JPS60249968A - Hollow fiber 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 a hollow fiber membrane oxygenator.

Prior Art Generally, in heart surgery, etc., a patient's blood is guided outside the body.
In order to add oxygen to this, a hollow fiber type M oxygenator is used in the extracorporeal circulation circuit.

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 thickness can be reduced to 1 for strength.
It cannot be made below OO-, and therefore there is a limit to gas permeation, and in particular, permeation of carbon dioxide gas is poor. Moreover, when the drinking method is changed, the device becomes larger and the amount of priming increases, and there are also disadvantages in that the processability is poor and the cost is high.

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

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

In order to eliminate these drawbacks of porous membranes,
A hollow fiber has been proposed in which a non-permeable, air-permeable thin film of methylhydrodiene polysiloxane is formed on the side wall of a hollow fiber substrate having a side wall having penetrating micropores of 0 microns or less (Japanese Patent Publication No. 17052/1986). issue).

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 base is formed by that amount. As the hollow inner diameter of the body becomes smaller, not only the exchange capacity decreases, but also the amount of methylhydrodiene polysiloxane filled in the micropores (filling thickness) increases accordingly, so that oxygen, carbon dioxide, etc. It had the disadvantage of low gas permeability.

Furthermore, although the hollow fibers can be used in Aqua Lungs and the like, 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 (@Gan-Sho No. 58-92325).

In this proposal, after the oxygenator module is assembled, the hollow fibers are impregnated with a silicone oil solution, the silicone oil is then removed, and a mixture of silicone oil solvent and non-solvent is poured onto the hollow fiber substrate wall. The aim is to remove the silicone oil adhering to the pores and block only the inside of the micropores with silicone oil.

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

In response to this, the present inventors have previously proposed blocking the micropores with silicone rubber or a mixture of silicone rubber and silicone oil.

This eliminates the aforementioned drawbacks of the '4F.

II. OBJECTS OF THE INVENTION The object of the present invention is to improve the CO2 removal ability, plasma leakage amount, etc. when the micropores of a porous hollow fiber membrane base material are plugged with silicone rubber or a mixture of silicone oil and silicone rubber. The purpose of this invention is to provide a hollow fiber membrane oxygenator that obtains optimal characteristics.

Such 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 hollow fiber membranes for gas exchange inserted into the housing, and a first fluid formed by the outer surface of the hollow fiber membranes and the inner surface of the housing. a first fluid inlet and an outlet communicating with the first fluid chamber; a partition supporting each end of the hollow fiber membrane, and a second fluid chamber communicating with the interior space of the hollow fiber membrane. In an oxygenator comprising a fluid inlet and an outlet, the hollow fiber membrane has an inner diameter of 100 mm.
~1000μs, wall thickness 5~200-, porosity 20~8
The base material is a porous hollow fiber having micropores with an average pore diameter of 0.01 to 5% at 0%, and the micropores are occluded with silicone rubber or a silicone mixture containing silicone oil and silicone rubber. Moreover, 02 Flux, = Q / ΔP
, O-50 mu/min-m'·n+m Hg, the hollow fiber membrane is an oxygenator.

Examples of implementation IEs of the present invention are as follows.

i) In the present invention, the silicone rubber is a room temperature curable silicone rubber.

i) In the present invention or i) above, the silicone oil is dimethyl silicone oil or methylphenyl silicone oil.

in1 the present invention or the above i) or rl),
The silicone mixture containing silicone oil and silicone rubber is a mixture of silicone oil and silicone rubber in a ratio of 2:8 to 8:2.

10 Specific structure of the invention Hereinafter, a specific configuration of the present invention will be explained in detail.

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

That is, as shown in FIG. 1, in the oxygenator according to the present invention, a fiber bundle 13 of a hollow fiber membrane 12 is housed in an internal space of a cylindrical housing 11 constituting an oxygenator 10. As shown in FIG.

Both ends of the hollow Hh fiber detachment 2 are held fluid-tightly in the housing 11 via partition walls 14.15.

Headers 16, 17 are fixed to both ends of the housing 11 by covers 18 which are 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, and the header 17 has a blood outflow chamber 21 as a second fluid outflow chamber. A blood outflow port 22 is formed.

