JPH0116504B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION (Technical Field) The present invention relates to a method for manufacturing an oxygenator. More specifically, the present invention provides a method for manufacturing an artificial lung that removes carbon dioxide from blood and adds oxygen to the blood during extracorporeal blood circulation. The present invention relates to a method for manufacturing a membrane oxygenator without the risk of leakage. (Prior Art) Membrane oxygenators, which perform gas exchange by bringing blood into contact with oxygen-containing gas through a gas exchange membrane with good gas permeability, have been used as an auxiliary means for open heart surgery. There is. There are two types of gas exchange membranes used in such membrane oxygenators: homogeneous membranes and porous membranes. Currently, silicone membranes are mainly used as homogeneous membranes. However, since the homogeneous membrane uses a silicone membrane, it is not strong enough and cannot have a membrane thickness of 100 μm or less, which limits gas permeation, particularly poor carbon dioxide gas permeation. In addition, in order to achieve the desired gas exchange capacity,
For example, when tens of thousands of hollow fiber membranes are bundled, the equipment becomes large and the amount of priming increases, and the cost is also high. On the other hand, porous membranes made of various materials such as polyethylene, polypropylene, polytetrafluoroethylene, polysulfone, polyacrylonitrile, polyurethane, and polyamide are known. This porous membrane has many fine pores that communicate in the membrane thickness direction, but since the membrane is hydrophobic, plasma does not pass through the pores.
In other words, oxygen in the gas can be added to the blood and carbon dioxide in the blood can be removed into the gas without causing plasma leakage from the blood flow path side of the membrane to the other gas flow path side. . However, since porous membranes have high water vapor permeability, not only do they degrade in performance due to condensation, but when blood is circulated for long periods of time, plasma may actually leak out. Such a phenomenon is also observed in artificial lungs that have been tested for water leakage during the manufacturing stage and found to be free of abnormalities, and is a phenomenon that occurs during use. In order to eliminate these various drawbacks of porous membranes, the present inventors first developed an artificial lung (patent application No. 1983-1983), which is made by plugging the micropores of a porous membrane with silicone oil.
He proposed an artificial lung (Japanese Patent Application No. 105384-1983), which was made by further improving the pores of a porous membrane and blocking them with silicone rubber. Although this artificial lung, which is made by blocking the microscopic pores of a porous membrane with silicone rubber, has solved the problem of plasma leakage seen in conventional oxygenators using porous membranes, its ability to remove carbon dioxide has cannot be said to be sufficient; for example,
It has been difficult to remove the amount of carbon dioxide produced by a living body with a small amount of extracorporeal circulation blood flow, as in ECCO ₂ R (Extra Corporeal CO ₂ Romoval). OBJECTS OF THE INVENTION Therefore, an object of the present invention is to provide a novel method for manufacturing a membrane oxygenator. The present invention also removes carbon dioxide from blood in extracorporeal blood circulation,
Another object of the present invention is to provide a method for producing a membrane oxygenator that adds oxygen to blood, which has a high carbon dioxide removal ability and is free from the risk of plasma leakage even when used for a long period of time. A further object of the present invention is to provide a method for manufacturing a membrane oxygenator optimal for ECCO ₂ R. The above purposes are as a gas exchange membrane with a wall thickness of 5 to 5.
A method for producing an oxygenator using a porous membrane having a diameter of 80 μm, a porosity of 20 to 80%, and a pore size of 0.01 to 5 μm, in which a dispersion of fine particles smaller than the pores of the porous membrane is filtered through the porous membrane. and clogging the pores of the porous membrane with the fine particles, and then removing the dispersion liquid remaining on the surface of the porous membrane with a cleaning fluid. Method (first invention)
This is achieved by The present invention also provides a method for manufacturing a membrane oxygenator using hydrophobic particles. The present invention also provides the gas exchange membrane with a wall thickness of 5 to 80 μm, a porosity of 20 to 80%, and a pore diameter of
This figure shows a method for manufacturing a membrane oxygenator using a hollow fiber porous membrane with an inner diameter of 0.01 to 5 μm and an inner diameter of 100 to 1000 μm. The present invention further provides a method for producing a membrane oxygenator, in which the fine particle dispersion is allowed to flow into the hollow fiber porous membrane and filtered. The above purposes are as a gas exchange membrane with a wall thickness of 5 to 5.
In a method for manufacturing an oxygenator using a porous membrane having a diameter of 80 μm, a porosity of 20 to 80%, and a pore diameter of 0.01 to 5 μm, a dispersion of hydrophilic fine particles smaller than the pores of the porous membrane is added to the porous membrane. After filtration to block the pores of the porous membrane with the fine particles, the dispersion remaining on the surface of the porous membrane is removed with a cleaning fluid, and at least the fine particles are removed from the blood. This is achieved by a method for manufacturing a membrane oxygenator (second invention) characterized in that the contact surface is hydrophobized. The present invention also provides a method for manufacturing a membrane oxygenator in which the particulates are silica. The above purposes are as a gas exchange membrane with a wall thickness of 5 to 5.
