JPH054125B2 - - Google Patents

Description

[Detailed description of the invention]

(Technical field) The present invention relates to an artificial lung for adding oxygen to blood and removing carbon dioxide in extracorporeal circulation of blood. In particular, even if blood is circulated for a long time, plasma in the blood does not leak to the oxygen side. It concerns an oxygenator with a high gas exchange capacity. (Prior art and its problems) In recent years, for the purpose of creating separation membranes with excellent selective separation and high flow rate permeability for use in oxygenators,
Many composite separation membranes and their manufacturing methods have been proposed, in which a polymer having high selective permeability for specific target substances is formed on the surface of a porous body in the form of a uniform thin film. Since the separation layer components permeate into the micropores on the surface of the porous support, it has a fairly thick permeation layer. Because of such a thick permeation layer, the permeation flow rate was extremely small. For example, JP-A-53-86684 (British patent publication
7707583), porous hollow fibers of aromatic polysulfone were mixed with polydimethylsiloxane and 1/10
Polydimethylsiloxane is cured and polymerized to form a silicone rubber by dipping an amount of curing agent into a solution dissolved in n-pentane and then heating and drying it, thereby forming a silicone rubber on the outer surface of the aromatic polysulfone porous hollow fiber. A composite separation membrane for gas separation coated with a silicone rubber thin film is obtained. However, in this composite separation membrane, the coated silicone rubber penetrates extremely thickly into the pores on the surface of the porous substrate, and therefore, when used as an oxygen enrichment membrane, for example, the permeation performance is approximately 10 ⁵ ml/
It is extremely small at 24HRS・m ²・Kg/cm ² , and in order to put it into practical use, the permeation rate must be improved about 100 times. Alternatively, since the selective separation layer-forming component easily penetrates into the micropores, it becomes difficult to completely cover the surface with micropores, and in this way, incomplete coverage may occur. In other words, it becomes a pinhole,
In this way, in a composite separation membrane having pinholes, it becomes impossible to obtain the original separation performance of the selective separation layer. Regarding the improvement in this point, Japanese Patent Publication No. 56-25451 discloses that after impregnating the microporous portion of a porous support with a liquid to temporarily make the surface of the porous support a non-porous smooth surface, It discloses a composite membrane structure without a permeation layer inside the micropores of a porous support, which is obtained by forming a selective separation layer on the surface and then removing the liquid impregnated into the micropores of the porous support. ,
However, since the surface of the support on which the selective separation layer is to be formed is always wetted by the impregnating liquid at least once, the adhesion between the porous membranous base material of the obtained composite membrane and the selective separation layer is reduced. The degree of separation cannot yet be completely perfect and therefore fundamentally eliminates the risk that the selective separation layer will peel off from the substrate during handling and that damage to the selective separation layer may occur as a result. It is not something that can be solved. In addition, Japanese Patent Publication No. 17589/1989 discloses a method consisting of a homogeneous porous substrate made by using a fine powder pore-forming agent, and a selectively permeable thin polymer film formed on the surface thereof without a permeable layer. A two-layer composite permselective membrane structure is disclosed. However, in this permselective membrane, the size of the micropores in the homogeneous porous substrate is as large as possible on the surface and inside, as is clear from the model diagram of Japanese Patent Publication No. 48-17589.
Equally, since it is extremely small at approximately 100 Å, the fluid permeation resistance of the porous substrate itself is extremely large, and no matter how thin the permselective polymer film is formed on the surface of the porous substrate without a penetrating layer, its permselectivity is Even if the fluid permeability of the polymer film itself is sufficiently high, the fluid permeability of the two-layer composite membrane as a whole is unavoidably small, and is still unsatisfactory for practical use in terms of permeation rate. . There are roughly two types of forms of such composite separation membranes. One of them is a flat membrane composite separation membrane in which a selective separation layer is formed on a flat membrane porous support. The essential problem is that the effective membrane area cannot be increased, and the separation system must therefore be larger. A solution to this problem was considered to be a composite hollow fiber separation membrane in which a selective separation layer was formed on the surface of a hollow fiber membrane porous support. In comparison, it is said that the effective membrane area per unit volume can be increased by 10 to 100 times when modularized, making it possible to develop a correspondingly smaller and more compact separation system. It is clear that it has some advantages. (Object of the Invention) Therefore, the object of the present invention is to have a very thin selective separation layer, and the selective separation layer does not have defects such as pinholes, so that even if blood is circulated for a long time, it will not be difficult to maintain blood flow. An object of the present invention is to provide an artificial lung made of a highly permeable composite hollow fiber membrane that prevents blood plasma from leaking into the oxygen side. (Structure and Effects of the Invention) The object of the present invention is to provide an artificial device that performs gas exchange between blood and gas through a membrane by allowing blood to flow through one side of the membrane and gas flowing through the other side of the membrane. The membrane is a composite hollow fiber having the three layers described above, in which a selective separation layer, an ultrafine porous layer, and a porous layer are formed in order from the inner surface, and the selective separation layer has an average thickness of 0.01 to It is a non-porous honey layer with a thickness of 5μ and which prevents plasma in blood from leaching into the gas side, and this ultra-fine porous layer has a surface where the presence of pores cannot be confirmed in a scanning electron micrograph at 24,000x magnification. , has a fluid permeability at least 10 times greater than that of the selective separation layer, and has a thickness of 0.08 μ or less, and the porous layer is