JPS6264372A - Membrane type artificial lung - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention 10 Background of the Invention (Technical Field) The present invention relates to an artificial lung. (Details) The present invention is an artificial lung that removes carbon dioxide from the blood and adds oxygen to the blood during extracorporeal blood circulation. This article concerns an excellent membrane oxygenator.

(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. Silicone membranes are mainly used as homogeneous membranes, while silicone membranes are used as porous membranes. Various materials such as polyethylene, polypropylene, polytetrafluoroethylene, polysulfone, polyacryloni-1-lyl, polyurethane, and polyamide are known. Such gas exchange membranes include 02
It has a large permeability coefficient to CO2 and CO2, and there is no leakage of plasma even when blood is circulated for a long time, and even if it comes into contact with blood, it can cause damage to the blood, such as blood coagulation, microthrombi formation, platelet loss, and plasma protein. performance such as not causing denaturation or hemolysis is required. However, no gas exchange membrane has yet been developed that satisfies all of these demands, and even silicone membranes, which are said to be the most excellent, are insufficient in terms of damage to blood, that is, biocompatibility.

For this reason, in extracorporeal circulation such as an artificial lung, antithrombotic therapy using drugs is usually used in combination, and heparin or the like is added to the blood. However, although heparin can be expected to have an anticoagulant effect, it has little effect on platelet adhesion and aggregation.

TI, OBJECTS OF THE INVENTION The present invention therefore aims to provide a novel membrane oxygenator. The present invention also provides a membrane-type artificial lung that is highly biocompatible, reduces platelet loss, and has excellent gas exchange ability in an oxygenator that removes carbon dioxide from the blood and adds oxygen to the blood during extracorporeal blood circulation. The purpose is to donate lungs.

The purpose of these developments is to use a membrane in an oxygenator, and at least the white liquid contact surface of the gas exchange membrane is coated with a vinyl copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component. Achieved by membrane oxygenator.

The present invention provides a membrane oxygenator in which the vinyl copolymer is a (meth)acrylate copolymer containing a (meth)acrylate monomer having a perfluoroargyl side chain as one component. The present invention also provides a membrane oxygenator in which the vinyl copolymer is a block copolymer. Roughly speaking, the present invention provides a block copolymer with a weight ratio of 0.25 to 1.5 between the polymer component consisting of a vinyl monomer having a perfluoroalkyl side chain and the polymer component consisting of other monomers constituting the copolymer. This shows a membrane oxygenator. The present invention generally provides a membrane oxygenator in which the perfluoroalkyl side chain is -CH2CH2(CF2)7CF3. The present invention also provides a membrane oxygenator in which the gas exchange membrane is a porous membrane.

The present invention further provides a membrane oxygenator in which the porous membrane is made of olefin resin. The present invention further includes:
This figure shows a membrane oxygenator in which the porous membrane is made of polypropylene. The present invention generally provides a membrane oxygenator in which the gas exchange membrane is a homogeneous membrane.

The present invention also provides a membrane oxygenator in which the homogeneous membrane is made of silicone rubber. The present invention also provides a membrane oxygenator in which the gas exchange membrane is in the form of a hollow fiber. The present invention further provides that a vinyl copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component has a 0.00%
This shows a membrane oxygenator coated with a film thickness of 1 to 10 μm.

IH, specific structure of the invention Hereinafter, the present invention will be explained in more detail based on the drawings.

FIGS. 1 and 2 are enlarged cross-sectional views showing the detailed structure of an embodiment of the demolding oxygenator of the present invention.

The gas exchange membrane 2 of the oxygenator 1 is a porous membrane as shown in FIG. 1, or a homogeneous membrane as shown in FIG. When the gas exchange membrane 2 is a porous membrane, hydrophobic polymers such as polypropylene, polyethylene, polytetrafluoroethylene, polysulfone, polyacrylonitrile, and cellulose acedate can be used as the material, but olefin resin is preferable. Particularly preferred is polypropylene, and polypropylene in which micropores are formed by a stretching method or a solid-liquid phase separation method is desirable.

