Electrode and manufacturing method, ion sensor, living body component measurement device and method

Abstract

The present invention provides an electrode with higher potential stability when repeatedly used and / or used for a long time in an ion sensor. The electrode includes an internal solid layer and an electrode material; wherein, the internal solid layer contains a metal oxide and a solid electrolyte.

Description

Technical Field

[0001] The present invention relates to an electrode, a method for manufacturing the electrode, an ion sensor, an in-vivo component measuring device, and an in-vivo component measuring method. Background Art

[0002] All-solid-state ion-selective electrodes and ion sensors using the all-solid-state ion-selective electrodes are known. For example, Non-Patent Document 1 discloses an all-solid-state ion-selective electrode that uses an insertion material (Na 0.33 MnO2, Li a FePO4, K b MnO2·mH2O) used as an electrode material for a storage battery as an internal solid layer. This is an electrode formed by laminating an internal solid layer obtained by mixing Na 0.33 MnO2, Li a FePO4, or K b MnO2·mH2O with a conductive agent (acetylene black) and a binder (PVDF) on a platinum electrode, and laminating an ion-selective membrane obtained by mixing an ionophore, a plasticizer, and an anion excluder in a base material (polyvinyl chloride) thereon.

[0003] Prior Art Documents

[0004] Non-Patent Documents

[0005] Non-Patent Document 1: Shinichi Komaba, et al., “All-solid-state ion-selective electrodes with redox-active lithium, sodium, and potassium insertion materials as the inner solid-contact layer” Analyst, 142(20), 3857-3866(2017). Summary of the Invention

[0006] Technical Problem to be Solved by the Invention

[0007] When the inventors of the present application conducted in-depth research to obtain electrodes of higher quality, they found that the conventional electrodes of ion sensors would cause potential instability and even potential changes due to repeated use several times and / or long-term use. This potential instability increases the calibration frequency and also increases the electrode replacement frequency. Therefore, the conventional ion sensors are calibrated each time a measurement is made or several times at regular intervals. The technical problem of the present invention is to provide an electrode with higher potential stability when repeatedly used and / or used for a long time in an ion sensor.

[0008] Technical means for solving the technical problem

[0009] In view of the above technical problems, the present inventors carefully studied and found that the above technical problems can be solved as long as the electrode includes an internal solid layer containing a metal oxide and a solid electrolyte and an electrode material. Based on this understanding, the present inventors further conducted in-depth research and finally completed the present invention.

[0010] That is, the present invention includes the following forms.

[0011] Item A. An electrode comprising an internal solid layer and an electrode material; wherein the internal solid layer contains a metal oxide and a solid electrolyte;

[0012] Item B. A method for manufacturing an electrode, comprising forming an internal solid layer containing a metal oxide and a solid electrolyte on an electrode material;

[0013] Item C. An ion sensor comprising an insulating substrate and the electrode described in Item A disposed on the insulating substrate;

[0014] Item D. An in-vivo component measurement device comprising the ion sensor described in Item C, the ion sensor measuring the sodium ion concentration contained in the tissue fluid collected from a subject;

[0015] Item E. An in-vivo component measurement method, comprising measuring the sodium ion concentration contained in the tissue fluid collected from a subject by the ion sensor described in Item C.

[0016] Advantages of the invention

[0017] The present invention can provide an electrode with higher potential stability when repeatedly used and / or used for a long time in an ion sensor. Description of the drawings

[0018] Figure 1 It is a cross-sectional schematic view of an electrode of the present invention as an example;

[0019] Figure 2 It is a cross-sectional schematic view of an ion-selective electrode of the present invention as an example;

[0020] Figure 3 Schematic cross-sectional view of a reference electrode of the present invention;

[0021] Figure 4 Schematic cross-sectional view of an ion sensor of the present invention;

[0022] Figure 5 Schematic cross-sectional view of a part of an ion sensor of the present invention;

[0023] Figure 6 Schematic cross-sectional view of an ion sensor of the present invention;

[0024] Figure 7 Schematic cross-sectional view of an ion sensor of the present invention;

[0025] Figure 8 Schematic top view of an ion sensor of the present invention;

[0026] Figure 9 In (a), it is a perspective view when the first flip cover of the in-vivo component measurement device is in the closed state, and (b) is a perspective view when the first flip cover of the in-vivo component measurement device is in the open state;

[0027] Figure 10 In (a), it is an explanatory diagram showing the general structure inside the in-vivo component measurement device in a side view, and (b) is an explanatory diagram showing the general structure inside the in-vivo component measurement device in a front view;

[0028] Figure 11 Perspective view of the detection unit;

[0029] Figure 12 In (a), it is a perspective view of the glucose sensor and the sodium ion sensor, and (b) is a side view of the glucose sensor and the sodium ion sensor;

[0030] Figure 13 Showing the configuration form of each material in the cross-sectional SEM (scanning electron microscope) image of the internal solid layer;

[0031] Figure 14 Showing the configuration form of each material in the cross-sectional SEM image of the internal solid layer;

[0032] Figure 15 Showing the potential measurement results of Test Example 1; the horizontal axis represents the Na concentration of the electrolyte solution, and the vertical axis represents the measured potential;

[0033] Figure 16To show the potential measurement results of Test Example 2; the horizontal axis represents the number of measurement repetitions, and the vertical axis represents the potential fluctuation (absolute value) compared to the potential of the first measurement;

[0034] Figure 17 To show the potential measurement results of Test Example 3; the horizontal axis represents the mass ratio of the solid electrolyte; for the vertical axis, a group is set as measuring a solution with a Na concentration of 2 mM six times, a solution with a Na concentration of 30 mM once, and a solution with a Na concentration of 2 mM once, and three groups are continuously implemented. The vertical axis represents the standard deviation of the potential at the sixth potential of the 2 mM solution with a stable measured potential in each group among the three groups;

[0035] Figure 18 To show the potential measurement results of Test Example 4; "1" on the horizontal axis represents the result of the first day, and "3" represents the result of the third day; the vertical axis represents the difference (absolute value) between the measured potentials of the electrolyte solutions with the same concentration obtained for the first and last times each day;

[0036] Figure 19 Schematic diagram of the outline of the potential measurement method for Test Example 5;

[0037] Figure 20 To show the potential measurement results of Test Example 5; the horizontal axis represents the Na concentration of the electrolyte solution, and the vertical axis represents the potential difference from the measured potential at a Na concentration of 0.3 mM;

[0038] Figure 21 To show the measured potential of Example 5 relative to a commercially available Ag / AgCl electrode with internal liquid (internal liquid: saturated KCl) in Test Example 5;

[0039] Figure 22 To show the potential measurement results of Test Example 6; each electrode is immersed in the electrolyte solution for one and a half hours, and the vertical axis represents the difference between the measured potential just after immersion and that after one and a half hours;

[0040] Figure 23 To show the potential measurement results of Test Example 7; the vertical axis represents the standard deviation of the potential of the 30 mM solution;

[0041] Figure 24 To show the potential measurement results of Test Example 8; the horizontal axis represents the K concentration of the electrolyte solution, and the vertical axis represents the measured potential;

[0042] Figure 25 To show the potential measurement results of Test Example 8'; the vertical axis represents the potential change rate between the first measured K1, 10, 100 mM solutions and the last measured K1, 10, 100 mM solutions after 4.8 - 5 hours;

[0043] Figure 26 To show the potential measurement results of Test Example 9; the vertical axis represents the potential change rate of the K1, 10, 100 mM solutions measured for the first time and the K1, 10, 100 mM solutions measured for the last time after 4.8 - 5 hours.

[0044] Figure 27 To show the potential measurement results of Test Example 10; the vertical axis represents the standard deviation of the potential of the K10 mM solution.

[0045] Figure 28 To show the potential measurement results of Test Example 11; regarding the vertical axis, after stabilizing each electrode with the K1 mM solution, each electrode was successively immersed in the 10 mM solution, 100 mM solution, and 1 mM solution, and the vertical axis represents the absolute value of the difference between the measured potential after 1 minute of immersion and the potential at the time of the last measurement of the K1 mM solution. Detailed implementation mode

[0046] In this specification, the expressions "containing", "comprising", and "including" include the concepts of "containing", "comprising", "substantially consisting of...", and "consisting only of...".

[0047] 1. Electrode

[0048] One aspect of the present invention relates to an electrode (which may also be referred to as "the electrode of the present invention" in this specification), comprising an internal solid layer and an electrode material, wherein the internal solid layer contains a metal oxide and a solid electrolyte. The following will explain this.

[0049] The metal oxide is not particularly limited as long as it can be used for the electrode of an ion sensor. When the electrode of the present invention is used as an ion - selective electrode in an ion sensor, it is possible to preferably use a substance (ion - electron conductor) that can perform insertion and extraction of the measured ion within the crystal structure accompanied by electron gain and loss as the metal oxide.

[0050] The measured ion is not particularly limited, and examples thereof include sodium ions, potassium ions, calcium ions, magnesium ions, etc., preferably sodium ions, potassium ions, etc., and particularly preferably sodium ions.

[0051] The metal oxide can be appropriately selected according to the measured ion. Specifically, examples of the metal oxide include M x MnO2, M x NiO2, M x CoO2, M x Ni 0.5 Mn 0.5 O2, M x FeO2, M 2 / 3 Fe 1 / 3 Mn 2 / 3 O2, Mx Ni 1 / 3 Co 1 / 3 Mn 1 / 3 O2, M x Ni 0.5 Ti 0.5 O2, M x VO2, M x CrO2, M x FePO4 (where M in the chemical formula is independently Na or K respectively, and x represents any positive number). Among them, M is more preferably x MnO2, and particularly preferably Na x MnO2.

