JPH0611319B2 - Membrane for artificial lung - Google Patents

Description

TECHNICAL FIELD The present invention relates to an artificial lung membrane that can be used to replace or support living lungs.

[Conventional technology]

Due to the extracorporeal circulation of blood, an oxygenator that diffuses carbon dioxide in blood and enriches oxygen, a bubble-type artificial lung that blows oxygen into the blood in a bubble shape, and gases such as carbon dioxide and oxygen permeate. There are two types of membrane oxygenators that allow gas exchange through a permselective membrane that does not substantially permeate blood. The bubble-type artificial lung has some advantages such as high gas exchange efficiency and low cost, but it has a drawback that blood is directly damaged by contact with gas. This drawback is fatal especially when used over a long period of time. (For example, Journal of Japanese Society of Thoracic Surgery, 22 (1974) P.904, artificial organs, 12 (1983) P.982, etc.) Membrane oxygenators have recently attracted attention as artificial lungs that can be used for a long period of time. However, membrane oxygenators are roughly classified into a dense membrane type and a porous membrane type.

The dense-membrane type oxygenator makes blood and gas indirectly contact with each other through a polymer membrane having high gas permeability, and utilizes the partial pressure difference between the blood side and the gas side to dissolve the gas into the membrane. Gas exchange is carried out by diffusion, then dissolution in blood, diffusion (or the reverse process). For such polymer membrane, a dense membrane made of a material such as polydimethylsiloxane having a homogeneous and dense structure is used. There is. (For example, Thoracic Surgery, 33 (1979) P.339) In addition, in a porous type artificial lung, gas can freely pass through a communication hole, whereas blood has a hydrophobic membrane, It utilizes the fact that it cannot pass through the membrane because the contact angle between blood and blood is large and the membrane pores do not get wet. As such a membrane, a membrane with a porous structure having hydrophobic communication holes of 50 to 2,000Å is used. Is used. (Eg artificial organs, 1
2 (1983) P.991, etc. [Problems to be Solved by the Invention] As described above, the membrane used in the membrane oxygenator of the porous membrane type has a large contact angle between the membrane and blood and has a membrane pore. Is an essential requirement, but since blood contains a component having surface activity such as protein, the membrane pores gradually get wet and the gas exchange capacity changes with time. If it is used for a longer time, the entire communication hole will get wet. Once wet, such a porous film is overwhelmed with blood and leaks blood plasma and the like to the gas side, so that it cannot be used.

On the other hand, the membrane used in the conventional dense membrane type membrane oxygenator does not have plasma and is not clogged because it is dense and does not have pores that allow liquid to permeate. It is superior to the porous membrane in this respect, with almost no deterioration in performance over time, but the gas permeates into the polymer membrane once, diffuses in the polymer to the other side, and is desorbed. Therefore, the gas permeation rate is slow, and it is not sufficiently satisfactory. Currently, most of the dense membrane type artificial lung membrane materials that are commercially available are polydimethylsiloxane-based polymers, which are said to have the best oxygen permeability among conventional polymers. It is hard to say that it has sufficient oxygen permeability. Further, the oxygen permeation rate is inversely proportional to the film thickness, so it is preferable to reduce the film thickness, but polydimethylsiloxane is an essentially flexible polymer, and it is difficult to form a thin film without pinholes because of its low mechanical strength. is there. Further, in order to improve the strength, it has been attempted to copolymerize various components such as carbonate, polymer blend, or to add an additive, but the oxygen permeability tends to decrease as the strength increases. . Therefore, the membrane used for the dense membrane type membrane oxygenator has a drawback that a larger gas exchange area is required.

Since the artificial lung is in direct contact with blood, it is also very important that it has good blood compatibility. The hemocompatibility of the membrane itself, which has an overwhelmingly large contact area, is particularly important. Poor membrane hemocompatibility produces thrombus. When a blood clot is generated, not only is the membrane in that part clogged and the gas exchange capacity is lost, but also
The flow of blood near the thrombus is obstructed, a blood pool is formed, and blood clots easily. Therefore, once a thrombus is generated, it becomes larger at an accelerating rate, and finally, the gas exchange capacity is significantly reduced. Therefore, the hemocompatibility of the membrane is important, especially when using artificial lungs for long periods of time. In addition, when blood compatibility is poor, formed components such as platelets and white blood cells in the blood are reduced during extracorporeal circulation, and troubles such as easy bleeding easily occur.

