JP2005230408A - Method for treating substrate and method for manufacturing separation membrane by using this treatment method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a manufacturing method of a substrate which needs nonionic hydrophilic properties on the surface without deactivating characteristics of a functional material existing on the substrate. <P>SOLUTION: A method for treating the substrate is characterized by that a nonionic hydrophilic polymer is brought into contact with the substrate on which the functional material exists. The method can be widely used for applications which need nonionic hydrophilic properties on the surface without deactivating the characteristics of the functional material existing on the substrate. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for imparting a functional substance and a nonionic hydrophilic polymer to a substrate. Without deactivating the properties of the functional substance, it can be widely used in applications that require nonionic hydrophilicity on the surface. Specifically, artificial blood vessels, catheters, blood bags, contact lenses, intraocular lenses, artificial kidneys, artificial lungs, surgical aids and other medical devices, water purifier membranes, water purification membranes, sewage purification membranes, RO membranes It is suitably used for separation membranes such as DDS, protein chips, DNA chips, biosensors, and biological component separation modules. In particular, it is preferably used in applications requiring blood compatibility, for example, in the manufacture of blood purification modules.

Many attempts have been made to introduce a functional substance into a substrate, remove a specific substance, or activate a specific substance. For example, functional substances include dextran sulfate and polyethyleneimine as substances having an ionic group, hexadecyl groups as hydrophobic groups, and polymyxin B as physiologically active substances. A negatively charged surface increases bradykin production and promotes thrombus formation. Further, the negatively charged surface has a problem that it adsorbs an anticoagulant having a positive charge such as fusan. Therefore, a method (Japanese Examined Patent Publication No. 62-56782) in which dextran sulfate is immobilized on porous beads with controlled pore diameters to remove low density lipoprotein (LDL) is disclosed. In addition, a highly hydrophobic functional group such as a hexadecyl group adsorbs coagulation-related proteins in addition to nonspecifically adsorbing various proteins, thereby causing blood activation. Accordingly, a method (artificial organ 27 (2), 571-577, 1998) in which a hexadecyl group is immobilized on a porous bead having a controlled pore diameter to remove β ₂ -microglobulin is disclosed. However, this method has a problem that the form of the carrier on which the functional substance is immobilized is limited. Polyethyleneimine interacts with oxidized low density lipoprotein (oxidized LDL) (Japanese Patent Laid-Open No. 2002-028461). It is known that the amino group not only causes platelet adhesion but also has a large release reaction. That is, in order to remove the target substance, it is effective to increase the density of the functional substance, but there is a problem that the activity of blood is increased correspondingly and the shape of the carrier is limited.
Japanese Examined Patent Publication No. 62-56782 JP 2002-28461 A Artificial organ 27 (2), 571-577, 1998

  An object of the present invention is to provide a method for producing a substrate in which nonionic hydrophilicity is introduced on the surface without improving the disadvantages of the prior art and deactivating the properties of the functional substance.

As a result of diligent studies to achieve the above-mentioned problems, the present inventors have found a treatment method for introducing nonionic hydrophilicity on the surface without deactivating the properties of the functional substance, and the present invention. It came to complete. That is, the present invention is achieved by the following configurations (1) to (22).
(1) A method for treating a substrate, comprising bringing a nonionic hydrophilic polymer into contact with a substrate on which a functional substance is present.
(2) The method for treating a substrate according to (1), wherein the functional substance is a constituent component of the substrate.
(3) The method for treating a substrate according to (1), wherein the substrate containing the functional substance is obtained by chemically bonding the functional substance after molding the substrate.
(4) The method for treating a substrate according to (1), wherein the substrate on which the functional substance is present is obtained by adsorbing the functional substance after molding the substrate.
(5) The method for treating a substrate according to any one of (1) to (4), wherein the functional substance is a substance having an ionic group.
(6) The substrate treating method according to any one of (1) to (4), wherein the functional substance is a substance having a hydrophobic group.
(7) The substrate treatment method according to any one of (1) to (4), wherein the functional substance is a physiologically active substance.
(8) The method for treating a substrate according to any one of (1) to (5), wherein the ionic group is a cationic polymer.
(9) The method for treating a substrate according to (8), wherein the cationic polymer is an amino group-containing polymer.
(10) The amino group-containing polymer is one kind selected from polyalkyleneimine, polyvinylamine, polyallylamine, diethylaminoethyldextran, polydiallyldimethylammonium chloride, and derivatives thereof. The processing method of the base material.
(11) The method for treating a substrate according to any one of (1) to (10), wherein the nonionic hydrophilic polymer is polyalkylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, and derivatives thereof. .
(12) The method for treating a substrate according to any one of (1) to (11), wherein the nonionic hydrophilic polymer is brought into contact with the substrate and then irradiated with radiation.
(13) The method for treating a substrate according to any one of (1) to (12), wherein the substrate is a medical substrate.
(14) The modified base material according to (13), wherein the medical base material is built in a biological component separation module.
(15) The method for treating a substrate according to (13), wherein the medical substrate is incorporated in a blood purification module.
(16) The method for treating a substrate according to (13), wherein the medical substrate is incorporated in an artificial kidney module.
(17) The method for treating a substrate according to any one of (13) to (16), wherein the medical substrate is a separation membrane.
(18) The method for treating a substrate according to (17), wherein the medical substrate is a hollow fiber membrane.
(19) The method for treating a substrate according to (17) or (18), wherein the separation membrane is a polysulfone-based polymer.
(20) A method for producing a separation membrane, wherein the separation membrane is treated by the method for treating a substrate according to any one of (1) to (19).
(21) A method for producing a blood purification module, comprising the method for treating a substrate according to any one of (1) to (20) in a production process.
(22) A method for producing an artificial kidney module, comprising the method for treating a substrate according to any one of (1) to (21) in a production process.

