodiment, the height h of the engagement element 13 and the holding 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 the auricle or skin flap of a living body, and for this purpose, it has a clamp opening 18 defined by an upper part 15 and a lower part 16 of the coupling receptacle 10. For example, the auricle or skin flap of a living body can be inserted and clamped using a torsion spring 17 or another friction locking fastener.

[0096] This type of coupling receptacle enables a safe and simple connection of the sensor to the auricle of a living body for reliably and trustworthily measuring blood gases. The work required of the user is simplified and reduced, and the reliability of the process is improved.

[0097] FIG. 4 shows the generation of potentiometric measurement values of humidified 10% CO2 gas using a sensor and a newly applied electrolyte according to the invention for gas exposure over several days. As is clear from the recorded voltage, the drift of the CO2 measurement value remains less than 2% over 7 days. Note that no drift correction algorithm was applied. Both the long-term stability of the measurement and the short-term drift behavior are excellent for clinical applications.

[0098] FIG. 5 shows the response time of the CO2 sensor according to the invention for dry gas exchange of a 5% - 10% CO2 composition using the newly applied electrolyte of the invention. The response time (T 90 ) is defined as the time required for the sensor to show a shift from 10% to 90% of the final stable value of the 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 potential difference measurements when the dry gas CO2 concentration shifts from 5 to 10% at ambient temperature. The data corresponds to the electrolyte present on the sensor according to an embodiment of the present invention over 8 months. During this time, the sensor was performing 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, despite multiple measurements in a clinical setting without any maintenance.

[0100] Figure 7 is a diagram showing the Nernst gradient of a sensor operating based on the Severinghaus principle. The gradient is measured by shifting the CO2 concentration from 5 to 10% CO2 for 800 minutes under ambient conditions after the electrolyte has been present on the sensor for 8 months. By evaluating the difference in 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 values remained within the range of 57 mV, reflecting the stability of the electrolyte composition over the 8-month measurement.

[0101] Figure 8 demonstrates the estimated arterial blood carbon dioxide blood gas from transcutaneous measurements of healthy adults performed by the electrolyte and sensor 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 algorithm correction. In Figure 8a, the electrolyte had an age exceeding 11 months from the time of application on the sensor without any maintenance in between. During this period, the sensor was either under regular dry calibration gas or set on healthy adults for multiple transcutaneous measurements. The measurements were within the expected values of 30 - 40 mmHg for healthy individuals without drift algorithm correction. Figure 8b demonstrates the results of the same type of measurements as 8a, but with newly applied electrolyte. These two measurements do not reflect significant changes within the acceptable performance of the physiological relevance during the 11 - month aging period of the electrolyte. These facts indicate that the electrolyte according to the present invention remained clinically functional without the required maintenance, reflecting approximately one - year electrolyte stability.

[0102] Overall, the observed performance of the electrolyte according to the preferred embodiment of the present invention meets the characteristics required for long - term stable measurements 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 comprises - at least one hygroscopic compound containing at least two moieties (HB) having a hydrogen bonding ability, preferably having 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; - at least one hydrophilic evaporation-inhibiting compound having a carbon-to-HB ratio of 2 or more and a molecular weight MW of more than 100 g / mol, preferably more than 400 g / mol, The evaporation-inhibiting compound has a lower viscosity and a lower surface tension than the hygroscopic compound, an electrolyte (22) composition.

2. The moiety having a hydrogen bonding ability is at least one of a hydroxyl group, a carboxyl group, an amine group, an imine group, and / or an amide group, 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 polyhydric alcohols, glycerol, triglycerol, diethylene glycol, triethylene glycol and / or diethanolamine, and most preferably glycerol and / or diethylene glycol, and / or The hygroscopic compound is preferably present in the electrolyte (22) in an amount of less than 90% based on the total weight of the electrolyte (22), the electrolyte (22) according to claim 1.

3. The evaporation-inhibiting compound is selected from the group consisting of polyethylene glycol, polyglycerol, polyoxazoline, polyhydroxy-functional acrylate, especially poly(2-hydroxyethyl methacrylate), polyethylene oxide, hydrophilic polycarbonate and / or their copolymers, graft copolymers and short-chain oligomers of block copolymers, The evaporation-inhibiting compound is preferably present in the electrolyte (22) in an amount of at least 10% based on the total weight of the electrolyte (22), the electrolyte (22) according to claim 1 or 2.

