JPH0360507B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hollow fiber membrane oxygenator and a method for manufacturing the same. Prior Art In general, in cardiac surgery and the like, a hollow fiber membrane oxygenator is used in an extracorporeal circulation circuit to lead a patient's blood outside the body and add oxygen to it. There are two types of hollow fiber membranes used in such oxygenators: homogeneous membranes and porous membranes. Since the homogeneous membrane uses a silicone membrane, the membrane thickness cannot be reduced to less than 100 μm due to its strength, and therefore there is a limit to gas permeation, and in particular, permeation of carbon dioxide gas is poor. Furthermore, when tens of thousands of pieces are bundled, the size of the device increases, resulting in an increase in the amount of plying, and there are also disadvantages in that processability is poor and costs are high. On the other hand, in a porous membrane, the fine pores of the membrane are significantly larger than the gas molecules to be passed through, so that the gas passes through the pores as a volumetric flow. For example, various oxygenators using porous membranes such as microporous polypropylene membranes have been proposed. However, since the porous membrane has a high permeability to water vapor, its performance not only deteriorates due to condensation water, but also causes plasma leakage when used with blood circulating for a long period of time. In order to eliminate these drawbacks of porous membranes, we formed an impermeable thin film of methylhydrogen polysiloxane on the sidewalls of a hollow fiber substrate that has sidewalls with penetrating micropores of 10 microns or less in diameter. A hollow fiber membrane has been proposed (Special Publication No. 54-17052). However, in such a hollow fiber membrane, a film of methylhydrodiene polysiloxane is formed not only in the micropores of the hollow fiber substrate but also on both the inner and outer surfaces of the hollow fiber substrate. Since the inner diameter of the hollow space becomes smaller, the replacement capacity decreases. Furthermore, the amount of methylhydrodiene polysiloxane filled in the micropores (filling thickness) increases as the size of the pores decreases, resulting in a disadvantage that the permeability of gases such as oxygen and carbon dioxide gas is low. Furthermore, although the hollow fibers can be used in Aqua Lungs and the like, they have the disadvantage that plasma begins to leak out when used as an artificial lung for a long time. In order to further improve these drawbacks, the present applicant has developed a hollow fiber membrane in which only the inside of the micropores are closed with silicone oil, without forming a silicone oil layer on the side wall having micropores of the hollow fiber membrane. -Proposed a silicone membrane composite oxygenator (Japanese Patent Application No. 58-92325). In this proposal, after assembling the oxygenator module, the hollow fibers are impregnated with a solution of silicone oil, and then the silicone oil is removed.
The purpose is to remove the silicone oil adhering to the wall surface of the hollow fiber substrate by flowing a mixture of a silicone oil solvent and a non-solvent, thereby blocking only the inside of the micropores with silicone oil. According to this, although the amount of plasma leakage was improved, silicone oil sometimes leaked into the blood. Purpose of the Invention The purpose of the present invention is to improve the above-mentioned drawbacks and to provide a hollow fiber that does not leak plasma even after long-term extracorporeal circulation, is compact, has good carbon dioxide removal performance, and has excellent blood compatibility. An object of the present invention is to provide a membrane oxygenator and a method for manufacturing the same. These objects are achieved by the invention described below. That is, the first invention includes a housing, a hollow fiber bundle consisting of a large number of hollow fiber membranes for gas exchange inserted into the housing, and a first invention formed by the outer surface of the hollow fiber membranes and the inner surface of the housing. a fluid chamber, a first fluid inlet and an outlet communicating with the first fluid chamber, and each end of the hollow fiber membrane,