  The method of the present invention can be widely used in applications that require nonionic hydrophilicity on the surface without deactivating the properties of the functional substance present on the substrate.

  The method of the present invention is characterized in that a substrate on which a functional substance is present is brought into contact with a nonionic hydrophilic polymer. That is, by using the method of the present invention, nonionic hydrophilicity can be introduced to the surface without deactivating the properties of the functional substance.

It is considered that the nonionic hydrophilic polymer is present so as to cover the functional substance by bringing the substrate on which the functional substance exists into contact with the nonionic hydrophilic polymer. Accordingly, large substances such as platelets and blood cells are repelled by the nonionic hydrophilic polymer layer and cannot approach the vicinity of the surface of the substrate. For this reason, undesirable phenomena such as blood activation can be suppressed. On the other hand, it is considered that relatively small substances such as LDL and β ₂ -microglobulin can interact with the functional substance through the nonionic hydrophilic polymer layer.

  The term “substrate” as used in the present invention refers to a material to which a nonionic hydrophilic property is desired, and a polymer material is preferred. Examples of the polymer material include polysulfone, polystyrene, polyurethane, polyethylene, and polypropylene. Furthermore, a nonionic hydrophilic polymer may be present in the substrate. For example, most of the polysulfone-based hollow fiber membranes for artificial kidneys are blends of polysulfone and polyvinylpyrrolidone, and these blends are also used as a base material. Examples of the shape of the substrate include, but are not limited to, fibers, films, resins, and separation membranes.

  In the present invention, the functional substance refers to a substance having an ionic group or a hydrophobic group or a physiologically active substance.

  The ionic group means a functional group having a charge, and is not particularly limited to a cationic group or an anionic group. For example, an amino group, an aminosulfuric acid group, an imidazole group, a carboxyl group, a sulfonic acid group, a phosphoric acid group An acid group etc. are mentioned.

  When the ionic group is an amino group, it not only causes platelet adhesion but also has a large release reaction, so that it is particularly preferable to use the technique of the present invention. As used herein, an amino group refers to a primary amine, secondary amine, tertiary amine, or quaternary amine.

  Further, as a substance having a cationic group, a cationic polymer is preferably used because it has a high adsorption effect on acidic proteins such as oxidized low density lipoprotein (oxidized LDL). This is considered to be likely to interact with an acidic protein because it has a large room for an optimal configuration with an acidic protein. Here, the cationic polymer means a polymer having a charge of 1 meq / g or more at pH 4.5. The weight average molecular weight of the cationic polymer is not particularly limited, but is preferably 1000 or more, more preferably 5000 or more, and further preferably 10,000 or more. Specifically, amino group-containing polymers such as polyalkyleneimine, polyvinylamine, polyallylamine, diethylaminoethyl dextran, polydiallyldimethylammonium chloride, vinyl imidazolium methochloride polymer, vinyl imidazole polymer, etc. Copolymers with these monomers and derivatives such as grafts may also be used. Two or more kinds of cationic polymers may be used in combination. Among cationic polymers, amino group-containing polymers such as polyalkyleneimine, polyvinylamine, polyallylamine, diethylaminoethyldextran, and polydiallyldimethylammonium chloride are easily available, oxidized low density lipoprotein (oxidized LDL) It is preferable in terms of the high adsorption and removal effect of acidic proteins such as.

  In addition, the hydrophobic group is preferably a group using a hydrocarbon having 6 to 50 carbon atoms, and means a group bonded to the base material by a chemical bond.

  The physiologically active substance in the present invention refers to a substance that affects biological functions. For example, protein, peptide, amino acid and the like can be mentioned. Specific examples include polymyxin B.

  In the present invention, the base material containing the functional substance means that the functional substance is contained in the base material or on the surface of the base material. As a method for causing the functional substance to be present on the substrate, 1) a method of introducing the functional substance as a constituent of the substrate, 2) a method of chemically bonding the functional substance to the substrate after molding the substrate, and 3) a group Examples include a method of adsorbing a functional substance to a base material after molding the material.

  The method of introducing as a constituent component of the substrate refers to a substance introduced into the substrate before the substrate is molded. For example, in the case of a blended hollow fiber membrane of polysulfone and polyvinyl pyrrolidone for an artificial kidney, polysulfone and polyvinyl pyrrolidone, which are constituent components, correspond to functional substances. Although details of the method for producing the hollow fiber membrane will be described later, in order to introduce a functional substance into the hollow fiber membrane as a constituent component, at least one of the membrane-forming stock solution, the injection solution, and the coagulation bath is added. There is a need. When adding a functional substance to the stock solution, add it as a third component in addition to polysulfone or polyvinylpyrrolidone, or use modified polysulfone or polyvinylpyrrolidone having an ionic group or hydrophobic group instead of polysulfone or polyvinylpyrrolidone. It may be used.