[0052] x is usually 0 < x ≤ 1. x is preferably 0.15 to 0.66, more preferably 0.2 to 0.5, further preferably 0.22 to 0.28, 0.30 to 0.36 or 0.41 to 0.47, and particularly preferably 0.245 to 0.255, 0.325 to 0.335 or 0.435 to 0.445.

[0053] The crystal structure of the metal oxide is not particularly limited as long as it can be used as an electrode of an ion sensor. Examples of the crystal structure include orthorhombic crystal system, tetragonal crystal system, trigonal system, hexagonal system, cubic crystal system, triclinic system, monoclinic crystal system, etc. Among them, the orthorhombic crystal system is preferred.

[0054] The form of the metal oxide is not particularly limited, and it is preferably in particle form. The particles of the metal oxide can be in any shape such as flaky, rod-shaped, columnar, spherical, ellipsoidal, etc., and are preferably flaky.

[0055] Regarding the average particle size of the metal oxide particles, from the viewpoint of improving the tight bonding property between the metal oxide and the solid electrolyte and improving the performance of the electrode of the ion sensor, it is preferably 1 to 20 μm, more preferably 2 to 15 μm, and further preferably 5 to 12 μm. And the average particle size can be measured by a laser diffraction / scattering particle size distribution measuring device.

[0056] The metal oxide can be a single type or a combination of two or more types.

[0057] Regarding the content of the metal oxide, it is, for example, 20 to 70% by mass, preferably 25 to 65% by mass, more preferably 30 to 60% by mass, relative to 100% by mass of the internal solid layer.

[0058] The solid electrolyte is not particularly limited as long as it is a solid capable of conducting ions. When the electrode of the present invention is used as an ion-selective electrode in an ion sensor, a solid electrolyte capable of conducting the measurement ions can be used. Typically, an ion (measurement ion)-conductive ceramic can be used as the solid electrolyte.

[0059] The measurement ions are not particularly limited, and examples thereof include sodium ions, potassium ions, calcium ions, magnesium ions, etc., preferably sodium ions, potassium ions, etc., and particularly preferably sodium ions.

[0060] The solid electrolyte can be appropriately selected according to the measurement ions. Specifically, examples of the solid electrolyte include oxide-based solid electrolytes such as β''-aluminum oxide, β-aluminum oxide, perovskite-type oxide, NASICON-type oxide, Garnet Type Oxide, sulfide-based solid electrolytes, stabilized zirconia, α-silver iodide, zeolite (the zeolite can contain cations such as Na ions, K ions, H ions, etc. inside). Among them, from the viewpoints of good stability to water and applicability to the electrodes of ion sensors, β''-aluminum oxide, β-aluminum oxide, zeolite, etc. are particularly preferred.

[0061] β'' / β-aluminum oxide has a layered structure, and the layered structure includes an ion-conducting layer and a spinel brick, and ion (measurement ion) movement occurs in the ion-conducting layer. β''-aluminum oxide and β-aluminum oxide are different in crystal structure, and among them, β''-aluminum oxide has a higher sodium ion content and relatively higher ion conductivity in its crystal structure. β'' / β-aluminum oxide is preferably Na-β'' / β-aluminum oxide capable of conducting sodium ions. Na-β''-aluminum oxide is usually a substance with a chemical composition of Na2O·xAl2O3 (x = 5 to 7). In addition, Na-β-aluminum oxide is usually a substance with a chemical composition of Na2O·xAl2O3 (x = 9 to 11).

[0062] The form of the solid electrolyte is not particularly limited, and a particulate form is preferred. The particles of the solid electrolyte can be in any shape such as flaky, rod-shaped, columnar, spherical, ellipsoidal, etc.

[0063] Regarding the average particle diameter of the particles of the solid electrolyte, from the viewpoint of improving the tight bonding property between the metal oxide and the solid electrolyte and improving the performance of the electrode as an ion sensor, in one embodiment of the present invention, it is preferably 0.02 to 3 μm, more preferably 0.1 to 1 μm, and further preferably 0.15 to 0.5 μm. Regarding the average particle diameter of the particles of the solid electrolyte, based on the same viewpoint, in another embodiment of the present invention, it is preferably 0.02 to 7, more preferably 0.05 to 5, and further preferably 0.1 to 3 μm. Moreover, the average particle diameter can be measured by a laser diffraction / scattering type particle size distribution measuring device.

[0064] In the internal solid layer, it is preferred that the average particle diameter of the solid electrolyte is smaller than that of the metal oxide. Specifically, in one embodiment of the present invention, relative to the average particle diameter 100 of the metal oxide, the average particle diameter of the solid electrolyte is, for example, 0.1 to 30, preferably 0.5 to 10, and more preferably 1 to 5. In another embodiment of the present invention, relative to the average particle diameter 100 of the metal oxide, the average particle diameter of the solid electrolyte is, for example, 0.1 to 70, preferably 0.5 to 60, and more preferably 1 to 5.

[0065] The solid electrolyte can be a single type or a combination of two or more types.

[0066] Regarding the content of the solid electrolyte, relative to 100% by mass of the internal solid layer, it is, for example, 15 to 70% by mass, preferably 20 to 65% by mass, and more preferably 25 to 60% by mass.

[0067] The mass ratio of the metal oxide to the solid electrolyte in the internal solid layer (metal oxide:solid electrolyte) is, for example, 5:1 to 1:5, preferably 2:1 to 1:2, more preferably 1.5:1 to 1:1.5, further preferably 1.2:1 to 1:1.2, and even more preferably 1.1:1 to 1:1.1.

[0068] The internal solid layer preferably contains a conductive agent. In this way, the conductivity of the internal solid layer can be improved, the buffering effect against volume changes caused by ion ingress and egress can be enhanced, and the electrode stability can be improved.

[0069] There is no particular limitation on the conductive agent. For example, carbon materials such as carbon black, acetylene black, Ketjen black, carbon nanotubes, graphene, carbon powder, and graphite powder, conductive fiber materials such as metal fibers, metal powder materials such as carbon fluoride and aluminum, conductive whisker materials such as zinc oxide and potassium titanate, conductive metal oxides such as titanium oxide, and organic conductive materials such as benzene derivatives and graphene derivatives can be used. Among them, carbon materials are preferred.

[0070] The conductive agent can be a single type or a combination of two or more types.

[0071] Regarding the content of the conductive agent, relative to 100% by mass of the internal solid layer, it is, for example, 0.1 to 20% by mass, preferably 1 to 15% by mass, and more preferably 2 to 10% by mass.

[0072] Regarding the mass ratio of the metal oxide (or solid electrolyte) to the conductive agent in the internal solid layer (metal oxide (or solid electrolyte): conductive agent), it is, for example, 20:1 to 1:1, preferably 15:1 to 3:1, and more preferably 10:1 to 6:1.

[0073] The internal solid layer preferably contains a binder. This can make the components in the internal solid layer bond more firmly.

[0074] There are no particular restrictions on the binder. For example, polyvinylidene fluoride, polyvinylpyrrolidone, polytetrafluoroethylene, polyethylene, polypropylene, aramid resin, polyamide, polyimide, polyamideimide, polyacrylonitrile, polyacrylic acid, methyl polyacrylate, ethyl polyacrylate, hexyl polyacrylate, polymethacrylic acid, polymethyl methacrylate, polyethyl methacrylate, polyhexyl methacrylate, acrylic emulsion, polyvinyl acetate, polyvinylpyrrolidone, polyether, polyethersulfone, hexafluoro polypropylene, styrene-butadiene rubber, carboxymethyl cellulose and other polymers, similar compounds having the same backbone as the above polymers, and synthetic agents containing several polymers can be used. Among them, polyvinylidene fluoride, a mixture of styrene-butadiene latex and carboxymethyl cellulose (SBR / CMC), a mixture of polyamideimide and carbodiimide, polytetrafluoroethylene, acrylic emulsion, etc. are preferred, and polyvinylidene fluoride is more preferred.

[0075] The binder can be a single type or a combination of two or more types.

[0076] Regarding the content of the binder, relative to 100% by mass of the internal solid layer, it is, for example, 0.1 to 20% by mass, preferably 1 to 15% by mass, and more preferably 2 to 10% by mass.

[0077] Regarding the mass ratio of the metal oxide (or solid electrolyte) to the binder in the internal solid layer (metal oxide (or solid electrolyte): binder), it is, for example, 20:1 to 1:1, preferably 15:1 to 3:1, and more preferably 10:1 to 6:1.

[0078] Other components other than the above components can be contained in the internal solid layer. Examples of other components can include solid electrolytes, raw materials for making metal oxides, such as MnCO3, Na2CO3, Al2O3, etc.

[0079] Regarding the total content of the metal oxide and the solid electrolyte in the internal solid layer (when also containing a conductive agent and a binder, including them in the total content), relative to 100% by mass of the internal solid layer, it is, for example, 70 to 100% by mass, preferably 80 to 100% by mass, more preferably 90 to 100% by mass, further preferably 95 to 100% by mass, and even more preferably 99 to 100% by mass.

[0080] There is no particular limitation on the layer structure of the internal solid layer. The internal solid layer may be a single-layer structure including a single layer made of a single component, or a multi-layer structure including several layers made of the same or different components from each other.