composed of pores with a pore size of 0.1 to 1 μ, excluding giant vacuoles. This is achieved by an artificial lung characterized by a composite hollow fiber separation membrane having a sponge structure with a porosity of 50% or more and a thickness of 10 to 500 microns. The composite hollow fiber separation membrane used in the oxygenator of the present invention is characterized by being composed of three layers: a selective separation layer, an ultrafine porous layer, and a porous layer, in order from the inner surface of the hollow fiber. The microporous layer and the porous layer are arranged, and each layer has a structure as described below. First, in the composite hollow fiber separation membrane used in the oxygenator of the present invention, a selective separation layer is formed on the inner surface. In conventional composite hollow fiber separation membranes, a selective separation layer is generally formed on the outer surface of the hollow fibers. When such composite hollow fiber separation membranes are actually used, they tend to be susceptible to various types of damage such as peeling or damage of the selective separation layer due to mutual contact between the composite hollow fibers on their outer surfaces, or they are extremely difficult to handle. It is clear that it is difficult and disadvantageous. The present invention does not have the above-mentioned drawbacks because it has a selective separation layer on the inner surface of the porous hollow fiber membrane substrate. Hereinafter, the three layers constituting the composite hollow fiber separation membrane used in the oxygenator of the present invention will be explained in order. (i) Selective Separation Layer In the present invention, the selective separation layer has a non-porous honey structure so that the polymer constituting the selective separation layer does not substantially penetrate into the ultrafine porous layer or even into the porous layer. It is important that this permeable layer is formed, and the presence or absence of this permeable layer can be confirmed by observation with a scanning electron microscope. In addition, its average thickness is 0.1~
The thickness must be within the range of 2μ, and the thickness variation rate must be 25% or less.
This average thickness and its rate of variation can be determined by observing at least 25 locations using a scanning electron microscope. If the thickness exceeds 2μ, the amount of transmission will be small and it is inappropriate. On the other hand, 0.01μ
If it is thinner, the strength of the selective separation layer itself becomes too low, and there is a high risk that it will easily break during handling and cause pinholes, which is not preferable. In order to provide a composite hollow fiber separation membrane with excellent operability and high flow rate permeability, it is more desirable that the thickness be in the range of 0.05 to 0.8μ. Furthermore, in conventional composite hollow fiber separation membranes, the selective separation layer usually has a structure with extremely uneven thickness. For example, the patent application filed earlier by the inventor in 1986-
Looking at the thickness unevenness of the silicone rubber thin film formed on the outer surface of the porous hollow fiber membrane-like base material obtained according to Example (1) of 137282, there are variations as shown in Table 2 in the comparative example described below. The rate = σ/x = 0.266, which is extremely large. In this way, when there is large thickness unevenness, for example, when actually used as an oxygen enrichment membrane, it is usually necessary to perform pressurization or depressurization, but in this case, the thinner part of the membrane is subjected to stress intensively. It is easily damaged by exposure to water and cannot exhibit the desired concentration performance. Therefore, the thickness unevenness must be small. One of the structural features of the composite hollow fiber separation membrane used in the oxygenator of the present invention is that the thickness unevenness of the thin polymer film formed on the inner surface is extremely small. In addition, even when subjected to decompression operation, stress is not concentrated in a specific location, and therefore, it is an excellent form that can completely solve the above-mentioned drawback that the polymer thin film is damaged during operation. This thickness unevenness can be easily measured by observing the thickness of at least 25 locations on the inner surface in detail using a scanning electron microscope, but in the present invention, the average value ( ) of the thickness of the 25 locations is used as a standard. The ratio (variation rate) of the deviation (σ) is: variation rate = σ/x≦0.25, more preferably variation rate = σ/x≦0.20, and there is extremely little thickness unevenness. Polymers forming such a selective separation layer include polyorganosiloxanes such as polydimethylsiloxane, polydiphenylsiloxane, and polymethylphenylsiloxane, and poly-4-methylpentene-1, depending on the purpose of separation of the composite hollow fiber. Various polymers with high selective separation permeability can be used, such as polytetrafluoroethylene, furfuryl alcohol resin, cellulose acetate, cellulose triacetate, and poly-4-vinylpyridine. It is a suitable polymer in the sense that it is the largest of all polymers. Furthermore, silicone rubber, which has improved strength and solvent resistance by three-dimensionally crosslinking such chain polyorganosiloxane with a crosslinking catalyst, has better strength and physical properties than a selective separation layer made of chain polyorganosiloxane. It has the great advantage of being able to be made into a thinner film because of its improved properties. (ii) Ultra-fine porous layer and porous layer Next, regarding the ultra-fine porous layer adjacent to the selective separation layer, the surface is so extremely fine that the presence of pores cannot be confirmed even in a scanning electron micrograph at 24,000x magnification. It is necessary that the layer has an ultra-fine porous structure. The fluid permeability of the ultrafine porous layer itself must be at least 10 times that of the selective separation layer, and its thickness must be 0.08 μm or less. The pore size on the surface of the ultra-fine porous layer is 24,000
If the size is larger than that which can be confirmed in a scanning electron micrograph at 200% magnification, there is a possibility that the extremely thin selective separation layer will be damaged and pinholes will occur if it is subjected to pressurization during practical use. increase,
Undesirable. Therefore, the smaller the pore size on the surface of the ultrafine porous layer is, the more desirable it is, but if it becomes too dense, it becomes undesirable as it becomes a resistance to fluid permeation. In that sense, the fluid permeability of the ultrafine porous layer itself is at least as high as that of the selective separation layer.