In view of the above circumstances, the inventors of the present invention have made extensive studies to obtain an artificial lung membrane having excellent gas exchange ability, small change with time in gas exchange ability, and excellent blood compatibility, and the present invention completed.

[Means and Actions for Solving Problems]

The present invention provides a substituted acetylene unit represented by the formula (A) with 50 units.
A membrane composed of a polymer or polymer mixture containing more than mol%, the membrane having a blood contact surface of 50 to 1,00.
A membrane for artificial lung, which is characterized in that it is composed of at least one dense layer in the cross section of the membrane except the network structure having 0Å holes and the blood contact surface. In formula (A), R ₁ is hydrogen, halogen such as chlorine or bromine, or an alkyl group having 1 to 5 carbon atoms such as methyl or ethyl; R ₂ is methyl, ethyl, normal propyl, isopropyl, isobutyl, tert-butyl, isopentyl, 1 to 20 carbon atoms (preferably 1 to 1) such as turkey pentyl
0) a linear or branched alkyl group, a phenyl group,
Further, as a substituent, alkyl, alkoxy, halogen,
It is a substituted phenyl group having a phenyl or the like or a substituted silyl group.

For the membrane material of the present invention, a polymer or polymer mixture containing 50 mol% or more of the substituted acetylene unit represented by the formula (A) is used. As such a polymer, the formula (A) is a structural unit. Not only a single polymer to
A polymer having the formula (A) as a constitutional unit, a copolymer containing another unit such as a siloxane unit in a range not exceeding 50 mol%, a polymer having the formula (A) as a constitutional unit, and A polymer blend containing a polymer such as polydimethylsiloxane in an amount not exceeding 50 mol% is included. A polymer having a substituted acetylene unit of the formula (A) is superior in gas permeability to a general polymer, and is tougher than polydimethylsiloxane which is conventionally considered to have the best gas permeability, and can be formed into a thin film. It is possible to reduce the gas exchange area and make it more compact. Among them, polytrimethylsilylpropyne, in which R ₁ is a methyl group and R ₂ is a trimethylsilyl group, has the highest oxygen permeability among existing polymers at 10 times the polydimethylsiloxane, and the polymer chain is rigid. It is particularly preferable because it is tough and can be formed into a thin film. The polymer used in the present invention may be prepared by using a halide of a metal such as W, Mo, Nb, or Ta (for example, WCl ₆ , NbCl ₅ or the like) alone as a catalyst, or by using the halide and an organometallic compound (for example, tetraalkyl). Tin), or by irradiating the Group VI transition metal carbonyl with light to polymerize it.

In the membrane oxygenator of the present invention, the blood contact surface is 50 to 1,00.
It is necessary to have a mesh structure having 0Å, preferably 100 to 500Å holes. The mesh structure referred to in the present invention is not only a mesh structure having the above pore size but also a micro-heterogeneous structure such as a lamella structure having the above layer thickness or a sea-island structure having islands of the above size. Is also included. The thickness of the mesh structure in the cross-sectional direction is not particularly limited, but in practice, a thickness of 10 to 1,000 L is used.

The dense layer referred to in the present invention means a layer having a substantially non-porous structure in which pores cannot be seen even with a scanning electron microscope of 20,000 times, and when the blood contact surface is such a dense layer, it has already been described. As such, it has poor blood compatibility and cannot withstand long-term use.

Also, if there is no dense layer and there are communication holes that communicate with all layers of the membrane cross section, the communication holes gradually wet with plasma, plasma leaks, plasma loss occurs, and the gas exchange capacity decreases over time. Then
Not preferable. This becomes a problem especially when used for a long period of time.

In the present invention, by forming the blood contact surface with the specific structure as described above, it is possible to prevent thrombus formation, reduction of formed components, etc., and to provide an artificial lung membrane with good blood compatibility.

Further, except for the blood contact surface of the artificial lung membrane of the present invention, the membrane cross section must be composed of at least one dense layer. That is, in the part other than the blood contact surface, the whole may be a dense layer, or if there is at least one dense layer, the other part may have the above-mentioned mesh structure. In short, in the other parts except the blood contact surface, at least one or more layers may be dense layers, and any film structure may be used. The thickness of the dense layer in this case is not particularly limited, but may be 0.1 μm or more for practical use.

