JPS6168104A - Composite membrane having excellent affinity for living body - Google Patents

Abstract

PURPOSE:To obtain the titled composite membrane showing substance permeability and having excellent suitability for a living body by spreading a copolymer of a hydrophilic monomer and a hydrophobic monomer on a liquid surface to obtain a monomolecular condensed membrane, and laminating the membrane on a supporting body layer with the hydrophilic segment-rich surface as the surface. CONSTITUTION:A soln. of a copolymer of a hydrophilic monomer and a hydrophobic monomer, such as an ethylene-vinyl alcohol copolymer, is diffused and developed on a water surface 6, and then compressed by reducing the area of the water surface to form a monomolecular condensed membrane wherein the hydrophilic condensed segment 2 of the copolymer is embedded into water. Then the condensed membrane is transferred onto a supporting body of an ethylene-vinyl alcohol copolymer film, etc. The composite membrane thus obtained has excellent suitability for blood, and reveals high substance permeability in addition to the affinity for a living body, when a filter membrane or a permeable membrane is used as the supporting body layer.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to composite membranes. More specifically, a monomolecular condensed film formed by spreading a copolymer of a hydrophilic monomer and a hydrophobic monomer on the liquid surface is laminated on a support layer with the side having many hydrophilic segments facing up. The present invention relates to a medical composite membrane that has excellent biocompatibility, particularly blood affinity.

[Conventional technology]

In recent years, there has been remarkable progress in membrane separation technologies, some of which have been put into practical use on an industrial scale.

Looking back at the history of this development, it can be seen that membranes have been made into composite structures with the aim of improving separation efficiency and improving membrane mechanical, chemical, and biological durability. The composite membrane in such a separation membrane consists of an active layer and a support layer, with the support layer maintaining membrane strength and the active layer controlling permeability. In general, the thinner the active layer is, the higher the permeability to substances, so ultra-thin films with a thickness of several thousand to several hundred angstroms14) are currently used.

One method for producing such an ultra-thin film is to spread a polymeric water-insoluble solvent on the water surface to form an ultra-thin layer of the solution.
There is a so-called water casting method that removes the solvent. Specifically, as a large-area ultra-thin layer manufacturing method, 1 layer is placed on the water surface.
A method in which a pair of partition rods is installed and a polymer solution is dripped into the area separated by the partition rods, and the distance between the partition rods is increased (Japanese Patent Application Laid-open No. 51-89564), A method of forcibly spreading a solution onto the water surface by passing a movable surface such as a rotating roll through a solution reservoir set below the water surface using a solvent (U.S. Pat. No. 3,767,737); A method of spreading a molecular solution by controlling the relative liquid level positions of the aqueous phase and the solution phase (Japanese Patent Application Laid-Open No. 58-92526)
etc. are known. However, since these ultra-thin membranes are considered as active layers in reverse osmosis, liquid-liquid separation, gas separation, etc., they essentially have only a homogeneous and smooth structure and are biocompatible. It cannot be said that it is excellent.

Furthermore, Japanese Patent Application Laid-Open No. 57-159506 discloses a composite membrane in which the active layer is composed of molecules of a crosslinked monomolecular film.

This film can be said to be a much more advanced film in that the active layer is an ultra-thin layer with a specific orientation and structure, but the surface of the active layer is still only a homogeneous and smooth structure, making it biocompatible. Not enough in terms of sex.

On the other hand, in terms of biocompatibility, in addition to conventional materials such as medical silicone rubber, polyhydroxyethyl methacrylate, and Teflon, blenders of hydrophilic polyether μ urethane and hydrophobic polydimethyμ siloxane, and segmented copolymer Ether-urethane-urea, etc. are being studied. In particular, the latter two have a micro-f-separated structure of hydrophilic and hydrophobic parts, so not only the primary structure of the polymer but also the higher-order structure of the surface is important for antithrombotic properties. It is recognized that it is a factor (in the field of chemistry, 519).

Another example of a highly biocompatible surface structure is a diffuse layer. (Polym.