It needs to be 10 times larger, and its thickness must be as thin as 0.08μ or less. Furthermore, regarding the porous layer adjacent to the ultrafine porous layer, except for special giant vacuoles, mainly 0.1
It consists of a sponge structure consisting of an accumulation of pores of ~1 μ in size, and the porosity is over 50% and the thickness is
Must be between 10μ and 500μ. Such structural features can be easily confirmed using a scanning electron microscope. If the pore size of the sponge structure is smaller than 0.1μ, the fluid permeation resistance of the porous layer itself becomes too large, which is not desirable. On the other hand, if the pore size of the sponge structure is larger than 1 μm, the pressure resistance during practical use will decrease and the sponge structure will no longer function as a support for the composite membrane. The porosity can also be determined by measuring the moisture content, but this value is 50%.
If it is smaller, fluid permeation resistance increases, which is undesirable. Regarding the thickness, if it is thinner than 10μ, the strength of the composite membrane as a whole will be low and it will be less practical. If it is larger than 500 μm, the composite hollow fiber becomes quite thick, which makes it difficult to create a compact separation membrane module, which is not preferable. As a support for the selective separation layer, it is sufficient for the ultrafine porous layer and the material for forming the porous layer to have mechanical strength and physical properties as a support, so in this sense, for example, polyvinyl alcohol A wide variety of polymeric materials such as , aromatic polysulfone, polyimide, and polyetheretherketone can be used, and among them, it is also possible to use a mixture of various compatible materials. Particularly desirable are aromatic polysulfones, which have various advantages such as excellent hollow fiber moldability and good heat resistance. Regarding the composite hollow fiber separation membrane used in the oxygenator of the present invention having a three-layer structure as described above,
Unlike the two-layer structure composite membrane disclosed in the above-mentioned Japanese Patent Publication No. 17589/1989, the selective separation layer is
Because it is formed on an extremely fine porous layer that cannot be confirmed to have pores even in a scanning electron microscope photograph taken at double magnification, the selective separation layer may be damaged even if pressure is applied during use. There are no holes at all. And the thickness of the ultrafine porous layer is
It is extremely thin, less than 0.08μ, so the fluid permeation resistance of the ultrafine porous layer itself is sufficiently small.
Furthermore, the supporting porous layer has a fairly large pore size of 0.1 to 1μ, a sponge structure, and has a low porosity.
It has the advantage that the fluid permeability of the support porous layer itself is also sufficiently high, which is as high as 50% or more. Therefore, the three-layer composite hollow fiber membrane as a whole has an excellently high fluid permeation rate and is also excellent in practicality such as pressure resistance. Next, a method for manufacturing the composite hollow fiber separation membrane used in the oxygenator of the present invention will be described. A feature of the method for producing the hollow fiber separation membrane used in the present invention is that the pore-forming polymer capable of forming micropores is mixed with the matrix polymer that is to form the porous hollow fiber membrane substrate from the beginning. The non-porous hollow fiber membrane is formed into a hollow fiber membrane with a non-porous inner surface, and the non-porous inner surface of the non-porous hollow fiber membrane has high selective separation permeability for specific substances. The purpose of this method is to apply a polymeric component having, for example, a solution state. By doing this, since the inner surface is a smooth surface with no pores, it is naturally impossible for it to penetrate into the pores, and as a result, it is impossible to achieve this with conventional methods for creating hollow fiber composite membranes. It is possible to form an extremely ultra-thin selective separation layer that has never been seen before without producing any pinholes. Then, by discharging and removing the pore-forming polymer, the hollow fiber base material is made porous and a composite hollow fiber separation membrane is obtained. Hereinafter, the method for manufacturing the composite hollow fiber separation membrane used in the oxygenator of the present invention will be described in order. (i) Production of non-porous hollow fiber substrate In order to obtain the composite hollow fiber separation membrane used in the oxygenator of the present invention, the matrix polymer and the pore-forming polymer are mixed in a common solvent that is highly compatible with both. After uniformly mixing using
As a result, a non-porous hollow fiber membrane substrate in which the matrix polymer and the pore-forming polymer are mixed extremely uniformly is obtained. Regarding the polymer that should form micropores, it can be used without any particular restrictions as long as it is sufficiently compatible with the matrix polymer that is to form the porous hollow fiber membrane substrate and can be mixed and molded. obtain. In particular, the combination of aromatic polysulfone and polyvinylpyrrolidone has extremely good compatibility, and the pores formed by extraction of polyvinylpyrrolidone are extremely fine, making it suitable for use as a support for the selective separation layer. It is truly suitable for this purpose. In addition to the above, polyethylene glycol, polyacrylic acid, and polyacrylamide can also be used as the pore-forming polymer. What is important in the method for producing the hollow fiber separation membrane described above is that the pore-forming polymer that will form micropores and the matrix polymer that will form the porous hollow fiber membrane substrate have extremely excellent compatibility. As a result, when the pore-forming polymer is extracted and removed later, the hollow fiber base material can be made into a porous body consisting of fine pores. If the compatibility is poor, the pores formed later in the porous support will be considerably larger. In this case, when a composite separation membrane having a selective separation layer in the form of a thin polymer film on its inner surface is put into practical use, the selective separation layer formed with great effort may be damaged, resulting in the separation performance that should not be expected. This can easily lead to a situation where the person is unable to fully demonstrate his/her abilities.
