JPS6158195B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel antithrombotic material, and more specifically, the present invention relates to a novel antithrombotic material. The present invention relates to a medical polymer material that has excellent antithrombotic properties and biocompatibility as well as good mechanical strength.

In recent years, many polymer materials have come into use as medical materials, and medical materials that use them in areas that come into direct contact with blood, such as artificial blood vessels, vascular catheters, artificial kidney tubes, heart-lung machines,
When used as blood bypass tubes, artificial heart pumping chambers, balloon pumping materials, etc., it must not only have antithrombotic properties but also excellent mechanical strength such as biocompatibility, elasticity, durability, and wet toughness. is necessary.

Among the polymer materials currently used as medical materials, for example, nylon, polyester, polyethylene, polypropylene, and polyurethane do not have antithrombotic properties, and when used in areas that come into direct contact with blood, Since blood coagulates and thrombi occur, efforts have been made to provide these polymeric materials with antithrombotic properties.

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 it to the material. Other known methods include coating the material surface 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, they are still insufficient for practical use, and no satisfactory material 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 amino 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 originally 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 a material surface with collagen, the surface of polyethylene, polypropylene, polyester, etc. is made hydrophilic by polarization treatment such as chromic acid mixture treatment or alkali treatment, and then collagen is applied. Next, the collagen is coated by irradiation with radiation (Japanese Patent Publication No. 46-37433), or the surface of the silicone rubber material is made hydrophilic by polarization treatment such as plasma glow discharge treatment or chemical treatment. , a method of coating collagen in the same manner as above (Japanese Patent Publication No. 49-4559) has been proposed. However, although the polymer material coated with collagen in this manner does not reduce the desirable mechanical strength inherent to the base polymer, it is not necessarily satisfactory in terms of antithrombotic properties.

In view of these circumstances, the present inventors have overcome the drawbacks of conventional antithrombotic polymer materials and have developed a polymer material that has excellent antithrombotic properties, biocompatibility, and good mechanical strength. As a result of intensive research to provide molecular materials, we focused on mucopolysaccharide's extremely excellent antithrombotic properties and biocompatibility, and developed a polymer whose surface was activated by plasma glow discharge treatment. It was discovered that the object obtained by bonding the material could be achieved, and based on this knowledge, the present invention was completed.

That is, the present invention provides an antithrombotic material in which mucopolysaccharide is bonded to the surface of a polymeric material activated by plasma glow discharge treatment.

Preferred examples of the polymer material used in the present invention include hydrophobic polymer compounds with excellent mechanical performance, such as nylon, polyester, polyethylene, polypropylene, polyurethane, and silicone rubber.

Mucopolysaccharides used in the present invention include, for example, chondroitin sulfate, hyaluronic acid, heparin, and chitosan, which have extremely excellent antithrombotic properties and biocompatibility. This is clear from the fact that the surface of blood vessels of living organisms containing these mucopolysaccharides has excellent antithrombotic properties and biocompatibility.

In the present invention, in order to firmly bond the mucopolysaccharide to the surface of the polymeric material, it is necessary to activate the surface by plasma glow discharge treatment.

This plasma glow discharge treatment is performed by cleaning the surface of the 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. Through this treatment, the surface of the polymeric material is activated and has the property of strongly binding to negatively charged mucopolysaccharides.

As a method for bonding mucopolysaccharide to the surface of a polymeric material activated by such plasma glow discharge treatment, for example, mucopolysaccharide at a concentration of 0.1 to 10% by weight (the concentration depends on the molecular weight of the mucopolysaccharide) is used. a method of applying an aqueous solution to the surface of the polymeric material;
The mucopolysaccharide can be prepared by immersing the polymer material in the aqueous mucopolysaccharide solution, or by injecting and discharging the aqueous mucopolysaccharide solution when bonding it to the inner surface of a container or tube. After uniformly binding to the surface of the polymer material, free mucopolysaccharide is removed by washing with water or physiological saline, and then air drying or vacuum drying at room temperature is used.

The antithrombotic material of the present invention thus obtained has excellent antithrombotic properties and biocompatibility, and has good mechanical performance, and is a material for various devices used in areas that come into direct contact with blood. It is extremely valuable.

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

Example 1 The surface of a nylon sheet was washed with acetone, then washed again with hot water, and then air-dried to clean the surface.

