JPH0370781B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION BACKGROUND OF THE INVENTION Technical Field The present invention relates to a PH sensor for blood. In detail, the blood PH consists of an electrode base coated with an ion permeable membrane and an antithrombotic impurity permeation prevention membrane.
It's about sensors. For more details,
PH for blood that can measure the concentration of hydrogen ions in blood such as serum and whole blood using electrode potential response or current response
It's about sensors. Prior Art and Problems Measuring the concentration of specific ions in blood, particularly the concentration of hydrogen ions, is an important test item in terms of diagnosis and treatment. However, although glass electrodes are mainly used as operating electrodes in current PH measurement devices, foreign substances such as blood are likely to adhere to the glass membrane. Due to the high glass membrane resistance, PH in blood such as serum and whole blood cannot be measured. Furthermore, in blood tests, external measurement methods are used. Therefore, the true pH may change due to changes in the carbonate partial pressure and oxygen partial pressure in the sample solution (blood), or the introduction of impurities.
Value information is difficult to obtain. Furthermore, denaturation of trace components in the sample solution may occur, which may affect test values. Furthermore, since it is used in blood, there is a problem that it is likely to cause blood clots. For this reason, it is desirable to insert an ion electrode into the blood to measure the true ion concentration in the body's blood without forming a thrombus. OBJECT OF THE INVENTION Accordingly, an object of the present invention is to provide a blood PH sensor having a novel antithrombotic and selective ion permeable membrane. Another object of the present invention is to provide a blood PH sensor that can measure the hydrogen ion concentration in blood such as serum or whole blood based on electrode potential response or current response. These objectives are to coat the surface of the conductor with a polymer film derived from at least one aromatic compound selected from the group consisting of nitrogen-containing aromatic compounds and hydroxy aromatic compounds to a thickness of 0.01 to 1 μm. This is achieved by a blood PH sensor formed by coating the polymer membrane with an antithrombotic contaminant permeation prevention membrane made of segmented polyurethane and having a thickness of 0.1 to 10 μm. The nitrogen-containing compound used in the present invention has the general formula
(However, in the formula, Ar is an aromatic nucleus, R is a substituent,
m is an integer of 0 or 1 or more, n is an integer of 1 or more, and m+n does not exceed the effective valence number of Ar. However, when Ar is a nitrogen-containing heterocycle, n may be 0). Specific examples include 1,2-diaminobenzene, aniline, 2-aminobenzotrifluoride, 2-aminopyridine, 2,3-diaminopyridine, 4,
At least one member selected from the group consisting of 4'-diaminodiphenyl ether, 4,4'-methyleneaniline, tyramine, N-(O-hydroxybenzyl)aniline, and pyrrole. Furthermore, polyaromatic amide or polyaromatic imide can be used as a polymer film obtained by polymerization in advance, dissolved in a solvent, applied and dried on the surface of the conductor. Ion sensors having polymeric membranes derived from these nitrogen-containing aromatic compounds are suitable for use as PH sensors. Hydroxyaromatic compounds have the general formula (However, in the formula, Ar is aromatic, R is a substituent, and l is the effective valence number of 0 to Ar). Specific examples include phenol, dimethylphenol, hydroxypyridine, o- and m-
Benzyl alcohol, o-, m- and p-hydroxybenzaldehyde, o- and m-hydroxyacetophenone, o-, m- and p-hydroxypropiophenone, o-, m- and p-
Benzophenol, o-, m- and p-hydroxybenzophenone, o-, m- and p-carboxyphenol, diphenylphenol, 2-
Methyl-8-hydroquinoline, 5-hydroxy-
These include 1,4-naphthoquinone, 4-(p-hydroxyphenyl)-2-butanone, 1,5'-dihydroxy-1,2,3,4-tetrahydronaphthalene, bisphenol A, or mixtures thereof.
