JPS641149B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for manufacturing a hollow fiber membrane oxygenator.

Prior Art In general, in cardiac surgery and the like, a hollow fiber membrane oxygenator is used in an extracorporeal circulation circuit to lead a patient's blood outside the body and add oxygen to it.

There are two types of hollow fiber membranes used in such oxygenators: homogeneous membranes and porous membranes.

Since the homogeneous membrane uses a silicone membrane, the membrane thickness cannot be reduced to less than 100 μm due to its strength, and therefore there is a limit to gas permeation, and in particular, permeation of carbon dioxide gas is poor. Furthermore, when tens of thousands of pieces are bundled, the size of the apparatus increases, resulting in an increase in the amount of priming, and there are also disadvantages in that processability is poor and costs are high.

On the other hand, in a porous membrane, the fine pores of the membrane are significantly larger than the base molecules to be passed through, so that the membrane passes through the fine pores as a volumetric flow. For example, various oxygenators using porous membranes such as microporous polypropylene membranes have been proposed.

However, since porous membranes have high water vapor permeability, their performance not only deteriorates due to condensation, but also
When used with blood circulating for a long period of time, plasma may leak out.

In order to overcome these drawbacks of porous membranes, we formed an impermeable thin film of methylhydrodiene polysiloxane on the sidewalls of a 10 hollow fiber substrate, which has sidewalls with penetrating micropores of 10 microns or less in diameter. Hollow fibers made of the same material have been proposed (Special Publication No. 17052/1983).

However, in such hollow fibers, a film of methylhydrodiene polysiloxane is formed not only in the micropores of the hollow fiber substrate but also on both the inner and outer surfaces of the hollow fiber substrate, so that the hollow fiber substrate is Not only does the exchange capacity decrease as the hollow inner diameter becomes smaller, but also the amount (filling thickness) of methylhydrodiene polysiloxane filled in the micropores increases accordingly, so gases such as oxygen and carbon dioxide gas The drawback was low transmittance.

Furthermore, although the hollow fibers can be used in Aquarug, etc., they have the disadvantage that plasma begins to leak out when used as an artificial lung for a long time.

In order to further improve these drawbacks, the present applicant has developed a hollow fiber membrane in which only the inside of the micropores are closed with silicone oil, without forming a silicone oil layer on the side wall having micropores of the hollow fiber membrane. We have proposed a silicone membrane composite oxygenator (Japanese Patent Application No. 58-92325).

In this proposal, after assembling the oxygenator module, the hollow fibers are impregnated with a solution of silicone oil, and then the silicone oil is removed.
The purpose is to remove the silicone oil adhering to the wall surface of the hollow fiber substrate by flowing a mixture of a silicone oil solvent and a non-solvent, and to block only the inside of the micropores with the silicone oil.

According to this, plasma leakage was improved, but silicone oil sometimes leaked into the blood.

In response to this, the present applicant has proposed that first, instead of using silicone oil, the micropores are plugged with room temperature curing silicone rubber or a mixture of room temperature curing silicone rubber and silicone oil.

In this case, there are no drawbacks as mentioned above.

As mentioned above, after the module is assembled, if silicone rubber or a mixture of silicone rubber and silicone oil is impregnated and then removed with a mixture of solvent and non-solvent, compared to impregnation before module assembly. As a result, the coating device becomes smaller, the adhesion between the hollow fibers disappears, and the separation between the partition wall and the hollow fiber membrane due to poor adhesion between the potting material and the silicone disappears.

In addition, by removing silicone from the side wall,
Uniform silicone within micropores. Also, fiber blockage is eliminated.

However, in the impregnation process, the silicone leaches onto the outer wall of the fiber and wraps around it, making the silicone in the micropores non-uniform and resulting in unstable performance.