[0081] Regarding the thickness of the internal solid layer, as long as it does not significantly impair conductivity, there is no particular limitation. This thickness is, for example, 1 to 200 μm. From the viewpoints of manufacturing efficiency, manufacturing cost, etc., this thickness is preferably 1 to 100 μm, more preferably 1 to 50 μm, and further preferably 1 to 20 μm.

[0082] Regarding the electrode material, there is no particular limitation as long as it contains a conductive material. Examples of the conductive material can include metals such as platinum, gold, silver, copper, carbon, palladium, chromium, aluminum, nickel, alloys containing at least one of the above metals, and metal halides such as metal chlorides of the above metals. Among them, platinum, gold, silver, palladium, aluminum, nickel, carbon, etc. are preferred. The conductive material can be a single kind or a combination of two or more kinds.

[0083] Regarding the content of the conductive material, relative to 100% by mass of the electrode material, it is, for example, 70 to 100% by mass, preferably 85 to 100% by mass, and more preferably 95 to 100% by mass.

[0084] There is no particular limitation on the shape of the electrode material, and it is generally flat.

[0085] There is no particular limitation on the layer structure of the electrode material. The electrode material may be a single-layer structure including a single layer made of a single component, or a multi-layer structure including several layers made of the same or different components from each other.

[0086] Regarding the thickness of the electrode material, as long as it does not significantly impair conductivity, there is no particular limitation. This thickness is, for example, 1 to 10 μm. From the viewpoints of manufacturing efficiency, manufacturing cost, etc., this thickness is preferably 1 to 5 μm.

[0087] In the electrode of the present invention, generally, the internal solid layer is disposed directly on the electrode material or with other layers interposed therebetween. Preferably, the internal solid layer is disposed directly on the electrode material. Figure 1 An embodiment of the electrode of the present invention is shown. In the electrode, in order not to expose the electrode material, it is preferred to dispose the internal solid layer and provide side walls, etc. in such a manner that the side surface of the electrode material is also covered.

[0088] The electrode of the present invention can preferably be used as an ion-selective electrode, a reference electrode, etc.

[0089] When the electrode of the present invention is used as an ion-selective electrode, the electrode of the present invention preferably further includes an ion-selective membrane. The ion-selective membrane contains an ion-selective substance.

[0090] Conventionally known ionophores or synthetic substances can be widely used as ion-selective substances. The ion-selective substance can be selected according to the ion to be measured. Ionophores are suitable for use as ion-selective substances. Ionophores can include valinomycin, monensin, rhodopsin, nonactin, monactin, ionomycin, gramicidin A, nigericin, CCCP (carbonyl cyanide m-chlorophenylhydrazone), FCCP (carbonyl cyanide p-trifluoromethoxyphenylhydrazone), etc. Synthetic substances can include crown ethers (a group of macrocyclic polyethers), and can also include non-cyclic nonylphenol polyethylene glycol, etc. The ion-selective substance can be a single kind or a combination of two or more kinds. Specifically, ion-selective substances such as DD16C5, Bis-12Crown-4, 12-Crown-4, 15-Crown-5, 18-Crown-6, calixarene can be listed.

[0091] The ion-selective membrane generally contains an adhesive resin. There is no particular limitation on the adhesive resin. Specifically, the adhesive resin can include polyvinyl chloride, polyvinylidene chloride, polyacrylonitrile, polyurethane, polyvinyl acetate, silicone elastomer, polyvinyl alcohol, cellulose ester, polycarbonate, vinyl chloride / vinyl acetate copolymer, vinyl chloride / vinyl acetate / vinyl alcohol copolymer, vinyl chloride / vinylidene chloride copolymer, etc. The adhesive resin can be a single kind or a combination of two or more kinds.

[0092] The ion-selective membrane preferably contains a plasticizer. The plasticizer can improve the flexibility of the ion-selective membrane, and thus can, for example, inhibit the ion-selective membrane from cracking. There is no particular limitation on the plasticizer. For example, TEHP (trioctyl phosphate), NPOE (2-nitrophenyl octyl ether), DOP (dioctyl phthalate), DOS (dioctyl sebacate), DBE (dibasic ester), BA (butyl acrylate), etc. can be listed. The plasticizer can be a single kind or a combination of two or more kinds.

[0093] The ion-selective membrane preferably contains an anion scavenger. The anion scavenger can be selected according to the ions to be measured. Examples of the anion scavenger include sodium tetrakis(4-chlorophenyl)borate (Na-TCPB), potassium tetrakis(4-chlorophenyl)borate (K-TCPB), sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (Na-TFPB), potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (K-TFPB), potassium tetraphenylborate (K-TPB), sodium tetraphenylborate (Na-TPB), and tetraphenylborate salts such as sodium tetrakis[3,5-bis(1,1,1,3,3,3-hexafluoro-2-methoxy-2-propyl)phenyl]borate. The anion scavenger can be a single type or a combination of two or more types.

[0094] Regarding the content of the above components, as long as the ion-selective membrane can function, there is no particular limitation. With respect to 100% by mass of the ion-selective membrane, the content of the ion-selective substance is, for example, 3 to 10% by mass, the content of the binder resin is, for example, 15 to 45% by mass, the content of the plasticizer is, for example, 50 to 80% by mass, and the content of the anion scavenger is, for example, 1 to 5% by mass.

[0095] There is no particular limitation on the layer structure of the ion-selective membrane. The ion-selective membrane can be a single-layer structure composed of a single component or a multilayer structure composed of several layers of the same or different components.

[0096] There is no particular limitation on the thickness of the ion-selective membrane. The thickness is, for example, 50 to 300 μm.

[0097] The use of the ion-selective membrane is not particularly limited. For example, it is a cation-selective membrane such as a sodium ion or potassium ion selective membrane.

[0098] The ion-selective membrane is disposed on the internal solid layer. Preferably, the ion-selective membrane is directly disposed on the internal solid layer. Figure 2 An embodiment of the ion-selective electrode of the present invention is shown. In the ion-selective electrode, in order not to expose the electrode material, it is preferred to dispose the internal solid layer and provide side walls, etc. in such a way that the side surface of the electrode material is also covered. In addition, in the ion-selective electrode, in order not to expose the internal solid layer, it is preferred to dispose the ion-selective membrane and provide side walls, etc. in such a way that the side surface of the internal solid layer is also covered.

[0099] When using the electrode of the present invention as a reference electrode, it is preferred that the electrode of the present invention further includes a layer (also referred to as a "salt bridge layer" in this specification) that functions as a salt bridge and can suppress the influence brought about by changes in the external ion concentration. An ionic liquid gel film can preferably be used as the above layer.

[0100] The ionic liquid is not particularly limited. For example, hydrophobic ionic liquids can be cited. The cation of the hydrophobic ionic liquid is at least one of an imidazole cation, a pyridine cation, a piperidinium cation, a pyrrolidinium cation, a quaternary ammonium cation, a phosphorus cation, or an arsenic cation, and the anion is [R 1 SO2NSO2R 2 -(R 1 、R 2 are each a perfluoroalkyl group having 1 to 5 carbon atoms), a borate ion containing fluorine and tetravalent boron, bis(2-ethylhexyl)sulfosuccinate, AlCl4 - 、Al3Cl7 - 、NO3 - 、BF4 - 、PF6 - 、CH3COO - 、CF3COO - 、CF3SO3 - 、(CF3SO2)2N - 、(CF3SO2)3C - 、AsF6 - 、SbF6 - 、F(HF)n - 、CF3CF2CF2CF2SO3 - 、(CF3CF2SO2)2N - or CF3CF2CF2COO - or more of these.

[0101] There is no particular limitation on the method for gelating the hydrophobic ionic liquid. Gelation can be achieved using a polymer compound. Examples of the above polymer compound include vinylidene fluoride-hexafluoropropylene copolymer, polymethyl methacrylate, polyethyl methacrylate, polyacrylonitrile, polybutyl acrylate, polyvinylpyridine, organic oligomeric electrolytes (such as those having a PICPM structure in the main chain cation part), polyvinyl chloride, and other synthetic rubbers. A polymer compound and a crosslinking agent can also be used together. For example, a gelling agent containing a crosslinking agent and a polymer compound can be used. The crosslinking agent has several fluoroalkylated sulfonamide groups, and the polymer compound has a group capable of forming an onium salt with the crosslinking agent. In addition, a polymer compound and a plasticizer can also be used together. For example, a plasticizer can be mixed with polyvinyl chloride and dried for gelation. The same plasticizer as that used in the ion-selective membrane can be used as the plasticizer.

[0102] There is no particular limitation on the layer structure of the salt bridge layer. This layer can be a single-layer structure composed of a single component or a multilayer structure composed of several layers of the same or different components.

[0103] The salt bridge layer is disposed on the internal solid layer. Preferably, the salt bridge layer is directly disposed on the internal solid layer. In Figure 3 Fig. shows an embodiment of the reference electrode of the present invention. In the reference electrode, in order not to expose the electrode material, it is preferable to dispose the internal solid layer in such a manner that, for example, the side surface of the electrode material is also covered, and side walls are provided on the side surface. Further, in the reference electrode, in order not to expose the internal solid layer, it is preferable to dispose the salt bridge layer in such a manner that, for example, the side surface of the internal solid layer is also covered, and side walls are provided on the side surface.

[0104] The method for manufacturing the electrode of the present invention is not particularly limited. The electrode of the present invention can preferably be manufactured by a method including forming an internal solid layer containing a metal oxide and a solid electrolyte on the electrode material.