In a method for producing an oxygenator using a porous hydrophobic membrane having a diameter of 80 μm, a porosity of 20 to 80%, and a pore diameter of 0.01 to 5 μm, the porous hydrophobic membrane is brought into contact with alcohol to perform a water immersion treatment. After that, a dispersion of fine particles smaller than the pores of the porous membrane using water as a dispersion medium is filtered through the porous membrane to block the pores of the porous membrane with the fine particles. A method for producing a membrane oxygenator (third invention), characterized in that the dispersion liquid remaining on the surface of the membrane is removed using a cleaning fluid.
This is achieved by The present invention also provides a method for manufacturing a membrane oxygenator in which the gas exchange membrane is made of olefin resin. The present invention provides a method for manufacturing a membrane oxygenator in which the gas exchange membrane is made of polypropylene. The above purposes are as a gas exchange membrane with a wall thickness of 5 to 5.
A method for producing an oxygenator using a porous membrane having a diameter of 80 μm, a porosity of 20 to 80%, and a pore size of 0.01 to 5 μm, in which a dispersion of fine particles smaller than the pores of the porous membrane is filtered through the porous membrane. After clogging the pores of the porous membrane with the fine particles, the dispersion liquid remaining on the surface of the porous membrane is removed with a cleaning fluid, and then the porous membrane is brought into contact with at least the blood. A method for producing a membrane oxygenator (method for manufacturing a membrane oxygenator) characterized in that the porous membrane is coated with a solution of a biocompatible hydrophobic resin, and then the solvent is evaporated to coat at least the blood-contacting surface of the porous membrane with the resin. 4 invention). The present invention also provides a method for manufacturing a membrane oxygenator in which the biocompatible hydrophobic resin is a fluorine-containing resin or silicone rubber. The present invention provides a method for producing a membrane oxygenator in which the biocompatible hydrophobic resin is a vinyl copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component. Specific Configuration of the Invention The present invention will be described in more detail below with reference to the drawings. 1a to 1c are enlarged sectional views showing the detailed structure of a gas exchange membrane in each step of an embodiment of the method for manufacturing a membrane oxygenator (first invention) of the present invention. As shown in FIG. 1a, the gas exchange membrane 2 of the membrane oxygenator 1 is a porous membrane with a wall thickness of 5 to 80 μm.
m, preferably 10 to 60 μm, porosity 20 to 80%,
Preferably 30 to 60%, and the pore diameter is 0.01 to 5 μm.
Preferably it is about 0.01 to 1 μm. In this embodiment, the gas exchange membrane has an inner diameter of 100~
It has a hollow fiber shape of 1000 μm, preferably 100 to 300 μm. As the material for the gas exchange membrane 2, hydrophobic polymers such as polypropylene, polyethylene, polytetrafluoroethylene, polysulfone, polyacrylonitrile, and cellulose acetate may be used, but polyolefin resins are preferred, and particularly preferred. is polypropylene, and most preferably polypropylene in which micropores are formed by a stretching method or a solid-liquid phase separation method. First, as shown in FIG. 1b, a dispersion of fine particles 3 smaller than the pores of the porous membrane is poured through the porous gas exchange membrane 2, and filtered through the porous gas exchange membrane 2. That is, a portion of the dispersion liquid is allowed to pass through the pores 4 of the gas exchange membrane 2. The material of the fine particles 3 includes inorganic substances such as silica, alumina, zirconia, magnesia, barium sulfate, calcium carbonate, silicate, titanium oxide, silicon carbide, carbon black, and white carbon, or polystyrene latex and styrene. Polymer latexes such as rubber (SBR) latex and nitrile rubber (NBR) latex may be used, but silica is particularly preferred. Further, the average diameter of the fine particles is 0.003 to 1.0 μm, preferably 0.003 to 1.0 μm.
It is about 0.5 μm. The fine particles 3 are made into a dispersion liquid and applied to the gas exchange membrane 2. Any dispersion medium may be used as long as it is stable for the fine particles and the gas exchange membrane 2.
