JPS6141467A - Membrane for 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 [Field of Industrial Application] The present invention relates to a membrane for an artificial lung that can be used to replace or supplement a living lung.

[Conventional technology]

There are two types of oxygenators: bubble-type oxygenators, which blow oxygen into the blood in the form of bubbles, and oxygenators, which diffuse carbon dioxide and enrich oxygen through extracorporeal blood circulation. There are two types of artificial lungs, which perform gas exchange through a selectively permeable membrane that does not substantially allow blood to pass through. Bubble oxygenators have the advantage of high gas exchange efficiency and low cost, but they have the disadvantage of causing significant damage to the blood due to the direct contact between blood and gas. This drawback is fatal, especially when used for a long period of time. (For example, Journal of the Japanese Society of Thoracic Surgery, 22 (1974) P, 904
, Artificial Organs, The (1983) P982, etc.) Recently, model oxygenators have been attracting attention as oxygenators that can be used over long periods of heat, but model oxygenators are broadly divided into dense membrane types and porous membrane types. Ru.

A dense membrane type oxygenator uses a high gas permeability polymer membrane to bring blood and waste into indirect contact, and uses the partial pressure difference between the blood side and the gas side to dissolve the gas in the membrane. Gas exchange is performed by diffusion, then dissolution into blood, and diffusion (or the reverse process) lζ, but such a polymer membrane is made of a material such as polydimethylsiloxane with a homogeneous and dense structure, and t: a dense membrane is used. It is being (For example, Thoracic Surgery, 33 (19
79) l', 339) In addition, in a porous type of oxygenator, gas can freely pass through the communication holes, whereas in blood, the membrane is hydrophobic, so there is no contact between the membrane and the material. This method takes advantage of the fact that the corners are large and the membrane pores do not get wet through the t-hole membrane.
A membrane having a porous structure having communicating pores of 0 to z and ooo'A is used. (For example, artificial 11Uii, 12(19
85) P, 991, etc.) [Problems to be solved by the invention] As mentioned above, the membrane used in the porous membrane type model oxygenator has a large contact angle between the membrane and blood, and the membrane pores become wet and f (
However, since blood contains components with surfactant properties such as proteins, the membrane pores gradually become wet and the gas exchange capacity changes over time. If you use it for a longer period of time, the entire communication hole will get wet. Once it gets wet,
In such a porous membrane, blood is filtered and plasma and the like leak to the gas side, making it unusable.

On the other hand, the membranes used in conventional dense membrane model artificial lungs have dense membranes that allow liquid to pass through and do not have large pores, so plasma does not pass through them and there is no clogging, resulting in gas exchange. There is almost no decrease in the temperature over time, and in this respect it is more collapsed than a porous membrane, but once the gas dissolves in the polymer membrane17,
Since the gas permeates through the membrane by a so-called dissolution-diffusion mechanism in which the gas diffuses to the other side of the polymer and is removed, the gas permeation rate is slow and is not completely satisfactory. Most of the membrane materials for dense membrane type oxygenators currently on the market are polydimethylsiloxane-based polymers, which are said to have the best oxygen permeability among conventional polymers. It is difficult to say that it has sufficient oxygen permeability. Furthermore, since the oxygen permeation rate is inversely proportional to the film thickness, it is preferable to reduce the film thickness, but polydimethylsiloxane is essentially a flexible polymer and has low mechanical strength, making it difficult to form a thin film without pinholes. be. In addition, attempts have been made to copolymerize divine ingredients such as carbonate, blend polymers, or add additives to improve strength, but as the looseness increases, oxygen permeability tends to decrease. be. Therefore, the membranes used in pII oxygenators of the dense membrane type have the disadvantage of requiring more gas exchange area.

Furthermore, since the oxygenator comes into direct contact with blood, good blood compatibility is also an extremely important requirement. Blood compatibility of the membrane itself, which has an overwhelmingly large contact area, is particularly important. If the blood compatibility of the membrane is poor, a thrombus will form. When a thrombus forms, the membrane in that area not only becomes occluded and loses its ability to exchange gas, but also the flow of blood near the thrombus is obstructed, creating a pool of blood and making it more likely to clot. Therefore, once a thrombus is formed, it increases in size at an accelerating rate, eventually leading to a significant decrease in gas exchange capacity. Therefore, the blood compatibility of the membrane is important, especially when using an oxygenator for a long period of time. If the blood compatibility is poor, the number of formed components such as platelets and white blood cells in the blood decreases during extracorporeal circulation, making it more likely that problems such as bleeding will occur.