and a partition separating from the first fluid chamber, and a second fluid inlet and outlet communicating with the interior space of the hollow fiber membrane formed by a header attached to the end of the housing. In the lung, the hollow fiber membrane has micropores passing through it, the micropores are occluded with a silicone mixture containing silicone oil and 20 to 80% by weight silicone rubber, and the hollow fiber membrane has micropores on the side wall of the hollow fiber membrane. is a hollow fiber membrane oxygenator characterized in that a layer substantially consisting of the silicone mixture is not formed therein. Moreover, the embodiment is as follows. ) In the first invention, the silicone rubber is a room temperature curable silicone rubber that does not contain silica. ) In ), the silica-free room-temperature curable silicone rubber is a polymer of vinylmethylsiloxane and methylhydrogensiloxane, and the silicone oil is dimethyl or methylphenyl silicone oil. A second invention also provides a housing, a hollow fiber bundle consisting of a large number of gas exchange hollow fiber membrane substrates inserted into the housing, and a hollow fiber bundle formed by the outer surface of the hollow fibers and the inner surface of the housing. a first fluid chamber, a first fluid inlet and an outlet communicating with the first fluid chamber, and a partition that respectively supports and isolates each end of the hollow fiber membrane substrate from the first fluid chamber; After assembling an oxygenator module consisting of a chamber and a second fluid inlet and outlet communicating with the inner space of the hollow fiber membrane base, a silicone oil of 20 to 80% by weight is placed inside the hollow fiber membrane base. A 20-80% by weight raw silicone solution of a silicone mixture containing 10% silicone rubber is introduced and impregnated, and then a cleaning solution containing a solvent capable of dissolving the silicone mixture and a liquid in which the silicone mixture is insoluble is introduced and impregnated. This is a method for producing a hollow fiber membrane oxygenator, characterized in that silicone rubber or a silicone mixture is filled into the micropores of the hollow fiber membrane substrate by flowing the silicone rubber or the silicone mixture. And the embodiment is, in the second invention,
The cleaning liquid must have a viscosity of 10 centipoise or more. Specific Configuration of the Invention The specific configuration of the present invention will be described in detail below. FIG. 1 shows an overall view of the hollow fiber membrane oxygenator of the present invention. That is, as shown in FIG. 1, in the oxygenator 10 according to the present invention, a fiber bundle 13 of a hollow fiber membrane 12 is housed in the inner space of a cylindrical housing 11 constituting the oxygenator 10. Both ends of the hollow fiber membrane 12 are fluid-tightly held in the housing 11 via partition walls 14 and 15. At both ends of the housing 11, headers 16,
17 is fixed to the housing 11 by a cover 18 screwed onto the housing 11. The inner surface of the header 16 and the partition wall 14 define a blood inflow chamber 19 as a second fluid inflow chamber that communicates with the internal space of the hollow fiber membrane 12. A blood inlet 20 is formed. The inner surface of the header 17 and the partition wall 15 define a blood outflow chamber 21 as a second fluid outflow chamber communicating with the internal space of the hollow fiber membrane 12. A blood outflow port 22 is formed. Furthermore, a gas chamber 23 as a first fluid chamber is formed between the partition walls 14 and 15, the inner wall of the housing 11, and the outer wall of the hollow fiber membrane 12.
A gas inlet 24 serving as a first fluid inlet and a gas outlet 25 serving as a first fluid outlet communicating with the gas chamber 23 are formed at both ends of the gas chamber 23 . Note that it is preferable that a restricting portion 26 for reducing the diameter of the outer diameter of the fiber bundle 13 is provided in the center of the inner wall of the housing 11 . As a result, as shown in FIG. 1, it is narrowed down at the center in the axial direction, and a narrowed portion is formed. Therefore, the filling rate of the hollow fiber membrane 12 differs in each part along the axial direction, and is highest in the central part. The partition walls 14 and 15 serve the important function of isolating the inside and outside of the hollow fiber membrane 12. Normally, the partition walls 14 and 15 are made by pouring a highly polar polymeric potting agent such as polyurethane, silicone, epoxy resin, etc. onto the inner wall surfaces of both ends of the housing 11 using a centrifugal injection method, and then hardening it. More specifically, first, a large number of hollow fiber membranes 12 that are long in the length of the housing 11 are prepared, both open ends of which are sealed with a highly viscous resin, and then placed side by side in the housing 11. After that, each end is completely covered with a cover, and the housing 11 is centered around the central axis of the housing 11.