4. The electrolyte (22) further comprises a surfactant, preferably a nonionic and non-metallic surfactant, the electrolyte (22) according to any one of the preceding claims.

5. The surfactant is selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polysaccharides, and their copolymers, graft copolymers and / or block copolymers. Preferably, the surfactant is selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polysaccharides, and their copolymers, graft copolymers and / or block copolymers. The electrolyte (22) according to claim 4, wherein the surfactant is present in the electrolyte (22) in an amount preferably less than 5%, more preferably less than 2%, based on the total weight of the electrolyte (22).

6. The electrolyte (22) according to any one of the preceding claims, wherein the electrolyte (22) further comprises a thickener, preferably a non-ionic and non-metallic thickener.

7. 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. Preferably, the thickener is selected from the group consisting of polyvinylpyrrolidone (PVP), polyethylene derivatives, polysaccharides, polycarbonates, and combinations thereof. The electrolyte (22) according to claim 6, wherein the thickener is present in the electrolyte (22) in an amount preferably less than 5%, more preferably less than 2%, based on the total weight of the electrolyte (22).

8. The electrolyte (22) further comprises an aqueous solution of at least one inorganic bicarbonate-based pH buffer having a buffer range of pH 7 to 9, Optionally, at least one chloride salt, and the concentration of the chloride salt in the buffer aqueous solution is less than 3 mol / L, preferably less than 1 mol / L. The electrolyte (22) according to any one of the preceding claims.

9. The electrolyte (22) 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, and / or the chloride salt is selected from the group consisting of LiCl, NaCl and / or KCl.

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

11. The electrolyte (22), based on the total weight of the electrolyte (22) respectively, - less than 90% of the hygroscopic compound, preferably glycerol, and - more than 10% of the hydrophilic evaporation-inhibiting compound, preferably polyethylene glycol, and An aqueous solution of less than -10% NaHCO ３ and KCl, wherein the concentration of NaHCO in the aqueous solution ３ is less than 0.1 mol / L, and the concentration of KCl in the aqueous solution is less than 0.2 mol / L, an aqueous solution, and - less than 5% of the surfactant, preferably polyvinylpyrrolidone, The electrolyte (22) according to any one of claims 4 to 10, comprising.

12. The electrolyte (22), based on the total weight of the electrolyte (22) respectively, - less than 35% of the hygroscopic compound, preferably glycerol, and - more than 60% of the hydrophilic evaporation-inhibiting compound, preferably polyethylene glycol, and - less than 2% of the surfactant, preferably polyvinylpyrrolidone, The electrolyte (22) according to claim 11, comprising.

13. A sensor (1) for detecting at least one target gas, in particular for electrochemically detecting carbon dioxide and optionally optically detecting oxygen, the electrochemical sensor comprising: - a measurement chamber (23) comprising an electrolyte (22), in particular the electrolyte (22) according to any one of claims 1 to 12; - an indicator electrode (5) and a reference electrode (24) in contact with the electrolyte (22); - an optional optical module (2) covered with a fluorescent indicator for reactive oxygen detection; - a gas-permeable membrane (6d) through which a sample gas containing the target gas can permeate the electrolyte (22); - means for attaching the electrochemical sensor (1) to a living body (100), in particular means such that the sensor (1) is configured to engage with a binding receptacle (10) attached to the living body (100), preferably a fastening clip or an adhesive holder; The electrolyte (22) is - at least one hygroscopic compound having a hydrogen-bonding ability, preferably having 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, and comprising at least two moieties (HB). - at least one hydrophilic evaporation-inhibiting compound having a carbon-to-HB ratio of -2 or more and a molecular weight MW of more than 100 g / mol, preferably more than 400 g / mol, and - the evaporation-inhibiting compound has a lower viscosity and a lower surface tension than the hygroscopic compound, sensor (1).

14. A method for detecting the partial pressure of a target gas in a sample gas, the method comprising - introducing the sample gas into the electrochemical sensor (1) according to claim 13, and - outputting an electrical signal from the electrochemical sensor (1) representing the target gas partial pressure. A method comprising.

15. Use of an electrolyte (22) according to any one of claims 1 to 12 for an electrochemical sensor (1) according to claim 13, in particular for detecting at least one target gas, in particular oxygen and / or carbon dioxide.

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