Further, 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 tlJMIH 12, and at both ends of the housing 11,
A gas inlet 24 as a first fluid inlet and a gas outlet 25 as a first fluid outlet are formed, each communicating with the gas chamber 23 .

Additionally, fiber bundles 13 are provided at the center of the inner wall of the housing 11.
It is preferable to provide an aperture restraining portion 26 that reduces the diameter of the outer shape. 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.

When the restraining portion is provided, the filling rate of the hollow fiber membrane 12 differs in each portion along the axial direction, and is highest in the central portion.

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

Normally, the partition walls 14 and 15 are made by pouring a highly polar polymer botting agent, such as polyurethane, silicone, epoxy resin, etc. onto the inner wall surface of both ends of the housing 11 (7) using a centrifugal injection method, and then curing it. It will be done.

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

After this, completely cover each end with a cover and
While rotating the housing 11 around the central axis of the housing 11, polymer bonding agent was poured from both ends and cured. After the force was removed, the outer surface of the hardened potting agent was sharpened. Cut the hollow fiber membrane 1 with a knife.
It is formed by exposing both open ends of 2 to the surface.

Therefore, the hollow AM membrane used in the oxygenator has a second
As shown in the figure, a side wall 32 having micropores 31 passing through it.
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 substantially forming a silicone layer on the wall surface 34 of the porous hollow fiber substrate 33. This is a hollow fiber membrane type gas exchange membrane.

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

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 x Δp Since the 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 wall thickness, as is clear from the above equation.

Therefore, in the present invention, the range of the hollow #j fiber detachment thickness range is from 5 to 200-1, preferably from lO to 50-1.

The inner diameter of the hollow fiber membrane is lOO~1000tffl, preferably 100~300p+a, and the porosity range is 20
~80%, preferably 40-80%. The average pore diameter of the micropores is 0.01 to 5-1, preferably 0.01 to 1-1.
It is.

If the inner diameter is less than 1O-, the pressure drop will be high, causing blood damage and increasing the risk of hollow fiber occlusion.

On the other hand, if it exceeds 1000-, the performance, especially the oxygen addition ability, decreases and the amount of priming also increases.

When the porosity is less than 20%, the effective membrane area decreases and gas exchange performance deteriorates.

Moreover, when it exceeds 80%, the strength of the hollow fiber membrane base material decreases.

The average pore diameter of the micropores is calculated according to the known mercury intrusion method or electron microscopy method, and is 0. If it is less than O1-, the silicone solution cannot be uniformly introduced into the pores.

Also, 5#I! If it exceeds 1, the strength of the silicone rubber that has blocked the pores or the mixture of silicone oil and silicone rubber will be low and there is a risk that it will leak into the blood.

In the oxygenator according to the present invention, the hollow fiber membrane is assembled into an oxygenator module, and then a silicone rubber or a solution of a mixture of silicone rubber and silicone oil is passed through the membrane to sufficiently impregnate the membrane, and then a gas is passed through the membrane to remove the solvent and the non-solvent. It is produced by flowing a mixture with a solvent over at least the inner surface of the hollow fiber, and further crosslinking with heating if necessary.

The silicone rubber used is room temperature curable (RTV). Also, either a so-called one-liquid type or a two-liquid type may be used.

Two-component rubbers are generally solid rubbers that are two-dimensional polymers that contain vinyl groups and/or hydrogen in the raw material monomers or oil, and are crosslinked between C and H after mixing.

A polymer of vinylmethylsiloxane and methyl/hydrogensiloxane is preferred.

Incidentally, in these curing and crosslinking processes, simple substances, oxides, compounds, etc. of platinum group metals, such as chloroplatinic acid, etc., are used.

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

In the present invention, only silicone rubber may be used. However, silicone rubber alone has a high viscosity when in a liquid state, and it may be difficult to heat the inside of the hollow space.

For this reason, it is preferable to use silicone oil and silicone rubber together.

The silicone oil used in the present invention is a liquid substance having a siloxane bond, and examples thereof include dimethyl silicone oil, methylphenyl silicone oil, methylchlorophenyl silicone oil, branched dimethyl silicone oil, methyl/hydrogen silicone oil, etc. dimethyl silicone oil and methylphenyl silicone oil, most preferably dimethyl silicone oil.