For example, water, alcohols, etc. are used. Also,
When the gas exchange membrane 2 is in the form of a hollow fiber as in the case of this embodiment, the fluid flow resistance at the side opposite to the inflow side end of the dispersion liquid, that is, at the outflow side end, can be increased by, for example, narrowing the outflow side end opening. By applying pressure, for example, about 1 to 3 kg/cm ² inside the hollow fiber gas exchange membrane 2, the dispersion of the fine particles 3 can more effectively pass through to the pores 4 side of the gas exchange membrane 2. become. However, if too much pressure is applied, the membrane structure may be destroyed, so it is necessary to ensure flow in the axial direction of the hollow fiber gas exchange membrane 2. In this way, when a dispersion of fine particles 3 is poured through the gas exchange membrane 2 and filtered, the fine particles 3 contained in the dispersion get caught in the pores 4 of the gas exchange membrane 2, and the particles 3 are immediately caught in the pores 4 of the gas exchange membrane 2. The fine particles 3 are filled into the pores 4 so as to cause clogging, and the pores 4 are blocked. After the pores 4 of the gas exchange membrane 2 are blocked by the fine particles 3, as shown in FIG. The dispersion is removed with a cleaning fluid, such as air, water, etc. In the cleaning operation in this embodiment, it is preferable that the cleaning fluid is introduced from the outflow side opposite to the inflow side of the dispersion liquid. As a result of each pore 4 of the gas exchange membrane 2 being blocked by the fine particles 3 as described above, the gas exchange membrane 2 is
It has ultra-fine pores that cannot be seen under an electron microscope. These ultra-fine pores penetrate the inner and outer surfaces of the gas exchange membrane. Further, a second invention is a method of making at least the surface of the fine particles 3 that have closed the pores 4 of the gas exchange membrane 2 hydrophobic, when the fine particles 3 are hydrophilic in the first invention. be. For example, in the case of this embodiment, this hydrophobic treatment is performed by flowing a hydrophobic resin solution into the inside of the hollow fiber gas exchange membrane 2, bringing the hydrophobic resin solution into contact with at least the blood contact surface of the fine particles 3, and A cleaning liquid that does not dissolve the hydrophobic resin is further introduced into the hollow fiber gas exchange membrane 2 to remove the solution adhering to other parts, and then the solvent is evaporated to form a hydrophobic resin film. It can be done in As the hydrophobic resin, silicone rubber, fluorine-containing resin, etc. are preferable from the viewpoint of biocompatibility and gas permeability. As the silicone rubber, a room temperature curable (RTV) type is used, and it may be either a one-component type or a two-component type. For example, as a two-component RTV silicone rubber, a polymer of vinylmethylsiloxane and methylhydrogensiloxane is preferred. Polytetrafluoroethylene, polytrifluoroethylene, etc. are also used as fluorocarbon resins, but vinyl copolymers containing vinyl monomers having perfluoroalkyl side chains as one component have excellent biocompatibility and gas It is particularly desirable because of its transparency. A vinyl copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component is a copolymer of any vinyl polymer and a vinyl monomer having a perfluoroalkyl side chain,
A block made of a homopolymer of a vinyl monomer having a perfluoroalkyl side chain is bonded to a base block preferably made of any vinyl polymer (that is, it may be a homopolymer, a block copolymer, a random copolymer, etc.). It is a so-called AB type block copolymer. Vinyl monomers having perfluoroalkyl side chains include _-CH2 ( _CF2 ) _2H , _-CH2
Perfluoroalkyl groups such _{as ( CF2} ) _4H , _{-CH2CF3 , -CH2CH2} ( _CF2 ) _{7CF3 ,} preferably _-CH2CH2
There are perfluoroacrylates and perfluoromethacrylates having (CF ₂ ) ₇ CF ₃ as a side chain. On the other hand, examples of the vinyl monomer constituting the base block include methyl methacrylate, ethyl methacrylate, butyl methacrylate, 2-
Examples include alkyl methacrylates such as ethylhexyl methacrylate, and alkyl acrylates such as methyl acrylate, ethyl acrylate, and butyl acrylate. In addition, in a vinyl block copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component, a polymer component consisting of a vinyl monomer having a perfluoroalkyl side chain and other vinyl monomers constituting the copolymer may be separated from each other. The molecular weight ratio with the polymer component is 0.25~
1.5, preferably 0.3 to 1.2. That is, if the weight ratio is less than 0.25, there is a risk that the microphase-separated structure required to suppress platelet adhesion may not appear, while if the weight ratio exceeds 1.5, it will be difficult to dissolve in a solvent, resulting in poor processability. This is because there is a risk that it will decrease. The block copolymer can be obtained by obtaining a vinyl polymer as a base block having a peroxy bond in the main chain, and then polymerizing perfluoroacrylate by dispersion polymerization using this polymer as a polymerization initiator. . This vinyl block copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component can be used to produce ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexquinone, etc.