The present invention In view of the above-mentioned situation, Oton et al. conducted intensive studies to obtain a membrane for an oxygenator that has excellent gas exchange ability, small change in gas exchange ability over time, and excellent blood compatibility, and developed the present invention. completed.

[Means and effects for solving the problems] The present invention has the following features:
A membrane composed of a polymer or polymer mixture containing 50 mol % or more of substituted acetylene units represented by the formula +A), the membrane having a blood contact surface of 50 to 1. o o
It is characterized by a network structure in which the pores of o i are present, and is composed of at least one layer of ridges in the cross section of the membrane other than the blood contact surface. , ethyl, etc., and B2 is an alkyl group having 1 to 20 carbon atoms (preferably 1 to 10 ), linear or branched alkyl groups, phenyl groups, and substituted phenyl groups and substituted silyl groups having alkyl, alkoxy, halogen, phenyl, etc. as direct substituted groups.

The membrane material of the present invention includes a polymer containing 50 mol% or more of substituted acetylene units represented by the formula (Al).
In this case, a polymer mixture is used, but such polymers include not only single polymers having the formula (A) as a constituent unit, but also polymers having the formula +A+ as a +A constituent unit, and other units f, such as white cow. A copolymer containing a Sun unit in an amount not exceeding 50 mol%, a polymer having the formula fA) as a constituent unit, and a polymer other than this, such as polydimethylsiloxane, in an amount not exceeding 50 mol%. Includes polymer blends. Formula (A)
Polymers having a-substituted acetylene units have higher gas permeability than general polymers, and are tougher than polydimethylsiloxane, which is said to have excellent gas permeability, and can be made into thin films. It is possible to reduce the gas exchange area, making it more compact. Among them, polytrimethylsilylpropyne, in which B1 is a methyl group and B2 is a trimethylsilyl group, has the highest oxygen permeability among existing polymers, which is 10 times that of polydimethylsiloxane, and has a rigid 6ζ polymer chain. It is highly preferable because it has a strong padding and can be made into a thin film. The polymer used in the present invention contains W, Mo, Nb,
Halogenation of metals such as 'l''a Q'fl (f Kotoe uses WCeb, Nb (M5 etc.) alone,
Alternatively, it can be obtained by polymerizing these halides and a suitable metal compound (for example, tetraalkyltin) in combination, or by irradiating light on group (I) transition gold-carbonyl.

In the model artificial lung of the present invention, the blood contact surface is 50 to 1.
It is necessary to have a network structure in which pores of 000A, preferably 100 to 500A are present. The network structure Iζ in the present invention is defined as $1ζ.If only the network structure with the above pore diameter is tr Uniform structures may also be included. The thickness of the network structure in the cross-sectional direction is not particularly limited, but practically it is usually 10 to 1. ooooo
; is used.

The dense layer referred to in the present invention is 1. ! , a layer with a substantially non-porous structure in which no pores are visible even with a 20,000x scanning electron microscope, but if the blood contact surface is made as dense as this +1, as already mentioned, blood compatibility is increased. It has poor properties and cannot withstand long-term use.

In addition, if there is no dense 1- and there are communicating pores that communicate with all layers of the membrane cross section, the communicating pores will gradually become wet with plasma and plasma will leak, causing plasma loss and decreasing the Cζ gas exchange ability over time. , I don't like J. It becomes a problem when used during the special Iζ艮 period.

In the present invention Cζ, by making the blood contact surface have a specific structure as described above, it is possible to prevent thrombus formation and reduction of formed components, and to obtain an oxygenator membrane with good blood compatibility. I can do it.

In addition, the membrane for an oxygenator of the present invention, other than the blood contacting surface, must be composed of at least one layer of dense 1-layer in the cross section of the membrane. In other words, all parts other than the blood contact surface may be densely packed, or at least as dense as 1-1 or more! ! As long as there is a dense layer, the other parts may have the above-mentioned fine structure.

