JPH0135666B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a tubular prosthetic organ that has an enhanced rate of organization within the body. For more details, see Artificial blood vessels,
In tubular artificial organs such as artificial tracheas and artificial esophagus, the rate of organization after implantation is increased by the action of coagulation factor (hereinafter abbreviated as F) immobilized on the wall of the tubular body. Concerning tubular human blood organs.

The development of tubular artificial organs as substitutes for tubular organs, such as artificial blood vessels, artificial tracheas, and artificial esophagus, has been actively developed in recent years, and clinical applications for various diseases have been widely carried out, and many reports have been published regarding these. . Generally required properties for tubular artificial organs include elasticity, extensibility, fatigue strength, and durability, which do not deteriorate within the body.
It has low reactivity, is non-toxic, has appropriate porosity, does not cause suture failure, and does not degenerate due to disinfection. A property that is strongly required is that there is no risk of ulcer formation or stenosis. In conventional tubular artificial organs,
Efforts are being made to provide the above properties by selecting the material, devising the weaving method, and devising the shape, such as by applying bellows processing. However, little research has been conducted on methods to increase the speed of organization described in 2010 and to reduce the risk of rapid thrombotic occlusion, ulcer formation, and stenosis due to long-term indwelling in the body. There are only reports that loop-shaped velvet or nonwoven fabrics have excellent antithrombotic properties due to their unique surface properties, and as a result, are less likely to cause vascular occlusion. All other attempts have been based on improvements in surgical techniques, such as suturing techniques.

The general course after transplantation of a tubular artificial organ into the body is as follows:
The process is thought to be as follows: transplantation → formation of endometrium and connective tissue → organization → becoming a host. In other words, in a tubular artificial organ transplanted into the body, it is incorporated into the living body by forming an endothelial lining with vascular endothelial cells on the inner wall, and connective tissue on the outer wall, with this as a core. It is considered that While this organization is not fully organized, the tubular artificial organ is still a foreign body to the living body and cannot be said to have the same functions as living tissue, leading to rapid thrombotic occlusion and granulation during placement. There is a high risk of stenosis and ulcer formation due to formation. However, in the case of conventional tubular artificial organs, due to the slow rate of organization, artificial blood vessels are exposed to the risk of thrombotic occlusion for a long time, and in the case of artificial tracheas and artificial esophagus, The formation of stricture ulcers is often observed in these patients.

The present applicant discovered that a wound protection material in which F was immobilized promoted the production of long-term stable fibrin, and previously proposed it (Japanese Patent Application Laid-Open No. 1989-1989).
135214), and in view of the above-mentioned current situation regarding tubular artificial organs, as a result of intensive research to eliminate the drawbacks of conventional tubular artificial organs, F was immobilized in tubular artificial organs such as artificial blood vessels, artificial tracheas, and artificial esophagus. The present invention was achieved based on the discovery that the presence of F significantly increases the rate of organization.

That is, the present invention is a tubular artificial organ consisting of a tubular body, characterized in that F is immobilized on the wall surface of the tubular body, and which has an increased organizing speed.

It is surprising that the tubular prosthesis of the present invention with immobilized F has a significantly better organization rate. The mechanism by which the rate of organization is increased is not clear, but it is probably due to the effective effect of F on both the processes of intima and connective tissue formation. It has the effect of making the stabilized fibrin network stronger by cross-linking between fibrin molecules, and also has the effect of helping fibroblasts to proliferate, thus reducing the intima and connective tissue. It is thought that the formation of the cells was accelerated, and as a result, the organization was completed quickly.

In the present invention, all existing tubular artificial organs to which F is immobilized can be used. For example, artificial blood vessels include polyamide-based, polyacrylate-based, polyvinyl chloride-based, polyester-based, and tetrafluoroethylene-based artificial blood vessels, and artificial tracheas include polyethylene mesh and polypropylene mesh.
Examples of artificial esophagus include silicone-based, collagen-treated silicone-based, and Teflon-based artificial esophagus.