The chemical bond in the present invention refers to a covalent bond or an ionic bond. As a specific method for introducing a functional substance by chemical bonding after molding the base material, if the functional substance is an ionic group, it may be introduced as a chemical bond to the base material by plasma irradiation or ion cluster beam. Is possible. Alternatively, the functional material may be cross-linked using a chemical reaction on the base material. At this time, a spacer may be interposed between the functional substance and the substrate. Further, the functional material may be introduced by polymer polymerization by dipping or wetting the monomer solution on the substrate. Further, some functional substances and base materials may cause chemical bonds to be formed between the functional substance and the base material by heating or radiation irradiation after the functional material is adsorbed to the base material.
The adsorption referred to in the present invention refers to a state where the concentration of the functional substance on the surface of the substrate is higher than the concentration of the functional substance solution, and the mechanism may be either chemical adsorption or physical adsorption. Moreover, you may adsorb | suck by indirect interaction. For example, the functional substance may be adsorbed by hydrogen bonding via the base material and water molecules. As a specific method for adsorbing the functional substance on the base material, the base material may be immersed or wetted in the functional substance solution. The term “wetting” as used in the present invention refers to a state where the aqueous solution in which the substrate is immersed is removed and not dried. Although not particularly limited, it preferably contains 3% by weight or more of moisture with respect to the dry weight of the substrate. As used herein, the dry weight refers to the weight in a state where the modified base material is dried and the weight change rate within 1 hour during drying is within 2%.

  The nonionic hydrophilic polymer referred to in the present invention refers to a polymer that has a charge of less than 1 meq / g and is soluble in water at both pH 4.5 and pH 9.5. Here, the term “soluble in water” means that the solubility in water at 25 ° C. is preferably 0.001% by weight or more, more preferably 0.01% by weight or more, and further preferably 0.1% by weight or more. For example, polyalkylene glycols such as polyethylene glycol and polypropylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, and the like, copolymers of these with other monomers, derivatives such as grafts, etc. are limited thereto. is not. Two or more kinds of nonionic hydrophilic polymers may be used in combination.

  In addition, the nonionic hydrophilic polymer referred to in the present invention is brought into contact with a substrate on which a functional substance is present. The nonionic hydrophilic polymer functions on a substrate on which a functional substance is present. It refers to a state of interacting directly or indirectly with a sex substance or substrate. The interaction includes chemical bonding and adsorption. As an example of indirect interaction, a chemical bond may include a case where a nonionic hydrophilic polymer and a functional substance or a substrate are chemically bonded via a spacer. Examples of the adsorption include a case where a nonionic hydrophilic polymer forms a hydrogen bond with a functional substance or a substrate via a water molecule.

    As a specific example of contact, if a substrate in which a functional substance is present is immersed or wetted in a solution containing a nonionic hydrophilic polymer, the nonionic hydrophilic polymer is adsorbed on the substrate. The In addition, since the adsorptive power of the nonionic hydrophilic polymer is weak, when the amount of the substance introduced is small and the functional substance cannot be sufficiently covered, or when elution of the substance becomes a problem, What is necessary is just to fix a substance to a functional substance or a base material by a chemical reaction.

  When the functional substance or the nonionic hydrophilic polymer is adsorbed on the base material, it may be immersed in the functional substance or the nonionic hydrophilic polymer aqueous solution if the shape of the base material is a film. Further, if the shape of the base material is a porous hollow fiber membrane, it can be adsorbed inside the porous body by using a substance smaller than the pore diameter of the porous portion. Moreover, if a substance larger than the pore diameter of the porous portion is used, it is possible to adsorb a portion as required, such as only the inner surface of the hollow fiber or only the outer surface. For example, in the case of an artificial kidney, a separation membrane is built in the module case. Therefore, when a functional substance or a nonionic hydrophilic polymer aqueous solution is filled in the module, the substance is adsorbed on the separation membrane. Alternatively, only the separation membrane may be once immersed in a functional substance or a nonionic hydrophilic polymer aqueous solution to adsorb the substance and then incorporated into the module. In the case of an artificial kidney in which the separation membrane is a hollow fiber membrane, the portion in contact with blood is the inner surface of the hollow fiber. Therefore, the nonionic hydrophilic polymer must be at least in contact with the inner surface of the hollow fiber.

  Further, after bringing the functional substance or the nonionic hydrophilic polymer aqueous solution into contact with the substrate, the aqueous solution attached to the substrate may be blown into a wet state.