In addition, the thickness of this porous membrane is, for example, 5 to 800 m.
, preferably 10 to 60 μm, porosity 20 to 80%, preferably 30 to 60%, and the diameter of the pores 3 is 0.01 to 5
．． 0 μm, preferably about 0.01 to 1.0 m, OA1 m. Note that in this embodiment, the gas exchange membrane 2
has an inner diameter of 100 to 1000 μm, preferably 100 to 30
It is said to have a hollow fiber shape of 0 μm. On the other hand, when the gas exchange membrane is a homogeneous membrane, silicone rubber, preferably silicone rubber not containing silica, is used as the material. The thickness of this homogeneous film is, for example, 50 to 300 mm.
μm1 is preferably 80 to 150 μm. In this embodiment, the gas exchange membrane 2 has an inner diameter of 100 to 1
000 μm, preferably 100 to 300 μm, in the form of hollow fibers.

Thus, at least on the blood contacting surface of the gas exchange membrane 2, a film of a vinyl copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component is formed.

1 vinyl monomer with perfluoroalkyl side chain
The vinyl block copolymer used as a component is a copolymer consisting of any vinyl monomer and a vinyl monomer having a perfluoroalkyl side chain, preferably any vinyl polymer (i.e., a homopolymer). It is a so-called A-B type block copolymer in which a block consisting of a homopolymer of vinyl monomer having a perfluoroalkyl side chain is bonded to a base block consisting of a block copolymer, a block copolymer, a random copolymer, etc. be. Vinyl monomers having perfluoroalkyl side chains include -CH2(CF2)2H, -CH2
(CF2 >4 H, -CH2CF3, -CH2C)-
Perfluoroalkyl groups such as 12(CF2)7C)-3, preferably -CH2CH2(CF2)7CF
Examples include perfluoroacrylate and perfluoromethacrylate having 3 as a side chain. On the other hand, examples of the vinyl monomer constituting the base block include alkyl methacrylates such as methyl methacrylate, ethyl methacrylate, butyl methacrylate, and 2-ethylhexyl methacrylate, and alkyl acrylates such as methyl acrylate, ethyl acrylate-1 and butyl acrylate. . In addition, in a vinyl block copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component, a polymer component consisting of a vinyl monomer having a perfluoroalkyl side chain and other vinyl monomers constituting the copolymer may be used. The weight ratio to the polymer content is
0.25 to 1.5, preferably 0.25 to 1.2. In other words, if the weight ratio is less than 0.25, there is a risk that the microphase separation structure required to suppress platelet adhesion may not be formed, while if the weight ratio exceeds 1.5, dissolution in the solvent may be difficult. This is because there is a risk that it will become difficult and the workability will deteriorate. The block copolymer can be obtained by obtaining a vinyl polymer as a base block having a peroxy bond in the main chain, and then polymerizing perfluoroacrylate by dispersion polymerization using this polymer as a polymerization initiator.

This vinyl block copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component can be used for acetone, ketones such as methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, methanol, ethanol,
Alcohols such as n-butanol and 5ec-butanol, esters such as ethyl acetate and butyl acetate, ethers such as dimethylformamide, te-1-rahydrofuran, diethyl ether, methyl cellosolve, and ethyl cellosolve, and organic solvents such as chloroform. It is soluble in

- In order to form the coating 4 of a vinyl copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component on at least the blood contacting surface of the waste exchange membrane 2, for example, it is easy to do as follows. can be done. That is, at least the blood-contacting surface of the gas exchange membrane 2 is brought into contact with a solution of the vinyl copolymer containing, for example, 1 to 10% by weight, preferably 3 to 5% by weight, by immersion or the like, and then the solvent is evaporated. It is formed by As the solvent used, any of the above-mentioned solvents can be used, but preferred are single or mixed solvents of ketones, and mixed solvents of these ketones and alcohols. However, it is necessary to control the evaporation of the solvent during film formation, for example, 4/6 (volume ratio) methyl ethyl ketone/methyl isobutyl ketone, (4/6)/10 (volume ratio) (methyl ethyl ketone/methyl isobutyl ketone). A mixed solvent such as /ethanol or the like is suitable. Note that such coating of the gas exchange membrane 2 with the vinyl copolymer can be performed even before the membrane oxygenator 1 is assembled.
It is more preferable to perform the coating after the module is assembled, since the blood-contacting surfaces of the membrane oxygenator 1 other than the gas exchange membrane can be coated at the same time.