When viewed as a film of a polymer that has been polymerized in advance, the polymer film is polyphenylene oxide, etc., which is obtained by dissolving the polymer film in a solvent, coating it on the surface, and drying it. It should be noted that the term polymer as known in this specification includes both homopolymers and interpolymers (eg, copolymers, terpolymers, etc.). DETAILED DESCRIPTION OF THE INVENTION The present invention will now be described in detail with reference to the accompanying drawings. As shown in FIG. 1A, the blood PH sensor according to the present invention basically consists of a platinum-based metal 11 having an arbitrary shape, for example, a rod shape, and an insulating material 12 such as polyolefin or Teflon coated on the surface of the tip disk. A predetermined polymer film 13 is adhered and fixed, and the surface thereof is coated with an impurity permeation prevention film 14. In addition, as shown in Figure 1B, conductors other than platinum (e.g., copper, aluminum, steel, etc.)
A platinum thin film 16 is formed on the surface of 15 by a method such as ion sputtering, a predetermined polymer film 13 is applied and fixed on the surface, and the impurity permeation prevention film 14 is coated on the surface of the platinum thin film 16. It is coated with an insulator 12 such as polyolefin or Teflon. The polymer film 13 deposited on the surfaces of the conductor disks 11 and 16 is made of a polymer of a nitrogen-containing aromatic compound. Such nitrogen-containing aromatic compounds may have, for example, the general formula (where, in the formula, Ar is an aromatic nucleus, R is a substituent,
m is an integer of 0 or 1 or more, n is an integer of 1 or more, and m+n does not exceed the effective valence number of Ar. However, when Ar is a nitrogen-containing heterocycle, n may be 0). Aromatic Ar
may be monocyclic (eg, benzene nucleus, pyridine nucleus) or polynuclear (eg, quinoline nucleus, naphthoquinone nucleus, bisphenol nucleus). N-substituted derivatives of the compounds of formula are also used. Examples of the substituent R include alkyl groups such as methyl groups, halogenated alkyl groups, aryl groups such as phenyl groups, alkylcarbonyl groups and arylcarbonyl groups.

[Formula] Hydroxyalkyl group (-R″OH), carboxyl group, aldehyde group, hydroxyl group, etc. Specific examples of such nitrogen-containing aromatic compounds include 1,2-diaminobenzene, aniline,
2-aminobenzotrifluoride, 2-aminopyridine, 2,3-diaminopyridine, 4,4'-diaminophenyl ether, 4,4'-methylene dianiline, tyramine, N-(O-hydroxybenzyl)aniline and Pyrrole etc. Polymers obtained by prepolymerization include polyaromatic amides and imides, such as polyamide/imide compounds of 4,4'-diaminophenyl ether and 4,4'-diaminodiphenylmethane derivatives, and bis-cyclo -[2,2,2]-oct-7-ene-2,3,5,6-tetracarboxylic dianhydride is converted to the acid chloride by reacting with thionyl chloride, which is converted into the 4,4'- Polyamide polymer obtained by reaction with diaminophenyl ether (Kobayashi et al., Nikka (12)
1929-32 (1980)). Alternatively, polymer membrane 13 may be derived from hydroxyaromatic compounds. Such hydroxyaromatic compounds may have, for example, the general formula
(where, in the formula, Ar is an aromatic nucleus, each R is a substituent,
and l is 0 to the effective valence number of Ar). The aromatic nucleus Ar is monocyclic (for example,
It may be a benzene nucleus, a pyridine nucleus) or a polynuclear type (for example, a quinoline nucleus, a naphthoquinone nucleus, a bisphenol nucleus). The substituent R is the same as described for formula (A). Specific examples of such hydroxyaromatic compounds include phenol, dimethylphenol (e.g. 2,6- and 3,5-dimethylphenol), 2-, 3- and 4-hydroxypyridine,
o- and m-benzyl alcohol, o-, m-
and p-hydroxybenzaldehyde, o-,
m- and p-hydroxyacetophenone, o
-, m- and p-hydroxypropiophenone, o-, m- and p-benzophenol, o
-, m- and p-hydroxybenzophenones,
o-, m- and p-carboxyphenols, diphenylphenols (e.g. 2,6 and 3,
5-diphenylphenol), 2-methyl-8-
Hydroquinoline, 5-hydroxy 1,4-naphthoquinone, 4-(p-hydroxyphenyl)-2-butanone, 1,5'-dihydroxy-1,2,3,4
-tetrahydronaphthalene, bisphenol A, etc. Polymers obtained by polymerization in advance include polyphenylene oxide, polyphenylene oxide derivatives, polydiphenylphenylene oxide,
Examples include polydimethylphenylene oxide and polycarbonate. The polymer film of the nitrogen-containing aromatic compound or hydroxy aromatic compound described above is used as the dielectric material 11, 16.