OBJECT OF THE INVENTION The object of the present invention is to improve the above-mentioned drawbacks, and to provide a method for effectively coating or impregnating a module with silicone rubber or a mixture of silicone oil and silicone rubber after assembling a module using porous hollow fibers. An object of the present invention is to provide a method for manufacturing an oxygenator that stably exhibits high gas exchange ability by impregnating porous hollow fibers with , or a mixture of the same and silicone oil.

These objects are achieved by the invention described below.

That is, the present invention provides a housing, a hollow fiber bundle consisting of a large number of porous hollow fiber membrane substrates for gas exchange inserted into the housing, and a first fiber bundle formed by the outer surface of the hollow fibers and the inner surface of the housing. a fluid chamber, a first fluid inlet and an outlet communicating with the first fluid chamber, partition walls supporting each end of the hollow fiber membrane base, an internal space of the hollow fiber membrane base, and After assembling an oxygenator module having a second fluid chamber consisting of a second fluid inlet and an outlet communicating with the internal space, wt% silicone mixture;
a raw silicone solution containing a solvent and having a weight ratio of silicone rubber to silicone oil of 2:8 to 8:2; and a surface in which the raw silicone solution is insoluble and has a critical surface tension greater than the critical surface tension of the hollow fiber substrate. Using a filling liquid with tension, fill either the first fluid chamber or the second fluid chamber with the filling liquid, and introduce the raw silicone solution into the other fluid chamber to fill the micropores with the filling liquid. After impregnating with the silicone mixture, the raw silicone solution is discharged, and then a cleaning liquid containing a liquid in which the raw silicone solution is insoluble is passed through the fluid chamber to remove the silicone mixture adhering to the wall surface of the hollow fiber substrate. , a method for manufacturing a hollow fiber membrane oxygenator, characterized in that the filling liquid is discharged.

Moreover, the embodiment is as follows.

() In the present invention, filling the first fluid chamber with a filling liquid.

() In the present invention or the above), the filling liquid is at least one of water, glycerin, ethylene glycol, diethylene glycol, an ethanol aqueous solution, and an isopropyl alcohol aqueous solution.
Being a seed.

() The silicone rubber is a room temperature curing silicone rubber.

() In the present invention or any one of () to () above, the ratio of silicone rubber to silicone oil is 2:8 to 8:2 by weight.

Specific Configuration of the Invention The specific configuration of the present invention will be described in detail below.

FIG. 1 shows an overall view of the hollow fiber membrane oxygenator of the present invention.

That is, as shown in FIG. 1, the oxygenator according to the present invention has a fiber bundle 1 of a hollow fiber membrane 12 in the inner space of a cylindrical housing 11 constituting the oxygenator 10.
3 is stored.

Both ends of the hollow fiber membrane 12 are fluid-tightly held in the housing 11 via partition walls 14 and 15.

At both ends of the housing 11, headers 16,
17 is fixed to the housing 11 by a cover 18 screwed onto the housing 11.

The inner surface of the header 16 and the partition wall 14 define a blood inflow chamber 19 as a second fluid inflow chamber that communicates with the internal space of the hollow fiber membrane 12. A blood inlet 20 is formed.

The inner surface of the header 17 and the partition wall 15 define a blood outflow chamber 21 as a second fluid outflow chamber communicating with the internal space of the hollow fiber membrane 12. A blood outflow port 22 is formed.

Furthermore, a gas chamber 23 as a first fluid chamber is formed between the partition walls 14 and 15, the inner wall of the housing 11, and the outer wall of the hollow fiber membrane 12.
A gas inlet 24 serving as a first fluid inlet and a gas outlet 25 serving as a first fluid outlet communicating with the gas chamber 23 are formed at both ends of the gas chamber 23 .

Note that it is preferable to provide a restricting portion 26 for reducing the diameter of the outer diameter of the fiber bundle 13 in the center of the inner wall of the housing 11 . As a result, as shown in FIG. 2, it is narrowed down at the center in the axial direction, and a narrowed portion is formed.