  Although the functional substance or nonionic hydrophilic polymer may be immobilized by adsorption, it is preferable that the functional substance or the nonionic hydrophilic polymer is immobilized by chemical bonding since there is less fear of elution. What is immobilized by adsorption can generate radicals by radiation and can easily form chemical bonds. As the radiation, α rays, β rays, γ rays, X rays, ultraviolet rays, electron beams and the like are used. In addition, medical devices such as artificial kidneys need to be sterilized, and in recent years, radiation sterilization methods are frequently used from the viewpoint of low residual toxicity and simplicity, and γ rays and electron beams are particularly preferably used. It has been. For example, in order to sterilize a blood purification module with γ-rays, it is considered preferable to apply a dose of 20 kGy or more. In addition, radicals are generated by irradiation, and the functional substance and the nonionic hydrophilic polymer form a chemical bond with the base material or between the functional substance and the nonionic hydrophilic polymer. The elution amount of the substance decreases. Therefore, irradiation with radiation of 20 kGy or more is a preferable treatment because the functional substance and the nonionic hydrophilic polymer can be immobilized and sterilized at the same time. However, at this time, it is preferable to pay attention to deactivation of the functional substance and excessive modification of the nonionic hydrophilic polymer. Excessive denaturation here refers to denaturation to such an extent that the ability to suppress adhesion of blood components such as platelets possessed by the nonionic hydrophilic polymer is lost. An antioxidant may be added at the same time in order to prevent denaturation and deactivation during irradiation. The term “antioxidant” as used herein refers to a molecule that has the property of easily giving electrons to other molecules, but it prevents the base material, functional substance, and nonionic hydrophilic polymer from being modified by radiation. It has properties. For example, water-soluble vitamins such as vitamin C, polyphenols, alcohols such as methanol, ethanol, propanol, ethylene glycol and glycerin, sugars such as glucose, galactose, mannose and trehalose, sodium hydrosulfite, sodium pyrosulfite, Examples include, but are not limited to, inorganic salts such as sodium dithionate, uric acid, cysteine, glutathione, oxygen, and the like. These antioxidants may be used alone or in combination of two or more. When the method of the present invention is used for a medical device, it is necessary to consider its safety, and therefore, an antioxidant having low toxicity is preferably used. About the density | concentration of the aqueous solution containing an antioxidant, since it changes with kinds, antioxidant dose, etc. of the contained antioxidant, what is necessary is just to use it by the optimal density | concentration suitably.

  The base material of the present invention is suitably used as a medical base material. Examples of medical base materials include artificial blood vessels, catheters, blood bags, contact lenses, intraocular lenses, surgical aids, etc., and separation membranes used in biological component separation modules, blood purification modules, etc. included.

  The substrate of the present invention is preferably used for a biological component separation membrane. The biological component separation membrane refers to a membrane that separates a biological substance by filtration or dialysis and collects a part thereof. For example, if a modified separation membrane is used, in which a cationic group is introduced into the separation membrane and the upper part is covered with a nonionic hydrophilic polymer, non-specific adsorption of biological components and activation of blood components are suppressed. However, acidic proteins can be separated efficiently.

  The blood purification module of the present invention refers to a module having a function of removing waste and harmful substances in blood by adsorption, filtration, and diffusion when circulating blood outside the body. There are adsorption columns.

  The form of the separation membrane incorporated in the blood purification module is not particularly limited, and is used in the form of a flat membrane, a hollow fiber membrane or the like. However, the hollow fiber membrane type is preferable in consideration of the processing efficiency, that is, securing the surface area in contact with blood.

  The medical substrate is preferably a separation membrane. The material to be the separation membrane is not particularly limited, but a material used for medical use is preferable, for example, polyvinyl chloride, cellulose polymer, polystyrene, polymethyl methacrylate, polycarbonate, polysulfone, such as polysulfone and polyethersulfone. Examples thereof include polymers and polyurethane. Of these, polysulfone is particularly suitable because it is easy to mold and has excellent material permeation performance when formed into a membrane.

  The polysulfone polymer used in the present invention has an aromatic ring, a sulfonyl group and an ether group in the main chain. For example, polysulfone represented by the chemical formulas of the following formulas (1) and (2) is preferably used. However, the present invention is not limited to these. N in the formula is an integer such as 50 to 80.

  Specific examples of polysulfone include Udel polysulfone P-1700, P-3500 (manufactured by Solvay), Ultrason S3010, S6010 (manufactured by BASF), Victrex (Sumitomo Chemical), Radel A (manufactured by Solvay), Ultra Polysulfone such as Son E (manufactured by BASF) is exemplified. In addition, the polysulfone used in the present invention is preferably a polymer composed only of the repeating unit represented by the above formula (1) and / or (2). However, it does not interfere with the effects of the present invention. It may be polymerized. Although it does not specifically limit, it is preferable that another copolymerization monomer is 10 weight% or less.

  There are various methods for producing a blood purification module according to the present invention, depending on its use. As a rough process, a process for producing a separation membrane for blood purification and incorporating the separation membrane into the module is described. Can be divided into processes. The substrate treatment method according to the present invention may be used before the step of incorporating the separation membrane into the module, or may be used after the separation membrane is incorporated into the module. If γ-ray irradiation is performed after modularization, sterilization can be performed at the same time, which is preferable.

  There are various methods for manufacturing a blood purification module depending on its application, but the rough process is divided into a process for manufacturing a separation membrane for blood purification and a step of incorporating the separation membrane into the module. Can do.

  An example about the manufacturing method of the hollow fiber membrane module used for an artificial kidney is shown. As a method for producing a hollow fiber membrane incorporated in an artificial kidney, there are the following methods. That is, a solution obtained by dissolving polysulfone and polyvinylpyrrolidone in a good solvent or a mixed solvent containing a good solvent is used as a stock solution. The polymer concentration is preferably 10 to 30% by weight, and more preferably 15 to 25% by weight. The weight ratio of polysulfone and polyvinylpyrrolidone is preferably 20: 1 to 1: 5, and more preferably 5: 1 to 1: 1. As the good solvent, N, N-dimethylacetamide, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dioxane and the like are preferable. The undiluted solution is discharged from the outer pipe of the double annular die, and after running through the dry section, it is led to the coagulation bath. An injection solution or a gas for forming a hollow portion is discharged from a tube inside the double annular base. At this time, the humidity of the dry part has an effect, so that the phase separation behavior near the outer surface is accelerated by replenishing moisture from the outer surface of the membrane while the dry part is running. It is also possible to reduce the diffusion resistance. However, when the relative humidity is too high, the solid solution coagulation on the outer surface becomes dominant, and the pore diameter is rather reduced, and as a result, the permeation / diffusion resistance during dialysis tends to increase. Therefore, the relative humidity is preferably 60 to 90%. Moreover, as an injection liquid composition, it is preferable to use what consists of a composition based on the solvent used for the undiluted | stock solution from process aptitude. For example, when dimethylacetamide is used as an injection solution concentration, an aqueous solution of 45 to 80% by weight, more preferably 60 to 75% by weight, is preferably used.