In order to deposit it on the surface, a nitrogen-containing aromatic compound or a hydroxy aromatic compound can be polymerized on the surface of the conductors 11 and 16 by electrolytic oxidation polymerization, or a pre-synthesized polymer can be dissolved in a solvent. , a method of fixing the polymer film on the conductor surface by dipping/coating and drying the solution, and a method of chemically treating the polymer film.
A method of directly fixing to the conductor surface by physical treatment or irradiation treatment can be adopted. The most convenient of the above deposition methods is by electrolytic oxidative polymerization. In this electrolytic oxidative polymerization, a nitrogen-containing aromatic compound or a hydroxy aromatic compound is electrolytically oxidized and polymerized in a suitable solvent to deposit a polymer film on the surface of a desired conductor as a working electrode. For example, the electrooxidative polymerization of 1,2-diaminobenzene, 2-aminobenzotrifluoride, and 4,4'-diaminophenylmethane is performed in a phosphate buffer solution at pH 7, and the polymerization of aniline is performed using pyridine and sodium perchlorate. The polymerization of 4,4'-diaminodiphenyl ether was carried out in an acetonitrile solution containing sodium perchlorate or the methanol solution containing sodium hydroxide, and the polymerization of pyrrole was carried out using tetrafluorophosphate as the supporting electrolyte. It is carried out in an acetonitrile solution containing butylammonium (abbreviated as Bu ₄ N (P ₆ )). Electrolytic oxidative polymerization of hydroxy aromatic compounds is carried out in an alkaline solvent such as methanol. A polymer film deposited by electrolytic oxidative polymerization has extremely good adhesion stability and a smooth film surface. There is no particular limit to the thickness of the polymer film, but approximately 0.01 μm to 1 μm is appropriate. The anti-contaminant permeation membrane is an anti-thrombotic membrane and is made of segmented polyurethane. The film thickness is usually
It is 0.1 to 10 μm. Segmented polyurethane consists of soft segment chains and hard segment chains, and each segment phase is mixed to form a hydrophilic/hydrophobic microphase-separated structure. Soft segment part type [where R is polytetramethylene glycol ( _-CH2 ) ₄ -O- and its copolymer, polypropylene glycol

[Formula] Polybutadiene (-CH ₂ CH = CHCH ₂ ) - _o ] Hard segment part type [where R′ is NH−NH−, −NH(CH ₂ ) _o
NH2- ;n=2-6

[Formula] -O- (CH ₂ ) ₄ -O-]. The molecular weight of the segmented polyurethane is about 10,000 or less. These materials can be Biomer (polyether segmented polyurethane from Ethcon Co.). Specific Effects of the Invention The selective ion permeable membrane according to the present invention can selectively permeate only hydrogen ions.
When used as a PH sensor, it can measure hydrogen ion concentration in blood such as serum and whole blood. In other words, ions such as Cl ^- , Mg ²⁺ , Ca ²⁺ , Na ⁺ , K ⁺ and other compounds such as albumin, glucose, bilirubin, urea, and uric acid sugar coexist in serum and whole blood. Even in that case, the hydrogen ion concentration can be measured with high accuracy. Examples of the present invention will be shown below. Example 1 The periphery of an aluminum wire (diameter 1 mm) was insulated with fluororesin (trade name "Teflon"), and its exposed tip was polished with silicon carbide paper (approximately 8.0 μm) and alumina powder (0.3 μm). After smoothing, washing with water and methanol, and drying, a basic body was obtained. This basic body 10 was irradiated with a power of 200 W for 15 seconds in an argon atmosphere at a vacuum pressure of 10 ^-3 Torr with an irradiation distance of 4 cm between the cathode and anode, and a platinum thin film was coated by sputtering to obtain the basic body. . The thickness of the platinum thin film in this case was 0.056 μm (In the following examples, unless otherwise specified,
This thin film electrode is used. ). A dipole magnetron discharge device was used as the sputtering device. Aluminum wire (diameter 1
mm) A thin platinum film is coated on the base, followed by a polyphenylene oxide film (hereinafter abbreviated as PPO film).