methanol, ethanol, n-butanol, sec
- Soluble in alcohols such as butanol, esters such as ethyl acetate and butyl acetate, ethers such as dimethylformamide, tetrahydrofuran, diethyl ether, methyl cellosolve and ethyl cellosolve, and organic solvents such as chloroform. For example, when a vinyl block copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component is used as the hydrophobic resin, for example, 1 to 10% by weight, preferably 3 to 5% by weight of the vinyl block copolymer. % lysis solution. As the solvent used, it is possible to use any of the above-mentioned solvents, but preferred are single or mixed solvents of ketones, and mixed solvents of these ketones and alcohols. However, it is necessary to control the evaporation of the solvent during film formation, for example, 4/6 (volume ratio) methyl ethyl ketone/methyl isobutyl ketone, (4/6)/10
A mixed solvent such as (methyl ethyl ketone/methyl isobutyl ketone)/ethanol in (volume ratio) is suitable. In addition, silicone rubber is used as a hydrophobic resin.
For example, when a polymer of vinylmethylsiloxane and methylhydrogensiloxane is used, it is brought into contact with a solution of 5 to 80% by weight, preferably 20 to 70% by weight of the silicone rubber. Further, the coating 5 is formed by reaction curing at 20 to 80°C. Solvents used include benzene, toluene, xylene, hexane, dichloromethane, methyl ethyl ketone, difluoroethane, ethyl acetate, trichlorotrichloroethane, and mixtures thereof, and the solution can be used as a curing crosslinking agent to contain platinum group metals, oxides, It contains compounds such as chloroplatinic acid. Furthermore, if silicone rubber alone has a high viscosity and it is difficult for the solution to flow into the hollow fiber, dimethyl silicone oil, methylphenyl silicone oil, methylchlorophenyl silicone oil, branched dimethyl silicone oil, etc. It is also possible to blend silicone oil in a silicone rubber (solid content):silicone oil (liquid content) weight ratio of about 2:8 to 8:2. In this case, the cleaning liquid includes toluene and propylene glycol, toluene and dipropylene glycol, dichloromethane and diethylene glycol, dichloroethane and ethylene glycol, methyl ethyl ketone and ethylene glycol, and the like. In the third invention, in the first invention, when the porous membrane is hydrophobic and the dispersion medium is water, an alcohol such as ethanol or isopropanol is applied to the surface of the gas exchange membrane 2 before flowing the dispersion liquid. This is a method of making the surface of the gas exchange membrane 2 hydrophilic by bringing it into contact with. 2a to 2e are enlarged sectional views showing the detailed structure of the gas exchange membrane in each step of an embodiment of the method for manufacturing a membrane oxygenator according to the fourth invention. As shown in FIGS. 2a to 2c, the manufacturing method of the fourth invention is the same as the manufacturing method of the first invention, and the operation until each pore 4 of the gas exchange membrane 2 is closed with the fine particles 3 is as follows:
The process is carried out in the same manner, and the materials used for the gas exchange membrane, particulates, dispersion medium, cleaning fluid, etc. are also the same. Therefore, in the manufacturing method of the fourth invention, each pore 4 of the gas exchange membrane 2 is blocked with fine particles 3, and after removing the dispersion of the fine particles 3 remaining on the surface portion of the gas exchange membrane 2 with a cleaning fluid, As shown in FIG. 2d, a biocompatible hydrophobic resin solution 5 is further brought into contact with at least the surface of the gas exchange membrane 2 that comes into contact with blood, and then the solvent is evaporated, and as shown in FIG. 2e, A coating 6 of the resin is formed on at least the blood contacting surface of the porous hydrophobic gas exchange membrane. As the biocompatible hydrophobic resin, silicone rubbers and fluorine-containing resins as described above are also preferred, and vinyl copolymers containing a vinyl monomer having a perfluoroalkyl side chain as one component are particularly preferred. . For example, when a vinyl copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component is used as the biocompatible hydrophobic resin, 1 to 10% by weight, preferably 3 to 5% by weight of the copolymer. % lysis solution. When a silicone rubber such as a polymer of vinyl methylsiloxane and methylhydrogensiloxane is used, it is brought into contact with a solution of 5 to 80% by weight, preferably 20 to 70% by weight of the silicone rubber. Moreover, as the solvent for each solution, the ones mentioned above are used. In this way, as shown in FIG. 2e, the resin coating formed on at least the blood contacting surface of the porous hydrophobic gas exchange membrane 2 has a thickness of about 0.001 to 10 μm, more preferably 0.001 to 5 μm. be taken as a thing.