When a mixture of silicone rubber and silicone oil is used, the ratio of silicone rubber (solid content) to silicone oil (liquid content) is 228 to 8:2, preferably 4:6 by weight. That's about it.

If the silicone rubber has a viscosity of 8 or more, it will be difficult to remove the silicone adhered to the wall surface of the hollow fiber membrane substrate due to the viscosity of the solution, and if the silicone rubber has a viscosity of 2 or less, the mixed silicone oil may enter the blood. There is a possibility of leakage.

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

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

The liquid (cleaning liquid) that substantially removes the silicone mixture adhering to the wall surface of the hollow fiber substrate is a mixed solvent of a solvent (alcohol-based) in which silicone does not dissolve and the above-mentioned solvent, since the impregnated silicone will be eluted with the above-mentioned solvent. Use.

For example, toluene and propylene glycol, toluene and dipropylene glycol, dichloromethane and diethylene glycol, dichloroethane and ethylene glycol,
A mixture of methyl ethyl ketone, ethylene glycol, etc. is used.

Further, the concentration of the solvent in the mixture of the solvent and the non-solvent is 0.
．． It is 5 to 1 Ovo1%.

If it is less than 0.5%, it may not be possible to completely remove the silicone rubber and silicone oil adhering to the hollow inner wall.
Moreover, if it is more than 10%, the silicone rubber and silicone oil that block the micropores may flow out, making it impossible to maintain the blockage.

The particularly preferable range varies depending on the combination of solvents used, but it can be said that 2 to 6v01% is suitable.

Here, "substantially removing the silicone rubber and silicone oil" means that the thickness of the silicone rubber and silicone oil attached to the inner wall of the hollow fiber membrane is 7%1500λ or less, and if the thickness is 500Å or less, gas permeation is prevented. This is because there is no substantial influence and sufficient CO2 permeation is ensured as described later.

Furthermore, all of the micropores do not need to be completely blocked with the silicone rubber compound.

In this case, "substantially closed" means that 90% or more of the micropores are closed.

Note that it is preferable that 95% or more of the pores are blocked.

In the hollow fiber membrane oxygenator of the present invention, in order to ensure that plasma is hardly exposed even when circulating for a long time and to have a practically sufficient CO2 removal ability, it is necessary to use silicone impregnated into the hollow fiber membrane having micropores. It is necessary to strictly control the flow rate of oxygen passing through the micropores of the silicone film by controlling the concentration of the mixture solution.

In the hollow fiber membrane oxygenator of the present invention, in order to have almost no plasma leakage even after long-term circulation and to have a practically sufficient CO2 removal ability, silicone impregnated into a hollow mm membrane having micropores is required. By controlling the concentration of the rubber or silicone mixture solution, it is necessary to tightly control the oxygen meteorite passing through the micropores of the silicone rubber or silicone mixture.

In other words, the following formula (2) is used, assuming that the oxygen flow rate is 02Flux.
In the case shown by , it is necessary that the value of 02Flux falls within the range of formula (1) below.

1.0 (mal/win@rn' * mm Hg)
< 02 Flux < 5.0 (m51/min@r
n' mm mm Hg)--1-(1) Here, Q: oxygen permeation amount (+nR/m1n), ΔP: pressure difference (mm
Hg), A: membrane area (m').

In this case, 02 Flux is configured with an oxygenator module and the gas flow per unit membrane area is 300 to 3000 ml.
The amount of permeation and the pressure difference may be actually measured under conditions that result in /win.

In addition, 02 Flux is 1,0 msl/m1ne
When it is less than rn'*mm Hg, the CO2 removal ability decreases rapidly.

Also, 50 m9/min@m' @ 101118g
If it exceeds , the amount of plasma outflow increases rapidly and is not practical.

■6 Specific Effects of the Invention The present invention impregnates a porous hollow fiber membrane with fine pores with a controlled amount of silicone rubber or a silicone mixture, and strictly controls the O 2 flux in the fine pores. There is almost no leakage of plasma even when circulating for hours, and it has sufficient CO2 removal ability.

As a result, the present invention can make the device smaller than a hollow fiber membrane oxygenator using a silicone membrane, and realize an oxygenator with good gas exchange efficiency, low cost, and good processability.

In this case, according to the above-mentioned embodiments i) to kneading, the performance is improved and the production is facilitated.