and poly(1,2-diaminobenzene film (hereinafter referred to as
A hybrid membrane of PDAB membrane (abbreviated as PDAB membrane) was coated by electrolytic oxidation polymerization, washed with water, and dried to fabricate an electrode using the polymer membrane. A membrane electrode was prepared on the surface of this electrode by immersing segmented polyurethane (ether-type polyurethane, a combination of polyether (Mm=1500) and polypropylene glycol) in a 0.1% by weight tetrahydrofuran solution and drying. A silver-silver chloride electrode was used as a reference electrode, and in combination with the electrode of the present invention, the hydrogen ion concentration in the arterial blood flow of a rabbit was measured. It took about 10 minutes for the equilibrium potential value of the electrode to reach a constant value, and even after 3 hours had passed, the equilibrium potential value remained constant at 170 mV. The PH value of the blood was measured using a blood analyzer (Model BMS-MK-2, manufactured by Radiometer) and was found to be 7.42 to 7.47. About carbon dioxide gas and oxygen concentration Pco ₂
Values of =37.2-43.1 mmHg and _Po2 =100-103 mmHg were obtained, respectively. In addition, when we investigated the relationship between the equilibrium potential (1 mV) of this fabricated electrode and the PH value (measured in advance with a commercially available PH meter) using standard serum, we found that the Nernst relational expression can be expressed as shown in Figure 3. Satisfied. The equilibrium potential value when the pH was 7.40 was 160 mV (measurement temperature 37±0.1°C), which was approximately the same potential value as the above experimental result. The above results are summarized in Table 1.

[Table] Example 2 Example 1 and PPO membrane as polymer membranes and
When a PPO membrane was used instead of the PDAB membrane, a membrane electrode (platinum/PPO membrane/segmented polyurethane) was produced in the same manner as in Example 1. A silver-silver chloride electrode was used as a reference electrode, and in combination with the electrode of the present invention, the hydrogen ion concentration in the arterial blood circulation of a rabbit was measured in the same manner as in Example 1. The results are shown in FIG. 2 (line A). It took about 10 minutes for the equilibrium potential value of the electrode to reach a constant value, and even after 140 minutes had passed, the equilibrium potential value remained constant at about 150 mV. The PH value of the blood was measured in the same manner as in Example 1 using a blood analyzer (Model BMS-MK-2, manufactured by Radiometer) and found to be 7.3 to 7.35. Values of _Pco2 = 37.0 to 41.2 mmHg and _Po2 = 93 to 105 mmHg were obtained for carbon dioxide and oxygen concentrations, respectively. Next, using the membrane electrode according to the present invention and a saturated calomel electrode as a reference electrode, hydrogen ion concentration was measured in a phosphate buffer solution (PH was adjusted with perchloric acid and sodium hydroxide solution). of the case
The potential value change with respect to the PH value change is 40mV/PH (37°
±1°C) [Figure 3 (line B)]. And the PH
The equilibrium potential value at 7.4 was 250 mV, and the equilibrium potential reaching speed was 3 to 10 minutes (PH range
4.0~8.0). For electrodes in which only a PPO film is coated on the surface of a platinum thin film, the equilibrium potential values around PH7.4 are almost the same.
The equilibrium potential value hardly changes whether or not a polyurethane film is coated. Furthermore, when standard serum (PH6.86) was used as the sample solution as in Example 1, the equilibrium potential value (mV) of this electrode was approximately 166 mV as shown in Figure 3 (line C).