Further, the thickness of the coating 4 of the vinyl copolymer is 0°01
~10 μm, more preferably 0.1 to 5 μm. In other words, if it exceeds 5 μm, there is a risk that the gas exchange ability of the gas exchange membrane will be reduced, and if the gas exchange membrane is in the form of a hollow fiber, there is a risk that the blood flow path will be reduced when blood is passed through the hollow fiber. This is because there is.

In this way, by coating the gas exchange membrane with a vinyl copolymer containing a vinyl monomer having perfluoroalkyl side chains as one component, damage to platelet components of blood that comes into contact with it can be kept to an extremely low level. Since the copolymer has very good gas permeability, it does not substantially reduce the 02 addition ability and CO2 removal ability of the membrane oxygenator.

FIG. 3 shows the 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 is equipped with a housing 5, which is provided with annular male-threaded mounting covers 7, 8 at both ends of a cylindrical body 6, and inside the housing 5. , the rest spreads out to a large number, for example 10,00
As described above, at least the blood contacting surface is a porous or homogeneous hollow fiber gas exchange coated with a vinyl copolymer containing a vinyl monomer having a perfluoroargyl side chain as one component. The membranes 2 are arranged parallel to each other along the longitudinal direction of the housing 5, one in each phase. Both ends of this gas exchange membrane 2 are
Inside the mounting cover 7.8, each opening is supported in a liquid-tight manner by partition walls 9, 10 in an unobstructed state.

Further, each of the above-mentioned partitions 9 and 10 constitutes and closes an oxygen chamber 11 which is a first mass transfer chamber together with the outer periphery of the gas exchange membrane 2 and the inner surface of the housing 5, and closes the oxygen chamber 11. The oxygen chamber 11 is separated from a blood circulation space (not shown), which is a second mass transfer fluid space formed inside the oxygen chamber 11 .

One of the mounting covers 7 is provided with an inlet 12 for supplying oxygen from the first mass transfer fluid. The other mounting cover 8 is provided with an outlet 13 for discharging oxygen.

It is preferable that the inner surface of the cylindrical main body 6 of the housing 5 is provided with a restricting portion 14 for aperture that protrudes and is located at the center in the axial direction. That is, the restraint part 14 is formed integrally with the inner surface of the cylindrical body 6, and tightens the outer periphery of the hollow fiber bundle 15 made up of a large number of gas exchange membranes 2 inserted into the cylindrical body 6. It looks like this. 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 is different in each part along the axial direction, and is highest in the central part. Incidentally, for reasons to be described later, the desirable filling rate of each part is as follows. First, the filling rate in the central constriction section 16 is approximately 60
The filling rate is about 30 to 60% within the narrow cylindrical body 6, and about 20 to 40% at both ends of the hollow fiber bundle 15, that is, on the outer surfaces of the partition walls 9 and 10.

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 at both ends of the housing 5 using a centrifugal injection method, and then hardening the material. In more detail, first, prepare a large number of hollow fiber membranes 2 that are longer than the length of the housing 5, seal both open ends with a resin with high viscosity, and then insert them into the cylindrical body 6 of the housing 5. Place them side by side. After that, the installation is carried out by completely covering both ends of the gas exchange membrane 2 with a mold cover having a diameter larger than that of the cover 7.8, and by rotating the housing 5 around the central axis of the housing 5. ``Polymer bodding material is poured from the end side. Once the resin has hardened after pouring, remove the mold cover and cut the outer surface of the resin with a sharp knife to open both open ends of the waste exchange 11!2. expose 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 channel forming members 17 and 18 having annular convex portions.

These channel forming members 17 and 18 are respectively liquid distribution members 19 and 19.
．． 20 and threaded rings 21.22, the end surfaces of protrusions 23.24 as annular convex portions provided near the peripheral edge of this liquid distribution member 19.20 are brought into contact with the partition walls 9, 10, respectively. 2.2 is installed with cover 7
．． 8, an inflow chamber 25 and an outflow chamber 26 for blood, which is a second mass transfer fluid, are respectively formed. This flow path forming member 1
7.18 are formed with a second mass transfer fluid, a blood population 27, and an outlet 28, respectively.