Therefore, the filling rate of the hollow fiber membrane 12 differs in each part along the axial direction, and is highest in the central part.

The partition walls 14 and 15 serve the important function of isolating the inside and outside of the hollow fiber membrane 12.

Normally, the partition walls 14 and 15 are made by pouring a highly polar polymeric potting agent such as polyurethane, silicone, epoxy resin, etc. onto the inner wall surfaces of both ends of the housing 11 using a centrifugal injection method, and then hardening it.

More specifically, first, a large number of hollow fiber membranes 12 longer than the length of the housing 11 are prepared, and both open ends of the membranes are sealed with a highly viscous resin.
They are placed side by side in the housing 11.

After that, each end is completely covered with a cover, and the housing 11 is centered around the central axis of the housing 11.
While rotating, a polymer potting agent is injected from both ends and cured. After the cover is removed, the outer surface of the hardened potting agent is cut with a sharp knife, and both open ends of the hollow fiber membrane 12 are cut on the surface. Formed by exposure to

As shown in FIG. 2, the hollow fiber membrane used in the oxygenator has a silicone layer substantially on the wall surface 34 of a porous hollow fiber substrate 33 having a side wall 32 having micropores 31 therethrough. This is a hollow fiber membrane type gas exchange membrane in which the inside of the micropores 31 of the side wall 32 are closed with silicone rubber or a silicone mixture 35 containing silicone rubber and silicone oil without forming any.

Porous hollow fiber substrates used in this hollow fiber membrane include polypropylene, polyethylene, polytetrafluoroethylene, polysulfone, polyacrylonitrile, polyethylene terephthalate,
Examples include polybutylene terephthalate, polycarbonate, polyurethane, nylon-6,6, nylon-6, cellulose acetate, etc., preferably polyolefin, and particularly preferably polypropylene.

In order to obtain practical performance as an oxygenator using a gas exchange membrane manufactured using this hollow fiber substrate, limitations naturally arise in membrane thickness and porosity. Generally, the amount of gas permeation q through a membrane is expressed by the following equation.

q=P×Δp×A/l (In the formula, P is the gas permeability coefficient, Δp is the pressure difference of the permeated gas, A is the membrane area, and l is the membrane thickness.) Hollow fiber membrane of the present invention Since the gas permeable portions are micropores blocked with a silicone mixture, the actual membrane area is much smaller than that of a porous membrane.

In order to compensate for this, it is necessary to reduce the film thickness, as is clear from the above equation.

Therefore, in the present invention, the thickness l of the hollow fiber membrane is in the range of 5 to 200 μm, preferably 10 to 50 μm.

The inner diameter of the hollow fiber membrane is 100-1000 μm, preferably 100-300 μm, and the porosity range is 20-80
%, preferably 40-80%. The average pore diameter of the micropores is 0.01 to 5 μm, preferably 0.01 to 1 μm.

The method for manufacturing an artificial lung according to the present invention is as follows.

That is, after the hollow fiber membrane substrate 33 is assembled into the oxygenator module, first, either the first fluid chamber or the second fluid chamber is filled with the filling liquid A.

In this state, the raw silicone solution is introduced into the fluid chamber which is not filled with the filling liquid A.

Note that the third fluid chamber is used as the fluid chamber into which the filling liquid flows.
Preferably, it is in the first fluid chamber as shown in Figures a and b. Therefore, it is preferable to introduce the raw material silicone solution into the second fluid chamber, that is, into the hollow fiber membrane substrate 33, as shown in FIGS. 4a and 4b.

The reason is that the outside of the hollow fiber membrane, that is, the first
This is because when the raw silicone solution is introduced into the fluid chamber of the fluid chamber, it may be difficult to remove the silicone mixture from the outer wall.

Hereinafter, an example will be described in which a filling liquid is introduced into the first fluid chamber and a raw silicone solution is introduced into the second liquid chamber.