As described above, a membrane formed by using a polymer or polymer mixture containing 50 mol% or more of the structural unit represented by the formula (A) so that the blood contact surface, the inside of the membrane, and the gas exchange surface have a specific structure. Oxygen permeation performance by using
A membrane oxygenator having excellent blood compatibility can be obtained.

Next, the method for producing the artificial lung membrane of the present invention will be described. In the present invention, the blood contact surface needs to have a network structure having 50 to 1,000Å holes, and such a network structure can be formed by a wet film forming method or a dry wet film forming method. . That is, the polymer solution is coagulated with a coagulating liquid or a mixed liquid of a coagulant and a solvent to control the phase separation of the polymer on the film surface, or to coagulate from one side of the film,
The other surface can be formed by contacting it with an incompatible liquid or an inert gas and adjusting the film forming conditions on one surface side to control the phase separation of the polymer on the surface on the other surface side. Conventionally, a polymer having a substituted acetylene unit has been formed into a film by the cast method. However, the cast method is a so-called dry film-forming method of evaporating a solvent from a polymer solution, and is a film method suitable for obtaining a homogeneous and dense film, but the film produced by this method has insufficient blood compatibility. .
If the size of the pores in the mesh structure is less than 50Å, the pores are too small to improve the blood compatibility. On the other hand, if the size of the pores of the mesh structure exceeds 1,000 Å, the blood compatibility tends to deteriorate. A more preferable range of the mesh-structured holes is 100 to 500Å. It is unclear why the presence of a network of pores in this area improves blood compatibility. Note that such a network structure can be confirmed by observing the surface with a scanning electron microscope.
That is, at a magnification of about 1,000 times, only a nearly smooth surface can be seen, and the mesh structure cannot be clearly confirmed.
The structure can be clearly confirmed when magnified to about double.
When the surface is coagulated with a coagulant, it has a slit-like structure parallel to the film forming direction, and when the film is formed with an inert gas, it has a normal network fine structure.

The membrane shape includes a flat membrane, a tube shape, and a hollow fiber shape. In the present invention, the shape is not particularly limited, but a hollow fiber membrane is preferable from the viewpoint of compactness. As a profile of the hollow fiber membrane for artificial lung, an inner diameter of 100 to 500 μm and a film thickness of 5 to 200 μm are preferable in view of the balance of blood pressure loss, strength and compactness. Blood can flow inside or outside the hollow fibers, but it is more preferable to flow inside the hollow fibers in order to obtain a laminar flow with less blood damage. Therefore, 5
A hollow fibrous membrane having a dense layer on the outer surface side on the inner surface side of the network structure having pores of 0 to 1,000Å is a preferred embodiment when the membrane of the present invention is used as an artificial lung.

〔Example〕

Trimethylsilyl propylene was dissolved in purified toluene at 1 mol / mol. Niobium pentachloride (NbCl ₅ ) as a catalyst was added to this so that the concentration was 20 mmol.
Polymerization was performed at 24 ° C. for 24 hours. The obtained polymerization solution was put into methanol to obtain white polytrimethylsilylpropyne. This polymer has an intrinsic viscosity of 0.99 in toluene at 30 ° C.
It was dl / g and the average molecular weight was 400,000.

A solution in which this polymer was dissolved in toluene was used as a spinning stock solution and subjected to dry-wet spinning using an annular nozzle. Methanol was used as the external coagulating liquid, and nitrogen was injected into the hollow fiber.
After sufficiently replacing toluene, it is dried to an inner diameter of 200μ and an outer diameter of 2
A 50μ hollow fiber membrane was obtained. The inner surface of this hollow fiber membrane was set to 20,0
When observed with a scanning electron microscope with a magnification of 00, a mesh-like structure was observed, and the pore size was estimated to be 200Å. Further, it was found that the outer surface had a dense layer without a clear structure observed even when magnified 20,000 times. This hollow fiber has a water permeability of 0.1 ml / m ² · hr · mmHg or less even after being completely wetted with ethanol, and the liquid permeability is extremely low due to the presence of a dense layer. It was

This hollow fiber membrane 20,000 was mounted in a housing, centrifugally adhered, and both end faces were cut to obtain a membrane oxygenator having an open end and a membrane area of 1.5 m ² .