Plasma generated from a plasma glow discharge generator is applied to this clean and exposed surface. During the discharge, the discharge was carried out by an inductive coupling method using 13.56MHz radio waves while controlling the plasma so that it hit the entire surface as uniformly as possible. The plasma was turned on with a discharge voltage of 25W. The surface of the nylon sheet was activated by this plasma glow discharge treatment, and became in a state where it could firmly bind to the negatively charged mucopolysaccharide.

Next, the cells were placed in a 0.15N normal saline solution (PH7.3) containing 10% by weight of chondroitin sulfate at 20°C.
The material was soaked in water for 10 minutes, washed with water, and air-dried to obtain an antithrombotic material.

In order to examine the surface structure of the antithrombotic material thus obtained, an infrared difference spectrum was determined by internal multiple total reflection Fourier transform infrared absorption spectroscopy. The results are shown in FIG.

In Fig. 1, A is a nylon sheet obtained by plasma glow discharge treatment as described above to which collagen is attached, and the pH is further adjusted and chondroitin sulfate is attached. B is a nylon sheet obtained as described above. It is an antithrombotic material. As is clear from this figure, A and B basically have the same spectra, and it can be seen that the surface of the antithrombotic material of the present invention is coated with chondroitin sulfate.

Next, the antithrombotic material obtained above was immersed in a solution of albumin, a plasma protein, dissolved in physiological saline at 35°C for 10 minutes, air-dried, and the structure of the adsorbed albumin was determined using infrared light as described above. I searched for the spectrum. For comparison, an untreated nylon sheet was treated in the same manner as above, and an infrared difference spectrum was determined. These results are shown in FIG.

In FIG. 2, B is the antithrombotic material obtained in the example, and C is the treated untreated nylon sheet. As can be seen from this figure, the shapes of the amide and amide peaks, which are characteristic of proteins, are different for those treated with the antithrombotic material of the present invention than for those treated with untreated nylon sheets. This shows that the structure of adsorbed albumin is different.

Furthermore, in place of the albumin solution, a plasma protein fibrinogen solution was used to carry out the same treatment as described above, and an infrared difference spectrum was obtained.
The results are shown in FIG.

In FIG. 3, B and C are the same as above.
As is clear from this figure, the untreated nylon sheet treated has a large amount of fibrinogen adsorbed and the structural change of fibrinogen is also large, but the one treated with the antithrombotic material of the present invention has a small amount of fibrinogen adsorbed. , it can be seen that there are few structural changes.

Next, in an in vitro experiment, the antithrombotic properties of the antithrombotic material and untreated nylon sheet obtained in the Examples were investigated using platelet-rich plasma from which red blood cells had been removed. Untreated nylon sheets are prone to formation of fibrin networks, deformation of platelets, and adsorption, but the antithrombotic material of the present invention does not form fibrin networks, causes little deformation of platelets, and has a small amount of adsorption.

Example 2 A filamentous antithrombotic material was obtained in the same manner as in Example 1, except that a nylon-based material was used instead of the nylon sheet in Example 1.

In an in vivo experiment, the thread-like antithrombotic material was suspended in the artery of a dog to examine its antithrombotic properties.

For comparison, the antithrombotic properties of untreated nylon threads were also examined in the same manner.

As a result, while the untreated nylon thread caused thrombus formation, the antithrombotic material of the present invention did not cause thrombus formation.

[Brief explanation of the drawing]

Figures 1, 2, and 3 are infrared difference spectra obtained by internal multiple total reflection Fourier transform infrared absorption spectroscopy to investigate the surface structure of nylon sheets subjected to various treatments. Infrared difference spectra of the antithrombotic material of the present invention and collagen and chondroitin sulfate sequentially applied after plasma glow discharge treatment, Figures 2 and 3.
The figure shows infrared difference spectra of the antithrombotic material of the present invention and an untreated nylon sheet with albumin and fibrinogen adsorbed, respectively.

Claims (1)

[Claims] 1. An antithrombotic material comprising mucopolysaccharide bonded to the surface of a polymeric material activated by plasma glow discharge treatment. 2. The antithrombotic material according to claim 1, wherein the polymeric material is nylon, polyester, polyethylene, polypropylene, polyurethane, or silicone rubber.