That is, if it exceeds 10 μm, there is a risk that the gas exchange ability of the gas exchange membrane 2 will be reduced, and if the gas exchange membrane is in the form of a hollow fiber, there is a risk that the blood flow path will be reduced. In the case of the manufacturing method of the fourth invention, even if the fine particles that block the pores 4 of the gas exchange membrane 2 are hydrophilic such as silica, the blood contact surface is made of a biocompatible hydrophobic resin. Since it is covered with the coating 6, there is no need to further perform a hydrophobic treatment as in the case of the manufacturing method of the second invention. The method for manufacturing a membrane oxygenator of the present invention can be carried out as described above, but in the first to fourth inventions, the above operations can be carried out even before assembling the oxygenator. It is more preferable to perform this after the module is assembled. FIG. 3 shows an assembled state of a hollow fiber membrane oxygenator manufactured in one embodiment of the method for manufacturing a membrane oxygenator of the present invention. That is, the hollow fiber membrane oxygenator 1 includes a housing 7,
This housing 7 is provided with annular male-threaded mounting covers 9 and 10 at both ends of a cylindrical body 8, respectively, and inside the housing 7 there are a large number of screws, for example 10,000 to 60,000, as described above. Hollow fiber gas exchange membranes 2 whose pores 4 are blocked by fine particles 3 or whose blood contact surfaces are coated with a biocompatible resin are arranged in parallel and spaced apart from each other along the longitudinal direction of the housing 7. ing.
Both ends of the gas exchange membrane 2 are fluid-tightly supported by partition walls 11 and 12 in mounting covers 9 and 10 with their respective openings not being closed. Further, each of the compartments 11 and 12, together with the outer peripheral surface of the gas exchange membrane 2 and the inner surface of the housing 7, constitutes an oxygen chamber 13, which is a first mass transfer chamber. The oxygen chamber 13 is isolated from a blood circulation space (not shown), which is a second mass transfer fluid space formed inside the oxygen chamber 13 . One mounting cover 9 is provided with an inlet 14 for supplying oxygen, which is the first mass transfer fluid. The other mounting cover 10 is provided with an outlet 15 for discharging oxygen. On the inner surface of the cylindrical main body 8 of the housing 7, there is a restricting portion 16 for aperture that protrudes from the center in the axial direction.
It is preferable to provide That is, the restraint part 16
is formed integrally with the inner surface of the cylindrical body 8, and is adapted to tighten the outer periphery of a hollow fiber bundle 17 consisting of a large number of gas exchange membranes 2 inserted into the cylindrical body 8. . In this way, the hollow fiber bundle 17 is narrowed at the center in the axial direction to form a narrowed portion 18, as shown in FIG. Therefore, the filling rate of the gas exchange membrane 2 differs in each part along the axial direction, and is highest in the central part. Note that, for reasons to be described later, the desirable filling rate of each part is as follows. First, the filling rate in the central constricted portion 18 is approximately 60 to 80%, and in the other cylindrical body 8 is approximately 30 to 60%, and the filling rate in the hollow fiber bundle 1 is approximately 60 to 80%.
The filling rate at both ends of the partition wall 7, that is, on the outer surfaces of the partition walls 11 and 12, is about 20 to 40%. Next, the formation of the partition walls 11 and 12 will be described. As described above, the partition walls 11 and 12 fulfill the important function of isolating the inside and outside of the gas exchange membrane 2. Usually, these partition walls 11, 12
is made by pouring a highly polar polymeric potting material such as polyurethane, silicone, epoxy resin, etc. onto the inner wall surfaces at both ends of the housing 7 using a centrifugal injection method and hardening the material. More specifically, first, a large number of hollow fiber membranes 2 that are longer than the length of the housing 7 are prepared, and after sealing both open ends with a resin with high viscosity, the inside of the cylindrical body 8 of the housing 7 is Place them side by side. After that, completely cover both ends of the gas exchange membrane 2 with mold covers having a diameter larger than that of the mounting covers 9 and 10, and while rotating the housing 7 about the central axis of the housing 7, The polymer potting material is introduced from the inside. When the resin has hardened after pouring, the mold cover is removed and the outer surface of the resin is cut with a sharp knife to expose both open ends of the gas exchange membrane 2 to the surface. The partition walls 11 and 12 are thus formed. The outer surfaces of the partition walls 11 and 12 are respectively covered with flow path forming members 19 and 20 having annular convex portions. The flow path forming members 19 and 20 are respectively composed of liquid distribution members 21 and 22 and threaded rings 23 and 24, and the end surfaces of protrusions 25 and 26 are formed as annular convex portions provided near the peripheral edges of the liquid distribution members 21 and 22. are in contact with the partition walls 11 and 12, respectively, and fixed by screwing the screw rings 23 and 24 to the mounting covers 9 and 10, respectively, thereby creating an inflow chamber 27 and an outflow chamber 28 for blood, which is the second mass transfer fluid. are formed respectively. A blood inlet 29 and an outlet 30, which are a second mass transfer fluid, are formed in the flow path forming members 19 and 20, respectively. These partition walls 11, 12 and flow path forming members 19, 2