First, the raw material silicone solution is filled into the hollow fiber membrane base 3 with the filling liquid A filled in the first fluid chamber.
After sufficiently impregnating the inside of the hollow fiber 3, the cleaning liquid is discharged, and as shown in FIGS.

Then, the filling liquid is discharged.

If necessary, after the raw silicone solution is discharged from the inside of the hollow fiber membrane base 33, it is preferable to flow gas into the base 33. Hollow fiber membrane substrate 3
3. Due to the blockage caused by silicone inside 3, and the excess silicone that adheres to the inner wall is washed out,
Later cleaning efficiency can be increased.

Further, after the washing liquid flows in, it is preferable to warm the entire oxygenator before discharging the filling liquid in the first fluid chamber, or to flow heated gas into the hollow fiber membrane substrate. This is because crosslinking of the silicone rubber progresses and the silicone does not flow to the outside of the hollow fiber membrane substrate after the filling liquid is discharged.

In such a case, the fill liquid used has a surface tension greater than the critical surface tension of the hollow fiber membrane substrate 33.

Here, the critical surface tension is a measure expressing the wettability of a solid surface, and the solid can be wetted by a liquid having a small surface tension due to the critical surface tension of the solid.

Then, the contact angles of several types of liquids with different surface tensions are measured on the solid surface, and the surface tension of the liquid and the cosine (cosθ) of the contact angle for each liquid are plotted, and the point where this straight line intersects cosθ = 1 is plotted. It can be measured by determining the surface tension of

Such filling liquids include water, glycerin,
One or more of ethylene glycol, diethylene glycol, ethanol aqueous solution, isopropyl alcohol aqueous solution, etc. is suitable.

In addition, when filling with the filling liquid, 0.5Kg/cm ² ~
Favorable results are obtained when pressurization is performed at a pressure of about 3.0 Kg/cm ² .

The silicone rubber used in the raw material silicone solution is a room temperature curing type (RTV), and may be either a one-part type or a two-part type.

The two-component rubber is a two-dimensional polymer solid rubber that contains vinyl groups and/or hydrogen in the raw material monomer or oil, and is crosslinked between C and H after mixing.

As the two-component RTV silicone rubber, a polymer of vinylmethylsiloxane and methylhydrogensiloxane is preferred.

In addition, in the case of these curing crosslinking, simple substance, oxide, compound, etc. of a platinum group metal, for example, chloroplatinic acid etc. are generally used.

Further, the curing temperature is 20°C to 30°C or higher.

The silicone oil used in the present invention is a liquid substance having a siloxane bond, such as dimethyl silicone oil, methylphenyl silicone oil, methylchlorophenyl silicone oil, branched dimethyl silicone oil, methylhydrogen silicone oil, etc. Preferred are dimethyl silicone oil and methylphenyl silicone oil, most preferably dimethyl silicone oil.

Silicone rubber can be used alone.

However, the use of a silicone mixture is advantageous because the viscosity of the silicone mixture is reduced, making it easier to remove silicone adhering to the wall surface of the hollow fiber substrate.

The ratio of silicone rubber to silicone oil (liquid content) in the silicone mixture is 2:
The ratio is preferably 8 to 8:2, more preferably about 4:6.

If the silicone rubber is greater than 8, the viscosity of the solution will increase, making it difficult to remove the silicone adhered to the wall of the hollow fiber substrate, and if the silicone rubber is less than 2, the mixed silicone oil will leak into the blood. there is a possibility.

This silicone rubber or silicone mixture is usually 20 to 80% by weight, preferably 30 to 60% by weight.
used as a solution.

In addition, the solvents include benzene, toluene, xylene, hexane, dichloromethane, methyl ethyl ketone, dichloroethane, ethyl acetate,
Examples include trifluorotrichloroethane (Freon).

As the liquid (cleaning liquid) for substantially removing the silicone rubber or silicone mixture adhering to the wall surface of the hollow fiber substrate, use a liquid (alcohol-based, etc.) in which silicone does not dissolve, since the impregnated silicone will be eluted with the above solvent. .

