JPS61191364A - Anti-thrombotic material - 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 novel antithrombotic material. More specifically, the present invention relates to a material suitable for medical use, which has excellent antithrombotic properties and biocompatibility, and is used for artificial blood vessels, artificial catheters, etc. At the same time, various medical devices 1, such as artificial blood vessels, vascular catheters, artificial kidney tubes, heart-lung machines, and blood bypass tubes, have come to be widely used in locations that come into direct contact with blood.

Medical equipment used in areas that come into direct contact with blood must not only have good elasticity, durability, and wet toughness, but also particularly excellent antithrombotic properties and biocompatibility. is necessary.

Therefore, as materials for these medical devices, polymeric materials such as nylon, polyester, polyethylene, polypropylene, and polyurethane, which have antithrombotic properties and biocompatibility, are used.

Conventionally, methods for imparting antithrombotic properties to the above-mentioned polymeric materials include methods of making the material itself less likely to cause blood clots, such as mixing a natural anticoagulant such as heparin into the material, or chemically bonding the material. There are also known methods for coating material surfaces with collagen, which has excellent biocompatibility.

Among the above methods, examples of methods to make the material itself less likely to cause blood clots include using a certain type of polyurethane compound with a structure in which hydrophobic and hydrophilic parts alternately appear on the surface; Some include hydrogels or hydrophilic polymers attached to a base polymer. However, although these polymeric materials exhibit fairly high antithrombotic properties,
It is still insufficient for practical use, and nothing satisfactory has yet been obtained.

In addition, as an example of a method for chemically bonding a natural anticoagulant such as heparin to a material, after graft polymerizing a vinyl compound having a tertiary amine group to a base polymer, Methods are known in which amino groups are quaternized and then heparinized. however,
The polymeric material heparinized in this manner has the disadvantage that the desirable mechanical strength inherent in the base polymer is reduced, making it impossible to obtain the strength and durability required for practical use.

Furthermore, as an example of a method of coating the surface of a material with collagen, the surface of polyethylene, polypropylene, polyester, etc. is made hydrophilic by polarization treatment such as chromium dispersion treatment or alkali treatment, and then collagen is applied, and then radiation is applied. (Japanese Patent Publication No. 46-37433), or after making the surface of the silicone rubber material hydrophilic by polarization treatment such as plasma glow discharge treatment or chemical treatment, the same method as described above can be used. A method (Japanese Patent Publication No. 49-4559) has been proposed in which collagen is coated on the skin. However, the polymeric material coated with collagen in this manner also has insufficient antithrombotic properties and is not necessarily satisfactory for medical use.

On the other hand, those using biomaterials such as collagen have better biocompatibility than the above-mentioned polymeric materials, but they also have problems in terms of antithrombotic properties.

As described above, a medical material that is fully satisfactory in terms of both antithrombotic properties and biocompatibility has not been found to date, and especially for artificial blood vessels with a diameter of 1 to 3 μm, rapid The reality is that nothing that can sufficiently prevent the formation of thrombus has yet been developed.

The present inventors have conducted extensive research to obtain medical materials with excellent antithrombotic properties and biocompatibility, and first bonded mucopolysaccharide to the surface of a polymeric material activated by plasma glow discharge treatment. We have developed a heparin layer on top of a collagen layer on the surface of a polymeric material with a fibronectin layer, which is known as a cell adhesion protein. Although antithrombotic materials have been considerably improved compared to conventional materials, they still cannot satisfy both antithrombotic properties and biocompatibility at the same time.
Further improvements were necessary.

Problems to be Solved by the Invention Under these circumstances, the purpose of the present invention is to provide a material suitable for use as a material for artificial blood vessels, which has excellent antithrombotic properties and biocompatibility, and has good durability. The objective is to provide materials suitable for medical use that grow.

Means for Solving the Problems As a result of extensive research, the present inventors have found that mucopolysaccharides exhibit excellent antithrombotic properties, while collagen from which antigenic groups have been removed or its gelatinized products exhibit excellent biocompatibility. By focusing on the points shown, mixing them, applying them to the surface of a predetermined material, and repeating cross-linking treatment with a polyvalent aldehyde compound, the above-mentioned objective is achieved. They discovered scales and completed the present invention based on this knowledge.

In other words, the present invention provides a material surface made of a polymeric material,
The present invention provides an antithrombotic material characterized by laminating layers of a mixture of an antithrombotic mucopolysaccharide and collagen from which antigenic groups have been removed, or a gelatinized product thereof, and further crosslinked with a polyvalent aldehyde compound.

Examples of materials used in the present invention include polymeric materials such as nylon, polyester, polyethylene, polypropylene, polyurethane, silicone rubber, and fluororesin.