The present inventors conducted various experiments to confirm the effects of the present invention.

An example is shown below.

Experimental Example 1 Inner diameter 200 mm formed by stretching in the axial direction by the stretching method
An oxygenator (membrane area 1.6 m' )
was produced.

The blood flow path was immersed for 3 minutes in a 60% Freon solution of dimethylsilicone oil and silicone rubber containing a catalyst such as chloroplatinic acid in a two-component type of vinylmethylsiloxane and methylhydrodienesiloxane.

After that, by circulating air and further circulating toluene/dipropylene glycol solution on the inner and outer surfaces,
A hollow fiber membrane oxygenator was obtained in which the silicone mixture of silicone rubber and silicone oil was filled substantially only in the micropores.

Then, by changing the toluene concentration in the toluene/dipropylene glycol solution, module A-
02 gas 500 nil as shown in Table 1 below
/minte cr+02 Flux was obtained.

Table 1 E 15.0, 98.0 For this oxygenator, fresh heparinized blood was used to prepare venous blood to give Ig (oxygen saturation: 65%, carbon dioxide partial pressure: 45 am), and this was transferred to the test oxygenator ( Performance evaluation was performed by distributing it to modules A-E). The hemoglobin content was 12 g/du and the temperature was 37°C.

Blood flow rate 1000dl/win/rn', oxygen flow rate 3
Fig. 3 shows the carbon dioxide removal ability when the temperature is 1/2/win/m''.

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

The relationship between the circulation time and the amount of plasma leakage was as shown in Figure 4. As is clear from Figure 4, plasma leaked violently from module E. Although plasma leaked from modules C and D, the amount did not reach a level that would pose a problem for biological management, and there was no tendency to increase. Module A@B did not leak.

Furthermore, as shown in FIG. 3, module A did not exhibit practical performance in terms of C02 removal ability.

[Brief explanation of the drawing]

Fig. 1 is a partial longitudinal sectional view showing an example of the hollow fiber double lung according to the present invention, Fig. 2 is an enlarged schematic diagram of the hollow fiber used in the oxygenator according to the present invention, and Fig. 3 is a CO2 of the oxygenator. FIG. 4 is a graph showing the relationship between venous-arterial partial extracorporeal circulation time and plasma leakage amount. 10... Artificial lung, 11... Housing, 12...
Hollow fiber membrane, 13... Hollow fiber bundle, 14.15...
Partition wall, 20... blood inlet, 21-... fear fluid outlet,
23...Gas chamber, 31...Minute hole, 33...Hollow #li fiber substrate Patent applicant Chirusen Co., Ltd. Representative Patent attorney Yo Ishii - Figure 1↑ Figure 2 33 Figure 3 Module

Claims (4)

[Claims] (1) a housing, a hollow fiber bundle consisting of a large number of hollow fiber membranes for gas exchange inserted into the housing, and a first fluid chamber formed by the outer surface of the hollow fiber membranes and the inner surface of the housing; , a first fluid inlet and an outlet communicating with the first fluid chamber, partition walls supporting each end of the hollow fiber membrane, and a second fluid communicating with the internal space of the hollow fiber membrane. In an oxygenator comprising an inlet and an outlet, the hollow fiber membrane has an inner diameter of 100 to 10'OO and a wall thickness of 5.
~200μs, porosity 20~80%, average pore size 0
．． The base material is a porous hollow fiber having micropores of 01 to 5-, the micropores are substantially blocked by silicone rubber or a silicone mixture containing silicone oil and silicone rubber, and 02 Flux = Q /△PXA [here,
Q is the oxygen permeation rate (mR/m1n), △P is the pressure difference (m+
aHg), A is membrane area (m')] is 1, 0 to 50 m
1 t/wins rrf*mm Hg TE. (2) The hollow fiber membrane oxygenator according to claim 1, wherein the silicone rubber is a room temperature curable silicone rubber. (3) The hollow fiber membrane oxygenator according to claim 1 or 2, wherein the silicone oil is dimethyl silicone oil or methylphenyl silicone oil. (4) Claims 1 to 3, wherein the silicone mixture containing silicone oil and silicone rubber is a mixture of silicone oil and silicone rubber in a ratio of 2:8 to 8:2. The hollow fiber membrane oxygenator according to any one of the above.