PrePrints, Japan, 28.1542
(1979) ). This is because hydrophilic flexible side chains stick out from the polymer surface into the water like seaweed.
It has a fluctuating higher-order structure, and is thought to exhibit high blood compatibility due to the molecular movement and electrical repulsion of its hydrophilic layer.

The highly biocompatible materials mentioned above include those that express their properties through a special chemical structure (primary structure).
Some exhibit their properties due to a specific three-dimensional structure (higher-order structure), or exhibit biocompatibility due to both properties, but all of these are blood tubes,
It has been developed as an implantable biomaterial for blood bags, artificial blood vessels, artificial hearts, catheters, and other devices.The material has been made into a thin layer to exhibit good substance permeability and has excellent biocompatibility. There are no research examples of composite membranes.

[Problem that the invention seeks to solve]

As mentioned above, conventional composite membranes made of ultra-thin films have poor biocompatibility, while the above biocompatible materials have poor substance permeability. At present, composite membranes are still unknown.

In view of this situation, the present inventors formed an ultra-thin layer with excellent biocompatibility and used it as an active layer to create a composite membrane with excellent biocompatibility that can also exhibit substance permeability. As a result of intensive studies to obtain this, it was unexpectedly possible to spread a solution of a copolymer of a hydrophilic monomer and a hydrophobic monomer on the water surface and compress it with a predetermined surface pressure to release the hydrophilic segment of the copolymer. After forming a monomolecular condensed film submerged in water, or while forming it, transfer the condensed film onto a support layer with the surface in contact with the water surface facing up, or transfer the copolymer to a non-aqueous solvent. After or during the formation of a monomolecular condensed film in which the hydrophobic segments of the copolymer are dispersed and expanded on a surface and compressed with a predetermined surface pressure in an embodiment in which the hydrophobic segments of the copolymer are squeezed into a nonaqueous solvent, the condensation is performed. The inventors have discovered that a composite membrane that satisfies the above objectives can be obtained by transferring the membrane onto a support layer with the side not in contact with the non-aqueous solvent facing up, leading to the present invention.

[Means and effects for solving the problem] The present invention spreads a copolymer of a hydrophilic layer and a hydrophobic portion on a liquid surface to form a monomolecular condensed film, and Although this is a composite membrane formed by laminating a condensed membrane on a support layer with the side having many hydrophilic segments facing up, the copolymerization form of the copolymer is not particularly limited, and a general-purpose random copolymer is generally used. It will be done. The effects of the present invention are great when block copolymers and graft copolymers are used, and ethylene-vinyl alcohol copolymers are particularly preferred.

Hydrophilic layer additives used in the copolymer include those containing vinyl alcohol, cellulose 'I (D hydroxyl M), and known neutral hydrophilic layer additives containing aldehyde groups, ethylene oxide groups, etc. In addition, compounds containing carboxy μ group, sulfate group, sulfite group, nitrate group, nitrite group, phosphoric acid group, phosphorous acid group, hypophosphorous acid group and ester groups thereof or It is also possible to use monomers that can be negatively ionized in water that contains ions. Monomers that can be positively charged in water that contain amino crystals, imino groups, etc. can also be used, but these can adsorb proteins in body fluids. When using the composite membrane of the present invention for such treatment, it is necessary to deactivate the active center before use.As a method for deactivating the active center, for example, loading with heparin, etc. Examples of the hydrophobic monomers used in the copolymer of the present invention include olefin-based, diene thread, acetylene-based, and aromatic-based monomers. , organosiloxane type, ) to oleethylene type.

In the present invention, various membranes such as filtration membranes and dialysis membranes having so-called pores are used as the support layer. Such M is desirably a membrane in which the average pore diameter of the surface in contact with the monomolecular condensed membrane is 100 OA or less, preferably 400 OA or less. If a membrane with an average pore size larger than 100 OA is used, defects will occur when a monomolecular condensation membrane is transferred to the membrane, and the permselectivity will likely be impaired. Further, as the support layer, a material generally referred to as a film or sheet, which has a substantially pore-free structure and extremely low permeability to substances, is also used. A substantially pore-free structure is defined by a magnification of 10
This refers to a structure in which the presence of pores cannot be confirmed even with a scanning electron microscope at 10,000 times magnification.