In this case, it is more preferable to use a mixed solvent of the above-mentioned solvent and a liquid in which silicone does not dissolve.

For example, toluene and propylene glycol,
Mixtures of toluene and dipropylene glycol, dichloromethane and diethylene glycol, dichloroethane and ethylene glycol, methyl ethyl ketone and ethylene glycol, etc. are used.

Further, the concentration of the solvent in the mixture of the solvent and the non-solvent is 0.5 to 10 vol%. If it is less than 0.5%, it may not be possible to completely remove the silicone rubber and silicone oil that have adhered to the hollow inner wall, and if it is more than 10%, the silicone rubber and silicone oil that are blocking the micropores will flow out and the blockage cannot be maintained. There are cases.

The particularly preferable range varies depending on the combination of solvents used, but it can be said that 2 to 6% is suitable.

The viscosity of the cleaning liquid is preferably 10 centipoise or more, particularly 30 to 80 centipoise or more at room temperature.

Note that "substantially removing the silicone rubber or the silicone oil" means reducing the layer of the silicone rubber or the silicone oil attached to the inner wall of the hollow fiber membrane to a thickness of 500 Å or less; This is because gas permeation is not substantially affected, and sufficient CO ₂ permeation is ensured as described later.

Specific Effects of the Invention According to the present invention, impregnation with silicone is performed after assembling an oxygenator using porous hollow fibers having micropores, so the equipment required for impregnation is simple and the manufacturing cost can be reduced. Compared to the case where the oxygenator is assembled after being impregnated with silicone, an oxygenator can be obtained in which there is no adhesion failure at the potting part due to poor adhesion of silicone.

Since the silicone membrane is formed substantially uniformly inside the micropores, there is no blockage of the hollow fibers and good blood circulation can be achieved.

It is possible to manufacture an artificial lung with very good gas exchange performance and stability.

Moreover, since impregnation and cleaning are performed after filling with a predetermined filling liquid, adhesion of silicone to the outer or inner wall of the hollow fiber membrane is reduced, the amount of silicone can be strictly controlled, and performance is stabilized.

Specific Examples of the Invention Hereinafter, examples of the present invention will be shown and the present invention will be explained in further detail.

Example 1 A through hole with an inner diameter of 200 μm, a wall thickness of 25 μm, and an average pore diameter of 700 Å, which was formed by stretching in the axial direction by a stretching method.
An artificial lung (Module C) (membrane area: 1 m ² ) as shown in FIG. 1 was prepared using polypropylene hollow fibers having micropores (porosity: 50%).

After this, as shown in Figure 3a and b, the first
The fluid chamber was filled with water at a pressure of 2.0 Kg/m ² .

Next, as shown in Fig. 4a and b, a silicone rubber containing chloroplatinic acid as a catalyst in a two-component type of vinyl methyl siloxane and methyl hydrogen siloxane was mixed with 60% dimethyl silicone oil.
The Freon solution was passed through for 3 minutes.

After this, air is circulated, and then Fig. 5a,
As shown in b, by flowing a 3% toluene/dipropylene glycol solution (cleaning liquid) to the inner and outer surfaces and draining the filling liquid, the silicone mixture of silicone rubber and silicone oil is formed substantially only within the micropores. A hollow fiber membrane filled with was obtained.

The surface tension of water was 72 dyn/cm, and the critical surface tension of the hollow fibers was 30 dyn/cm.

Note that the amount of silicone rubber in the silicone mixture was 40 wt%.

Further, the viscosity of the cleaning liquid was 100 centipoise.

For this oxygenator, fresh heparinized bovine blood was used to prepare venous blood with oxygen saturation of 65% and carbon dioxide partial pressure of 45 mmHg, and this was distributed to the test oxygenator (module A) for performance evaluation. Summer. The hemoglobin content was 12 g/dl and the temperature was 37°C.