The antithrombotic mucopolysaccharide used in the present invention has, for example, a trisaccharide repeating unit consisting of an amino sugar and uronic acid or galactose, which may have a sulfate group or It doesn't matter what you don't have. Mucopolysaccharides without sulfate groups include hyaluronic acid and chondroitin, and mucopolysaccharides with sulfate groups include chondroitin sulfate, such as chondroitin 4-sulfate, chondroitin 6-sulfate, and dermatan sulfate (chondocoitin sulfate B); There are heparin, heparan sulfate, and gratan sulfate. These mucopolysaccharides have extremely excellent antithrombotic properties and also have good biocompatibility. In the present invention, heparin, hyaluronic acid, and chondroitin sulfate are particularly preferably used. These mucopolysaccharides may be used alone or in combination of two or more, and may be used in combination with other anticoagulants as desired.

In the present invention, the collagen or gelatinized product thereof used in combination with the mucopolysaccharide has antigenic groups removed and is used as having excellent biocompatibility. Collagen from which the antigenic groups have been removed can be obtained, for example, by degreasing cow's fillet or hawthorn using an enzyme such as lipase, and then decomposing and removing the antigenic hebutide using an enzyme such as hebusin. Further, the gelatinized product can be obtained by heating the thus obtained antigen-free collagen in an aqueous medium at a temperature of, for example, about 60°C.

In addition, in the present invention, in order to crosslink a multilayered mixture layer of mucopolysaccharide and collagen from which antigenic groups have been removed or its gelatinized product, the polyvalent aldehyde compound may be glutaraldehyde or dialdehyde starch. Compounds having two or more aldehyde groups are used.

Next, a preferred method for producing the antithrombotic material of the present invention will be explained. First, a mixture of mucopolysaccharide and antigen-free collagen or its gelatinized product is laminated in multiple layers on the surface of the material. As a method of laminating multiple layers,
For example, a method in which an aqueous medium solution containing 0.05 to 10% by weight of at least one type of mucopolysaccharide and 0.1 to 10% by weight of collagen from which antigenic groups have been removed or its gelatinized product is applied to the surface of the material. The surface of the material is immersed in the aqueous medium, or when laminated on the inner surface of a container or tube, the aqueous medium is injected into and drained from the surface of the material. By providing a layer of the mixture on the surface and repeating this operation a desired number of times,
The mixture is laminated into multiple layers. At this time, if desired, two or more types of aqueous media each containing the collagen or its gelatinized product and a different mucopolysaccharide may be used to form multiple layers.

Further, when a polymeric material is used as the raw material, the surface of the polymeric material may be activated in advance by plasma glow discharge treatment, if necessary, in order to more firmly adhere the mixture layer to the surface of the polymeric material. This plasma glow discharge treatment is carried out by cleaning the surface of a polymeric material according to a conventional method, and then uniformly applying plasma generated by a plasma glow discharge generator to the surface of the polymeric material.

Next, the surface of the mixture layer thus laminated in multiple layers on the surface of the material is crosslinked using a polyvalent aldehyde compound such as glutaraldehyde or dialdehyde starch. This crosslinking treatment is carried out, for example, by using a physiological saline solution containing 0.05 to 0.3 weight ratio of a polyvalent aldehyde compound and treating a material formed by laminating the mixture in multiple layers as described above. . Such cross-linking treatment makes the resulting antithrombotic material highly durable, and when using highly porous materials, prevents blood leakage.
To explain one preferred example of manufacturing an artificial blood vessel made of a multilayered collagen material as an artificial blood vessel made of the antithrombotic material of the present invention, first, the artificial blood vessel has an outer diameter corresponding to the inner diameter of a desired blood vessel. The surface of a rod-shaped body such as a glass rod, a Teflon rod, or a rust-proof (acid-resistant, alkali-resistant) metal rod is soaked using an aqueous medium containing mucopolysaccharide and collagen from which antigenic groups have been removed or its gelatinized product. These mixtures are laminated into multiple layers by a coating method.

Next, using an acidic solution of collagen, collagen is laminated in multiple layers, for example, 20 to 50 layers, in the same manner as described above until a desired thickness is achieved. This collagen is also preferably one from which antigen groups have been removed. Next, on the surface of the multi-layered collagen layer as described above, an aqueous medium containing mucopolysaccharide and collagen from which antigenic groups have been removed or a gelatinized product thereof is further used, and a mixture thereof is applied in the same manner as described above. Stacked in multiple layers. Next, the rod-shaped body is pulled out, and the inner and outer surfaces of the obtained tubular body are treated in the same manner as above using an aqueous solution of a polyvalent aldehyde compound, thereby obtaining an artificial blood vessel with excellent antithrombotic properties and biocompatibility. It will be done.

The antithrombotic material thus obtained has superior antithrombotic properties compared to conventional materials, and for example, in an in vivo experiment using dog veins,
Almost no thrombus formation was observed.