The gaps at the peripheral edges of the partitions 9, 10 formed by the partitions 9, 10 and the flow path forming members 17, 18 are filled with one of at least two holes 31, 32 communicating with the gaps. The partition walls 9, 1 are filled with the agent 33, 34.
sealed in contact with 0. Alternatively, it is sealed via an O-ring (not shown).

In addition, in the hollow fiber membrane oxygenator, the first mass transfer fluid is an oxygen-containing gas such as air or blood,
The second mass transfer fluid may be blood or an oxygen-containing gas. Thus, if the first mass transfer fluid is a gas, the second mass transfer fluid is blood, while if the first mass transfer fluid is blood, the second mass transfer fluid is a gas.

The above explained the case of a hollow fiber membrane oxygenator.
Flat membrane oxygenators, such as stacked membranes, membranes wound into a coil, or folded into a zigzag pattern, also contain perfluoroalkyl side chains in the gas exchange membrane that comes into contact with blood. If it is coated with a vinyl copolymer containing a vinyl monomer as one component,
A membrane oxygenator can be obtained that is highly biocompatible, causes very little damage to blood platelets, etc. that come in contact with it, and has excellent gas exchange performance.

EXAMPLES Hereinafter, the present invention will be roughly described in detail with reference to Examples.

Example 1 and σ Comparative Example 1 Using a silicone rubber hollow fiber membrane with an inner diameter of 200 μm and a wall thickness of 100 μm, a hollow fiber membrane oxygenator as shown in FIG. 3 with a membrane area of 1.6 mm was created. .

On the other hand (methyl methacrylate/butyl methacrylate)
-Perfluoropropyl acrylate block copolymer (molecular weight ratio (25:25):50) was dissolved in a 476 mixed solvent of methyl ethyl ketone/methyl imbutyl ketone to form a 3% by weight solution.

This (methyl methacrylate/butyl methacrylate)
- After filling the blood circulation surface of the hollow fiber membrane oxygenator with the perfluoropropyl acrylate copolymer solution for 1 minute,
The liquid was drained and air was blown through to remove the solvent and form a film. To the membrane Jvj on which the coating was formed] [Lungs (Example 1 and membrane oxygenator without coating treatment (Comparative Example 1) M gas partial pressure 35 mm
Venous blood with a partial pressure of carbon dioxide gas of 45 mm t (g) was prepared and was passed through the blood flow path of the oxygenator to evaluate the performance.The hemoglobin content of the fresh blood used was 1
2 g/old and the temperature was 37°C.

Table 1 shows the relationship between the blood flow rate and the oxygen gas addition ability and carbon dioxide removal ability when the ratio of oxygen flow rate to blood flow ♀ is 1. As is clear from Table 1, no substantial difference in gas exchange capacity was observed between the membrane oxygenator of Example 1 and the membrane oxygenator of Comparative Example 1.

Furthermore, when these membrane oxygenators were subjected to partial venous-arterial extracorporeal circulation for 6 hours using a dog, the decrease in platelets was only 5% in the membrane oxygenator of Example 1, whereas the decrease in platelets was only 5%. The membrane of Example 1 failed in the oxygenator by 15%.

Example 2 and Comparative Example 2 Inner diameter 200μm, wall thickness 25μ771s'jE porosity 45%
A hollow fiber membrane oxygenator as shown in FIG. 3 with a membrane area of 1.671 i was prepared using a porous polypropylene hollow fiber membrane with an average pore diameter of 700.

On the other hand (methyl methacrylate/butyl methacrylate)
- Prepare a 30% by weight solution by dissolving perfluoropropyl acrylate copolymer (molecular weight ratio (25:25): 50) in a 4/6 mixed solvent of methyl ethyl ketone/methyl isobutyl ketone, and then add 3% by weight in ethanol. Diluted to . Using this diluted solution, a film was formed on the blood circulation surface of a hollow fiber membrane oxygenator in the same manner as in Example 1. Gas exchange ability was evaluated in the same manner as in Example 1 and Comparative Example 1 for the membrane oxygenator in which a coating was formed (Example 2) and the membrane oxygenator not subjected to coating treatment (Comparative Example 2). The results are shown in Table 1. As is clear from Table 1, no substantial difference in gas exchange capacity was observed between the membrane oxygenator of Example 2 and the membrane oxygenator of Comparative Example 2.