  The method of incorporating the hollow fiber membrane in the module is not particularly limited, but an example is as follows. First, the hollow fiber membrane is cut into a required length, bundled in a necessary number, and then put into a cylindrical case. Then, a temporary cap is put on both ends, and a potting agent is put on both ends of the hollow fiber membrane. At this time, the method of putting the potting agent while rotating the module with a centrifuge is a preferable method because the potting agent is uniformly filled. After the potting agent is solidified, both ends are cut so that both ends of the hollow fiber membrane are open to obtain a hollow fiber membrane module.

  In order to introduce a functional substance into the base material in the above, modified polyvinylpyrrolidone covalently bonded with an ionic group or a hydrophobic group or a physiologically active substance is used instead of polyvinylpyrrolidone in the stock solution, or ionicity is used instead of polysulfone. This can be achieved by using a modified polysulfone to which a group or a hydrophobic group or a physiologically active substance is covalently bonded. Specific examples of the modified polyvinyl pyrrolidone include cationic polyvinyl pyrrolidone commercially available from BASF as represented by the following formula (3). M and n in a formula are integers, such as 10-1000, for example.

  In addition to polysulfone and polyvinylpyrrolidone in the stock solution, a functional substance may be added as the third component. For example, cationic polymers and physiologically active substances such as the above modified polyvinyl pyrrolidone and polyalkylenimine are preferably used. Furthermore, it is also possible to introduce the functional substance into the base material by adding the functional substance to the injection solution or the coagulation bath. Further, after forming into a hollow fiber membrane, the hollow fiber membrane may be immersed or wetted in an aqueous functional substance solution to adsorb the substance. Further, after modularization, the inside of the module may be filled with a functional substance aqueous solution or wetted to adsorb the substance to the hollow fiber membrane.

  If a functional substance is introduced before the hollow fiber membrane is incorporated into the module, a nonionic hydrophilic polymer aqueous solution may be brought into contact with the hollow fiber membrane. May be filled or wetted with a nonionic hydrophilic polymer aqueous solution. When the functional substance is introduced after the hollow fiber membrane is incorporated in the module, the nonionic hydrophilic polymer must be introduced after the functional substance is introduced.

  In addition, in the case of a substance larger than the pore diameter of the hollow fiber membrane, it is an effective method for increasing the surface density because it is concentrated on the surface of the membrane when filled through filtration through the hollow fiber membrane. Furthermore, since the filtered and filled material is strongly pressed against the membrane surface and becomes difficult to release, it is a method that is preferably used. The substance used may be a high molecular weight functional material or a high molecular weight nonionic hydrophilic polymer. On the other hand, in the case of a substance smaller than the pore diameter of the hollow fiber membrane, the substance can be brought into contact with the inside of the membrane pore. For example, when a functional substance adsorbs and removes a part of a biological component, and the target substance is smaller than the membrane pore diameter, the functional substance is more efficiently removed if it exists up to the inside of the membrane pore. it can. In order to obtain selectivity, it is preferable that the nonionic hydrophilic polymer is also present in the membrane pores.

  An example of the basic structure of an artificial kidney using the hollow fiber membrane module obtained as described above is shown in FIG. A bundle of hollow fiber membranes 5 is inserted into a cylindrical plastic case 7, and both ends of the hollow fiber are sealed with a resin 10. The case 7 is provided with an inlet 8 and an outlet 9 for dialysate, and dialysate, saline, filtered water and the like flow outside the hollow fiber membrane 5. An inlet port portion 1 and an outlet port portion 2 are provided at the ends of the case 7, respectively. The blood 6 is introduced from the blood introduction port 3 provided in the inlet side port portion 1 and is guided into the hollow fiber membrane 5 by the funnel-shaped port portion 1. The blood 6 filtered by the hollow fiber membrane 5 is collected by the outlet side port portion 2 and discharged from the blood outlet 4. A blood circuit 11 is connected to the blood inlet 3 and the blood outlet 4.

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.
1. Production of Hollow Fiber Membrane Module 18 parts by weight of polysulfone (Udelpolysulfone (registered trademark) P-3500 manufactured by Solvay) and 9 parts by weight of polyvinylpyrrolidone (K30 manufactured by BASF) 72 parts by weight of N, N′-dimethylacetamide and water In addition to 1 part by weight of the mixed solvent, it was dissolved by heating at 90 ° C. for 14 hours to obtain a film forming stock solution. This film-forming stock solution was discharged from an outer tube of an orifice type double cylindrical die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm. A solution consisting of 58 parts by weight of N, N′-dimethylacetamide and 42 parts by weight of water was discharged from the inner tube as the core liquid. The discharged film-forming stock solution passed through a dry length of 350 mm, and was then introduced into a 100% water coagulation bath to obtain a hollow fiber.

