JP2853353B2 - Bioimplant material and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical material to be implanted in a living body for a long period of time and a method for producing the same. More specifically, the present invention relates to a medical material excellent in affinity with a living body and a method for producing the same.

[0002]

2. Description of the Related Art In a medical device, such as a peritoneal catheter, which is implanted in a living body for a long period of time, the quality of fixation to the living body at the implanted portion is important for enabling long-term indwelling. A factor. Therefore, in order to promote the invasion and integration of the living tissue into the implanted portion, various devices have been conventionally devised. The most common method conventionally performed is a method of providing a cuff made of polyester fiber called "Dacron cuff" on the outer periphery of a catheter. In addition, the use of a sponge such as polyurethane or polyethylene for the cuff has been studied in part.

[0003] Further, in order to increase the affinity with the living body,
A method of coating collagen on the surface of a material is also disclosed in
It is known in, for example, JP-A-119798, and application to various uses is being studied.

[0004]

The cuff made of polyester fiber is not sufficiently fixed to the living body, and often bacteria enter the boundary of the living body to cause infection. Further, sponges made of polyurethane or polyethylene also have insufficient affinity for living bodies and are not practical. Furthermore, polyurethane has problems in durability and safety when implanted for a long period of time, and polyethylene sponge has insufficient flexibility and is unsuitable as a cuff.

In the method of increasing the biocompatibility by coating the surface with collagen, the mere physical coating not only has insufficient binding force between the substrate and collagen, but also has almost no effect of improving the affinity with the living body. It was not expressed. Furthermore, a method of activating the surface of the base material by glow discharge or corona discharge, graft-copolymerizing acrylic acid or the like with this, and then reacting with collagen to chemically bond them is also conceivable, but an expensive apparatus is required. Not only that, it was difficult to always obtain a product of stable quality, and there was a problem in practicality.

As a result of various studies conducted by the applicant to solve these problems, a porous body made of a polyvinyl alcohol-based polymer was used, and a diisocyanate compound was bonded using a hydroxyl group on the surface. A method for binding collagen was found, and a patent application was previously filed as Japanese Patent Application No. 1-207398. Although this material had better biocompatibility than the conventional material, the use of diisocyanate caused problems such as generating an unpleasant odor during the reaction and the reaction being easily affected by humidity. Was. It was also found that there was a problem that the amount of binding could not be increased sufficiently.

The present invention has been made in order to solve such a problem, and a method for easily binding a sufficient amount of collagen to the surface of a porous body made of a polyvinyl alcohol-based polymer, and a method for such a method. An object of the present invention is to provide a biological implant material obtained by the method.

[0008]

According to the present invention, a carboxyl group is introduced into a polyvinyl alcohol-based polymer,
The above object was achieved by binding collagen using the carboxyl group. That is, the bioimplant material of the present invention comprises a porous body of a polyvinyl alcohol-based polymer having a carboxyl group, and collagen is bonded to the surface of the porous body via the carboxyl group. Is what you do. Further, the production method is characterized by producing a porous body from a polyvinyl alcohol-based polymer having a carboxyl group, reacting the carboxyl group with collagen, and binding collagen to the surface of the porous body. is there.

[0009]

The bonding between the porous body and collagen is carried out by reacting the carboxyl group of the polymer constituting the porous body with the amino group of collagen. Then, when a medical device made of the living body implant material of the present invention is implanted in a living body, the living tissue quickly enters the pores and is firmly integrated with the tissue. Therefore, it is possible to prevent bacteria from invading from the boundary with the tissue and causing infection.

[0010]

EXAMPLES The polyvinyl alcohol polymer referred to in the present invention is a polymer mainly composed of vinyl alcohol units, and includes partially saponified polyvinyl acetate. In order to introduce a carboxyl group into a polyvinyl alcohol-based polymer, a compound containing a carboxyl group can be obtained by reacting the compound with a reactive group of the polyvinyl alcohol-based polymer. It can also be obtained by copolymerizing a monomer. Such a polymer is commercially available as carboxylic acid-modified polyvinyl alcohol, and can be easily obtained in the market. The content of the carboxyl group in the polymer is suitably about 0.1 to 10 mol% per vinyl alcohol unit.

In order to produce a porous body from the above polymer,
First, the polymer may be crosslinked in a state where harmless particles such as starch are dispersed in the polymer solution, and then the particles may be dissolved and removed. For crosslinking of the polymer, acetalization with formalin is preferred. In order to bind collagen to the surface of the porous body thus obtained, the porous body is immersed in a collagen solution and subjected to 0 to 90 ° C in the presence or absence of a catalyst.
The reaction may be performed at about the same temperature. The reaction time depends on the temperature and the presence or absence of the catalyst, but an appropriate time may be selected depending on the amount of collagen to be bound.

Hereinafter, the present invention will be described in more detail with reference to specific examples. In addition. Parts in the examples mean parts by weight unless otherwise specified.