Roughly speaking, when these membrane oxygenators were subjected to 30 hours of venous-arterial partial extracorporeal circulation using a mongrel dog, the membrane oxygenator of Example 2 showed a decrease in platelets of 10%. In the membrane oxygenator of Comparative Example 2, it was 25%.

(Left below) % = 5 = IV, Specific Effects of the Invention As described above, the present invention provides a membrane oxygenator in which a vinyl monomer having a perfluoroalkyl side chain is added to at least the blood contacting surface of the gas exchange membrane. Since this is a membrane oxygenator coated with a vinyl copolymer having one component, even if blood is circulated to the lungs of the human model, blood will not be absorbed by contact with the membrane oxygenator. It has extremely low damage to blood components such as coagulation, microthrombi formation, platelet loss, plasma protein denaturation, and hemolysis, and is highly biocompatible, as well as its gas exchange ability, as it has a perfluoroalkyl side chain. The vinyl copolymer film containing vinyl monomer as one component has extremely high gas permeability and is sufficient because it does not inhibit the gas exchange ability inherent in the gas exchange membrane, making it an extremely excellent membrane. It is a type of artificial lung.

In the membrane oxygenator of the present invention, the vinyl copolymer is a (meth)acrylate copolymer containing as one component a (meth)acrylate monomer having a perfluorofurkyl side chain; When the vinyl copolymer is a block copolymer, a polymer component consisting of a vinyl monomer having a perfluoroalkyl side chain in the block copolymer and a polymer component consisting of other monomers constituting the copolymer are further combined. When the weight ratio is 0.25 to 1.5, the per"noroloalkyl side chain is -CH
When 2CH2 (CF2>vCF3), the biocompatibility becomes even higher, and when the gas exchange membrane is a porous membrane made of olefin resin, more preferably polypropylene, or a homogeneous membrane of silicone rubber type, , its dregs exchange ability becomes even better.

[Brief explanation of drawings]

1 and 2 are enlarged cross-sectional views of respective gas exchange membranes in an embodiment of the membrane oxygenator of the present invention,
FIG. 3 is a partial cross-sectional view of a hollow fiber membrane oxygenator, which is an embodiment of the membrane oxygenator of the present invention. DESCRIPTION OF SYMBOLS 1... Membrane oxygenator, 2... Gas exchange membrane, 3... Pore, 4... Coating, 5... Housing, 6...
Cylindrical body, 9.10... Partition wall, 11... First mass transfer end, 12.13... First mass transfer fluid introduction outlet, 15... Hollow fiber bundle, 27.28. ...Second mass transfer fluid introduction outlet.

Claims (12)

[Claims] (1) A membrane oxygenator characterized in that at least the blood contacting surface of the gas exchange membrane is coated with a vinyl copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component. . (2) The membrane-type artificial material according to claim 1, wherein the vinyl copolymer is a (meth)acrylate copolymer containing as one component a (meth)acrylate monomer having a perfluoroalkyl side chain. lung. (3) The membrane oxygenator according to claim 1 or 2, wherein the vinyl copolymer is a block copolymer. (4) The weight ratio of the polymer component made of a vinyl monomer having a perfluoroalkyl side chain in the block copolymer to the polymer component made of other monomers constituting the copolymer is 0.25 to 1.5. Claim 3
Membrane oxygenator described in section. (5) Perfluoroalkyl side chain is -CH_2CH_2
(CF_2)_7CF_3 The membrane oxygenator according to any one of claims 1 to 4. (6) The membrane oxygenator according to any one of claims 1 to 5, wherein the gas exchange membrane is a porous membrane. (7) The membrane oxygenator according to claim 6, wherein the porous membrane is made of olefin resin. (8) The membrane oxygenator according to claim 7, wherein the porous membrane is made of polypropylene. (9) The membrane oxygenator according to any one of claims 1 to 5, wherein the gas exchange membrane is a homogeneous membrane. (10) The membrane oxygenator according to claim 9, wherein the homogeneous membrane is made of silicone rubber. (11) The membrane oxygenator according to any one of claims 1 to 10, wherein the gas exchange membrane has a hollow fiber shape. (12) A vinyl copolymer containing a vinyl monomer having a perfluoroalkyl side chain as one component is 0.001 to
The membrane oxygenator according to any one of claims 1 to 11, which is coated with a film thickness of 10 μm.