[0105] The method for forming the internal solid layer is not particularly limited. It is preferable to form the internal solid layer by forming a composition containing a metal oxide and a solid electrolyte into a film on the electrode material and drying it. Film forming methods such as electrostatic coating, coating using a dispenser, screen printing, sputtering, and evaporation can be used, and from the viewpoint of improving the tight bonding property between the metal oxide and the solid electrolyte, electrostatic coating is preferable.

[0106] Regarding the forming method of other layers such as the ion selective membrane and the salt bridge layer, a method corresponding to the above can be adopted. That is, other layers can be formed by forming a composition (paste, solution, etc.) containing each component constituting the layer into a film on the internal solid layer and drying it.

[0107] 2. Ion Sensor

[0108] One aspect of the present invention relates to an ion sensor (which may also be referred to as "the ion sensor of the present invention" in this specification), which includes an insulating substrate and the electrode of the present invention disposed on the insulating substrate. The following will describe this.

[0109] The insulating substrate only needs to contain an insulating material that does not affect the conductivity of the electrode, and there is no particular limitation. Examples of the insulating material can include polyester resins such as polyvinyl alcohol, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, and polybutylene naphthalate; polyimide; glass epoxy resin; glass; ceramic; and fibrous substrates such as paper.

[0110] In one aspect of the present invention, the ion sensor of the present invention includes the electrode of the present invention as an ion selective electrode. In Figure 4 Fig. shows a cross-sectional schematic view in this case.

[0111] As the reference electrode, it is possible to use a reference electrode containing an internal liquid, an all-solid-state reference electrode, etc. Specifically, for example, it is possible to use an electrode designed to maintain a fixed Cl concentration on the surface of an Ag / AgCl electrode (for example, having a resin film with Cl ions), and the electrode of the present invention including a salt bridge layer as the reference electrode. In Figure 5 Fig. shows a schematic cross-sectional view of a part of the ion sensor of the present invention in the latter case.

[0112] In one aspect of the present invention, the ion sensor of the present invention includes the electrode of the present invention as an ion-selective electrode and a reference electrode. In Figure 6 Fig. shows a schematic cross-sectional view in this case.

[0113] In one aspect of the present invention, the ion sensor of the present invention includes the electrode of the present invention as an ion-selective electrode and the electrode of the present invention as a reference electrode. In Figure 7 Fig. shows a schematic cross-sectional view in this case.

[0114] The ion sensor of the present invention optionally includes other parts such as an electrode lead. In Figure 8 Fig. shows an example of a preferred aspect of the ion sensor of the present invention.

[0115] The ion sensor of the present invention can preferably be used as a sodium ion sensor.

[0116] By bringing the object to be measured (for example, tissue fluid collected from a subject, a substance for placing tissue fluid, etc.) into contact with the electrode of the ion sensor of the present invention and measuring the potential between the ion-selective electrode and the reference electrode, the ion concentration in the object to be measured can be calculated based on the obtained measurement value.

[0117] 3. In-Vivo Component Measuring Device

[0118] One aspect of the present invention relates to an in-vivo component measurement device (which may also be referred to as "the in-vivo component measurement device of the present invention" in this specification), which includes the ion sensor of the present invention, and the ion sensor measures the sodium ion concentration contained in the tissue fluid collected from a subject. The following will explain this.

[0119] The in-vivo component measurement device of the present invention is not particularly limited as long as it includes the ion sensor of the present invention and can measure the ion concentration such as sodium ions in the object to be measured. The in-vivo component measurement device of the present invention preferably includes the ion sensor of the present invention, a detection unit, a control module, an operation display unit, and a power supply (preferably further includes a glucose ion sensor, a reagent storage unit, and a liquid delivery unit). The following will refer to Figures 9 - 12 explain a preferred aspect of the in-vivo component measurement device of the present invention.

[0120] The in-vivo component measurement device 1 includes: a placement unit 20 for placing a tissue collector 110 that has collected tissue fluid; a glucose sensor 21 that, in a state of being in contact with the tissue fluid collector 110 placed in the placement unit 20, acquires a signal reflecting the amount of the component to be measured contained in the tissue fluid; and a moving unit 60 that changes the relative positions of the placement unit 20 and the glucose sensor 21 to a certain positional relationship, so that the tissue fluid collector 110 placed in the placement unit 20 comes into contact with the glucose sensor 21. The in-vivo component measurement device 1 acquires a signal reflecting the amount of glucose contained in the tissue fluid through the glucose sensor 21 and measures the glucose concentration in the tissue fluid. In addition, in the present embodiment, the in-vivo component measurement device 1 further includes a sodium ion sensor 22 that, in a state of being in contact with the tissue fluid collector 110 placed in the placement unit 20, acquires a signal reflecting the amount of electrolyte contained in the tissue fluid, and the moving unit 60 changes the relative positions of the placement unit 20 and the sodium ion sensor 22 to a certain positional relationship, so that the tissue fluid collector 110 placed in the placement unit 20 comes into contact with the sodium ion sensor 22, thereby acquiring a signal reflecting the amount of sodium ions contained in the tissue fluid and measuring the sodium ion concentration in the tissue fluid.

[0121] As Figure 9 and Figure 10 shown, the in-vivo component measurement device 1 at least includes a detection unit 2, a reagent storage unit 3, a liquid delivery unit 4, a control module 5, an operation display unit 6, and a power supply 7, and the above components are provided in a housing 10.

[0122] At the upper part of the front surface of the housing 10, a first flip cover 11 is provided at a position adjacent to the operation display unit 6. The first flip cover 11 is a push-open flip cover. After the first flip cover 11 is pressed, it stands up, changing from the closed state shown in Figure 9 (a) to the open state shown in Figure 9 (b), exposing the placement unit 20 for placing the tissue fluid collector 110. In addition, a second flip cover 12 is provided on the upper side surface of the housing 10. The second flip cover 12 is also a push-open flip cover. After the second flip cover 12 is pressed, it stands up, changing from the closed state to the open state, exposing the glucose sensor 21 and the sodium ion sensor 22 of the detection unit 2 described later, and the illustration is omitted. In addition, a third flip cover 13 is provided at the lower part of the front surface of the housing 10. Opening the third flip cover 13 exposes various slots of the reagent storage unit 3.

[0123] The detection unit 2 acquires relevant signals regarding the amounts of components (glucose, electrolyte) contained in the tissue fluid collected in the tissue fluid collector 110 and relevant signals regarding the amounts of components (electrolyte) contained in the sweat collected in the sweat collector 111. As Figure 11 shown, the detection unit 2 includes a placement unit 20, a glucose sensor 21, a sodium ion sensor 22, and a drive unit 23.

[0124] The placement part 20 is used for placing the tissue fluid collector 110 and the sweat collector 111. The placement part 20 includes a sample tray 200 and a sample stage 201 for placing the sample tray 200. The sample tray 200 is used for placing and supporting the support sheet 114 of the tissue fluid collector 110 and the sweat collector 111.

[0125] The sample tray 200 is rectangular in a top-down view, and its outline is one circle larger than the support sheet 114. The upper side surface of the sample tray 200 is a flat surface, and the support sheet 114 can be stably placed on the sample tray 200. Thus, when measuring the tissue fluid collector 110 and the sweat collector 111, the sensors 21 and 22 can be in good contact with the tissue fluid collector 110 and the sweat collector 111.

[0126] Two corner portions on one end side in the longitudinal direction of the sample tray 200 are respectively provided with small protrusions 2001. The two small protrusions 2001 serve as positioning portions for positioning the tissue fluid collector 110. When the support sheet 114 is placed on the sample tray 200, the two small protrusions 2001 are inserted into two through holes formed in the support sheet 114. Thus, the support sheet 114 is placed on the sample tray 200 without any position offset, so that the tissue fluid collector 110 etc. can be positioned at an appropriate position on the sample tray 200. In addition, two corner portions on the other end side in the longitudinal direction of the upper side surface of the sample tray 200 are respectively provided with standing walls 2002A and 2002B. The heights of the standing walls 2002A and 2002B are the same as or slightly larger than the thickness of the support sheet 114. When the support sheet 114 is placed on the sample tray 200, one of the two standing walls 2002A abuts against the cut of the support sheet 114, and the other standing wall 2002B is along the side edge of the support sheet 114 on the side opposite to the cut. Thus, the support sheet 114 can be more effectively positioned at an appropriate position on the sample tray 200. In this way, the support sheet 114 is placed on the sample tray 200 without any position offset, so that when measuring the tissue fluid collector 110 and the sweat collector 111, the sensors 21 and 22 can be in good contact with the tissue fluid collector 110 and the sweat collector 111.

[0127] In addition, in the other end side in the longitudinal direction of the sample tray 200, a horizontal rod 2003 is installed on two vertical walls 2002A and 2002B, and an insertion hole 2004 is formed between the upper side surface of the sample tray 200 and the horizontal rod 2003. When the support piece 114 is placed on the sample tray 200, a part of the other end side in the longitudinal direction of the support piece 114 is inserted into the insertion hole 2004. Thus, the horizontal rod 2003 can be used to prevent the support piece 114 from floating on the sample tray 200, so that the support piece 114 can be stably placed on the sample tray 200. Thus, when measuring the tissue fluid collector 110 and the sweat collector 111, the respective sensors 21 and 22 can be brought into good contact with the tissue fluid collector 110 and the sweat collector 111.

[0128] The sample stage 201 is rectangular in a top view, and its outline is one circle larger than that of the sample tray 200. The sample tray 200 is placed on the upper side surface of the sample stage 201. The sample stage 201 reciprocates in the X direction along the horizontal plane by a horizontal movement drive unit 230 of a drive unit 23 described later. Thus, the tissue fluid collector 110 and the sweat collector 111 are transported to positions below the respective sensors 21 and 22.