In short, in other parts except the blood contact surface, it is sufficient that at least 1j- or more of the glandular layer is a dense layer, and that the glands of more than 1
The structure doesn't matter. Further, the thickness of the six-shell dense layer in this case is not particularly limited, but it may be 0.1 μ or more in practice.

In this way, 50 mol% of the structural unit represented by formula (A)
Using a polymer or polymer mixture containing the above,
By using a membrane formed so that the blood contact surface, the inside of the membrane, and the gas exchange surface have a specific structure, a model oxygenator with excellent cumulative acid permeation performance and blood compatibility can be obtained.

Next, the production method number ζ of the oxygenator membrane of the present invention will be described.

In the present invention ζζ, the number of contact surfaces is 50 to 1.0 OOA
However, such a network structure can be formed by a wet film forming method or a wet/dry film forming method. That is, the four polymer solutions are coagulated by a coagulating liquid or a mixture of a coagulant and a solvent to control phase separation of the polymer on the membrane surface.
By coagulating from one side of the gland and contacting the other side with a non-abrasive liquid or inert gas to adjust the film formation conditions on one side, the phase separation of the polymer on the other side can be controlled. l
ζ can be formed. Conventionally, polymers having substituted acetylene units have been formed into films by a casting method. However, the casting method is a so-called dry film forming method in which the solvent is evaporated from the polymer solution. Although it has film properties suitable for obtaining a homogeneous dense film, the film made by this method is ! Insufficient compatibility.

If the size of the pores in the network structure is too small, the pores will be too small and the improvement in blood H+a compatibility will be small.

- If the size of the pores in the network structure exceeds 1,000 mm, the blood f&iH compatibility will deteriorate on the contrary.
i1~50 mouths A. It is unclear why the presence of a network structure that extends from the pores in this range improves blood compatibility.
This can be confirmed by observing it on your computer. i.e. 1
At a magnification of about ,000 times, only a nearly smooth surface ζζ can be seen, and the network structure cannot be clearly recognized, or 2.
When magnified to a magnification of about 0,000 times, the structure can be clearly confirmed. When the surface is coagulated with coagulant 1j, it becomes a slit-like structure parallel to the film formation direction, and when it is formed with an inert gas, it has a normal 0! It becomes a ■-shaped fine structure.

The membrane shape includes flat membrane, tube shape, hollow fiber shape, etc. In the present invention, the shape is not limited, but a hollow border membrane is preferable from the point of view of compactness! Yes. Hollow M for artificial lungs! The fibrosal profile is characterized by blood pressure loss, strong IW.
, the inner diameter is 100-50μ due to the balance of compactness,
Membrane #5 to 200μ is preferred. Although blood can flow both inside and outside the hollow fibers, it is more preferable to flow inside the hollow fibers in order to achieve a flow with less damage to the dish fluid.

Therefore, a hollow fibrous membrane having a network structure with 50 to 1,000 pores on the outer surface and a dense 1-6ζ on the outer surface is a preferred embodiment when the gland of the present invention is used as an oxygenator. It is.

[Example] Trimethylsilylpropyne (p5%il) was dissolved in toluene at a concentration of 1 mol/l. To this was added 20 mmol of niobium pentachloride (NbGea) as a catalyst, and the mixture was stirred at 80°C for 24 hours.The resulting combined solution was poured into methanol to slowly dissolve white polytrimethylsilylpropyne. This polymer has an intrinsic viscosity of 0.99 dB/g in toluene at 60°C and an average molecular weight of 4.
I got cPl at 00,000.

This polymer was dissolved in toluene and aM was used as a spinning stock solution for dry-wet spinning using a block nozzle.

Methanol was used as the external coagulation liquid, and nitrogen was injected into the inside of the hollow fiber. After replacing toluene sufficiently, dry and reduce the inner diameter to 2.
A hollow fiber membrane with a diameter of 0.00μ and an outer diameter of 250μ was obtained. When the inner surface of this hollow fiber membrane was observed with a scanning electron microscope at a magnification of 20,000 times, a network structure was observed, with a pore size of 200
It was estimated that X. Furthermore, no clear structure was observed on the outer surface even when magnified by 1 O,000 times, indicating that it had a dense layer.

This hollow fiber has a pure water permeability of 0.1ml〆d・hr・■H even after being completely treated with ethanol to make it ζWet.
g or less, and the liquid permeability was extremely low due to the presence of the dense layer.