F in the present invention is also called a fibrin stabilizing factor, and is a factor that directly acts on non-stabilized fibrin and is involved in the generation of isopeptide bonds between fibrin molecules. F is isolated from plasma of human and bovine animals, but when applied to humans, human-derived F
It is preferable to use

F is immobilized on the inner wall, outer wall, or inner and outer walls of the tubular body by a known oxygen fixing method such as a carrier binding method or a crosslinking method.

The carrier binding method is a method in which F is bound or adsorbed to a tubular body that is a carrier. The tubular body is a carboxyl group, an amino group, a chloroformyl group, a chlorotriazinyl group, an azide group, a diazonium group, an epoxy group, a formyl group, an acid anhydride group,
Reactive functional groups that can form covalent bonds such as promoacetyl groups, isocyanate groups, iminocarbonate groups, or amino groups, ammonium groups, carboxyl groups, carboxylate groups, sulfoxyl groups, sulfonate groups, phosphonium groups, sulfonium groups, etc. If it has an ion exchange group, F
By treating the tubular body with a solution containing F, F can be covalently or ionically bonded to the tubular body. In addition, if the tubular body does not have a tubular functional group or an ion exchange group that can form a covalent bond, it is possible to introduce those groups into the tubular body in advance by a polymer reaction and then bond F to the tubular body. can. In addition to the above-mentioned covalent bonding method and ionic bonding method, F can also be physically adsorbed onto the tubular body. In order to manufacture tubular artificial organs by the carrier binding method, in addition to the method of binding or adsorbing F to the tubular body as described above, first, F is bound or adsorbed to the material itself before being processed into the tubular body. Afterwards, the material to which F is bound or adsorbed can be processed into a tubular body. for example,
The tubular artificial organ of the present invention with an increased organizing speed can be manufactured by obtaining a tubular body using a polymeric substance in which F is bound or adsorbed in advance.

The crosslinking method is a method in which F is crosslinked on the surface of a tubular body using a reagent having two or more functional groups (hereinafter referred to as a polyfunctional reagent) to form a film made of F on the surface of the tubular body. be.
Examples of the polyfunctional reagent include glutaraldehyde, dialdehyde starch, bisdiazobenzidine, N,N'-polymethylene biiodoacetamide, N,N'-ethylene bismaleimide, and the like.

When manufacturing the tubular artificial organ of the present invention, F
can immobilize thrombin and Ca, which are involved in the activation of Furthermore, when manufacturing the tubular artificial organ of the present invention, pharmaceuticals such as bactericides, antibiotics, hormones, etc. can be immobilized on the tubular body along with F, if necessary.

The tubular artificial organ of the present invention can be easily sterilized using a gaseous disinfectant such as ethylene oxide. Furthermore, sterilization can also be carried out by methods such as irradiation with X-rays, gamma rays, neutrons, electrons, and the like.

Next, the present invention will be explained in more detail with reference to Examples. In addition, F is the method of Curtis et al.
in Enthvmology, Vol. 45, p. 177 (1976)]. The activity measurement of F.
Methods in Enzymology, 19
Vol., p. 770 (1970)], and the incorporation of dansyl katabalin into casein was measured. The immobilization rate is the value obtained by dividing the activity titer of the immobilized F by the activity titer of the F used for immobilization.

Example 1, Comparative Example 1 A polyester artificial blood vessel (Woven Dacron manufactured by Yufu Seiki Co., Ltd.) was immersed in a mixed solution consisting of 1 part by volume of a 10 wt% polyethyleneimine aqueous solution and 5 parts by volume of methanol at room temperature for 2 hours, and then Two parts by volume of a 6 wt % N,N'-dicyclohexylcarbodiimidomenol solution was added, and the mixture was shaken at room temperature for 6 hours. At the same time, the artificial blood vessel was taken out, washed with water-containing methanol, and dried. Continue using artificial blood vessels
It was added to a 5wt% methyl vinyl ether-maleic anhydride copolymer acetone solution, shaken at room temperature for 5 hours, washed with acetone, then left in an aqueous solution containing F at 4°C for 24 hours, and then added to physiological saline. After washing, an artificial blood vessel with F immobilized on its inner and outer walls was obtained. The immobilization rate of F to the artificial blood vessel is
It was 7.3%. When the fixed artificial blood vessel of F was transplanted into the abdominal aorta of a dog, a pseudointima was formed and organized within 3 months.