[0129] The glucose sensor 21 is a component detection sensor that acquires a signal reflecting the amount of the measurement target component, i.e., glucose, contained in the tissue fluid, and functions as an acquisition unit. In addition, the sodium ion sensor 22 is a component detection sensor that acquires a signal reflecting the amount of the auxiliary component, i.e., sodium ion, contained in the tissue fluid, and functions as a second acquisition unit.

[0130] As Figure 12 shown, the respective sensors 21 and 22 include: main body parts 210 and 220, which are made of plastic, for example; sliding parts 211 and 221, which are installed on the main body parts 210 and 220 and can slide, and are made of plastic, for example; cartridge parts 216 and 226, which are installed on the sliding parts 211 and 221 and can be attached and detached, and are made of plastic, for example; and electrode parts 212 and 222, which are installed on the lower side surfaces of the cartridge parts 216 and 226.

[0131] The shapes of the main body parts 210 and 220 are such that they have an upper part and a lower part with a height difference therebetween, and the lower side surfaces of the upper parts are provided with ends 213 and 223 connected to the control module 5. Openings are formed in the lower parts of the main body parts 210 and 220, and the sliding parts 211 and 221 protrude from these openings. Pressure absorption members 217 and 227 are provided in the main body parts 210 and 220. For example, spring members such as coil springs can be used as the pressure absorption members 217 and 227. The pressure absorption members 217 and 227 constitute a pressure adjustment part 61 that adjusts the contact pressure when each of the sensors 21 and 22 contacts the tissue fluid collector 110 to a fixed contact pressure, and is a structure included in the above-mentioned moving part 60. The sliding parts 211 and 221 are connected to the pressure absorption members 217 and 227 and slide up and down relative to the main body parts 210 and 220 by the expansion and contraction of the pressure absorption members 217 and 227. When each of the sensors 21 and 22 contacts the tissue fluid collector 110 and the sweat collector 111, the pressure absorption members 217 and 227 expand and contract, and further the electrode parts 212 and 222 move up and down, so that the contact pressure of the electrode parts 212 and 222 contacting the tissue fluid collector 110 and the sweat collector 111 can be adjusted to a fixed contact pressure. Thus, even if the shapes of the tissue fluid collector 110 and the sweat collector 111 are inconsistent, the electrode parts 212 and 222 can contact the tissue fluid collector 110 and the sweat collector 111 with a fixed contact pressure. Moreover, instead of providing one, several pressure absorption members 217 and 227 connected to the sliding parts 211 and 221 can be provided in the main body parts 210 and 220.

[0132] Openings are formed in the lower parts of the sliding parts 211 and 221, and the box parts 216 and 226 can be assembled to the lower parts of the sliding parts 211 and 221 through these openings. Engagement holes 215 and 225 are formed on both side surfaces of the lower parts of the sliding parts 211 and 221.

[0133] The cartridge parts 216 and 226 are consumables and will be discarded after being used for a certain number of measurements for a tissue fluid collector 110 or the like. The cartridge parts 216 and 226 are provided with a pair of engaging claws 214 and 224 corresponding to the respective engaging holes 215 and 225 of the sliding parts 211 and 221. Each of the engaging claws 214 and 224 is engaged with the corresponding engaging hole 215 and 225 respectively, whereby the cartridge parts 216 and 226 are placed on the sliding parts 211 and 221. At this time, it is preferable that the cartridge parts 216 and 226 are not in a fixed position relative to the sliding parts 211 and 221, but are placed on the sliding parts 211 and 221 and can swing by slightly shaking, for example. The cartridge parts 216 and 226 constitute an angle adjusting part 62 for adjusting the angle at which the respective sensors 21 and 22 contact the tissue fluid collector 110, and are structures included in the above-mentioned moving part 60. Thus, when the respective sensors 21 and 22 contact the tissue fluid collector 110 and the sweat collector 111, the cartridge parts 216 and 226 swing relative to the sliding parts 211 and 221 to follow the surfaces of the tissue fluid collector 110 and the sweat collector 111. Therefore, the angle of the surfaces of the electrode parts 212 and 222 in contact with the tissue fluid collector 110 and the sweat collector 111 can be adjusted, and even if the shapes of the tissue fluid collector 110 and the sweat collector 111 are inconsistent, the electrode parts 212 and 222 can be brought into good contact with the tissue fluid collector 110 and the sweat collector 111.

[0134] The electrode parts 212 and 222 include a working electrode and a counter electrode as a pair, and a reference electrode. Regarding the electrode part 212 for glucose measurement of the glucose sensor 21, for example, the working electrode is formed by forming a glucose oxidase enzyme film on a platinum electrode, and the counter electrode includes a platinum electrode. On the other hand, regarding the electrode part 222 for sodium ion measurement of the sodium ion sensor 22, for example, the working electrode is composed of an ion-selective electrode having a sodium ion selective membrane, and the counter electrode is composed of a reference electrode.

[0135] In addition, the glucose sensor 21 includes a circuit for glucose measurement (not shown) as an electrical circuit connected to the electrode portion 212. The electrode portion 212 contacts the tissue fluid collector 110, applies a fixed voltage to the tissue fluid collected in the tissue fluid collector 110, and obtains the current at this time as a detection value. This current value depends on the glucose concentration in the tissue fluid. On the other hand, the sodium ion sensor 22 includes a circuit for sodium ion measurement (not shown) as an electrical circuit connected to the electrode portion 222. The electrode portion 222 contacts the tissue fluid collector 110 and the sweat collector 111, and obtains the voltages of the tissue fluid collected in the tissue fluid collector 110 and the sweat collected in the sweat collector 111 as detection values. These voltage values depend on the sodium ion concentrations in the tissue fluid and sweat. The glucose sensor 21 and the sodium ion sensor 22 are connected to the control module 5, and output the obtained current value and voltage value to the control module 5 as detection signals. The control module 5 measures the glucose concentration and the sodium ion concentration based on the current value and voltage value included in the detection signals and the calibration curve stored in the storage unit.

[0136] The glucose sensor 21 and the sodium ion sensor 22 are mounted on the mounting member 24 and then placed in the detection unit 2. The mounting member 24 is mounted on a pair of left and right side plates 16 ( Figure 11 as shown) provided on the bottom plate 14 of the detection unit 2 and can move up and down. On both side surfaces of the frame portion, several protrusions are provided in the vertical direction. Each protrusion slides in the vertically long hole-shaped guide holes 17 ( Figure 11 as shown) formed in each side plate 16, so that the mounting member 24 moves straight up and down.

[0137] Regarding the drive unit 23, in the present embodiment, in order to bring the tissue fluid collector 110 placed in the placement unit 20 into contact with the respective sensors 21 and 22, the drive unit 23 moves the placement unit 20 and the respective sensors 21 and 22. It is a structure included in the above-mentioned moving unit 60. The drive unit 23 includes a horizontal movement drive unit 230 that moves the placement unit 20 in the horizontal direction, and a vertical movement drive unit 231 that moves the glucose sensor 21 and the sodium ion sensor 22 in the vertical direction. The vertical movement drive unit 231 is provided in the detection unit 2 corresponding to the glucose sensor 21 and the sodium ion sensor 22 respectively.

[0138] The placement unit 20 is transported between the placement position, the first measurement position, the second measurement position, and the third measurement position by the horizontal movement drive unit 230. In addition, the method of positioning the placement unit 20 at each measurement position can be designed as follows: an object detection sensor such as a photoelectric sensor is assembled at each measurement position, and the placement unit 20 is detected by the object detection sensor at each measurement position to detect that the placement unit 20 has reached each measurement position.

[0139] Each of the sensors 21 and 22 is transported between a standby position, a measurement position, and a cleaning position by a vertical movement driving unit 231.

[0140] In addition, a method for positioning each of the sensors 21 and 22 to each position may use a position detection sensor mounted on a frame member of the mounting member 24. The position detection sensor is fixed to a sensor support plate mounted on the frame portion via a fixing member and moves in the vertical direction together with the mounting member 24. In this example, a detection plate 92 is fixed to one side plate 16 of the detection unit 2 ( Figure 11 as shown), and the detection plate 92 faces the position detection sensor. The position detection sensor detects the highest position (standby position) and the lowest position (cleaning position) of each of the sensors 21 and 22 that move in the vertical direction by the vertical movement driving unit 231 by detecting the upper end and the lower end of the detection plate 92.

[0141] The reagent storage unit 3 is provided with a waste liquid tank, a first tank for storing a cleaning liquid, a second tank for storing a low-concentration calibration liquid for glucose, a third tank for storing a high-concentration calibration liquid for glucose, a fourth tank for storing a medium-concentration calibration liquid for sodium ions, and a fifth tank for storing a high-concentration calibration liquid for sodium ions. The cleaning liquid in the first tank is used to clean the glucose sensor 21 and the sodium ion sensor 22, and also serves as a low-concentration calibration liquid for sodium ions to prepare a calibration curve for sodium ions. A PB-K solution can be exemplified as the cleaning liquid. The calibration liquids for glucose in the second and third tanks are used to prepare a calibration curve for glucose. A PB-K solution added with glucose can be exemplified as the calibration liquid for glucose. Regarding the glucose concentration of the PB-K solution, the low concentration is, for example, 0.5 mg / dL, and the high concentration is, for example, a concentration determined within the range of 10 mg / dL to 40 mg / dL. The calibration liquids for sodium ions in the fourth and fifth tanks are used to prepare a calibration curve for sodium ions. A saline solution can be exemplified as the calibration liquid for sodium ions. Regarding the sodium ion concentration of the saline solution, the medium concentration is, for example, a concentration determined within the range of 1 mM to 2 mM, and the high concentration is, for example, a concentration determined within the range of 20 mM to 50 mM. Other examples of calibration liquids for sodium ions include, for example, Tris solution and PB-K solution. The glucose concentration or sodium ion concentration of each liquid in each tank is stored in the storage unit of the control module 5.