Effects of the Invention The antithrombotic material of the present invention has excellent antithrombotic properties and biocompatibility, and can be used in various medical devices used in areas that come into direct contact with blood, such as artificial blood vessels, vascular catheters, and artificial kidney tubes. It is extremely valuable as a material for artificial heart-lung machines, blood bypass tubes, artificial heart pumping chambers, etc.

Example Next, the present invention will be explained in more detail with reference to Examples.

Example 1 Uboro was defatted with lipase, and then antigenic hebutide was decomposed using heptanoide, followed by removal and purification to obtain acid-solubilized atelocollagen.

This acid-solubilized atelocollagen is dissolved in an acid aqueous solution and p
A 0.5 weight liter aqueous solution of H2.8 was prepared.

Next, dilute caustic soda aqueous solution was added dropwise to this solution 100+d while stirring to precipitate atelocollagen rut fibers by isoelectric focusing, and dilute caustic soda aqueous solution was added while stirring to homogenize on the alkaline side. acid sodium 0.12 and heparin sodium (163 heparin units/l) 0.
An aqueous solution of 2F dissolved in distilled water was added, and finally 200
After adjusting the mixture and stirring thoroughly until it becomes homogeneous,
Vacuum defoaming was performed.

Add a glass rod with a diameter of 8CTn to the solution prepared in this way.
After soaking to the length of , drying to form a layer consisting of a mixture of the above compounds (first layer).
In the same manner as above, a liquid containing mucopolysaccharide and collagen is prepared, and the glass rod on which the first layer is formed is dipped into this liquid, and the process of drying is repeated three times to form the first layer. A laminated layer (second layer) was provided on top of the .

Next, an acid-solubilized atelocollagen aqueous solution of paz, s (solid content 0.6 weight ratio, viscosity 3000 cps/20
The treated glass rod was vertically immersed in the glass solution (200°C), then pulled up while rotating, and then neutralized and dried 40 times. Next, a mixture of sodium hyaluronate and atelocollagen was layered three times on top of this collagen layer in exactly the same manner as for forming the second layer, and then the glass rod was pulled out to obtain a tubular body.

Next, the tubular body was immersed for 30 minutes in an aqueous solution of dialdehyde starch 152 dissolved in 10 tons of water, dried, and further washed with distilled water.

Next, this product was dissolved in a 30 ml glycerin aqueous solution.
After soaking for a period of time, it was dried to obtain an artificial blood vessel with an inner diameter of 2.

After sterilizing the artificial blood vessels obtained in this way at 38°C for 6 hours using ethylene oxide gas, we conducted in vivo experiments using the veins of rabbits and dogs. No thrombi formed for at least 3 hours, respectively.

Example 2 In Example 1, gelatinized atelocollagen (stirred at 60°C for 30 minutes) was added as a substitute for atelocollagen in the solution containing sodium hyaluronate, sodium heparin, and atelocollagen, and the solution containing sodium hyaluronate and atelocollagen. An artificial blood vessel with an inner diameter of 2 mm was obtained in exactly the same manner as in Example 1, except that a gelatinized blood vessel was used.

Using this product, in which the veins of rabbits and dogs are used
When an in vivo experiment was conducted, the same results as in Example 1 were obtained.

Example 3 Both surfaces of a nylon sheet were washed with acetone, then washed again with hot water, and then air-dried to clean both surfaces. Plasma treatment was performed by uniformly applying plasma generated from a plasma glow discharge generator to both surfaces thus cleaned.

On the other hand, in the same manner as in Example 1, a solution containing sodium hyaluronate, sodium heparin, and atelocollagen was prepared, and the plasma-treated nylon sheet was immersed in this solution, and the drying process was repeated three times. A mixture of the above compounds was laminated in three layers on both surfaces. Next, this product was immersed in an aqueous solution containing 15f of dialdehyde starch and 10 tons of water for 30 minutes, dried, and further washed with distilled water. Next, this material was immersed in a 30% glycerin aqueous solution for 1 hour and then dried to obtain an antithrombotic material.

After this antithrombotic material was sterilized, it was implanted into the vein of a dog and an in vivo experiment was conducted, and almost no thrombus formation was observed within 3 hours.

Patent applicant Tatsu Todoroki, Director of the Agency of Industrial Science and Technology (and 1 others)
Name) Sub-Agent Akira Agata

Claims (1)

[Scope of Claims] 1. A mixture layer of antithrombotic mucopolysaccharide and collagen from which antigenic groups have been removed or a gelatinized product thereof is laminated on the surface of a material made of a polymeric material, and further crosslinked with a polyvalent aldehyde compound. Thrombotic material characterized by. 2. The antithrombotic material according to claim 1, wherein the antithrombotic mucopolysaccharide is at least one selected from heparin, hyaluronic acid, and chondroitin sulfate. 3. The antithrombotic material according to claim 1, wherein the polyvalent aldehyde compound is dialdehyde starch or glutaraldehyde.