JPH0119902B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION (Technical Field) The present invention relates to an artificial lung. Specifically, the present invention provides an artificial lung that removes carbon dioxide from the blood and adds oxygen to the blood during extracorporeal blood circulation, which has a high carbon dioxide removal ability and is free from the risk of plasma leakage even after long-term use. This article concerns a membrane oxygenator that has no 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. Furthermore, in order to achieve the desired gas exchange performance, for example, when tens of thousands of hollow fiber membranes are bundled, the size of the device increases, 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 confirmed to be free of water leakage, 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 filed in 1983-1983), which is made by plugging the micropores of a porous membrane with silicone oil.
92325), he proposed an artificial lung (Japanese Patent Application No. 105384-1984), 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,
ECCO ₂ R (Extra Corporeal CO ₂ Removal;
It has been difficult to remove the amount of carbon dioxide produced by a living body with a small amount of extracorporeal circulating blood flow, as in the case of extracorporeal carbon dioxide removal. OBJECTS OF THE INVENTION Therefore, an object of the present invention is to provide a novel membrane oxygenator. The present invention also provides an oxygenator that removes carbon dioxide from the blood and adds oxygen to the blood during extracorporeal blood circulation, 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. The purpose is to provide a membrane oxygenator. A further object of the present invention is to provide a membrane oxygenator most suitable for ECCO ₂ R. The above purposes are as a gas exchange membrane with a wall thickness of 5 to 5.
80μm, porosity 20~80% and pore size 0.01~5μm
In a membrane oxygenator using a porous hydrophobic membrane,
The pores have an ultra-microporous structure due to particles smaller than the pores filled in the pores without adhering to the surface of the gas exchange membrane. This is achieved by a membrane oxygenator whose contact surfaces are hydrophobic. The present invention provides a membrane oxygenator in which the gas exchange membrane is a hollow fiber membrane. The present invention also provides a membrane oxygenator in which the hollow fiber membrane has an inner diameter of 100 to 1000 μm. The present invention provides a membrane oxygenator in which the fine particles are made of a hydrophobic substance.
The present invention further provides a membrane oxygenator in which the gas exchange membrane is made of olefin resin.
The present invention further provides a membrane oxygenator in which the gas exchange membrane is made of polypropylene.
The present invention also provides a membrane oxygenator in which the microparticles have a particle size of about 0.003 to 1.0 μm. Specific Structure of the Invention The present invention will be explained in more detail below based on the drawings. FIG. 1 is an enlarged sectional view showing the detailed structure of a gas exchange membrane in an embodiment of the membrane oxygenator of the present invention. As shown in FIG. 1, the gas exchange membrane 2 of the membrane oxygenator 1 is a hydrophobic porous membrane with a wall thickness of 5.
~80μm, preferably 10-60μm, porosity 20-80
%, preferably 30-60%, and the pore size is 0.01-
It is about 5 μm, preferably about 0.01 to 1 μm.