For comparison (Comparative Example 1), when F unimmobilized woven Dacron was similarly transplanted, it took 6 months for it to become organised.

In addition, in both Example 1 and Comparative Example 1, no thrombotic occlusion occurred.

Example 2 The same artificial blood vessel as in Example 1 was immersed in an aqueous solution of 5 wt% aminoacetalized polyvinyl alcohol (degree of aminoacetalization 9.6 mol%) at room temperature for 5 hours, and then thoroughly washed with ion-exchanged water.
After drying this product, it was shaken for 5 hours in a 5 wt % methyl vinyl ether-maleic anhydride copolymer acetone solution. Next, after washing this product with acetone, it was left in an aqueous solution containing F at 40°C for 24 hours, then washed with physiological saline, and the inner and outer walls were coated with F.
An artificial blood vessel with immobilized was obtained. The immobilization rate of F to the artificial blood vessel was 8.2%. When an artificial blood vessel with immobilized F was transplanted into the abdominal aorta of a dog, a pseudoviscera was formed and organized within 3 months.

Example 3, Comparative Example 2 A Teflon-based artificial blood vessel [Edwards (Woven Teflon) manufactured by Yufu Seiki Co., Ltd.] was immersed in an acetone solution of 3 wt% methyl vinyl ether-maleic anhydride, left at room temperature for 1 hour, and then soaked in acetone. Washed thoroughly. This product was dried, left in an aqueous solution containing F at 4°C for 24 hours, and then washed with physiological saline to obtain an artificial blood vessel with F immobilized on its inner and outer walls. The F immobilization rate was 5.8%.
When the immobilized artificial blood vessel of F was transplanted in the same manner as in Example 1, it was organized in 100 days.

For comparison (Comparative Example 2), when the above-mentioned Teflon-based artificial blood vessel in which F was not immobilized was similarly transplanted, it took 6 months to organize it.

Example 4, Comparative Example 3 F was immobilized on an artificial trachea made of polyethylene mesh (low porosity) in the same manner as in Example 3. This artificial trachea was used to replace the dog's trachea. The replacement method was a 6-8 ring tubular resection and a tube graft. As a result, the inner surface of the mesh was covered with the inner membrane at an early stage, and in all but 4 out of 10 cases,
No ulcer formation or stenosis due to granulation was observed.

For comparison (Comparative Example 3), supplementation was performed in the same manner as in the above case using one in which F was not immobilized, and all but one of the 10 cases died due to stenosis due to granulation.

Example 5 A silicone collagen composite artificial esophagus was left in an aqueous solution containing F at 4° C. for 24 hours, and then washed with physiological saline to obtain an artificial esophagus with F immobilized on its inner and outer walls. The immobilization rate of F was 4.9%. Approximately 5 cm of this material was inserted into the dog's buccal esophagus using an end-to-end approach. Two of the five cases were successful (long-term survival: 6 months or more), but no stenosis occurred postoperatively in either case.

In addition, when using a device in which F was not immobilized, stenosis occurred after the surgery even in successful surgical cases, and it was necessary to incise and dilate the stenotic part endoscopically.

Example 6 A methyl vinyl ether-maleic anhydride copolymer-treated artificial blood vessel obtained in the same manner as in Example 1 was placed in an aqueous solution containing F and thrombin at 4°C24.
After leaving it for a while, wash it with physiological saline and F
An artificial blood vessel with immobilized was obtained.

When an artificial blood vessel immobilized with F and thrombin was transplanted into the abdominal aorta of a dog, a pseudointima was formed and organized in less than 3 months.

Claims (1)

[Scope of Claims] 1. A tubular artificial organ consisting of a tubular body, characterized in that a coagulation factor is immobilized on the wall surface of the tubular body, with an increased organizing speed. 2. The artificial organ according to claim 1, wherein the tubular artificial organ consisting of a tubular body is selected from the group consisting of an artificial blood vessel, an artificial trachea, and an artificial esophagus.