The voids at the peripheral edges of the partition walls 11, 12 formed by 11 and 12. Alternatively, it is sealed via an O-ring (not shown). In the hollow fiber membrane oxygenator, the first mass transfer fluid is an oxygen-containing gas such as air or blood, and the second mass transfer fluid is blood or an oxygen-containing gas. Thus, if the first mass transfer fluid is a gas, the second mass transfer fluid is blood, whereas if the first mass transfer fluid is blood, the second mass transfer fluid is a gas. be. The above describes the method for manufacturing hollow fiber membrane oxygenators, but manufacturing of flat membrane oxygenators such as laminated type, one membrane wound into a coil shape, and one membrane folded in a zigzag shape etc. Regarding the method, a membrane oxygenator can be obtained which has a high gas exchange capacity, particularly a high CO ₂ removal capacity, and which substantially does not cause plasma leakage even when used for a long time. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 and Comparative Example 1 Using a polypropylene hollow fiber membrane with an inner diameter of 200 μm, a wall thickness of 25 μm, a porosity of 45%, and an average pore diameter of 700 Å,
A hollow fiber membrane oxygenator 1 as shown in FIG. 3 with a membrane area of 1.6 m ² was assembled. Ethanol is introduced through the blood inlet 27 of the hollow fiber membrane oxygenator 1 to make the hollow fiber gas exchange membrane 2 hydrophilic, and then the blood inlet 27
Silica (colloidal silica, average diameter 100
Å)/aqueous dispersion was introduced and filtered through the gas exchange membrane 2, and the pores of the gas exchange membrane were filled with silica. Next, distilled water was introduced to thoroughly remove the silica/water dispersion remaining inside the hollow fiber gas exchange membrane, and then drying was performed. After drying, an additional 2% by weight methylhydrodiene polysiloxane/Freon solution is flowed inside the hollow fiber gas exchange membrane. Furthermore, by drying, the silica particles filled in the pores of the gas exchange membrane were coated with silicone. When the gas exchange membrane of the obtained membrane oxygenator was observed under an electron microscope (magnification: 10,000 times), the pores had almost disappeared. From this, it was inferred that it would be an ultra-microporous membrane. When the air permeation flow rate of the obtained membrane oxygenator (Example 1) was measured, it was 1000 ml/min・m ²・mmHg, which was the same as that of the membrane oxygenator (Comparative Example 1) before filling with silica particles. Flow rate is 1900ml/min・
It was lower than that of ^m2・mmHg. Furthermore, in vitro and animal tests were conducted to evaluate the gas exchange capabilities of these oxygenators. (1) In vitro evaluation Using fresh heparinized bovine blood, oxygen gas partial pressure 35
Venous blood with a carbon dioxide partial pressure of 45 mmHg and 45 mmHg was prepared and was passed through the blood flow path of the oxygenator to evaluate its performance. The hemoglobin content of the bovine blood used was 12 g/dl, and the temperature was 37°C. The relationship between the blood flow rate and the oxygen gas addition ability and carbon dioxide removal ability when the ratio of the oxygen flow rate to the blood flow rate is 1 is as shown in Table 1 and FIG. 4. Furthermore, the relationship between the oxygen flow rate and carbon dioxide removal ability when the blood flow rate was 1500 ml/min was as shown in Table 2 and FIG. 5. (2) Animal test A 30-hour venous-arterial partial extracorporeal circulation test was conducted using mongrel dogs. The relationship between circulation time and plasma leakage amount was as shown in Table 3 and Figure 6. In addition, the rate of thrombocytopenia after 30 hours was measured as
Shown in the table. Example 2 Using a polypropylene hollow fiber membrane with an inner diameter of 200 μm, a wall thickness of 25 μm, a porosity of 45%, and an average pore diameter of 700 Å,
A hollow fiber membrane oxygenator with a membrane area of 1.6 m ² as shown in Figure 3 was assembled. Ethanol is flowed in through the blood inlet of the hollow fiber membrane oxygenator 1 to make the hollow fiber gas exchange membrane hydrophilic, and then silica (colloidal silica, average diameter 100 Å)/aqueous dispersion is flowed in through the blood inlet. was filled into the pores of the gas exchange membrane. Next, distilled water was introduced to thoroughly remove the silica/water dispersion remaining inside the hollow fiber gas exchange membrane, and then drying was performed. After blocking the pores with silica fine particles in this way, (methyl methacrylate/butyl methacrylate)-perfluorobutyl acrylate copolymer (weight ratio (2:5:
25): A mixed solvent solution of 3% by weight of methyl ethyl ketone/methyl isobutyl ketone (volume ratio 4:6) of 50) was placed inside the hollow fiber gas exchange membrane.