While rotating, a polymer potting agent is injected from both ends and cured. After the cover is removed, the outer surface of the hardened potting agent is cut with a sharp knife, and both open ends of the hollow fiber membrane 12 are cut on the surface. Formed by exposure to As shown in FIG. 2, the hollow fiber membrane used in the oxygenator has a silicone layer substantially on the wall surface 34 of a porous hollow fiber substrate 33 having a side wall 32 having micropores 31 therethrough. This is a hollow fiber membrane type gas exchange membrane in which the inside of the micropores 31 of the side wall 32 are closed with silicone rubber or a silicone mixture 35 containing silicone rubber and silicone oil without forming any. Porous hollow fiber substrates used in this hollow fiber membrane include polypropylene, polyethylene, polytetrafluoroethylene, polysulfone, polyacrylonitrile, polyethylene terephthalate,
Examples include polybutylene terephthalate, polycarbonate, polyurethane, nylon-6,6, nylon-6, cellulose acetate, etc., preferably polyolefin, and particularly preferably polypropylene. In order to obtain practical performance as an oxygenator using a gas exchange membrane manufactured using this hollow fiber substrate, limitations naturally arise in membrane thickness and porosity. Generally, the amount of permeation q of a substrate through a membrane is expressed by the following formula. q=P×Δp×A/l (In the formula, P is the gas permeability coefficient, Δp is the pressure difference of the permeated gas, A is the membrane area, and l is the membrane thickness.) Hollow fiber membrane of the present invention Since the gas permeable portions are micropores blocked with silicone rubber or a silicone mixture, the actual membrane area is much smaller than that of a porous membrane. In order to compensate for this, it is necessary to reduce the film thickness, as is clear from the above equation. Therefore, in the present invention, the thickness l of the hollow fiber membrane is in the range of 5 to 200 μm, preferably 10 to 50 μm. The inner diameter of the hollow fiber is 100-1000μm, preferably
100~300μm, porosity range is 20~80%,
Preferably it is 40-80%. The diameter of the micropore is 0.01
-5μm, preferably 0.01-1μm. To manufacture the oxygenator according to the present invention, first, as shown in FIG. to be sufficiently impregnated. Next, gas is caused to flow, and as shown in FIGS. 4a and 4b, a predetermined cleaning liquid is caused to flow through at least the inner surface of the hollow fibers, and if necessary, heat crosslinking is performed. The silicone rubber used is a room temperature curing type (RTV), and either one-component type or two-component type may be used. Two-component rubbers are generally solid rubbers that are two-dimensional polymers that contain vinyl groups and/or hydrogen in raw material monomers or oils, and are crosslinked between C and H after mixing. For example, as a two-component RTV silicone rubber, a polymer of vinyl methylsiloxane and methylhydrodiene polysiloxane is preferred. Incidentally, for these curing and crosslinking, platinum group metals, oxides, compounds, etc., such as chloroplatinic acid, are used. Further, the curing temperature is 20°C to 30°C or higher. Further, the silicone rubber used here is preferably an RTV rubber that does not contain silica from the viewpoint of antithrombotic properties. However, silicone rubber alone has problems such as high viscosity in a liquid state, making it difficult to flow into the hollow fiber membrane. For this reason, silicone oil is used in combination with silicone rubber. The silicone oil used in the present invention is a liquid substance having a siloxane bond, such as dimethyl silicone oil, methylphenyl silicone oil, methylchlorophenyl silicone oil, branched dimethyl silicone oil, methylhydrogen silicone oil, etc. Preferred are dimethyl silicone oil and methylphenyl silicone oil, most preferably dimethyl silicone oil. The ratio of silicone rubber (solid content) to silicone oil (liquid content) in a silicone mixture consisting of silicone rubber and silicone oil is preferably 2:8 to 8:2 by weight, more preferably about 4:6. It is. When the silicone rubber is larger than 8, the viscosity of the solution increases, making it difficult to remove the silicone adhering to the wall surface of the hollow fiber membrane substrate. Furthermore, if the number of silicone rubbers is less than 2, the mixed silicone oil may leak into the blood. This silicone rubber or silicone mixture is usually 20 to 80% by weight, preferably 30 to 60% by weight.