10000 hollow fibers obtained were inserted into a cylindrical plastic case having a dialysate inlet and a dialysate outlet, as shown in FIG. 1, and both ends were sealed with a resin to obtain an effective membrane area of 1.6 m. ^Two artificial fiber hollow fiber membrane modules were prepared.
2. Measurement Method (1) Human Platelet Adhesion Test Method for Hollow Fiber Membrane A double-sided tape was affixed to an 18 mmφ polystyrene circular plate, and the hollow fiber membrane was fixed thereto. The attached hollow fiber membrane was cut into a semicylindrical shape with a single blade to expose the inner surface of the hollow fiber membrane. If dirt, scratches, folds, etc. are present on the inner surface of the hollow fiber, platelets will adhere to the part and may not be evaluated correctly. The circular plate was attached to a Falcon (registered trademark) tube (18 mmφ, No. 2051) cut into a cylindrical shape so that the surface on which the hollow fiber membrane was attached was inside the cylinder, and the gap was filled with parafilm. The cylindrical tube was washed with physiological saline and then filled with physiological saline. Immediately after collecting human venous blood, heparin was added to 50 U / ml. After discarding the physiological saline in the cylindrical tube, 1.0 ml of the blood was placed in the cylindrical tube and shaken at 37 ° C. for 1 hour within 10 minutes after blood collection. Thereafter, the hollow fiber membrane was washed with 10 ml of physiological saline, blood components were fixed with 2.5% glutaraldehyde physiological saline, and washed with 20 ml of distilled water. The washed hollow fiber membrane was dried under reduced pressure at room temperature of 0.5 Torr for 10 hours. This film was attached to a sample stage of a scanning electron microscope with double-sided tape. Thereafter, a thin film of Pt—Pd was formed on the surface of the hollow fiber membrane by sputtering to prepare a sample. The inner surface of the hollow fiber membrane was observed with a field emission type scanning electron microscope (S800 manufactured by Hitachi, Ltd.) at a magnification of 1500 times. In one field of view (4.3 × 10 ³ μm ² ) The number of adherent platelets was counted. The average value of the number of adhering platelets in 10 different visual fields near the center in the longitudinal direction of the hollow fiber was defined as the number of adhering platelets (pieces / 4.3 × 10 ³ μm ² ). This is because the end portion in the longitudinal direction of the hollow fiber is likely to form a blood pool.
(2) Oxidized LDL adsorption / removal test method (a) Production of antioxidant LDL antibody The one prepared according to the method of Itabe et al. (H. Itabe et al., J. Biol. Chem. 269: 15274, 1994) was used. . That is, human atherosclerotic lesion homogenate was injected into a mouse for immunization, a hybridoma was prepared from the spleen of the mouse, and one that reacted with copper sulfate-treated LDL was selected to obtain an antioxidant LDL antibody. The antibody class of the obtained antioxidant LDL antibody is mouse IgM and does not react with untreated LDL, acetyl LDL, or malondialdehyde LDL. On the other hand, the antioxidant LDL antibody reacts with several phosphatidylcholine peroxidation products including aldehyde derivatives of phosphatidylcholine and hydroperoxide. The antioxidant LDL antibody dissolved in 10 mM borate buffer (pH 8.5) containing 150 mM NaCl was used (protein concentration 0.60 mg / ml).
(B) Preparation of oxidized LDL Commercially available LDL (HUMAN, manufactured by Biomedical Technologies Inc.) was applied to a desalting column (HiTrap Desalting, manufactured by Pharmacia) to remove ethylenediaminetetraacetic acid (EDTA) and 0.2 mg / ml. The solution was diluted with a phosphate buffer (hereinafter abbreviated as PBS). Thereafter, 2 ml each was dispensed into a Falcon (registered trademark) tube (18 mmφ, No. 2051). Incubated at 37 ° C. for 3 minutes. 2 wt% of 0.5 mM copper sulfate aqueous solution was added and reacted at 37 ° C. for 5 hours. At this time, a 0.5 mM aqueous copper sulfate solution was prepared. During the reaction at 37 ° C. for 5 hours, the tube was not covered, but was in contact with air, and pipetting was performed every 2 hours. A solution obtained by adding 25 mM ethylenediaminetetraacetic acid (EDTA) to 1 wt% and 10 wt% sodium azide to 0.02 wt% to the obtained solution was used as an oxidized LDL preparation. The total protein amount of this oxidized LDL was 0.171 mg / ml, and the malondialdehyde amount was 86.3 nM / mg LDL.
(C) Measurement of oxidized LDL concentration The above-mentioned oxidized LDL antibody was diluted with PBS to 5 μg / ml and dispensed into a 96-well plate at 100 μl / well. The mixture was shaken at room temperature for 2 hours and then allowed to stand at 4 ° C. overnight or longer to allow the antibody to be adsorbed on the wall.

  The antibody solution in the well was discarded, and Tris-HCl buffer (pH 8.0) containing 1% Bovine Serum Albumin (BSA, Fraction V, Seikagaku Corporation) was dispensed at 200 μl / well. After blocking the wall by shaking for 2 hours at room temperature, the BSA solution in the well was discarded, and 100 μl / well of plasma containing oxidized LDL and a standard for preparing a calibration curve were dispensed. Then, after shaking at room temperature for 30 minutes, it was left at 4 ° C. overnight.