After filling for a minute, the liquid was discharged and air was blown through to remove the solvent and form a film. When the gas exchange membrane of the obtained membrane oxygenator was observed under an electron microscope (magnification: 10,000 times), the pores had almost disappeared. However, the result of measuring the air flux of the obtained membrane oxygenator was 10 ml/min・m ²・
mmHg, and from this it was inferred that it was an ultra-microporous membrane. Furthermore, in order to evaluate the performance of this membrane oxygenator, in vitro tests and animal tests were conducted in the same manner as in Example 1. The results are shown in Tables 1 to 3 and Figures 4 to 6, respectively.

【table】

【table】

【table】

[Table] Specific Effects of the Invention As described above, the present invention can be used as a gas exchange membrane with an inner thickness of 5 to 80 μm, a porosity of 20 to 80%, and a pore diameter.
In a method for manufacturing an oxygenator using a porous membrane of 0.01 to 5 μm, a dispersion of fine particles smaller than the pores of the porous membrane is filtered through the porous membrane, and the pores of the porous membrane are Since the method for producing a membrane oxygenator (first invention) is characterized in that the dispersion liquid remaining on the surface of the porous membrane is removed with a cleaning fluid after the porous membrane is blocked by fine particles, gas exchange is not possible. Despite its extremely high ability to remove carbon dioxide, there is no risk of plasma leakage even after long-term use.
It is possible to easily manufacture an excellent membrane oxygenator like ECCO ₂ R, which can remove the amount of carbon dioxide produced by living organisms with a small amount of extracorporeal circulation. The present invention also provides a gas exchange membrane with an inner thickness of 5 to
In a method for manufacturing an oxygenator using a porous membrane having a diameter of 80 μm, a porosity of 20 to 80%, and a pore diameter of 0.01 to 5 μm, a dispersion of hydrophilic fine particles smaller than the pores of the porous membrane is added to the porous membrane. After filtration to block the pores of the porous membrane with the fine particles, the dispersion remaining on the surface of the porous membrane is removed with a cleaning fluid, and at least the fine particles are removed from the blood. Since the method for manufacturing a membrane oxygenator (second invention) is characterized in that the contact surface is hydrophobized, the gas exchange ability,
In particular, despite its extremely high carbon dioxide removal ability, there is no risk of plasma leakage even when used for long periods of time, so it is possible to remove the amount of carbon dioxide produced by the living body with a small extracorporeal circulation volume like ECCO ₂ R. This makes it possible to easily manufacture a membrane oxygenator that has been treated to be hydrophobic and has superior gas exchange performance. The present invention also provides a gas exchange membrane with an inner thickness of 5 to
In a method for producing an oxygenator using a porous hydrophobic membrane having a diameter of 80 μm, a porosity of 20 to 80%, and a pore diameter of 0.01 to 5 μm, the porous hydrophobic membrane is brought into contact with alcohol to perform a water immersion treatment. After that, a dispersion of fine particles smaller than the pores of the porous membrane using water as a dispersion medium is filtered through the porous membrane to block the pores of the porous membrane with the fine particles. A method for manufacturing a membrane oxygenator, characterized in that the dispersion liquid remaining on the surface of the membrane is removed using a cleaning fluid (third invention)
Therefore, there is no risk of plasma leakage even if used for a long time, even though the gas exchange ability, especially the carbon dioxide removal ability, is extremely high.
It is possible to easily manufacture an excellent membrane oxygenator like ECCO ₂ R, which can remove the amount of carbon dioxide produced by living organisms with a small amount of extracorporeal circulation. The present invention also provides a gas exchange membrane with an inner thickness of 5 to
A method for producing an oxygenator using a porous membrane having a diameter of 80 μm, a porosity of 20 to 80%, and a pore size of 0.01 to 5 μm, in which a dispersion of fine particles smaller than the pores of the porous membrane is filtered through the porous membrane. After the pores of the porous membrane are blocked by the fine particles, the dispersion liquid remaining on the surface of the porous membrane is removed with a cleaning fluid, and the porous membrane is brought into contact with at least the blood. A method for producing a membrane oxygenator (method for manufacturing a membrane oxygenator) characterized in that the porous membrane is coated with a solution of a biocompatible hydrophobic resin, and then the solvent is evaporated to coat at least the blood-contacting surface of the porous membrane with the resin. 4 invention), there is no risk of plasma leakage even after long-term use, even though the gas exchange capacity, especially the carbon dioxide removal capacity, is very high.Therefore, there is no need for extracorporeal circulation as with ECCO ₂ R. An excellent membrane oxygenator that can remove the amount of carbon dioxide produced by a living body can be easily produced, and the obtained membrane oxygenator also has high biocompatibility.