The relationship between blood flow rate and oxygenation capacity when the oxygen flow rate is 1/min/m ² is shown by curve A in FIG. 6.

The relationship between oxygen flow rate and carbon dioxide removal ability when the blood flow rate is 1000 ml/min/m ² is shown by curve A in FIG.

Furthermore, a venous-arterial partial extracorporeal circulation test was performed using a mixed dog.

The relationship between circulation time and plasma leakage amount was as shown by curve A in FIG. 8, respectively.

On the other hand, for comparison, a similar experiment was conducted without filling with the filling liquid (Module B).

These results are shown as B in FIGS. 6, 7, and 8.

Incidentally, curve C in FIGS. 6, 7, and 8 indicates that no silicone is impregnated.

These results show that the present invention improves performance.

[Brief explanation of drawings]

FIG. 1 is a partial vertical sectional view showing an example of an oxygenator according to the present invention, and FIG. 2 is an enlarged schematic diagram of a hollow fiber membrane used in the oxygenator according to the present invention. Third
The figures are diagrams for explaining the filling process of the present invention, of which a is an overall view and b is an enlarged sectional view. FIG. 4 is a diagram for explaining the impregnation process of the present invention, of which a is an overall view and b is an enlarged sectional view. FIG. 5 is a diagram for explaining the cleaning process of the present invention, in which a is an overall view and b is an enlarged sectional view. FIG. 6 is a graph showing the relationship between oxygenation capacity and blood flow rate of an artificial lung. FIG. 7 is a graph showing the relationship between oxygen flow rate and CO ₂ removal ability, and FIG. 8 is a graph showing the relationship between the venous-arterial portion, extracorporeal circulation time, and plasma leakage amount. Explanation of symbols, 10... Artificial lung, 11... Housing, 12... Hollow fiber membrane, 14, 15... Partition wall, 21, 22... Blood port, 24, 25...
Gas port, 31... Micropore, 33... Hollow fiber membrane substrate, A... Filling liquid, B... Raw silicone solution, C... Cleaning liquid.

Claims (1)

[Scope of Claims] 1. A hollow fiber bundle consisting of a housing, a plurality of porous hollow fiber membrane substrates for gas exchange inserted into the housing, an outer surface of the hollow fibers, and an inner surface of the housing. a first fluid chamber, a first fluid inlet and an outlet communicating with the first fluid chamber, a partition wall that supports each end of the hollow fiber membrane base, and an interior of the hollow fiber membrane base. After assembling an oxygenator module having a space and a second fluid chamber consisting of a second fluid inlet and an outlet communicating with the inner space, a module containing room temperature curing silicone rubber and silicone oil is prepared. ~80% by weight silicone mixture,
a raw silicone solution containing a solvent and having a weight ratio of silicone rubber to silicone oil of 2:8 to 8:2; and a surface in which the raw silicone solution is insoluble and has a critical surface tension greater than the critical surface tension of the hollow fiber substrate. Using a filling liquid with tension, fill either the first fluid chamber or the second fluid chamber with the filling liquid, and introduce the raw silicone solution into the other fluid chamber to fill the micropores with the filling liquid. After impregnating with the silicone mixture, the raw silicone solution is discharged, and then a cleaning liquid containing a liquid in which the raw silicone solution is insoluble is passed through the fluid chamber to remove the silicone mixture adhering to the wall surface of the hollow fiber substrate. . A method for manufacturing a hollow fiber membrane oxygenator, characterized in that the filling liquid is discharged. 2. The method for manufacturing a hollow fiber membrane oxygenator according to claim 1, wherein the first fluid chamber is filled with a filling liquid. 3. The method for producing a hollow fiber membrane oxygenator according to claim 1 or 2, wherein the filling liquid is at least one of water, glycerin, ethylene glycol, diethylene glycol, an aqueous ethanol solution, and an aqueous isopropyl alcohol solution.