JPS60190966A - 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 The present invention is a novel antithrombotic material, and more specifically, a medical high-grade material with unclear antithrombotic properties and biocompatibility, which is used in artificial blood 11, blood thinning catheters, etc. It concerns molecular materials.

In recent years, many polymeric 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, organ catheters, artificial kidney tubes, and heart-lung machines. , blood bypass tube,
When used as materials for artificial heart pumping chambers, balloon pumping, etc., it is important to have excellent mechanical strength such as biocompatibility, elasticity, durability, and wet toughness, as well as antithrombotic properties. is necessary.

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

Conventionally, as a method of imparting antithrombotic properties to the above-mentioned polymeric material, methods have been used to make the material itself less likely to cause thrombosis, such as mixing a natural anticoagulant such as heparin into the material. Alternatively, methods of chemical bonding and methods of coating the material surface with biocompatible crushed collagen are known.

Among the methods described in AiJ, examples of methods for making 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; Alternatively, a hydrogel or hydrophilic polymer may be bonded 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 polymerizing a vinyl compound with a tertiary amino group to the base polymer, amines in the grafted polymer are used. Methods are known to quaternize groups and then heparinize them. however,
The polymeric material heparinized in this manner has the disadvantage that the desirable mechanical strength originally possessed by 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, polynisdel, etc. is made hydrophilic by polarization treatment such as chromic acid mixed a treatment or alkali treatment, and then collagen is applied. Then, 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 polymeric material coated with collagen in this manner does not reduce the desirable mechanical strength inherent to the base polymer, its antithrombotic properties are not necessarily satisfactory.

In view of these circumstances, the present inventors have improved the drawbacks of conventional antithrombotic polymer materials, and developed a polymer that has excellent antithrombotic properties, biocompatibility, and good mechanical strength. Research has been carried out to obtain the materials.

As a result, it was discovered that a polymer material in which mucopolysaccharide was bonded to the surface of a polymer material that had been activated by plasma glow discharge treatment had poor antithrombotic properties compared to conventional materials. My younger sister was a girl with a nose.

However, although this antithrombotic material has considerably improved the drawbacks of conventional antithrombotic materials, its antithrombotic properties are not necessarily satisfactory.

Therefore, the present inventors have conducted further intensive research in order to provide an even better antithrombotic material.As a result, we have added cell adhesion proteins to the collagen layer provided on the surface of the polymeric material. We discovered that a material with a heparin layer interposed between a fibronectin layer, which is known as a polymer material, has excellent antithrombotic properties and biocompatibility without losing the mechanical strength of the polymer material. Based on this, the present invention has been completed.

That is, one aspect of the present invention provides an antithrombotic material in which a collagen layer is provided on the surface of a polymeric material, and a heparin layer is further provided thereon via a fibronectin layer.

Examples of polymeric materials used in the present invention include nylon, polyester, polyethylene, polypropylene,
Preferred examples include polymer compounds with excellent mechanical properties such as polyurethane and silicone rubber.

In the antithrombotic material of the present invention, a collagen layer is first provided on the surface of the polymer material. The method of providing this collagen layer includes, for example, a method of applying an aqueous collagen solution of o, i to 1% a degree to the surface of the polymeric material;
A method is used in which the polymeric material is injected into the collagen aqueous solution, or when a collagen layer is provided on the inner surface of a container or tube-like object, a method in which the collagen aqueous solution is injected into and drained from the container or tube.

When using a highly porous polymeric material, it is preferable to crosslink the collagen layer with glutaraldehyde in order to prevent blood leakage. This cross-linking treatment with glutaraldehyde is performed by, for example, 0.05 to 0.25% (V
The polymer material provided with the collagen layer is treated in the same manner as described above using a physiological saline solution containing glutaraldehyde of /V).

Furthermore, in order to more firmly adhere the collagen layer to the surface of the polymeric material, the surface of the polymeric material may be activated in advance by plasma glow radiation M1 treatment if necessary. 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.

Although the polymeric material provided with the collagen layer thus has a slight antithrombotic property, it is still insufficient, and in the present invention, a heparin layer is further provided thereon via a fibronectin layer.

Fibronectin is known as a cellular mM protein and is present in the blood. The molecular structure of this substance has not yet been clearly elucidated, but it has a domain that binds to collagen, especially heat-denatured gelatin, and a domain that binds to heparin, so it can be used to bind to collagen, especially heat-denatured gelatin, and heparin. Yes, the heparin layer and collagen 1- are relatively tightly bound.

Furthermore, heparin is a mucopolysaccharide and 5. It has excellent antithrombotic properties and biocompatibility.