used as a solution. In addition, the solvents include benzene, toluene, xylene, hexane, dichloromethane, methyl ethyl ketone, diflorethane, ethyl acetate,
Examples include trifluorotrichloroethane (Freon). The liquid (cleaning liquid) that substantially removes the silicone rubber or silicone mixture adhering to the wall surface of the hollow fiber substrate should be an organic liquid, especially an alcoholic liquid, in which the silicone mixture does not dissolve, since the impregnated silicone will be eluted with the above solvent. Use. The viscosity thereof is preferably 10 centipoise or more, particularly 30 to 80 centipoise or more at room temperature. This effectively removes excess silicone rubber or silicone mixture, homogenizes them, and stabilizes performance. Further, it is preferable that the cleaning liquid maintains such a viscosity and then mixes 10 vol% or less, particularly 0.5 to 10 vol%, of the silicone solvent. This makes it easier to remove excess silicone and improves performance. However, if it exceeds 10 vol%, silicone will be eluted, which is not preferable. A particularly preferred range is 2 to 6 vol%. Such cleaning liquid compositions include 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 present invention, "substantially removing the silicone rubber or silicone mixture" means that the layer of silicone rubber or silicone mixture adhered to the inner wall of the hollow fiber membrane has a thickness of 500 Å or less. This is because if the thickness is 500 Å or less, gas permeation will not be substantially affected and sufficient CO ₂ permeation will be ensured as described later. Specific Examples of the Invention Hereinafter, examples of the present invention will be shown and the present invention will be explained in further detail. Example 1 Polypropylene hollow fibers (porosity 50%) with an inner diameter of 200 μm, wall thickness of 25 μm, and penetrating micropores of 700 Å in diameter were formed by stretching in the axial direction by a stretching method. An artificial lung (module A) as shown in Figure 1 was prepared. In the blood flow path of this module A,
As shown in b, a two-component type silicone rubber made of vinyl methyl siloxane and methylhydrodiene siloxane, containing a chloroplatinic acid catalyst (does not contain silica), and a silicone mixture of dimethyl silicone oil (silicone rubber 40wt). %) of 60
% freon solution (silicone solution),
Soaked for 3 minutes. Thereafter, air was allowed to flow, and a 3% toluene/dipropylene glycol solution (cleaning solution) was allowed to flow through the inner and outer surfaces. The viscosity of the cleaning solution is 100 centipoise. As a result, a hollow fiber membrane oxygenator (module C) in which a silicone mixture of silicone rubber and silicone oil is filled substantially only in the micropores.
I got it. About this oxygenator module C, fresh heparinized bovine blood is used, oxygen saturation is 65%, and carbon dioxide gas partial pressure is 45%.