After returning to room temperature, the solution in the well was discarded, and the well was washed 3 times with Tris-HCl buffer (pH 8.0) containing 0.05% Tween®-20. 100 μl / well of sheep anti-apo B antibody diluted 2000 times with PBS was dispensed into the washed wells. After shaking at room temperature for 2 hours, the anti-apo B antibody in the well was discarded, and the well was washed three times with Tris-HCl buffer (pH 8.0) containing 0.05% Tween-20. To the washed wells, 100 μl / well of alkaline phosphatase-labeled donkey anti-sheep IgG antibody diluted 2000 times with Tris-HCl buffer (pH 8.0) containing 2% Block Ace (Dainippon Pharmaceutical Co., Ltd.) was dispensed. Shake for 2 hours at room temperature. Thereafter, the labeled antibody in the wells is discarded, and the wells are washed three times with Tris-HCl buffer (pH 8.0) containing 0.05% Tween-20, and further 2 with Tris-HCl buffer (pH 8.0). Washed twice. Subsequently, a 1 mg / ml solution of p-nitrophenyl phosphate (0.0005 M MgCl ₂ , 1 M diethanolamine buffer, pH 9.8) was dispensed at 100 μl / well. After reacting at room temperature for an appropriate time, absorbance at a wavelength of 415 nm was measured with a plate reader. A calibration curve was drawn from the standard results to determine the oxidized LDL concentration.
(D) Measurement of the adsorption removal rate of oxidized LDL Healthy plasma (Japanese, 30 years old, LDL (β lipoprotein) concentration 275 mg / dl, HDL-cholesterol concentration 70 mg / dl), and the oxidized LDL concentration of 2 μg / ml It added so that it might become.

70 hollow fiber membranes were bundled and inserted into a glass tube module case having a diameter of about 7 mm and a length of 12 cm. Both ends of the hollow fiber membrane were fixed with an epoxy potting agent so as not to block the hollow portion of the hollow fiber membrane, and a mini module (inner surface area 53 cm ² ) was prepared. The mini module was washed with ultrapure water at 37 ° C. for 30 minutes. Then, the inner diameter of 0.8 mm, the outer diameter of 1 mm, and the length of 37 cm are connected to both ends of the mini-module through a silicone tube (product name: ARAM (registered trademark)) having an inner diameter of 7 mm (outer diameter of 10 mm) and a length of 2 cm and a deformed connector. A silicone tube (product name: ARAM (registered trademark)) was connected, and 1.5 ml of the plasma was perfused into the hollow fiber membrane at a flow rate of 0.5 ml / min at 25 ° C. for 4 hours under a nitrogen atmosphere. The amount of plasma per 1 m ^{2 of the} surface area of the hollow fiber membrane was 2.8 × 10 ² ml / m ² . Furthermore, the perfusion operation was also performed only with the silicone tube without attaching the mini module. By quantifying the oxidized LDL concentration in plasma before and after perfusion, each adsorption removal rate was calculated by the following equation.