A polymer material provided with a collagen layer as described above,
Furthermore, as a method for providing a heparin layer through a fibronectin layer, for example, the polymer material is treated with a physiological saline solution containing fibronectin at a concentration of 0.2 to 2 ht%, and then 0.5 to 5 wt% A method of treatment with a saline solution containing heparin is used. The treatment with these aqueous solutions is carried out in the same manner as the treatment with collagen water r&r& described above.

In this way, the polymeric material provided with the collagen-fibronectin-heparin binding layer can be used as a collagen single layer,
It has poor antithrombotic properties compared to polymer materials with a single layer of chondroitin sulfate or a composite layer of collagen and chondroitin sulfate 841, and for example, in vivo experiments using dog veins. However, almost no thrombus formation was observed.

The antithrombotic material of the present invention has excellent antithrombotic properties and biocompatibility, has good mechanical performance, and is suitable for use in various medical devices used in areas that come into direct contact with blood, such as It is extremely valuable as a material for artificial surfaces, vascular catheters, artificial kidney tubes, heart-lung machines, blood bypass tubes 7", artificial stone AI pumping chambers, balloon pumping, etc.

In addition, since fibronectin itself is a plasma protein component, when the material of the present invention is used in vivo for a period of time, heparin is removed too much, and in vivo cells and plasma proteins bind to fibronectin and become organized ( It can be expected that the composition area will be the same as that of a living body.

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

Example 1 Polyester fiber (manufactured by DuPont, Dacron) was used as a polymeric material.
) Plasma glow discharge treatment is performed using a double gueroa type artificial blood vessel (manufactured by Meedox).

In order to effectively treat only the inner surface of the sample, this plasma glow discharge treatment was performed using a Pyrex glass reaction tube with an inner diameter approximately 1 m thicker than the outer diameter of the sample and a length of 25 cJn.

On the other hand, after solubilizing pig skin by pepsin treatment, collagen (2,5 MNa
After dissolving this in an acetic acid aqueous solution rt (0.21), dialysis was performed against water to prepare a 0.4% by weight collagen aqueous solution 18.

The artificial blood vessel treated with plasma glow discharge was immersed in this aqueous collagen solution for 1 hour at room temperature, and then further immersed in a physiological saline solution α containing 0.2% (V/V) glutaraldehyde. A collagen layer crosslinked with glutaraldehyde was provided on the surface of the artificial blood vessel.

Next, the collagen-treated artificial blood vessel was immersed in ice cubes at 40°C for 1 hour, and then placed under neutral conditions in a fibronectin solution (concentration 5 μ/ml) prepared by affinity chromatography from pig blood. I soaked it in Next, excess fibronectin was washed away with physiological saline, and then heparin (manufactured by Sigma) at a concentration of 10~/- was added.
After 4 hours of immersion in a physiological saline solution containing the following under neutral conditions, excess heparin was removed with physiological saline.

In this way, an antithrombotic material was obtained in which a heparin layer was further provided on the collagen layer provided on the surface of the artificial blood vessel with a fibronectin layer interposed therebetween.

In addition, by crosslinking the collagen layer with glutaraldehyde, this product became a cap with almost no blood leakage.

Example 2 Polyester fiber (manufactured by DuPont,
Dacron) with high porosity (2000cc/min/
+u4) A collagen-fibronectin-heparin composite layer was provided on the surface of the batch in exactly the same manner as in Example 1, except that a double velour fabric type batch (manufactured by Meedox) was not treated with plasma glow discharge. An antithrombotic material was created.

Reference Example The antithrombotic properties of the artificial blood vessel provided with the collagen-fibronectin-heparin composite layer obtained in Example 2 and the batch provided with the collagen-fibronectin-heparin composite layer obtained in Example 2 were evaluated as follows. I looked it up.

The artificial blood vessel provided with the collagen-fibronectin-heparin composite layer obtained in Example 1 was placed in the abdominal vena cava of a dog, and removed after 40 minutes, and the surface was observed. I was not able to admit.

When the antithrombotic properties of an artificial blood vessel provided with only a collagen layer were similarly investigated, red blood clots accompanied by fibrin network formation were observed.

The batch with the collagen-fibronectin-heparin composite layer obtained in Example 2 was immersed in pig blood containing an aqueous sodium citrate solution at 37°C for 1 hour, then taken out and the surface observed. There was no fibrin network formation, and almost no red blood cell aggregates were observed.

When the antithrombotic properties of the batch provided with only the collagen layer were examined in the same manner, aggregates of red blood cells were observed.

Claims (1)

[Claims] 1. An anti-thrombotic T1 material comprising a collagen layer on the surface of a polymeric material and a heparin layer on top of the collagen layer via a fibronectin layer.