In the present invention, when the above-mentioned films and sheets are used as a support layer, the effect of the present invention is to modify their surfaces and impart high biocompatibility. The effect when used as a layer is not only to modify the membrane surface, but also to provide excellent biocompatibility with high substance permeability. Therefore, when such a membrane is used as a support layer, the effect is more clearly expressed. Furthermore, as a special support layer, for example, a monomolecular film of the same or different materials or a composite film in which a cumulative film thereof is fixed can be used, or a hollow fiber membrane can also be used. Although the thickness of these supports is not particularly defined in the present invention, they are practically used in the range of several μ to several mm.

The composite film of the present invention is composed of these support layers and the monomolecular N4 layer, but the monomolecular condensed layer may be used as a single layer or as a multilayer as a cumulative film. . However, in either case, it is necessary that the surface has a large number of hydrophilic segments.

Next, a method for manufacturing the composite membrane of the present invention will be described. A monomolecular condensed film of a hydrophilic monomer and a hydrophobic monomer can be produced using a known method. For example, according to the Langmuir method, a polymer copolymer is dissolved in a solvent that is as insoluble in water as possible and light in water resistance, and the solution is spread on a water surface H having a movable partition rod. When the solvent evaporates or dissolves, a monomolecular film of the copolymer remains on the water surface.
The partition rod is moved to reduce the area of the water surface and compress the monolayer on the water surface. As the compression ratio is increased, the segment begins to be buried in water from the point where the hydrophilic monomer density is high, and the single molecule protrudes into the water where the hydrophilic monomer density is highest and where the hydrophobic monomer density is highest into the air. A condensed film is obtained. In the case where the copolymer is a block copolymer or a graft copolymer made of a hydrophilic monomer and a hydrophobic monomer, the effect appears more clearly because of the presence of long segments of the hydrophilic monomer.

Furthermore, by performing the above operation using a non-aqueous solvent, it is also possible to make a region with a high hydrophilic heptamer density protrude into the air. The process by which such a monomolecular condensed film is produced on the water surface is schematically shown in FIGS. 2 to 4. Figure 2 shows the state in which a copolymer consisting of a hydrophilic monomer and a hydrophobic monomer is spread on the water surface, Figure 3 shows the state in which the hydrophilic segments protrude into the water by compression, and Figure 4 shows the state in which the copolymer consists of a hydrophilic monomer and a hydrophobic monomer. FIG. 2 is a schematic diagram of a combined state. Moreover, FIG. 1 is a schematic diagram of a composite membrane of the present invention manufactured by such a method.

The degree of protrusion of the hydrophilic segments can be controlled with good reproducibility by determining a predetermined compression ratio and temperature depending on the composition and structure of the copolymer. In order to increase the strength of the monomolecular condensed film obtained, it is also an effective method to add salts or substances reactive with the copolymer in advance into the water or on the water surface.

The monomolecular condensed film can be transferred onto the support by known methods such as the Fungmuir-Prodgett method, the rotating cylinder method, and the horizontal deposition method.

In the composite membrane obtained as described above, the bond between the surface layer consisting of a monomolecular condensed membrane and the support layer may not be sufficient depending on the application. Therefore, it is also practically effective to firmly bond the monomolecular condensed film to the support layer using known techniques such as photocrosslinking, radiation crosslinking, and chemical reaction.

Why does the composite membrane of the present invention exhibit excellent biocompatibility?
Although this cannot be made completely clear, the surface of the composite membrane of the present invention differs from the conventional homogeneous and smooth structure as shown in Figure 1, and the monomolecular condensed membrane has a prominent hydrophilic structure. Because it has a so-called diffuse N structure with segments,
It is thought that the movement of the layer eliminates approaching blood coagulant substances, and that albumin is adsorbed to the layer, thereby covering the surface of the layer and reducing the adhesion of platelets, blood cells, etc.

Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples in any way.

[Example 1] Ethylene content fk 32 mo~%, saponification degree 99. s mol % of the ethylene-vinyl acop copolymer was dissolved in a mixed solvent of benzene and dimethyl sulfoxide, and the solution was dropped onto distilled water at room temperature and diffused to form a monomolecular condensed film. After standing for 1 hour, the monomolecular film was compressed until the surface pressure reached 20 dyne/cm. As shown in Figure 5,
According to the surface pressure-area curve of the ethylene-vinyl alcohol μ copolymer, the copolymer has a surface pressure of 10 dyne/a.
Below 15 dyne/am, it becomes a liquid expansion film, and below 15 dyne/am, it becomes a liquid condensation film.

The area occupied by this condensed film is approximately 2.5
A: The area occupied by the molecular model is approximately 11A.
The hydrophilic segment is clearly buried in the water, or the hydrophobic segment is folded into the air. Next, a clean ethylene-viny μ-alcohol μ copolymer film was gently placed on the monomolecular condensed film, and the monomolecular condensed film was transferred onto the support film by a horizontal adhesion method.

The composite membrane thus obtained was placed in a cell with an internal volume of 1.5 cc, the fresh side of the dog was injected, and the cell was kept airtight for 10 minutes, the blood was discarded, and the cell was rinsed with phosphate buffer. When the surface of the composite membrane was fixed with glutaraldehyde and then subjected to t-microscopic observation, it was found that there was little adhesion of platelets and almost no change in the morphology of the platelets was observed.

From the above results, it is clear that the composite membrane of the present invention has excellent blood compatibility.

[Example 2] An ethylene-vinyl alcohol film with an average surface pore size of about 300^ (as determined by scanning electron microscopy) was used as the support layer,
A composite membrane was obtained in the same manner as in Example 1 except that the monomolecular condensed membrane was transferred onto a support by the Hungmuir-Prodgett method,
When the platelet adhesion behavior was investigated, the number of platelets attached was small, and almost no change in platelet morphology was observed.

Furthermore, the water permeability and albumin rejection rate of this composite membrane were measured, and the results were as shown in Table 1. For comparison, W4 Table-1 also includes the results measured using only the support layer. As a result, it is clear that the composite membrane of the present invention exhibits excellent blood affinity and high permselectivity.

Table 1 [Effects of the Invention] According to the present invention, a monomolecular condensed film of a copolymer of a hydrophilic monomer and a hydrophobic monomer is laminated on a support layer with the side having many hydrophilic segments facing up. It is possible to supply a composite membrane made of When a so-called film or sheet that is substantially non-porous and exhibits no substance permeability is used as the support layer of the composite membrane, it exhibits good biocompatibility, particularly excellent blood compatibility.

Furthermore, when a so-called porous membrane such as a filtration membrane or a dialysis membrane is used as the support layer, it exhibits not only excellent biocompatibility but also high substance permeability.

The composite membrane of the present invention can be used for biomaterials for implantation in artificial organs such as artificial kidneys and artificial lungs, blood tubes, blood bags, and artificial blood vessels.
Widely used in medical applications such as the detection end of medical sensors.

[Brief explanation of drawings]

FIG. 1 is a schematic diagram showing a composite membrane of the present invention. Figure 2 shows the state in which a copolymer consisting of a hydrophilic monomer and a hydrophobic monomer is spread on the water surface, Figure 3 shows the state in which hydrophilic segments protrude into the water by compression, and Figure 4 shows the support layer. FIG. Figure 5 shows
It is a curve showing the surface pressure-area of the ethylene-vinyl alcohol-μ copolymer used in Examples. 1. Monomolecular condensed film with a surface having many hydrophilic segments

Claims (1)

[Claims] A copolymer of a hydrophilic monomer and a hydrophobic monomer is spread on the liquid surface to form a monomolecular condensed film having many hydrophilic segments on one surface and many hydrophobic segments on the other surface, A composite membrane formed by laminating the condensed membrane on a support layer with the side having many hydrophilic segments facing up.