Therefore, a composite hollow fiber separation membrane having a pinhole-free selective layer that is formed extremely thin so as not to penetrate into the fine pores on the inner surface of a porous substrate has been put into practical use and is expected. In order to exhibit the original separation performance, for example, it is essential that the micropores that are formed later during extraction be sufficiently small in size. It is important to select as the pore-forming agent a pore-forming polymer that is sufficiently compatible with the matrix polymer to form the membranous substrate. Regarding the ratio of matrix polymer to pore-forming polymer, the weight ratio is 100:25 to 100:
The ratio is preferably 200, and more preferably in the range of 100:50 to 100:100. The ratio of pore-forming polymer to matrix polymer is 100:
When it is smaller than 25, the number of micropores obtained by removing the pore-forming polymer is small, and therefore the amount of permeation through the composite hollow fiber separation membrane obtained using the same is small, which is poor in practicality. On the other hand, when the ratio of the pore-forming polymer to the matrix polymer is greater than 100:200, the number of micropores obtained by removing the pore-forming polymer becomes too large; Although the permeation rate of the composite hollow fiber separation membrane is large enough and highly practical, the proportion of the porous portion is extremely large, and the porous hollow fiber membrane-like substrate formed by the matrix polymer is The relative strength of the selective separation layer decreases, and the selective separation layer cannot sufficiently function as a strong support, making it unsuitable. As described above, a matrix polymer and a pore-forming polymer are selected, mixed in a predetermined ratio, and dissolved in a common solvent to prepare a spinning dope.
Non-porous hollow fibers can be obtained by discharging this spinning stock solution into a coagulation bath through an annular nozzle. For example, when polyvinylpyrrolidone or polyethylene glycol is selected as a pore-forming polymer, by selecting dimethylformamide as a solvent, they are easily and uniformly compatible with aromatic polysulfone, and this uniform When the compatible spinning dope is discharged into the water coagulation bath from an annular nozzle while injecting room temperature water into the inner surface and formed into a hollow fiber membrane, the common solvent dimethylformamide etc. is removed and the result is A non-porous hollow fiber curtain in which polyvinylpyrrolidone or polyethylene glycol as a polymer for forming micropores and aromatic polysulfone as a matrix polymer to form a porous hollow fiber membrane substrate are extremely uniformly mixed. A membrane material is obtained. When this spinning stock solution is discharged into a coagulation bath from a ring-shaped nozzle, it is important to solidify the inner surface quickly.For this purpose, water or a coagulant mainly composed of water is applied to the inner surface of the hollow fiber as an inner coagulant. It is preferable to perform injection molding while pouring. For example, when an aqueous dimethylformamide solution (dimethylformamide is 50% by weight or more) is used as an inner coagulant, especially at a high temperature of 50°C or higher, coagulation on the inner surface is slow, and the resulting hollow fiber base material can be used as a pore-forming polymer. After extraction, the pores on the inner surface become larger, making it difficult to obtain an extremely fine porous layer, which is not suitable. (ii) Formation of a selective separation layer The non-porous inner surface of the thus obtained non-porous hollow fiber membrane base material is coated with
A polymer component with high selective separation permeability is prepared in the form of a thin film. As mentioned above, the polymer thin film components include polyorganosiloxanes, poly-4-methylpentene-1, polytetrafluoroethylene, furfuryl alcohol resin, cellulose acetate, cellulose triacetate, Various polymers with high selective separation permeability can be used, such as poly-4-vinylpyridine, but polyorganosiloxane is suitable because it has the largest oxygen permeation rate constant, and it also has stronger physical properties. In terms of improved performance, silicone rubber obtained by three-dimensionally crosslinking such a chain polyorganosiloxane using a crosslinking catalyst is most desirable. These polymers are usually used after being dissolved in a suitable solvent, but the concentration of the mixed solution used is 1 to 50.
% by weight, preferably 3-30% by weight. Too low a concentration is undesirable because it tends to cause pinholes. On the other hand, if the concentration is too high, the thickness of the thin film formed tends to be large, which is undesirable as it leads to a decrease in the permeation flow rate. In the composite separation membrane used in the oxygenator of the present invention, it is important that the selective separation layer formed on the inner surface of the porous hollow fiber is extremely thin, has very little unevenness in thickness, and has a uniform thickness. As a result of various studies on this point, the inventor of the present invention unexpectedly found that, for example, a polysiloxane prepolymer solution containing a crosslinking catalyst was supplied to the inner surface of the hollow fiber base material and allowed to drip naturally to remove the liquid. Then, by passing gas through the inner surface of the hollow fiber and then crosslinking it to form a three-dimensionally crosslinked silicone rubber thin film on the inner surface of the hollow fiber, the rate of variation in the thickness unevenness of the thin film is as follows: Rate of variation = σ/x≦0.25, more preferably, the variation rate=σ/x≦0.20, which is extremely small and uniformly formed. The mechanism of the phenomenon that occurs when gas is passed through the inner surface of the hollow fibers is not clear, but when gas is passed through the coating solution to form a selective separation layer, the vaporization of the coating solution It seems that there is a complex interaction between the concentration effect of the coating stock solution due to the evaporation of the solvent as the gas passes through, and the effect of wiping off the coating stock solution as the gas passes. However, the formation of such a uniform thin film with very