This lung was hypoventilated with a respirator and weighed 15 kg.
The dog was used for a 48-hour perfusion experiment. The arterial blood before perfusion had a pH of 7.34, an oxygen partial pressure (Po ₂ ) of 65 mmHg, and a carbon dioxide partial pressure (Pco ₂ ) of 47 mmHg, but the arterial blood was bypassed with a blood flow of 1.2 l / min and an oxygen flow of 1.2 l / min. However, the blood gas properties improved immediately, pH 7.41, Po ₂ 240mmHg, Pco ₂ 35mm
It became Hg. Hematocrit decreased a little with the passage of perfusion time, but there was almost no change in the number of platelets and white blood cells, and the experiment proceeded smoothly without any trouble such as bleeding.
After the perfusion was completed, it returned to normal when the ventilation status was restored. Moreover, when the artificial lung was disassembled and examined, no thrombus was formed.

Comparative Example 1 A hollow fiber membrane having an inner diameter of 200 μ and an outer diameter of 260 μ was obtained by a dry spinning method using a solution prepared by dissolving the polymer used in the example in toluene as a spinning stock solution. Both the inner and outer surfaces of this hollow fiber membrane were observed with a scanning electron microscope at 20,000 times, but no network structure was observed, and it was found that the hollow fiber membrane had a dense surface layer.
The water permeability of pure water after ethanol wetting is 0.1 ml / m ² · hr · mmHg.
Below, the liquid permeability was very low due to the presence of the dense layer.

Using this hollow fiber membrane, a membrane oxygenator having a membrane area of 1.5 m ² was produced, and a dog perfusion experiment was conducted in the same manner as in the example. Although the improvement of blood gas properties was satisfactory, the intrapulmonary resistance increased after 18 hours, hemolysis proceeded, and the plasma free hemoglobin amount exceeded 200 mg / dl, so the perfusion was stopped after 24 hours. When the artificial lung was disassembled and examined,
Many clogged hollow fibers were observed.

Comparative Example 2 20,000 hollow silicon hollow fiber membranes having a dense membrane structure with an inner diameter of 200 μm and an outer diameter of 400 μm were mounted in a housing, and one end of each was statically adhered to produce a 1.5 m ² membrane oxygenator. Using this lung, a static artery bypass test was conducted in the same manner as in the example. Blood gas properties improved immediately after perfusion, but the oxygen partial pressure (Po ₂ ) of arterial blood was 190 mmHg and the CO ₂ partial pressure (Pco ₂ ) was 40 mmHg. There were few.

〔The invention's effect〕

As described in detail above, according to the present invention, a polymer or a polymer mixture containing 50 mol% or more of a substituted acetylene unit capable of forming a thin film due to its excellent gas permeability and toughness is used. It is possible to provide an artificial lung membrane which is composed of at least one dense layer in the membrane cross section except for the network structure having pores of up to 1,000 Å and the blood contact surface.

In particular, since the membrane of the present invention has a small change in gas exchange capacity over time and is excellent in blood compatibility, it is extremely useful when used for a long period of time, and is a useful substitute for living lungs or lungs of patients with lung disease. Compact and safe to use as an auxiliary device.

Claims (3)

[Claims] 1. A substituted acetylene unit represented by the formula (A) is 5
A membrane composed of a polymer or a polymer mixture containing 0 mol% or more, the membrane having a blood contact surface of 50-1,
A membrane for artificial lung, characterized in that it has a mesh structure having 000 Å holes and is composed of at least one dense layer in the cross section of the membrane except the blood contact surface. (However, in the formula, R ₁ is hydrogen, halogen, or has 1 to 5 carbon atoms.
R ₂ is a linear or branched alkyl group having 1 to 20 carbon atoms, a phenyl group, a substituted phenyl group or a substituted silyl group. ) 2. The artificial lung membrane according to claim 1, wherein the blood contact surface has a mesh structure in which 100 to 500Å holes are present. 3. The artificial lung membrane according to claim 1 or 2, wherein the polymer is polytrimethylsilylpropyne.