This hollow fiber membrane 20,000 is attached to a housing and centrifugally bonded, and both end faces are cut to make an open end.1.
A model artificial lung having a membrane area of 5 resistant was obtained.

Body 31k with this lung in a hypoventilated state with a resurvirator
A 48-hour perfusion experiment was conducted on dogs with an area of 15 ha.
Ivy. Arterial blood before perfusion has a pH of 7.34 and oxygen partial pressure (P
O+)651MIHg, □Partial pressure of carbon dioxide (Pang)
It was 47 ug, but the blood flow ill 1, 2 #/
When the patient underwent venoarterial bypass with an oxygen flow of 1.2 #/1 nin, the blood gas properties immediately improved, with a pfi of 7.41 and a Po of 2240 sklg, l'
co235mskiglζt (Ivy. With the passage of blood flow time! (Hematocrit decreased slightly, but platelet count,
There was almost no change in the white blood cell count, and the experiment proceeded smoothly without any problems such as bleeding. After the FFI style ended, I added the chivalry state to it and it returned to normal. Furthermore, when the oxygenator was dismantled and examined, no blood clots had formed at all.

Comparative Example 1 A hollow fiber membrane having an inner diameter of 200 μm and an outer diameter of 260 μm was obtained by dry spinning using a solution prepared by dissolving the polymer used in the example in toluene as a spinning stock solution. When the internal and external surfaces of this hollow fiber membrane were observed using a 20,000x magnification, it was found that the membrane had a dense surface layer with an observable network structure. The permeability of pure water after wetting with ethanol is 0.1
me/rd-hr-vtsk1g or less, and the liquid permeability was extremely low due to the presence of the compact layer.

A membrane oxygenator having a membrane area of 1.5 nl was prepared using this hollow fiber membrane, and a dog feeding experiment was conducted in the same manner as in the examples. Blood gas properties improved well, but 18
After time t#Jff, intrapulmonary resistance increased, the bath surface began to leak, and the amount of plasma free hemoglobin exceeded 200 mVd1l, so perfusion was discontinued after 24 hours. When the oxygenator lung was dismantled and examined, threads were found in many of the occluded areas.

Comparative Example 2 20,000 silicone hollow fibers having a dense membrane structure with an inner diameter of 200μ and an outer diameter of 4QOμ were placed in a housing, and each end was placed in a static filter to form a 1.5-door membrane type prosthesis. Lungs were created. Using this lung, a venoarterial bypass experiment was conducted in the same manner as in the example. After drifting, the blood gas properties immediately improved, but the oxygen partial pressure (Pot) in the arterial strip was 190.
rmnkig, CO□ partial pressure (Pco2) is 40 KHg
, and the amount of oxygen added to the blood was lower than in Examples.

〔Effect of the invention〕

As detailed above, according to the present invention, a polymer or a polymer mixture containing 50 mol% or more of substituted acetylene units that have excellent gas permeability and are strong and can be formed into a linear film is used. Blood contact surface is 50-1. ooooo
It is possible to provide an oxygenator membrane having a network structure in which pores are present, and a dense layer having a thickness of 1111 or more in the cross section of the membrane except for the blood contact surface.

In particular, the membrane of the present invention has a small change in gas exchange capacity over time.
In addition, it has excellent blood compatibility, so it is extremely useful when used for a long period of time, and can be safely used as a substitute for living lungs or as a compact auxiliary bag for moss lungs suffering from lung disease.

Claims (3)

[Claims] (1) A membrane composed of a polymer or polymer mixture containing 50 mol% or more of substituted acetylene units represented by formula (A), the membrane having a blood contact surface of 50 to 1,0
1. A membrane for an artificial lung, characterized in that it has a network structure in which pores of 00 Å exist, and is composed of at least one or more dense layers in a cross section of the membrane except for the blood contact surface. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(A) (However, in the formula, R_1 is hydrogen, halogen, or has 1 to 1 carbon atoms.
The alkyl group in No. 5, 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 membrane for an artificial lung according to claim (1), wherein the blood contacting surface has a network structure in which pores of 100 to 500 Å are present. (3) The membrane for an oxygenator according to claim (1) or (2), wherein the polymer is polytrimethylsilylpropyne.