Venous blood with a concentration of mmHg was prepared and was passed through the test oxygenator to evaluate its performance. The bemoglobin content was 12 g/dl and the temperature was 37°C. The relationship between blood flow rate and oxygenation capacity when the oxygen flow rate is 1/min/m ² is shown by curve C in FIG. 5. The relationship between oxygen flow rate and carbon dioxide removal ability when the blood flow rate is 1000 ml/min/m ² is shown by curve C in FIG. 6. Furthermore, a venous-arterial partial extracorporeal circulation test was performed using a mixed dog. The relationship between circulation time and plasma leakage amount was as shown by curve C in FIG. 7, respectively. Comparative Example 1 The same measurements as in Example 1 were carried out using an oxygenator in which the hollow fibers of module A of Example 1 remained penetrated and no silicone membrane was formed. Curve A in FIG. 7 was obtained. Comparative Example 2 An artificial lung (Module B) similar to that in Example 1 was manufactured using a silicone hollow fiber membrane. The same measurements as in Example 1 were carried out on this module B, and curve B was obtained in FIGS. 5, 6, and 7. As shown in FIG. 5, there was no significant difference in O ₂ addition ability between the porous membrane (Module AA curve), the silicone membrane (Module B curve), and the present invention (Module CC curve). As shown in FIG. 6, the silicone membrane (Module B curve) showed a very low CO ₂ removal ability. In Figure 7 from a long-term animal experiment, the amount of plasma leaked from the porous membrane (module A curve) increased over time, whereas the plasma leaked from the present invention (curve C) plugged with a silicone mixture. I didn't. From these results, it can be seen that Module C of the present invention provides the best results in overall properties of carbon dioxide removal ability, oxygen addition ability, and plasma leakage prevention ability. Comparative Example 3 A hollow fiber membrane oxygenator module E was obtained under exactly the same conditions as in Example 1, except that a cleaning solution of 3% toluene/dipropylene glycol solution was not passed through the inner and outer surfaces of the hollow fibers. The artificial lungs of modules C and E were cut, the hollow fibers inside were taken out, the hollow fiber membranes were cut in the axial direction, and observed under an electron microscope at a magnification of 10,000 times. In module C, there was no continuous layer of silicone mixture on the inner and outer surfaces, but in module E, there was a continuous layer of silicone mixture on the inner and outer surfaces, with a thickness of about 2 μm on the inner surface and on the outer surface. The thickness was approximately 1 μm. Comparative Example 4 Hollow fiber membrane module F was produced under exactly the same conditions as in Example 1, except that the silicone solution was replaced with a 50% Freon solution of dimethylpolysiloxane (silicone oil) and the cleaning solution was not circulated. Obtained. There is a continuous layer of silicone oil on the inner and outer surfaces, with a thickness of approximately 3 μm on the inner surface and approximately 3 μm on the outer surface.
It was 1 μm. Comparative Example 5 In Example 1, the silicone solution was
Module G was obtained under exactly the same conditions as in Example 1, except that the silicone rubber was replaced with a 50% Freon solution and the cleaning solution was not circulated. There is a continuous layer of silicone rubber on the inner and outer surfaces, with a thickness of approximately 8 μm on the inner surface and approximately 8 μm on the outer surface.
It was 1 μm. For each of these modules C, E, F, and G, the oxygen addition capacity, carbon dioxide removal capacity, and plasma leakage amount were measured in the same manner as described above. Blood flow rate is 1000ml/min/
mm ² , and the oxygen flow rate was 3000 ml/min/mm ² , and the amount of plasma leakage after 24 hours of circulation was measured. The results are shown in Table 1.

[Table] From the results shown in Table 1, it can be seen that by using a mixture of oil and rubber as the silicone and removing the continuous layers on the inner and outer surfaces, the carbon dioxide removal ability and oxygen addition ability are significantly improved. Example 2 Using a module of the same size as Example 1,
An oxygenator (module D) was obtained in the same manner as in Example 1 using a mixture of silica-containing silicone rubber (SiO ₂ 30 vol %) and silicone oil as the silicone mixture. This module D and the module C of Example 1
We conducted an extracorporeal circulation experiment using rabbits. As a result, as shown in Figure 8, the product C without silica
The platelet count remained at 90% after 6 hours, while the silica-containing silicone mixture decreased to 70%. Specific Effects of the Invention The present invention has no leakage of plasma even when used for a long time compared to an oxygenator using a porous membrane, has better processability, and has a smaller device than an oxygenator using a silicone membrane. Not only can the cost be lowered, but also the gas exchange rate is good because a silicone layer is not substantially formed on the wall surface of the hollow fiber membrane. In particular, by adding silicone rubber to silicone oil, the CO ₂ removal ability is greatly improved compared to silicone oil alone. Furthermore, by using a room temperature curing silicone rubber that does not contain silica, a hollow fiber membrane with excellent antithrombotic properties can be obtained.