In this embodiment, the gas exchange membrane has an inner diameter of
It has a hollow fiber shape of 100 to 1000 μm, preferably 100 to 300 μm. However, the gas exchange membrane 2
Each of the pores 3 is blocked by microparticles 4 that are smaller than the pore diameter and whose surfaces that come into contact with blood are hydrophobic. Therefore, at least the surface of the gas exchange membrane 2 whose pores 3 are blocked by the fine particles 4 that come into contact with blood is kept hydrophobic. Each pore 3
In this embodiment, the pores 3 are filled with fine particles 4 and are closed. and,
As shown in FIG. 1, there are no particles on the surface of the gas exchange membrane 2, and the surface of the gas exchange membrane 2 is smooth. As a result of each of the pores 3 being blocked by the fine particles 4 in this manner, the gas exchange membrane 2 has ultra-fine pores that cannot be confirmed under an electron microscope. As the material of the gas exchange membrane 2, hydrophobic polymers such as polypropylene, polyethylene, polytetrafluoroethylene, polysulfone, polyacrylonitrile, and cellulose acetate may be used, but polyolefin resins are preferably used, and polyolefin resins are particularly preferred. , polypropylene, and polypropylene in which micropores are formed by a stretching method or a solid-liquid phase separation method is most desirable. On the other hand, the materials of the fine particles 4 that block the pores 3 of the gas exchange membrane 2 include silica, alumina, zirconia, magnesia, barium sulfate, calcium carbonate, silicate, titanium oxide, silicon carbide, carbon black, and white. Inorganic substances such as carbon, or polymer latexes such as polystyrene latex, styrene rubber (SBR) latex, and nitrile rubber (NBR) latex may be used. However, if the material of these particles 4 is hydrophobic, they can be used as is to close the pores 3, but if the material of the particles is hydrophilic, the pores 3 may be closed before or after being blocked. After occlusion, at least the surface of the microparticles 4 that comes into contact with blood must be coated with a hydrophobic material, such as silicone. Moreover, the diameter of the fine particles 4 is
It is 0.003 to 1.0 μm, preferably 0.003 to 0.5 μm. The pores 3 of the gas exchange membrane 2 can be blocked with fine particles 4, for example, as follows. That is, the pores 3 of the hollow fiber gas exchange membrane 2
The gas exchange membrane 2 is filled with fine particles to block it.
First, make it hydrophilic with alcohol or the like. Next, an aqueous dispersion of the fine particles as described above is poured into the hollow fibers of the gas exchange membrane 2 and filtered. Then, the fine particles 4 contained in the aqueous dispersion get caught in the pores 3 of the gas exchange membrane 2, and the pores 3 are filled with the fine particles 4, causing clogging. 3
is occluded. Next, the inside of the hollow fiber is washed with a suitable fluid such as air or water to remove the dispersion liquid remaining inside the hollow fiber, and the fine particles on the surface of the gas exchange membrane 2 are removed. Furthermore, when the fine particles 4 are hydrophilic,
For example, dimethylpolysiloxane, methylphenylpolysiloxane, methylvinylpolysiloxane.
Examples of silicones such as methylphenyl vinyl polysiloxane, aminoalkyl siloxane, and dimethyl siloxane copolymers include 1,1,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane, 1,1,2, A solution of halogenated hydrocarbon such as 2-tetrachloro-1,2-difluoroethane is poured into the inside of the hollow fiber to make the silicone solution adhere to the surface of the fine particles 4 filled inside the hollow fiber. After removing the remaining silicone solution, it is dried, and the surface of the fine particles 4 is coated with a hydrophobic thin film of silicone. Furthermore, before drying, it is preferable to wash the inside of the hollow fiber with a fluid that does not dissolve the silicone. Although the pores 3 of the gas exchange membrane 2 can be clogged with particulates before the oxygenator is assembled, it is more preferable to perform the operation after the module is assembled. FIG. 2 shows an assembled state of a hollow fiber membrane oxygenator, which is an embodiment of the membrane oxygenator of the present invention. That is, the hollow fiber membrane oxygenator 1 includes a housing 5, and the housing 5 is provided with annular male-threaded mounting covers 7 and 8 at both ends of a cylindrical main body 6. for,
Hollow fiber-shaped gas exchange membranes 2, which are expanded as a whole and have a large number of pores 3 as described above, for example, 10,000 to 60,000, blocked by fine particles 4, are spaced apart from each other in parallel along the longitudinal direction of the housing 5. It is located. Both ends of the gas exchange membrane 2 are fluid-tightly supported by partition walls 9 and 10 in mounting covers 7 and 8 with their respective openings not being closed. Further, each of the compartments 9 and 10 together with the outer peripheral surface of the gas exchange membrane 2 and the inner surface of the housing 5 constitute an oxygen chamber 11 which is a first mass transfer chamber, and closes this, and The oxygen chamber 11 is isolated from a blood circulation space (not shown), which is a second mass transfer fluid space formed inside the oxygen chamber 11 . One mounting cover 7 is provided with an inlet 12 for supplying oxygen, which is the first mass transfer fluid. The other mounting cover 8 is provided with an outlet 13 for discharging oxygen. On the inner surface of the cylindrical main body 6 of the housing 5, a restricting portion 14 for aperture is located at the center in the axial direction and protrudes.