little thickness unevenness has never been possible with conventional techniques.The present invention described above has made it possible to form a uniform thin film with very little thickness unevenness. This became possible for the first time with the discovery of a process in which gas is passed through after passing liquid. It is especially important to repeat the process of passing the coating stock solution through the inner surface of the hollow fibers and then passing the gas through it two or more times, especially when obtaining a selective separation layer with less uneven thickness. It is valid. In addition, when passing the coating stock solution through the inner surface of the hollow fiber, if a gold thread of, for example, about 100 mesh is placed close to the inlet end face of the coating stock solution, the fine mesh of the gold thread will be removed after the coating stock solution has passed through the hollow fiber. A large amount of coating stock solution is held inside,
After that, when the gas is passed through, the coating stock solution held in the mesh of the gold wire near the inlet end face of the hollow fiber is very efficiently concentrated and supplied to the inner surface of the hollow fiber. When repeating the process of passing the coating stock solution and subsequently passing the gas many times, the number of repetitions can be efficiently reduced. Of course, the above-mentioned installation of about 100 meshes of gold wire is just one example, and there is no restriction on the type of the liquid reservoir mechanism as long as it can hold the coating stock solution near the inlet end of the hollow fiber. As the gas to be used, it is advantageous to use air from various viewpoints, and 0.1
It is sufficient to pass it for 1 sec or more at a linear velocity of ~50 m/sec. In the case of a slow speed of 0.1 m/sec or less, the effect of reducing thickness unevenness is small. On the other hand, in the case of extremely high speeds of 50 m/sec or more, the mixed solution supplied to the inner surface is blown away, which is undesirable because it also causes uneven thickness. As for the time, it is sufficient if it is performed for 1 second or more each time. The coating operation for forming the selective separation layer as described above may be performed after the hollow fibers are tied together to form a module, or may be performed on the hollow fibers before the module is formed. (iii) Extraction of pore-forming polymer After forming the selective separation layer as described above, the polyvinyl pore-forming polymer can be easily extracted by contacting the outer surface of the hollow fiber with water, ethanol, or methanol, for example. Pyrrolidone or polyethylene glycol can be extracted and removed. Regarding the extraction and removal method, water extraction is the simplest, and in that sense, it is convenient to use a water-soluble polymer such as polyvinylpyrrolidone or polyethylene glycol as the pore-forming polymer because water extraction is possible. However, when attempting to extract in a short time, it is usually necessary to extract with hot water such as boiling water, and the selective layer formed during the extraction may be damaged due to convection of the extracted water, or There is a risk of it peeling off. In order to avoid this danger, even at a relatively low temperature of, for example, 60℃,
It is desirable to use ethanol or methanol as an extraction solvent, which has a sufficient extraction rate.
Of course, when selecting an extraction solvent, it goes without saying that an extraction solvent must be used that does not dissolve the matrix polymer and the selective layer portion on the inner surface. As a result, the fluid permeability is
Although it is at least 10 times larger than the selective separation layer, its surface is so honeyed and thick that the presence of pores cannot be seen even in a scanning electron micrograph at 24,000x magnification.
Extremely thin, less than 0.08μ. Except for the extremely fine porous layer and the giant vacuoles adjacent to it, it has a sponge structure of 0.1 to 1μ, with a porosity of 50% or more.
It consists of a porous layer whose thickness is 10 to 500μ.
A porous hollow fiber substrate is formed. The membrane oxygenator should be a composite hollow fiber consisting of three layers, in order from the inner side: a selective separation layer with excellent oxygen gas permeation performance and carbon dioxide gas permeation performance, an ultrafine porous layer, and a porous layer. is important, and in particular, although the presence of pores cannot be confirmed on the surface even in a scanning electron micrograph at 24,000x magnification,
The fluid permeability is at least 10 times that of the selective separation layer, and the thickness is 0.08μ or less.
It has been recognized that the presence of an extremely fine porous layer is an essential requirement for obtaining a practically excellent membrane oxygenator. In other words, although the ultra-fine porous layer is so microporous that the presence of pores cannot be confirmed even in a scanning electron microscope photograph taken at 24,000x magnification, it is still a dense layer, so it is microscopic. When viewed from above, it is an extremely smooth surface with no irregularities, so the selective separation layer formed on it is also
The thickness is sufficiently thin, and there is little unevenness in thickness. Regarding the above-mentioned conventional composite hollow fiber membrane oxygenator that lacks the presence of the ultrafine porous layer, that is, it is composed of two layers: a selective separation layer and a porous layer (Japanese Patent Application Laid-Open No. 52-117)
15483, Japanese Patent Application Laid-open No. 1548-160098), the surface of the porous layer on which the selective separation layer is to be formed is inevitably uneven and cannot be called extremely smooth when viewed microscopically. The selective separation layer formed on top is
Inevitably, the layer tends to be thick, and also tends to have uneven thickness. In a composite hollow fiber separation membrane used in an oxygenator, the selective separation layer may be a non-porous honey layer with an average thickness of 0.01 to 5μ, and is not required to be as strict as when used as an oxygen enrichment membrane. However, when the thickness is less than 0.01 μm, the selective separation layer becomes too thin and easily damaged, making it impractical.