[Brief explanation of drawings]

Figures 1a-c and 2a-e are enlarged sectional views of gas exchange membranes in each step of the manufacturing method of the present invention, and Figure 3 is a diagram of a hollow fiber membrane oxygenator obtainable by the manufacturing method of the present invention. A partial cross-sectional view, FIG. 4 is a graph showing the relationship between the oxygen gas addition ability and carbon dioxide removal ability with respect to the blood flow rate of the artificial lung, and FIG. 5 is a graph showing the relationship between the oxygen gas removal ability and the oxygen flow rate of the artificial lung. 6 is a graph showing the relationship between extracorporeal circulation time and plasma leakage amount. 1... Membrane oxygenator, 2... Gas exchange membrane, 3...
Fine particle, 4... Pore, 5... Biocompatible hydrophobic resin solution, 6... Coating, 7... Housing, 8...
Cylindrical body, 11, 12... Compartment, 13... First mass transfer medium, 14, 15... First mass transfer fluid introduction outlet, 17... Hollow fiber bundle, 29, 30... Second mass transfer fluid inlet outlet.

Claims (1)

[Claims] 1. As a gas exchange membrane, the wall thickness is 5 to 80 μm, the porosity is
In a method for manufacturing an oxygenator using a porous membrane with a pore size of 20 to 80% and a pore size of 0.01 to 5 μm, a dispersion of fine particles smaller than the pores of the porous membrane is filtered through the porous membrane. 1. A method for manufacturing a membrane oxygenator, which comprises clogging the pores of the porous membrane with the fine particles, and then removing the dispersion liquid remaining on the surface of the porous membrane with a cleaning fluid. 2. The method for producing a membrane oxygenator according to claim 1, wherein the microparticles are hydrophobic. 3 The gas exchange membrane has a wall thickness of 5 to 80 μm, a porosity of 20 to 80%, a pore diameter of 0.01 to 5 μm, and an inner diameter of 100 μm.
A method for manufacturing a membrane oxygenator according to claim 1 or 2, using a hollow fiber porous membrane of ~1000 μm. 4. The method for manufacturing a membrane oxygenator according to claim 3, wherein the dispersion of fine particles is caused to flow into the hollow fiber porous membrane and filtered. 5 As a gas exchange membrane, the wall thickness is 5 to 80 μm, the porosity is
20 to 80%, and a method for producing an oxygenator using a porous membrane with a pore size of 0.01 to 5 μm, in which a dispersion of hydrophilic fine particles smaller than the pores of the porous membrane is filtered through the porous membrane, After the pores of the porous membrane are blocked by the fine particles, the dispersion liquid remaining on the surface of the porous membrane is removed with a cleaning fluid, and at least the surface of the fine particles that comes into contact with blood is made hydrophobic. A method for manufacturing a membrane oxygenator, which comprises: 6. The method for producing a membrane oxygenator according to claim 5, wherein the fine particles are silica. 7 As a gas exchange membrane, wall thickness 5-80 μm, porosity
In a method for manufacturing an oxygenator using a porous hydrophobic membrane with a pore size of 20 to 80% and a pore size of 0.01 to 5 μm, the porous hydrophobic membrane is brought into contact with alcohol to undergo a water immersion treatment, and then water is dispersed. After filtering a dispersion of fine particles smaller than the pores of the porous membrane as a medium through the porous membrane and blocking the pores of the porous membrane with the fine particles, the surface portion of the porous membrane is A method for producing a membrane oxygenator, comprising removing the dispersion liquid remaining in the membrane oxygenator using a cleaning fluid. 8. The method for manufacturing a membrane oxygenator according to claim 7, wherein the gas exchange membrane is made of olefin resin. 9. The method for manufacturing a membrane oxygenator according to claim 8, wherein the gas exchange membrane is made of polypropylene. 10 In a method for producing an oxygenator using a porous membrane having a wall thickness of 5 to 80 μm, a porosity of 20 to 80%, and a pore diameter of 0.01 to 5 μm as a gas exchange membrane, fine particles smaller than the pores of the porous membrane After filtering the dispersion through the porous membrane to block the pores of the porous membrane with the fine particles, and removing the dispersion remaining on the surface of the porous membrane with a cleaning fluid. A solution of a biocompatible hydrophobic resin is brought into contact with at least the surface of the porous membrane that comes into contact with blood, and then the solvent is evaporated to coat at least the blood-contacting surface of the porous membrane with the resin. A method for manufacturing a membrane oxygenator. 11. The method for manufacturing a membrane oxygenator according to claim 10, wherein the biocompatible hydrophobic resin is a fluorine-containing resin or silicone rubber. 12 Claim 11, wherein the biocompatible hydrophobic resin is a vinyl copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component.
The method for manufacturing a membrane oxygenator described in section 1.