It is preferable to provide That is, the restraint part 14
is formed integrally with the inner surface of the cylindrical body 6, and is adapted to tighten the outer periphery of a hollow fiber bundle 15 consisting of a large number of gas exchange membranes 2 inserted into the cylindrical body 6. . In this way, the hollow fiber bundle 15 is narrowed at the center in the axial direction to form a narrowed portion 16, 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 16 is approximately 60 to 80%, and in the other cylindrical body 6 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 5, that is, on the outer surfaces of the partition walls 9 and 10, is about 20 to 40%. Next, the formation of the partition walls 9 and 10 will be described. As mentioned above, the partition walls 9 and 10 perform the important function of isolating the inside and outside of the gas exchange membrane 2. Usually, the partition walls 9 and 10 are made by pouring a highly polar polymeric potting material such as polyurethane, silicone, epoxy resin, etc. onto the inner wall surfaces of both ends of the housing 5 using a centrifugal injection method, and then hardening the material. More specifically, first, a large number of hollow fiber membranes 2 longer than the length of the housing 5 are prepared, both open ends of which are sealed with a high viscosity resin, and then inside the cylindrical body 6 of the housing 5. Place them side by side. After that, completely cover both ends of the gas exchange membrane 2 with a mold cover having a diameter larger than that of the mounting covers 7 and 8, and while rotating the housing 5 about the central axis of the housing 5, 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 9 and 10 are thus formed. The outer surfaces of the partition walls 9 and 10 are respectively covered with flow path forming members 17 and 18 having annular convex portions. The flow path forming members 17, 18 are respectively composed of liquid distribution members 19, 20 and screw rings 21, 22, and the end surfaces of protrusions 23, 24 are formed as annular convex portions provided near the peripheral edges of the liquid distribution members 19, 20. are brought into contact with the partition walls 9 and 10, respectively, and fixed by screwing the screw rings 21 and 22 onto the mounting covers 7 and 8, respectively, thereby creating an inflow chamber 25 and an outflow chamber 26 for blood, which is the second mass transfer fluid. are formed respectively. A blood inlet 27 and an outlet 28, which are a second mass transfer fluid, are formed in the flow path forming members 17 and 18, respectively. These partition walls 9, 10 and flow path forming members 17, 18
The gaps at the peripheral edges of the partitions 9, 10 formed by the above-mentioned partitions 9, 10 are filled with fillers 33, 34 from one of at least two holes 31, 32 communicating with the gaps. sealed in contact with. 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 explanation has been about hollow fiber membrane oxygenators, but flat membrane oxygenators such as stacked membranes, single membranes wound into a coil, and folded in a zigzag pattern can also be used. If the pores of the gas exchange membrane are smaller than the pore diameter and at least the surface in contact with blood is similarly blocked by hydrophobic fine particles, the gas exchange capacity, especially the CO ₂ removal capacity, will be high and long. A membrane oxygenator can be obtained in which substantially no plasma leakage occurs even after use 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. 4 with a membrane area of 1.6 m ² was assembled. Ethanol is introduced through the blood inlet 25 of the hollow fiber membrane oxygenator 1 to make the hollow fiber gas exchange membrane 2 hydrophilic.
Silica (colloidal silica, average diameter 100
Å)/aqueous dispersion was flowed in and filtered through the gas exchange membrane 3, 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. After 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. However, as will be explained later, this artificial lung allows air to pass through it, so it can be inferred that the pores of the gas exchange membrane are not completely obstructed, but instead become an ultra-microporous membrane. Ta. 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 ability of these artificial lungs. 1 In vitro evaluation Using fresh heparinized bovine blood, oxygen gas partial pressure 35mm
Venous blood with a partial pressure of Hg and carbon dioxide gas of 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 blood flow rate and oxygen gas addition ability and carbon dioxide removal ability when the ratio of oxygen flow rate to blood flow rate is 1 is as shown in Table 1 and FIG. 3. The relationship between oxygen flow rate and carbon dioxide removal ability when blood flow rate is 1500ml/min is shown in Tables 2 and 4.