If it is thicker than 5μ, the gas exchange rate will be poor and this is also not practical. Furthermore, if the selective separation layer has uneven thickness, stress tends to concentrate on the thinner portions, which tends to cause damage to the selective separation layer. Therefore,
It is desirable to have less thickness unevenness, and the above-mentioned variation rate is 25
% or less. In particular, when a membrane oxygenator with a high gas exchange rate is required,
It is desirable that the selective separation layer is formed such that the polymer component constituting the selective separation layer does not penetrate into the ultrafine porous layer. By doing this, the thickness of the selective separation layer becomes even thinner, and therefore,
Furthermore, an extremely excellent membrane oxygenator with a high gas exchange rate can be obtained. Regarding the ultrafine porous layer and the material of the porous layer of the composite hollow fiber membrane oxygenator using the composite hollow fiber membrane having a three-layer structure of the present invention, the reasons are the same as those described above. Therefore, aromatic polysulfone is particularly desirable.As for the material for the selective separation layer, polyorganosiloxane-based polymers that have excellent blood compatibility and extremely high oxygen permeation rates and carbon dioxide gas permeation rates are particularly desirable. , three-dimensionally crosslinked polyorganosiloxane polymers are particularly desirable in the sense that they have higher strength. Furthermore, by using a large number of bundles of composite hollow fiber membranes having a three-layer structure, for example, a cylindrical membrane oxygenator module can be easily produced by a conventional method, and this cylindrical membrane oxygenator module can be incorporated. A membrane oxygenator system can be formed. Such an artificial lung is used as follows. First, from a venous reservoir that stores venous blood removed from the patient's veins, the blood is heated to a constant temperature by using a blood roller pump, for example, and passed through a multi-tubular heat exchanger, and then pumped into the membrane oxygenator module. (Oxygen gas/carbon dioxide gas)
The function as an artificial lung is achieved by exchanging the blood and returning the blood, which has been enriched with a predetermined amount of oxygen gas, to the patient's artery via the blood supply line. In addition to the oxygenator, the above-mentioned devices are included to form an oxygenator system. Furthermore, a composite module in which a multi-tubular heat exchanger is also integrally attached to the venous blood inlet of a cylindrical membrane oxygenator module is simpler and more practical. Furthermore, there is no problem in installing additional equipment other than the above, such as a recirculation line, if necessary. Hereinafter, the present invention will be specifically explained using Examples, but the Examples are only one aspect of the present invention, and the present invention is not limited only to the Examples. [Example] Example 1 Aromatic polysulfone (trade name: Udel polysulfone: P-1700: manufactured by Union Carbide)
A spinning stock solution was prepared by mixing and dissolving 100 parts by weight of polyvinylpyrrolidone and 100 parts by weight of polyvinylpyrrolidone in 500 parts by weight of dimethylformamide, which is a common solvent for both.
This stock solution is discharged from an annular nozzle and formed into a hollow fiber by supplying water to the hollow part. After spinning, the hollow fiber is passed through a water bath to remove dimethylformamide, and then dried to form a final product. A nonporous hollow fiber membrane substrate having an outer diameter of 800 μm, an inner diameter of 500 μm, and a membrane thickness of 150 μm was obtained, in which 100 parts by weight of aromatic polysulfone and 100 parts by weight of polyvinylpyrrolidone were mixed extremely uniformly. On the other hand, room temperature curing silicone rubber (product name:
Silpot 184w/c: manufactured by Dow Corning) and
Dissolve 1/10 of that amount of curing catalyst in n-pentane.
A 10% by weight silicone solution was prepared. The silicone solution prepared in this way was applied to the inner surface of each hollow fiber of the 200 non-porous hollow fiber membrane base materials described above in a bundle at a feeding rate of about 30 ml/min. Supplied for minutes. Thereafter, the silicone solution was drained by natural dripping, and then air was passed through the solution at a linear speed of 15 m/sec for about 1 minute. This process was repeated 10 times. After this, crosslinking treatment was performed at 100℃×1HR.
Thereafter, polyvinylpyrrolidone was extracted and removed by immersion in 60°C ethanol for 16 hours. By this method, the final result is a porous hollow fiber membrane-like base material consisting of an ultrafine porous layer formed from aromatic polysulfone and an adjacent porous layer, and a porous hollow fiber membrane-like base material with ultrafine porous layers on the inner surface. A selective layer of silicone rubber thin film formed so as not to substantially penetrate into the porous layer and having an extremely uniform thickness both in the circumferential direction of the inner surface of the hollow fiber and in the fiber axial direction. A composite hollow fiber separation membrane was obtained. Regarding the structure of the obtained composite hollow fiber separation membrane, first, regarding the selective separation layer part, 25 locations on the inner surface were observed in detail using a scanning electron microscope, and it was found that the thickness of the silicone rubber thin film formed on the inner surface was The results were as shown in Table 1. In the obtained composite film, the average thickness of the thin film-like selective layer is = 3300 Å, and the standard deviation is and therefore the average thickness () with standard deviation (σ)
The ratio (variation rate) to It was clearly observed that it was a completely new form that had not invaded the country.

【table】

[Table] Next, the silicone rubber thin film was peeled off from the inner surface of the obtained composite hollow fiber membrane, being careful not to destroy the ultrafine porous layer, and the exposed ultrafine porous layer was Scanning electron microscopy observation was performed.
The resulting photograph is shown in Figure 3, and the structure is so dense that no pores can be seen under 24,000x magnification, and its thickness is about 0.05 μm, as shown in the same photograph. In Figure 3,
At the same time, the state of the porous layer is also shown;
It is clear that it has a sponge structure consisting of an accumulation of pores. The porosity of this porous layer was determined to be 76% based on the water content. Next, the permeation performance of the obtained composite hollow fiber separation membrane when used as an oxygen enrichment membrane will be described in detail. Air pressurized to 7 kg/cm ² gauge pressure is supplied onto the inner surface of the composite hollow fiber separation membrane having a selective layer of silicone rubber thin film with an average thickness of 3300 Å on the inner surface, and the oxygen in the air and Selective separation of nitrogen was carried out. When the composition of the permeated gas was analyzed by gas chromatography, it was found that oxygen was about 35 vol% and nitrogen was about 65 vol%. This oxygen concentration is exactly the same as the oxygen concentration when pressurized air at 7 kg/cm ² gauge pressure is supplied to a silicone rubber film with no pinholes.