Example 1 A 10% by weight aqueous solution of a carboxylic acid-modified polyvinyl alcohol (Gosenal T-330 manufactured by Nippon Synthetic Chemical Industry) was prepared, and a 100% aqueous solution of 5% by weight of potato starch (dispersion) was prepared based on 100 parts of this solution. Parts were added. 85 ° C
After stirring and stirring at room temperature for 1 hour,
And 20 parts of formalin were added to remove bubbles. Then 30 ° C
After performing the acetalization reaction for 12 hours at 50 ° C. and then for 5 hours at 50 ° C., the reaction product was washed with warm water to obtain a sponge-like porous body (average pore diameter: 150 μm).

Collagen (manufactured by Nitta Gelatin, Cellmatrix
TypeI-P) was dissolved in a 0.001N hydrochloric acid solution to obtain 0.1%.
A 5 mg / ml aqueous collagen solution was prepared, and the porous body obtained above was immersed in the aqueous solution to remove bubbles. Then, the temperature was maintained at 70 ° C. for 10 hours to allow the carboxyl groups of the porous body to react with collagen. After the completion of the reaction, the porous body was washed with a 0.001N hydrochloric acid solution, and the amount of collagen bound was measured by the ninhydrin method described later. The result was 102 μg / g.

(Ninhydrin method) A test tube was charged with 0.1 g of a porous material, 1.57 ml of ultrapure water and 4N
0.93 ml of hydrochloric acid is charged, heated in a pressure cooker without sealing, and treated at a pressure of 2.5 kg / cm ² for 30 minutes to hydrolyze collagen. Next, 1 ml of a 3.75N aqueous sodium hydroxide solution was added to neutralize the mixture, and then ninhydrin solution (0.4 ml of ninhydrin and 0.06 g of hydrindantin was added to 15 ml of methylcellosolve to dissolve, and further, sodium acetate buffer was added). 5 ml of liquid added) 1
Add ml. Then cover the test tube, and add 10 ml in boiling water.
After heating for a minute to cause a color reaction, and after cooling to room temperature, the absorbance at a wavelength of 570 nm is measured.

Example 2 A porous body was produced in the same manner as in Example 1 except that carboxylic acid-modified polyvinyl alcohol (KL-118) manufactured by Kuraray Co., Ltd. was used. Then, when the collagen was reacted with the porous body in the same manner as in Example 1, 66.5 μg
/ G of collagen was obtained.

Example 3 Using the porous material obtained in Example 1, a reaction with collagen was carried out using carbodiimide as a catalyst. That is, the porous body was immersed in a 10 mg / ml aqueous solution of a water-soluble carbodiimide at 4 ° C. for 30 minutes, and then immersed in a collagen solution at 4 ° C.
And reacted for 2 hours. The amount of collagen bound in the obtained porous body was measured and found to be 63.7 μg / g.

Example 4 (Biological Implantation Test) In order to test the affinity with the living body, the collagen-bonded porous material (sample A) prepared in Example 1 was subcutaneously implanted in the back of a plurality of rats. . For comparison, a porous body (sample B) before binding collagen prepared in Example 1,
A commercially available sponge made of polyvinyl alcohol containing no carboxyl group (Sanwa Kako) was contacted with a collagen aqueous solution (concentration: 0.5 mg / ml) at 70 ° C. for 10 hours (sample C), and Dacron cuff (sample D) Was also implanted at the same time.

Two weeks after the implantation, the sample was excised, and the degree of penetration of the tissue into the porous body was observed. Further, a tissue section was prepared, and the adhesion between the tissue and the porous body in the pore was observed. As a result, the penetration of the tissue was most advanced in the sample A, and reached the center. Then, the sample D was almost the same as that of the sample B, but the sample B and the sample C invaded only the surface layer. In sample A, there was no gap between the surface of the pores of the porous body and the tissue, and the adhesion to the tissue was good. In the case of samples B and C, a clear gap was recognized. Furthermore, for sample D, a large number of foreign body giant cells were observed around the fibers. This result indicates that the material of the present invention has good biocompatibility.

[0020]

According to the present invention, a predetermined amount of collagen can be bonded with good reproducibility to the surface of a porous body made of a polyvinyl alcohol-based polymer. In addition, it is practically excellent because it does not generate unpleasant odor during the reaction and the reaction is not affected by humidity

Therefore, the medical device using the material of the present invention is excellent in biocompatibility, and firmly adheres to the living body when implanted in the living body. When used as a cuff for a peritoneal catheter, it is possible to produce a medical device which is less likely to cause infection and which is excellent in safety.

Claims (2)

(57) [Claims] 1. A living body implant comprising a porous body of a polyvinyl alcohol polymer having a carboxyl group, wherein collagen is bonded to the surface of the porous body via the carboxyl group. material. 2. A bio-implant material comprising producing a porous body from a polyvinyl alcohol-based polymer having a carboxyl group, and reacting the carboxyl group with collagen to bind collagen to the surface of the porous body. Manufacturing method.