[0142] The liquid delivery unit 4 supplies the liquids stored in the respective tanks to the glucose sensor 21 and the sodium ion sensor 22 disposed in the detection unit 2, and recovers the liquid after liquid delivery to the waste liquid tank.

[0143] The control module 5 controls the drive unit 23 so that the tissue fluid collector 110 placed on the placement unit 20 comes into contact with each of the sensors 21 and 22, which is a structure included in the moving unit 60. The control module 5 includes a microcomputer having a processor (such as a CPU, etc.) and a memory (such as a ROM and a RAM, etc.), a substrate for user interface control, an I / O substrate, an analog substrate, and other circuits for processing various signals. The control module 5 controls the operations of each unit such as the detection unit 2, the liquid delivery unit 4, and the operation display unit 6 by the CPU reading and executing the program stored in the ROM. The RAM is used as an extended area for the program when executing the program stored in the ROM. The control module 5 has functions such as a control unit, an analysis unit, and a storage unit. The control unit controls the drive unit 23 of the detection unit 2, and the analysis unit calculates the blood glucose AUC based on the signals received from each of the sensors 21 and 22 of the detection unit 2 that reflect the amount of the measurement target component (glucose) and the signals that reflect the amount of the electrolyte (sodium ion) as an auxiliary component.

[0144] The operation display unit 6 is used for giving an instruction to start measurement or displaying an analysis result, etc. The operation display unit 6 can be constituted by a touch screen type display. Also, the operation display unit 6 can be divided into an operation unit and a display unit. In this case, the operation unit can be constituted by buttons, switches, a keyboard, or a mouse.

[0145] The power supply 7 converts the AC power supply voltage input from a power plug (not shown) into a DC voltage and supplies it to the control module 5. In addition, the power supply 7 is also connected to other units and supplies power to each of them respectively. Examples

[0146] The present invention will be described in detail based on the examples below, but the present invention is not limited to the following examples.

[0147] The average particle diameter shown in the following test examples is the value at a cumulative frequency of 50% measured by a laser diffraction / scattering type particle size distribution measuring device. In addition, the thickness of each layer was measured by a contact type height difference gauge after coating the layer and drying it.

[0148] Test Example 1. Potential Responsiveness of Ion-Selective Electrode to NaCl Concentration

[0149] <Test Example 1-1. Fabrication of an Ion Selective Electrode (Example 1)>

[0150] An ion selective electrode (Example 1) was fabricated as follows. An electrode material with a diameter of 5 mm was formed by laminating a platinum paste on a ceramic substrate. A metal oxide (Na 0.33 MnO2 (tetragonal crystal structure), average particle diameter 8.9 μm, flaky), a solid electrolyte (β” alumina: Na2Al 10.6 O 15.9, a slurry of a solid electrolyte (average particle size 0.26 μm), a conductive agent (AB: acetylene black), and a binder (PVDF: polyvinylidene fluoride) was used to form an internal solid layer with a film thickness of 10 μm. A slurry containing 3 parts by mass of an ionophore (DD16C5: 16-crown-5 derivative with two decalino subunits), 68 parts by mass of a plasticizer (TEHP: tris(2-ethylhexyl) phosphate) (Phosphoric acid, tris(2-ethylhexyl) ester), 1 part by mass of an anion scavenger (Na-TFPB: sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate), and 29 parts by mass of a substrate (PVC: polyvinyl chloride) was repeatedly laminated 4 times on the internal solid layer to form a Na ion-selective membrane with a film thickness of 170 - 190 μm, and an ion-selective electrode was obtained.

[0151] The cross-section of the ion-selective electrode was observed by scanning electron microscopy (SEM). In addition, the distribution of each material in this cross-section was examined by EDX mapping. The distribution patterns of each material in the SEM image of the cross-section of the internal solid layer are shown in Figure 13 and 14 . From this, it was found that solid electrolyte particles smaller than the particle size of the metal oxide covered the periphery of the metal oxide particles.

[0152] The mass ratios of the solid electrolyte, metal oxide, conductive agent, and binder in the internal solid layer are shown in the following table.

[0153] [Table 1]

[0154]

[0155] <Test Example 1-2. Fabrication of Reference Electrode>

[0156] A reference electrode including a silver / silver chloride slurry was formed by screen printing. A polyvinyl alcohol (PVA) film was laminated on the silver / silver chloride slurry. The PVA film was made to contain a solution with a chloride ion concentration of 282 mM, and the potential was measured after it became stable.

[0157] <Test Example 1-3. Potential Measurement>

[0158] After connecting an ion sensor including the ion-selective electrode (Example 1) and the reference electrode to a potentiometer, it was immersed in the following electrolyte solution (a mixed solution of NaCl and KCl, Na concentration: 0.3 mM, 2 mM, or 50 mM; K concentration: 280 mM; Cl concentration: Na concentration (mM) + 280 mM) to measure the potential. After each potential measurement, the electrode was cleaned with a cleaning solution (phosphate K buffer, Na concentration: 0.3 mM, K concentration: 280 mM).

[0159] <Results of Test Example 1>

[0160] The results are shown in Figure 15 . From this, it is known that the ion-selective electrode having an internal solid layer containing a solid electrolyte and a metal oxide responds to the Na concentration.

[0161] Test Example 2. Potential Stability 1 of Ion-Selective Electrode

[0162] <Test Example 2-1. Fabrication of Ion-Selective Electrode (Comparative Example 1)>

[0163] An ion-selective electrode (Comparative Example 1) was obtained in the same manner as in Example 1 without using a solid electrolyte. The mass ratio of the internal solid layer of the ion-selective electrode used in the following potentiometric measurements is shown in the table below.

[0164] [Table 2]

[0165]

[0166] <Test Example 2-2. Potentiometric Measurement>

[0167] Potentiometric measurements were carried out in the same manner as in Test Example 1-3, except that ion-selective electrodes (Example 1 and Comparative Example 1) were used and a solution with a Na concentration of 30 mM was used instead of a solution with a Na concentration of 50 mM as the electrolyte solution. The measurements were repeated several times, and after each measurement, the electrodes were cleaned in the same manner as in Test Example 1-3. The potential change (absolute value) of each measured value compared to the potential of the first measurement was calculated.

[0168] <Results of Test Example 2>

[0169] The results are shown in Figure 16 . From this, it is known that in the internal solid layer, adding a solid electrolyte to the metal oxide can improve the potential stability during repeated use.

[0170] Test Example 3. Potential Stability 2 of Ion-Selective Electrode

[0171] <Test Example 3-1. Fabrication of Ion-Selective Electrodes (Examples 2 to 3 and Comparative Example 2)>

[0172] Ion-selective electrodes (Example 2: mass ratio of solid electrolyte is 4, Example 3: mass ratio of solid electrolyte is 12) were obtained in the same manner as in Example 1, except that the mass ratio of the solid electrolyte was changed. Also, an ion-selective electrode (Comparative Example 2) was obtained in the same manner as in Example 1 without using a metal oxide. The mass ratio of the internal solid layer of the ion-selective electrode used in the following potentiometric measurements is shown in the table below.

[0173] [Table 3]

[0174]

[0175] <Test Example 3-2. Potential Measurement>

[0176] Except for using an ion-selective electrode (Examples 1 to 3 and Comparative Examples 1 and 2), and using a solution with a Na concentration of 2 mM and a solution with a Na concentration of 30 mM as the electrolyte solution, potential measurement was carried out in accordance with Test Example 1-3. In this test, a set was defined as measuring the solution with a Na concentration of 2 mM six times, measuring the solution with a Na concentration of 30 mM once, and then measuring the solution with a Na concentration of 2 mM once, and three sets were continuously implemented. For the 2 mM solution with stable measured potential in each set, the sixth potential was calculated, and the standard deviation of this potential in the three sets was calculated.

[0177] <Results of Test Example 3>

[0178] The results are shown in Figure 17 From this, it was found that in the internal solid layer, adding a metal oxide in addition to the solid electrolyte can improve the potential stability during repeated use. And it was found that when the solid electrolyte is added without adding the metal oxide, the potential fluctuation is large. From this, it was found that the combination of the metal oxide and the solid electrolyte is important for the potential stability during repeated use.

[0179] Test Example 4. Potential Stability 3 of Ion-Selective Electrode

[0180] <Test Example 4-1. Fabrication of Ion-Selective Electrode (Example 4)>

[0181] Except for using β-alumina (Na2O - 11Al2O3, average particle size 0.26 μm) as the solid electrolyte, an ion-selective electrode (Example 4) was obtained in the same manner as in Example 1. The mass ratio of the internal solid layer of the ion-selective electrode used in the following potential measurement is shown in the table below.

[0182] [Table 4]

[0183]

[0184] <Test Example 4-2. Potential Measurement>

[0185] Potential measurement was carried out in accordance with Test Example 1-3 using the ion-selective electrodes (Examples 1 and 4). In this test, repeated measurements were carried out within one day and this was done for three days. Based on the measured values, the difference (absolute value) between the measured potentials of the electrolyte solutions with the same concentration obtained for the first and last times each day was calculated and the average value was obtained.