From this fact, the silicone rubber thin film formed on the inner surface of the porous hollow fiber membrane substrate made of aromatic polysulfone has no defects such as pinholes, and the film does not break even when pressurized. There was no problem at all, and it is clear that the original separation performance was fully demonstrated. Furthermore, the permeation flow rate of oxygen-enriched air with an oxygen concentration of approximately 35 vol% is approximately 2×10 ³ ml/
It is excellent and practical at 24HRS・m ²・Kg/cm ² . Furthermore, when air pressurized to 7 kg/cm ² gauge pressure is supplied to the inner surface of the above-mentioned material with a thin silicone rubber film peeled off, the amount of air permeation is 3 x 10 ¹¹ ml/
It was 24HRS・m ²・Kg/cm ² , which was 1500 times the amount of enriched air permeation mentioned above. By the way, regarding the air permeability of this hollow fiber base material, which consists of two layers: an ultra-fine porous layer and a porous layer with a silicone rubber thin film peeled off from the inner surface, the porous layer has a sponge structure of 0.1 to 1μ. In addition, the porosity is extremely high at 76%, which means that the air permeation resistance is extremely small and can be ignored compared to the air permeation resistance of the ultra-fine porous layer.
Therefore, the above-mentioned air permeation amount of 3×10 ¹¹ ml/24 HRS·m ² ·Kg/cm ² is the air permeation amount controlled by the ultrafine porous layer. Comparative Example 1 In the same manner as in Example 1, aromatic polysulfone
100 parts by weight and 100 parts by weight of polyvinylpyrrolidone are uniformly mixed, outer diameter 800μ, inner diameter 500μ, film thickness
A 150μ non-porous hollow fiber membrane substrate was obtained. This material was immersed in ethanol at 60° C. for 16 hours to first extract and remove polyvinylpyrrolidone, thereby obtaining a porous hollow fiber membrane-like substrate made of aromatic polysulfone. The inner surface of this thing,
When observed with a scanning electron microscope at a magnification of 24,000 times, an ultrafine porous layer with a thickness of 0.05 μm was observed, but the presence of pores could not be confirmed. The porous layer adjacent thereto was also clearly observed and had substantially the same structure as described in Example 1 above. A bundle of 200 such porous hollow fibers was prepared, and a 10% by weight silicone solution prepared in the same manner as in Example 1 was supplied to the inner surface of each hollow fiber at a rate of about 30ml/min. The silicone solution was supplied for about 3 minutes, and then the silicone solution was drained by natural dripping, and then air was passed through it for about 1 minute at a linear speed of about 15 m/sec. This process was repeated 10 times.
Thereafter, a composite hollow fiber separation membrane was obtained by crosslinking for 1 hour at 100°C. When pressurized air of 7 kg/cm ² gauge pressure was supplied to the inner surface of this material to perform separation, the composition of the permeated gas was as follows: oxygen = approximately 35 vol%, nitrogen = approximately 65 vol.
%, and although a pinhole-free composite hollow fiber separation membrane was obtained, the permeate gas flow rate was approximately 10 ⁶
It was extremely small at ml/24HRS・m ²・Kg/cm ² and could hardly be put to practical use. When the cross section of this hollow fiber composite membrane was observed using a scanning electron microscope, it was found that an extremely thick silicone rubber penetration layer of about 4μ was formed on the inner surface of the porous hollow fiber base material within the ultrafine porous layer and into the porous layer. It was clearly observed that This 4μ
Due to the formation of an extremely thick layer of silicone rubber that penetrates into the pores, the flow rate of the permeated gas obtained as described above must be extremely small, making the composite hollow fiber membrane extremely impractical. It seems that he had no choice but to become. On the other hand, in order to increase the permeation gas flow rate, it was thought that it would be better to reduce the thickness of the silicone rubber penetration layer, and for that purpose, it was thought that it would be better to lower the concentration of the silicone solution used. When the same experiment as above was carried out using a 1% by weight silicone solution with a concentration lowered by one order of magnitude, the permeate gas flow rate was extremely large, approximately 10 ³ ml/24 HRS m ² Kg/cm ² . Nevertheless, when its composition was analyzed by gas chromatography, oxygen = approximately 21 vol%, nitrogen = approximately
It is not concentrated at all at 79vol%, which means that the silicone rubber membrane formed on the inner surface of the porous hollow fiber base material has an extremely large number of pinholes. Therefore, it cannot exhibit its original separation performance at all. Comparative Example 2 100 parts by weight of aromatic polysulfone and 100 parts by weight of polyvinylpyrrolidone were uniformly mixed.
A non-porous hollow fiber membrane substrate having a diameter of 640μ, an inner diameter of 320μ, and a membrane thickness of 160μ was obtained. On the other hand, room temperature curing silicone rubber (product name:
Silpot 184w/c: manufactured by Dow Corning) and
Dissolve 1/10 of that amount of curing catalyst in n-pentane.