It was as shown in the figure. 2 Animal Test A 30-hour venous-arterial partial extracorporeal circulation test was conducted using mongrel dogs. The relationship between the circulation test and the amount of plasma leakage was as shown in Table 3 and Figure 5. Comparative example 2 Inner diameter 200μ, wall thickness 25μ, porosity 45%, average pore diameter
An oxygenator module with an effective membrane area of 1.6 m ² was fabricated using a polypropylene-silicone composite membrane consisting of 700 Å polypropylene hollow fibers coated with silicone rubber. Similar to Example 1 and Comparative Example 1, in vitro tests and animal tests were conducted on this artificial lung module. The results are shown in Tables 1 to 3 and Figures 3 to 5, respectively.

【table】

【table】

【table】

[Table] Specific Effects of the Invention As described above, the present invention provides a gas exchange membrane with a wall thickness of 5 to 80 μm, a porosity of 20 to 80%, and a pore diameter.
In a membrane oxygenator using a porous hydrophobic membrane of 0.01 to 5 μm, the inside of the pore has an ultra-microporous structure due to particles smaller than the pore filled with the pore, and The membrane oxygenator is characterized in that at least the surface of the fine particles that comes into contact with blood is a hydrophobic surface, and the gas exchange membrane is presumed to have an ultra-microporous structure, and the gas exchange membrane is presumed to have an ultra-microporous structure. Despite its very high ability to remove carbon dioxide, there is no risk of plasma leakage even after long-term use. For this reason, it becomes possible to remove the amount of carbon dioxide produced by the living body with a small amount of extracorporeal circulation like ECCO ₂ R. In addition, the gas exchange membrane is a hollow fiber membrane, preferably an inner diameter
A hollow fiber membrane of 100 to 1000 μm and made of polyolefin, preferably polypropylene, has better gas exchange ability, and on the other hand, the pores have fine particles inside, preferably about 0.003 mm in diameter. If the device is filled with particles of ~0.5 μm, the risk of plasma leakage is smaller.

[Brief explanation of drawings]

FIG. 1 is an enlarged sectional view of a gas exchange membrane in an embodiment of the membrane oxygenator of the present invention, and FIG. 2 is an enlarged sectional view of a hollow fiber membrane oxygenator that is an embodiment of the membrane oxygenator of the present invention. Partial cross-sectional view, FIG. 3 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. 4 is a graph showing the relationship between the oxygen gas removal ability and the oxygen flow rate of the artificial lung. FIG. 5 is a graph showing the relationship between extracorporeal circulation time and plasma leakage amount. 1... Membrane oxygenator, 2... Gas exchange membrane, 3...
Pore, 4... Particulate, 5... Housing, 6...
Cylindrical body, 9, 10... Partition wall, 11... First mass transfer chamber, 12, 13... First mass transfer fluid introduction outlet, 15... Hollow fiber bundle, 27, 28... 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 membrane 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 pores filled in the gas exchange membrane do not adhere to the surface of the gas exchange membrane. A membrane oxygenator characterized in that the pores have an ultra-fine pore structure made of small particles, and further, at least the surface of the particles that comes into contact with blood is a hydrophobic surface. 2. The membrane oxygenator according to claim 1, wherein the gas exchange membrane is a hollow fiber membrane. 3. The membrane oxygenator according to claim 2, wherein the hollow fiber membrane has an inner diameter of 100 to 1000 μm. 4. The membrane oxygenator according to any one of claims 1 to 3, wherein the fine particles are made of a hydrophobic substance. 5. The membrane oxygenator according to any one of claims 1 to 4, wherein the gas exchange membrane is made of olefin resin. 6. The membrane oxygenator according to claim 5, wherein the gas exchange membrane is made of polypropylene. 7. The membrane oxygenator according to any one of claims 1 to 6, wherein the fine particles have a particle size of about 0.003 to 1.0 μm.