The equilibrium potential was reached in about 2 minutes. Specific Effects of the Invention As described above, the present invention provides a conductor using a polymer film derived from at least one aromatic compound selected from the group consisting of nitrogen-containing aromatic compounds and hydroxy aromatic compounds. Film thickness 0.01~ on the surface
This is a PH sensor for blood, which is coated with a membrane of 1 μm thick and is coated with an anti-thrombotic contaminant permeation prevention membrane made of segmented polyurethane with a film thickness of 0.1 to 10 μm on the polymer membrane, so it can be used for serum, whole blood, etc. It can measure hydrogen ion concentration as a PH sensor in blood. In other words, serum and whole blood contain ions such as Cl ^- ,
Mg ²⁺ , Ca ²⁺ , Na ⁺ , K ⁺ and others, including albumin,
Medium molecular weight compounds such as glucose, bilirubin, urea, and uric acid coexist, but these ions and medium molecular weight compounds that interfere with the equilibrium potential response are blocked by an impurity permeation prevention membrane, and only hydrogen ions are removed. It can be selectively transmitted. Therefore,
Hydrogen ion concentrations in body fluids, especially blood, can be measured during in vivo perfusion. Furthermore, since the impurity permeation prevention membrane is an antithrombotic material, problems such as thrombosis can be solved even when used in vivo.

[Brief explanation of drawings]

Figure 1 A and B are cross-sectional views of the PH sensor, Figure 2
The figure is a graph showing changes over time in the equilibrium electrolyte value in the circulating bloodstream of a rabbit.
(PPO+PDAB) membrane/segmented polyurethane membrane] is a PH-electromotive force relationship diagram of the electrode. 11...Platinum-based metal, 12...Insulator, 13...
...polymer membrane, 14... impurity permeation prevention membrane, 15...
...Conductor, 16...Platinum thin film.

Claims (1)

[Claims] 1. A polymer film derived from at least one aromatic compound selected from the group consisting of nitrogen-containing aromatic compounds and hydroxy aromatic compounds is coated on the surface of a conductor with a film thickness of 0.01 to 1 μm. A PH sensor for blood comprising a polymer membrane coated with an antithrombotic contaminant permeation prevention membrane made of segmented polyurethane and having a thickness of 0.1 to 10 μm. 2 Nitrogen-containing aromatic compounds have the general formula (However, in the formula, Ar is an aromatic nucleus, R is a substituent,
m is 0 or an integer of 1 or more, and n is an integer of 1 or more, m+n does not exceed the effective valence number of Ar, and when Ar is a nitrogen-containing heterocycle, n is 0.
It may be. ), and hydroxyaromatic compounds have the general formula (However, in the formula, Ar and R are as described above, and l is 0 or the effective valence number of Ar.) Claim 1
PH sensor for blood described in section. 3. The blood PH sensor according to claim 1 or 2, wherein the polymer membrane is an electrolytically oxidized polymer membrane. 4 The nitrogen-containing aromatic compound is 1,2-diaminobenzene, aniline, 2-aminobenzotrifluoride, 2-aminopyridine, 2,3-diaminopyridine, 4,4'-diaminodiphenyl ether,
4,4'-methylene dianiline, tyramine, N-
The blood PH sensor according to claim 3, which is at least one selected from the group consisting of (O-hydroxybenzyl)aniline and pyrrole. 5 Hydroxyaromatic compounds include phenol, dimethylphenol, hydroxypyridine, o- and m-benzyl alcohol, o-, m- and p
-Hydroxybenzaldehyde, o- and m-
Hydroxyacetophenone, o-, m- and p
-Hydroxypropiophenone, o-, m- and p-benzophenol, o-, m- and p-
Hydroxybenzophenone, o-, m- and p
-carboxyphenol, diphenylphenol, 2-methyl-8-hydroquinoline, 5-hydroxy-1,4-naphthoquinone, 4-(p-hydroxyphenyl)-2-butanone, 1,5'-dihydroxy-1, The blood PH sensor according to claim 3, which is at least one selected from the group consisting of 2,3,4-tetrahydronaphthalene and bisphenol A. 6. The blood PH sensor according to claim 3, wherein the polymer film is a hybrid film derived from a nitrogen-containing aromatic compound and a hydroxy aromatic compound. 7. The blood PH sensor according to claim 6, wherein the nitrogen-containing aromatic compound is 1,2-diaminobenzene and the hydroxy aromatic compound is phenol. 8 The polymer film is polyphenylene oxide, polyphenylene oxide derivative, polydiphenylphenylene oxide, polydimethylphenyl oxide,
The blood PH sensor according to claim 1, which is selected from the group consisting of at least one polycarbonate derivative.