A 30% by weight silicone solution was prepared. The aforementioned non-porous hollow fiber membrane substrate was sealed at its ends and immersed in the 30% by weight silicone solution prepared in this manner for 10 minutes without the silicone solution penetrating inside the hollow fibers. ℃ for 60 min.
Silpot 184w/c was cured and polymerized on the outer surface of the non-porous hollow fiber by hot air drying.
After this, the non-porous hollow fibers were immersed in a 30% silicone solution again and then dried with hot air at 100°C for 60 minutes to form a strong bond with the aromatic polysulfone base material and free of pinholes on the outer surface of the non-porous hollow fibers. We created an ultra-thin film completely free of silicone rubber. Next, polyvinylpyrrolidone is extracted and removed from the inner surface by passing ethanol at 60°C inside the non-porous composite hollow fibers obtained in this way, thereby forming a porous hollow fiber-like membrane group made of aromatic polysulfone. A hollow fiber-like composite separation membrane was obtained, which consisted of a material and a selective separation layer of a silicone rubber thin film formed on the outer surface of the material. Regarding the thickness of the silicone rubber thin film of this product, the thickness at 25 locations was observed in detail using a scanning electron microscope, and the results shown in Table 2 were obtained. and therefore the average thickness () with standard deviation (σ)
The ratio (variation rate) to

【table】

[Table] Example 2 150 composite hollow fiber separation membranes with an outer diameter of 800μ, an inner diameter of 500μ, and a membrane thickness of 150μ, each having a silicone rubber thin film with an average thickness of 3300Å on the inner surface obtained in Example 1, were bundled in parallel. It is concentrated and filled into a transparent cylindrical polycarbonate container having an oxygen gas inlet and an outlet, and then both ends of the composite hollow fiber bundle and the end of the polycarbonate cylindrical container are connected using resin. After adhesive molding to prevent leakage of gas, etc., both ends of the composite hollow fiber bundle were cut to open the inner hole of each hollow fiber. In this way, we prototyped an extremely small composite hollow fiber oxygenator with an effective length of 10 cm and an effective internal surface area of 240 cm ² . Fresh bovine blood was passed through the inner surface of the hollow fibers of such a composite hollow fiber oxygenator at a flow rate of 230 ml/min, while oxygen gas was introduced onto the outer surface of the hollow fibers through the oxygen gas inlet of the polycarbonate container. The oxygen gas was passed through the membrane at a flow rate of 230 ml/min, and the oxygen gas was exchanged through the composite hollow fiber membrane. Gas exchange time was 24 hours. At this time, the amount of oxygen gas transferred into the cow's blood was actually measured to be 63 ml/min・m ² at 15 minutes after the start of gas exchange, and 58 ml/min・m ² after 24 hours, which is an extremely large amount of oxygen gas permeation. The speed remained stable for a long time. Furthermore, during this period, there was no problem of plasma components or water in the blood leaking out to the outer surface of the hollow fibers, and no clogging of the hollow fibers was observed when the blood was returned after completion of the test. The degree of hemolysis of oxygenated blood is low, and the occurrence of microthrombi is at a sufficiently low level, and the composite hollow fiber oxygenator according to the present invention, which has a silicone rubber thin film on its inner surface, is an excellent material that can withstand long-term use. He was put on an artificial lung.

[Brief explanation of the drawing]

FIG. 1 is a model diagram of a composite hollow fiber separation membrane used in the oxygenator of the present invention. In FIG. 1, 1 is a selective separation layer, 2 is an extremely fine porous layer, and 3 is a porous layer. FIG. 2 is a 24,000x scanning electron micrograph showing one embodiment of the cross-sectional structure of the composite hollow fiber separation membrane used in the oxygenator of the present invention. FIG. 3 is a 24,000x scanning electron micrograph showing an embodiment of the ultrafine porous layer exposed by peeling off the selective separation layer from the inner surface of the composite hollow fiber separation membrane used in the oxygenator of the present invention. . Fourth
The figure is a 24,000x electron micrograph of the ultrafine porous layer shown in Figure 3, viewed from the side.

Claims (1)

[Scope of Claims] 1. An oxygenator that performs gas exchange between blood and gas through a membrane by flowing blood on one side of the membrane and gas on the other side of the membrane, the membrane is a composite hollow fiber having the above three layers, in which a selective separation layer, an extremely fine porous layer, and a porous layer are formed in order from the inner surface, and the selective separation layer has an average thickness of 0.01 to 5μ, and This is a non-porous honey layer that prevents blood plasma from leaching out to the gas side, and although this ultra-fine porous layer has a surface where the presence of pores cannot be confirmed in a scanning electron micrograph at 24,000x magnification, it is more sensitive than the selective separation layer. has a fluid permeability of at least 10 times, and a thickness of 0.08μ or less, and the porous layer is composed of pores with a pore diameter of 0.1 to 1μ, excluding giant vacuoles, and has a porosity of 50% or more. It has a sponge structure with a thickness of 10~
An artificial lung characterized by having a composite hollow fiber separation membrane of 500μ. 2. The selective separation layer of the composite hollow fiber separation membrane is a selective separation layer formed on the ultrafine porous layer without penetrating into the ultrafine porous layer and having a thickness variation rate of 25% or less. The artificial lung according to scope 1. 3. The artificial lung according to claim 1, wherein the ultrafine porous layer and the porous layer are layers consisting essentially of aromatic polysulfone. 4. The artificial lung according to claim 1, wherein the selective separation layer is a layer made of a three-dimensionally crosslinked polyorganosiloxane polymer.