Oxidized LDL adsorption / removal rate (%) = Oxidized LDL adsorption / removal rate (%) in the mini module-Oxidized LDL adsorption / removal rate (%) only in the silicone tube
Oxidized LDL adsorption removal rate (%) = 100 × (concentration before perfusion−concentration after perfusion) / concentration before perfusion (Example 1)
Polyethyleneimine (BASF Corp., weight average molecular weight 750,000) was used as the functional substance, and polyvinylpyrrolidone (BASF K90) was used as the nonionic hydrophilic polymer. A polyethyleneimine 0.01% by weight aqueous solution was introduced from the blood outlet 4 of the hollow fiber membrane module and exited from the dialysate outlet 9 to introduce polyethyleneimine into the hollow fiber membrane. The flow rate was 1 L. At this time, the blood inlet 3 and the dialysate inlet 8 were plugged. Thereafter, 1 L of a polyvinylpyrrolidone 0.001% by weight aqueous solution was passed in the same manner as the polyethyleneimine aqueous solution to introduce polyvinylpyrrolidone into the hollow fiber membrane. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The hollow fiber of the module was cut out and the platelet adhesion number was evaluated. Furthermore, a mini-module was created using the cut out hollow fiber membrane and subjected to an oxidized LDL adsorption experiment. As a result, it was as shown in Table 1.
(Comparative Example 1)
Polyethyleneimine (BASF Corp., weight average molecular weight 750,000) was used as the functional substance, and polyvinylpyrrolidone (BASF K90) was used as the nonionic hydrophilic polymer. A mixed aqueous solution of 0.01% by weight of polyethyleneimine and 0.001% by weight of polyvinylpyrrolidone is introduced from the blood outlet 4 of the hollow fiber membrane module, and is discharged from the outlet 9 of the dialysate so that polyethyleneimine and polyvinylpyrrolidone are simultaneously added. It introduced into the hollow fiber membrane. The flow rate was 1 L. At this time, the blood inlet 3 and the dialysate inlet 8 were plugged. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The hollow fiber of the module was cut out and the platelet adhesion number was evaluated. Furthermore, a mini-module was created using the cut out hollow fiber membrane and subjected to an oxidized LDL adsorption experiment. As a result, it was as shown in Table 1.
(Comparative Example 2)
Polyethyleneimine (BASF Corp., weight average molecular weight 750,000) was used as the functional substance, and polyvinylpyrrolidone (BASF K90) was used as the nonionic hydrophilic polymer. A polyvinylpyrrolidone 0.001 wt% aqueous solution was introduced from the blood outlet 4 of the hollow fiber membrane module and exited from the dialysate outlet 9 to introduce polyvinylpyrrolidone into the hollow fiber membrane. The flow rate was 1 L. At this time, the blood inlet 3 and the dialysate inlet 8 were plugged. Thereafter, 1 L of a polyethyleneimine 0.01% by weight aqueous solution was passed in the same manner as the polyvinylpyrrolidone aqueous solution to introduce polyethyleneimine into the hollow fiber membrane. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The hollow fiber of the module was cut out and the platelet adhesion number was evaluated. Furthermore, a mini-module was created using the cut out hollow fiber membrane and subjected to an oxidized LDL adsorption experiment. As a result, it was as shown in Table 1.
(Comparative Example 3)
Polyethyleneimine (BASF, weight average molecular weight 750,000) was used as a functional substance. A polyethyleneimine 0.01% by weight aqueous solution was introduced from the blood outlet 4 of the hollow fiber membrane module and exited from the dialysate outlet 9 to introduce polyethyleneimine into the hollow fiber membrane. The flow rate was 1 L. At this time, the blood inlet 3 and the dialysate inlet 8 were plugged. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The hollow fiber of the module was cut out and the platelet adhesion number was evaluated. Furthermore, a mini-module was created using the cut out hollow fiber membrane and subjected to an oxidized LDL adsorption experiment. As a result, it was as shown in Table 1.
(Comparative Example 4)
Polyvinyl pyrrolidone (BA90 K90) was used as the nonionic hydrophilic polymer. A polyvinylpyrrolidone 0.001 wt% aqueous solution was introduced from the blood outlet 4 of the hollow fiber membrane module and exited from the dialysate outlet 9 to introduce polyvinylpyrrolidone into the hollow fiber membrane. The flow rate was 1 L. At this time, the blood inlet 3 and the dialysate inlet 8 were plugged. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The hollow fiber of the module was cut out and the platelet adhesion number was evaluated. Furthermore, a mini-module was created using the cut out hollow fiber membrane and subjected to an oxidized LDL adsorption experiment. As a result, it was as shown in Table 1.
(Comparative Example 5)
Pure water was introduced from the hollow fiber membrane module blood outlet 4 and out of the dialysate outlet 9. The flow rate was 2L. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The hollow fiber of the module was cut out and the platelet adhesion number was evaluated. Furthermore, a mini-module was created using the cut out hollow fiber membrane and subjected to an oxidized LDL adsorption experiment. As a result, it was as shown in Table 1.

1 shows an embodiment of an artificial kidney used in the present invention.

Claims (22)

A method for treating a substrate, comprising bringing a nonionic hydrophilic polymer into contact with a substrate on which a functional substance is present. The method for treating a substrate according to claim 1, wherein the functional substance is a constituent component of the substrate. The substrate processing method according to claim 1, wherein the substrate on which the functional substance exists is obtained by chemically bonding the functional substance after molding the substrate. The substrate processing method according to claim 1, wherein the substrate on which the functional substance is present is obtained by adsorbing the functional substance after molding the substrate. The method for treating a substrate according to claim 1, wherein the functional substance is a substance having an ionic group. The substrate processing method according to claim 1, wherein the functional substance is a substance having a hydrophobic group. The method for treating a substrate according to any one of claims 1 to 4, wherein the functional substance is a physiologically active substance. The substrate treatment method according to claim 1, wherein the ionic group is a cationic polymer. The method for treating a substrate according to claim 8, wherein the cationic polymer is an amino group-containing polymer. The base material according to claim 9, wherein the amino group-containing polymer is one selected from polyalkyleneimine, polyvinylamine, polyallylamine, diethylaminoethyldextran, polydiallyldimethylammonium chloride, and derivatives thereof. Processing method. The method for treating a substrate according to any one of claims 1 to 10, wherein the nonionic hydrophilic polymer is polyalkylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol and derivatives thereof. The method for treating a substrate according to any one of claims 1 to 11, wherein the substrate is irradiated with radiation after the nonionic hydrophilic polymer is brought into contact with the substrate. The substrate processing method according to claim 1, wherein the substrate is a medical substrate. The modified base material according to claim 13, wherein the medical base material is built in a biological component separation module. The method for treating a substrate according to claim 13, wherein the medical substrate is incorporated in a blood purification module. The method for treating a base material according to claim 13, wherein the medical base material is built in a module for an artificial kidney. The method for treating a substrate according to any one of claims 13 to 16, wherein the medical substrate is a separation membrane. The substrate treatment method according to claim 17, wherein the medical substrate is a hollow fiber membrane. The substrate treatment method according to claim 17 or 18, wherein the separation membrane is a polysulfone-based polymer. A method for producing a separation membrane, wherein the separation membrane is treated by the substrate treating method according to claim 1. A method for producing a blood purification module, comprising the method for treating a substrate according to any one of claims 1 to 20 in a production process. A method for manufacturing an artificial kidney module, comprising the base material treatment method according to any one of claims 1 to 21 in a manufacturing process.

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