[0186] <Results of Test Example 4>

[0187] InFigure 18 The results shown herein indicate that high potential stability during repeated use can be achieved both when using β''-alumina and when using β-alumina.

[0188] Test Example 5. Potential Stability 1 of Electrode for Reference Electrode

[0189] <Test Example 5-1. Fabrication of the Electrode for the Reference Electrode (Example 5)>

[0190] The electrode (Example 5) was fabricated as follows. A platinum paste was laminated on a ceramic substrate to form an electrode material with a diameter of 5 mm. A paste containing a metal oxide (Na 0.33 MnO2 (tetragonal crystal structure), average particle size 8.9 μm, flaky), a solid electrolyte (β''-alumina: Na2Al 10.6 O 15.9 , average particle size 0.26 μm), a conductive agent (AB: acetylene black), and a binder (PVDF: polyvinylidene fluoride) was laminated on the electrode material by electrostatic coating to form an internal solid layer with a film thickness of 10 μm. An ionic liquid gel film was formed on the internal solid layer as follows. Specifically, PVDF-HFP (manufactured by ARKEMA, Kynar Flex 2751-00 (HFP 15 mol%)) was mixed with acetone at a ratio of 1:10 (wt) and stirred overnight, and ionic liquid PP13-TFSI (manufactured by Tokyo Chemical Industry Co., Ltd., 1-Methyl-1-propylpyrrolidinium bis(trifluoromethanesulfonyl)imide) was added thereto until the ratio of PVDF-HFP:PP13-TFSI was 2:8. The resulting solution was coated on the internal solid layer and laminated 10 times while drying at 50 °C, and then finally dried at 150 °C to form an ionic liquid gel film, thereby obtaining the electrode. The mass ratios in the internal solid layer are shown in the table below.

[0191] [Table 5]

[0192]

[0193] <Test Example 5-2. Potential Measurement>

[0194] Potential measurement was carried out in the same manner as in Test Example 1-3, except that the electrode (Example 5) or the electrode formed from a silver-silver chloride paste (Comparative Example 3) was used instead of the ion-selective electrode, a solution with Na concentrations of 0.3, 1, 2, 10, and 30 mM was used as the electrolyte solution, and a commercially available Ag / AgCl electrode containing an internal liquid (internal liquid: saturated KCl) was used as the reference electrode. The Figure 19 outline of the measurement method is shown.

[0195] <Test Example 5 Results>

[0196] The results of the potential difference between the measured potential of each electrolyte solution calculated and the measured potential of the solution with a Na concentration of 0.3 mM are shown in Figure 20 . As a result, Comparative Example 3 is an Ag / AgCl electrode without internal liquid and responds to the Cl concentration, while Example 5 does not respond to the Na concentration and the Cl concentration. Thus, it can be seen that by forming an ionic liquid gel film on the internal solid layer containing a solid electrolyte and a metal oxide, an electrode that does not respond to the Na concentration and the Cl concentration can be obtained. In addition, the measured potential of Example 5 relative to a commercially available Ag / AgCl (internal liquid: saturated KCl) electrode with internal liquid is shown in Figure 21 . It can be seen that when measuring solutions with changing Na concentration and Cl concentration, the potential difference between the commercially available reference electrode with internal liquid and Example 5 is also approximately 0, and Example 5 has the same performance as the commercially available reference electrode with internal liquid. Therefore, this electrode can be used as a reference electrode.

[0197] Test Example 6. Potential Stability 2 of Electrode for Reference Electrode

[0198] <Test Example 6-1. Fabrication of Electrodes for Reference Electrodes (Example 6 and Comparative Example 4)>

[0199] An electrode (Example 6) was obtained in the same manner as in Example 5 except that β-alumina (Na2O - 11Al2O3, average particle size 0.26 μm) was used as the solid electrolyte. And an electrode (Comparative Example 4) was obtained in the same manner as in Example 5 except that the solid electrolyte was not used. The mass ratio of the internal solid layer of the electrodes used in the following potential measurements is shown in the table below.

[0200] [Table 6]

[0201]

[0202] <Test Example 6-2. Potential Measurement>

[0203] Potential measurements were carried out in the same manner as in Test Example 1-3 except that electrodes (Examples 5-6 and Comparative Example 4) were used instead of ion-selective electrodes, a solution with a Na concentration of 2 mM and a K concentration of 268 mM was used as the electrolyte solution, and a commercially available Ag / AgCl (internal liquid: saturated KCl) electrode with internal liquid was used as the reference electrode. In this test, each electrode was immersed in the electrolyte solution for one and a half hours, and the measured potential just after immersion and the measured potential after immersion for one and a half hours were measured and the difference between the two was calculated.

[0204] <Test Example 6 Results>

[0205] The results are shown inFigure 22 It can be seen from this that in the internal solid layer, the addition of metal oxide and solid electrolyte can improve the potential stability during long-term use.

[0206] Test Example 7. Potential Stability 3 of Na Ion-Selective Electrode

[0207] <Test Example 7-1. Fabrication of Na ion selective electrode (Examples 7 and 7’)>

[0208] A Na ion selective electrode (Example 7) was obtained in the same manner as in Example 1 except that K-TCPB was used as the anion scavenger. A Na ion selective electrode (Example 7’) was obtained in the same manner as in Example 1 except that zeolite (Zeolum A-4 100# Tosoh, average particle size after processing: 3 μm) was used as the solid electrolyte. The mass ratio of the internal solid layer of the electrodes used in the following potential measurements and the anion scavenger in the Na ion selective membrane are shown in the following table.

[0209] [Table 7]

[0210]

[0211] <Test Example 7-2. Potential measurement>

[0212] Potential measurements were carried out in accordance with Test Example 1-3 except that ion selective electrodes (Example 1, Example 7 and Example 7’) were used and a solution with a Na concentration of 30 mM was used as the electrolyte solution. In this test, two measurements of a solution with a Na concentration of 2 mM, one measurement of a solution with a Na concentration of 0.3 mM, one measurement of a solution with a Na concentration of 2 mM and one measurement of a solution with a Na concentration of 30 mM were set as one group, and 11 groups were continuously carried out. The standard deviation of the potential of the solution with a Na concentration of 30 mM measured in 11 groups was calculated. The standard deviation of this potential in 3 groups was calculated, and the average value of the amounts of 3 sensors was obtained (for Example 7’ only, it is the average value of the amount of 1 sensor).

[0213] <Results of Test Example 7>

[0214] The results are shown in Figure 23 . The results show that the potential is stable regardless of the ion species in the selective membrane and the type of solid electrolyte.

[0215] Test Example 8. K Ion Concentration Responsiveness 1 of K Ion-Selective Electrode

[0216] <Test Example 8-1. Fabrication of Na ion selective electrode (Example 8)>

[0217] A K-ion selective electrode was fabricated as described below (Example 8). An electrode material with a diameter of 5 mm was formed by laminating platinum paste on a ceramic substrate. A paste containing a metal oxide (Na 0.33 MnO2 (tetragonal crystal structure), average particle size 7.3 μm, flaky), a solid electrolyte (β″-alumina: Na2Al 10.6 O 15.9 , average particle size 0.99 μm), a conductive agent (AB: acetylene black), and a binder (PVDF: polyvinylidene fluoride) was laminated on the electrode material by electrostatic coating to form an internal solid layer with a film thickness of 10 μm. A paste containing 7 parts by mass of an ionophore (valinomycin), 65 parts by mass of a plasticizer (TEHP: tris(2-ethylhexyl) phosphate), 1 part by mass of an anion scavenger (K-TCPB: potassium tetrakis(4-chlorophenyl)borate), and 27 parts by mass of a substrate (PVC: polyvinyl chloride) was laminated 4 times on the internal solid layer to form a K-ion selective membrane with a film thickness of 170 - 190 μm, thereby obtaining a K-ion selective electrode.

[0218] <Test Example 8-2. Potential Measurement>

[0219] Measurement was performed with respect to Ag / AgCl, and the potential was converted from the solution concentration to the potential with respect to Ag / AgCl (saturated KCl). In a solution with a fixed NaCl concentration of 140 mM, solutions with K concentrations of 1, 2, 4, 6, 8, 10, and 100 mM were measured.

[0220] <Results of Test Example 8>

[0221] The results are shown in Figure 24 . From this, it was found that the K-ion concentration can also be measured by using the K-ion selective membrane.

[0222] Test Example 8'. Potential Stability 1 of K Ion-Selective Electrode

[0223] <Test Example 8'-1. Fabrication of K-Ion Selective Electrodes (Examples 9 - 10 and Comparative Example 5)>

[0224] K-ion selective electrodes were obtained in the same manner as in Example 8 except for changing the mass ratio of the solid electrolyte (Example 9: mass ratio of the solid electrolyte is 2.8, Example 10: mass ratio of the solid electrolyte is 1.2). Also, a K-ion selective electrode was obtained in the same manner as in Example 8 except for not using the solid electrolyte (Comparative Example 5). The mass ratio of the internal solid layer of the ion selective electrode used in the following potential measurement and the anion scavenger in the K-ion selective membrane are shown in the table below.

[0225] [Table 8]

[0226]

[0227] <Test Example 8'-2. Potential Measurement>

[0228] After measuring the K1, 10, 100 mM solution with a fixed NaCl concentration of 140 mM, and repeating the measurement of 6 groups with the K1, 2, 4, 6, 8, 10 mM solution with a fixed NaCl concentration of 140 mM as one group, the K1, 10, 100 mM solution with a fixed NaCl concentration of 140 mM was measured for the last time. For each measurement, the sensor was cleaned with the cleaning solution of Na 140 mM each time. The potential change rate of the K1, 10, 100 mM solution measured for the first time and the K1, 10, 100 mM solution measured for the last time after 4.8 - 5 hours is shown in Figure 25 .