[Brief explanation of drawings]

FIG. 1 is a longitudinal sectional view showing an example of the hollow fiber membrane oxygenator of the present invention, FIG. 2 is an enlarged schematic diagram of the hollow fiber membrane used in the oxygenator of the present invention, and FIGS. Figures 4a and 4b are diagrams for explaining the method for manufacturing an oxygenator of the present invention, of which Figures 3a and 4a are front views, Figures 3b and 4b are
are enlarged sectional views of Figures 3a and 4a, and Figure 5.
The figure is a graph showing the relationship between oxygenation capacity and blood flow rate of an artificial lung, and Figure 6 is a graph showing the relationship between oxygen flow rate and CO ₂
Graph showing the relationship between removal capacity, Figure 7 is a graph showing the relationship between venous-arterial partial extracorporeal circulation time and plasma leakage amount, and Figure 8 is a graph showing the relationship between change in platelet count and extracorporeal circulation time. It is. 10...Artificial lung, 11...Housing, 12...
...Hollow fiber membrane, 13...Hollow fiber bundle, 14,15
...Partition wall, 20...Blood inlet, 21...Blood outlet, 23...Gas chamber, 31...Minute hole, 33...
...Hollow fiber base.

Claims (1)

[Scope of Claims] 1. A housing, a hollow fiber bundle consisting of a large number of hollow fiber membranes for gas exchange inserted into the housing, and a first cavity formed by the outer surface of the hollow fiber membranes and the inner surface of the housing. a fluid chamber, a first fluid inlet and an outlet communicating with the first fluid chamber, and each end of the hollow fiber membrane,
and a partition separating from the first fluid chamber, and a second fluid inlet and outlet communicating with the interior space of the hollow fiber membrane formed by a header attached to the end of the housing. In the lung, the hollow fiber membrane has micropores passing through it, the micropores are occluded with a silicone mixture containing silicone oil and 20 to 80% by weight silicone rubber, and the hollow fiber membrane has micropores on the side wall of the hollow fiber membrane. A hollow fiber membrane oxygenator characterized in that a layer substantially consisting of the silicone mixture is not formed therein. 2. The hollow fiber membrane oxygenator according to claim 1, wherein the silicone rubber is a room temperature curable silicone rubber that does not contain silica. 3. The hollow space according to claim 2, wherein the silica-free room-temperature curable silicone rubber is a polymer of vinylmethylsiloxane and methylhydrogensiloxane, and the silicone oil is dimethyl or methylphenyl silicone oil. Fiber membrane oxygenator. 4. A housing, a hollow fiber bundle consisting of a large number of porous hollow fiber membrane substrates for gas exchange inserted into the housing, and a first fluid chamber formed by the surface of the hollow fiber and the inner surface of the housing. , a first fluid inlet and an outlet communicating with the first fluid chamber, a compartment that respectively supports each end of the hollow fiber substrate and isolates it from the first fluid chamber, and the hollow fiber membrane. After assembling an oxygenator module comprising a second fluid inlet and an outlet communicating with the internal space of the base, the hollow fiber membrane base contains silicone oil and 20 to 80% by weight of silicone rubber. A raw silicone solution having a concentration of 20 to 80% of the silicone mixture is introduced and impregnated, and then a cleaning liquid containing a solvent that can dissolve the silicone mixture and a liquid in which the silicone mixture is insoluble is passed through the hollow fiber membrane. A method for producing a hollow fiber membrane oxygenator, which comprises filling micropores in a base with a silicone mixture. 5. The method for manufacturing a hollow fiber membrane oxygenator according to claim 4, wherein the washing liquid has a viscosity of 10 centipoise or more.