[0229] <Test Example 8' Results>

[0230] The results are shown in Figure 25 . The results show that the higher the addition amount of β-alumina, the higher the potential stability.

[0231] Test Example 9. Potential Stability 2 of K Ion-Selective Electrode

[0232] <Test Example 9-1. Fabrication of K Ion Selective Electrode (Examples 11 - 13)>

[0233] Except for using zeolite (Zeolum A-4 100# Tosoh, average particle size after processing is 3 μm) as the solid electrolyte, K ion selective electrodes were obtained in the same manner as in Example 8 (Example 11: mass ratio of solid electrolyte is 8, Example 12: mass ratio of solid electrolyte is 2.8, Example 13: mass ratio of solid electrolyte is 1.2). The mass ratio of the internal solid layer of the ion selective electrode used in the following potential measurement and the anion scavenger in the K ion selective membrane are shown in the following table.

[0234] [Table 9]

[0235]

[0236] <Test Example 9-2. Potential Measurement>

[0237] Potential measurement was carried out in the same manner as in Test Example 8'-2.

[0238] <Test Example 9 Results>

[0239] The results are shown in Figure 26 . The results show that the higher the addition amount of zeolite, the higher the potential stability.

[0240] Test Example 10. Potential Stability 3 of K Ion-Selective Electrode

[0241] <Test Example 10-1. Fabrication of K Ion Selective Electrodes (Example 14 and Comparative Example 6)>

[0242] A K ion selective electrode (Example 14) was obtained in the same manner as in Example 8, except that Na-TFPB was used as the anion scavenger. A K ion selective electrode (Comparative Example 6) was obtained by using non-solid electrolyte Na2CO3 instead of the solid electrolyte used in Example 8. The mass ratio of the internal solid layer of the ion selective electrode used in the following potentiometric measurements and the anion scavenger in the K ion selective membrane are shown in the table below.

[0243] [Table 10]

[0244]

[0245] <Test Example 10-2. Potentiometric Measurement>

[0246] Potentiometric measurements were carried out using K ion selective electrodes (Example 8, 11, 14, Comparative Examples 5, 6) according to Test Example 8'. The standard deviation of the potential of the K 10 mM solution measured 8 times in one day of measurement was calculated, and the average value of the amounts of 3 sensors was obtained (for Example 11, only the average value of the amount of 1 sensor).

[0247] <Results of Test Example 10>

[0248] The results are shown in Figure 27 . The results showed that the potential changed when using the non-solid electrolyte Na2CO3, while when using the solid electrolytes β-alumina and zeolite, the potential change was small regardless of the ion species in the selective membrane.

[0249] Test Example 11. Potential Stability 3 of Electrode for Reference Electrode

[0250] <Test Example 11-1. Fabrication of Reference Electrodes (Example 15 and Example 16)>

[0251] The ratio of PVC to plasticizer was 1:2, and 4 parts by mass of the ionic liquid [TBMOEP + [ClClN -Dissolved in a THF solution, 20 μL was dropped onto the inner solid layer and heated and dried at 60 °C to fabricate a PVC membrane of an ionic liquid gel. The plasticizer in Example 15 was NPOE, and the plasticizer in Example 16 was TEHP. Also, TBMOEP refers to tributyl(2-methoxyethyl)phosphonium bis-(trifluoromethanesulfonyl)imide. The mass ratio of the inner solid layer of the ion-selective electrode used in the following potential measurement and the plasticizer in the ionic liquid gel PVC membrane are shown in the table below.

[0252] [Table 11]

[0253]

[0254] <Test Example 11-2. Potential Measurement>

[0255] Except for using electrodes (Examples 15, 16) instead of the ion-selective electrode, using a solution with a K concentration of 1, 10, 100 mM and a Na concentration of 140 mM as the electrolyte solution, and using a commercially available Ag / AgCl (inner liquid: saturated KCl) electrode with an inner liquid as the reference electrode, the potential measurement was carried out in the same manner as in Test Example 1-3. In this test, after stabilizing each electrode with a K 1 mM solution, each electrode was successively immersed in a 10 mM solution, a 100 mM solution, and a 1 mM solution, and the absolute value of the difference between the measured potential after soaking for 1 minute and the potential at the time of the last measurement with the K 1 mM solution was calculated.

[0256] <Results of Test Example 11>

[0257] The results are shown in Figure 28 . Regardless of the plasticizer, the potential difference is not affected by the KCl concentration and is below 1 mV, and the potential is stable.

[0258] Symbol Explanation

[0259] A Inner solid layer

[0260] B Electrode material

[0261] C1 Ion-selective membrane

[0262] C2 Salt bridge layer

[0263] D Ion-selective electrode of the present invention

[0264] E Reference electrode of the present invention

[0265] F Insulating substrate

[0266] G Reference electrode

[0267] 1 In-vivo component measurement device of the present invention

Claims

1. An ion sensor, comprising: Insulating substrate; An ion-selective electrode on the insulating substrate; And A reference electrode on the insulating substrate, wherein the ion-selective electrode comprises: A first inner solid layer containing a metal oxide and a solid electrolyte; A first electrode material; and An ion-selective membrane, wherein the first inner solid layer is sandwiched between the first electrode material and the ion-selective membrane in its thickness direction, the ion-selective membrane is a multilayer structure comprising several layers made of the same or different components from each other, the first inner solid layer is used to cover the side surface of the first electrode material, and the ion-selective membrane is used to cover the side surface of the first inner solid layer so as not to expose the first inner solid layer, and the reference electrode comprises: A second inner solid layer containing a metal oxide and a solid electrolyte; A second electrode material; and A salt bridge layer, wherein the second inner solid layer is sandwiched between the second electrode material and the salt bridge layer in its thickness direction, and the salt bridge layer is a multilayer structure comprising several layers with different components from each other; Among them, the solid electrolyte is β”-aluminum oxide or β-aluminum oxide, and the metal oxide is M x MnO2; wherein M represents Na or K, and x is 0.2 to 0.

5.

2. The ion sensor according to claim 1, characterized in that: The solid electrolyte of at least one of the first inner solid layer and the second inner solid layer is an ion-conductive ceramic.

3. The ion sensor according to claim 1 or 2, characterized in that: The solid electrolyte of at least one of the first inner solid layer and the second inner solid layer is a sodium ion or potassium ion-conductive ceramic.

4. The ion sensor according to claim 1 or 2, characterized in that: The metal oxide of at least one of the first inner solid layer and the second inner solid layer is an ion-electron conductor for sodium ions or potassium ions.

5. The ion sensor according to claim 1 or 2, characterized in that: The solid electrolyte and the metal oxide of at least one of the first inner solid layer and the second inner solid layer are in particle form.

6. The ion sensor according to claim 5, characterized in that: The average particle size of the solid electrolyte of at least one of the first inner solid layer and the second inner solid layer is smaller than the average particle size of the metal oxide of at least one of the first inner solid layer and the second inner solid layer.

7. The ion sensor according to claim 1 or 2, characterized in that: The mass ratio of the metal oxide to the solid electrolyte in at least one of the first inner solid layer and the second inner solid layer is: The metal oxide: the solid electrolyte is 2:1 to 1:

2.

8. The ion sensor according to claim 1 or 2, characterized in that: At least one of the first inner solid layer and the second inner solid layer contains a binder and a conductive agent.

9. The ion sensor according to claim 8, wherein: The binder is at least one selected from the group consisting of: (a) polyvinylidene fluoride, (b) a mixture containing styrene-butadiene latex and carboxymethyl cellulose, (c) a mixture containing polyamideimide and carbodiimide, (d) polytetrafluoroethylene, (e) acrylic emulsion.

10. The ion sensor according to claim 8, wherein: The conductive agent is at least one selected from the group consisting of carbon black, acetylene black, Ketjen black, carbon nanotubes, graphene, carbon powder, and graphite powder.

11. The ion sensor according to claim 1 or 2, wherein: The first inner solid layer is directly disposed on the first electrode material of the ion-selective electrode, and the second inner solid layer is directly disposed on the second electrode material of the reference electrode.

12. The ion sensor according to claim 1, wherein: The ion-selective membrane contains an ionophore.

13. The ion sensor according to claim 1, wherein: The ion-selective membrane is directly disposed on the first inner solid layer.

14. The ion sensor according to claim 1 or 2, wherein: An ionic liquid gel film is further included.

15. The ion sensor according to claim 14, wherein: The ionic liquid gel film is directly disposed on the first internal solid layer.

16. The ion sensor according to claim 1 or 2, wherein: At least one of the first electrode material and the second electrode material contains at least one selected from the group consisting of platinum, gold, silver, palladium, aluminum, nickel, and carbon.

17. A method for manufacturing an electrode in an ion sensor, which is used for manufacturing the electrode in the ion sensor according to any one of claims 1 to 16 above, wherein Comprising: Forming an internal solid layer containing a metal oxide and a solid electrolyte on the electrode material, Forming an ion-selective membrane or an ionic liquid gel film on the internal solid layer.

18. The manufacturing method according to claim 17, wherein: The method for forming the internal solid layer is electrostatic coating.

19. A method for measuring components in vivo, wherein Comprising: Measuring the sodium ion concentration contained in the tissue fluid collected from a subject by the ion sensor according to claim 1.

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