JP2010069013A - Material for regeneration of bile duct tissue - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a material for regeneration of bile duct tissue, which prevents stenosis of a bile duct tissue and can early regenerate a bile duct by working as a scaffolding of regeneration of the bile duct tissue. <P>SOLUTION: A material 1 for regeneration of bile duct tissue consist of a cylindrical object which includes a stent substrate 2 made of a bioabsorbable material and a porous material 3 covering an outside and/or inside of the stent substrate and made of a bioabsorbable material and a tube 4 which is located on the inside of the cylindrical object and of which the outer diameter is smaller than the inner diameter of the cylindrical object. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

The present invention relates to a bile duct tissue regeneration material that serves as a scaffold for regeneration of bile duct tissue and can regenerate the bile duct tissue at an early stage.

When a tumor occurs in the bile duct or stenosis occurs for some reason, surgical treatment is performed in which the site is removed and the liver bile duct and the intestine are anastomosed. However, postoperative complications such as intestinal infection and anastomotic stenosis often occur. In such cases, re-anastomosis is required, and in the worst case, the bile flow is worse, although the failure is limited to the bile duct, resulting in bile stagnation and liver transplantation. It may become.
In addition, in the case of liver transplantation, if chronic rejection of the transplanted organ occurs, the bile duct narrows, and the transplanted liver stops functioning even though there is a problem only with the bile duct, so re-transplantation of the liver may be necessary. is there.
Furthermore, in the case of a child who has congenital bile duct stenosis, treatment is performed to connect the bile duct to the ileum. However, after operation, cholangitis may occur repeatedly and jaundice may occur, resulting in a need for liver transplantation.

In such a case, if the bile duct substitute that exhibits the same function as the normal function can be regenerated after excision of the affected area, it can be used as a substitute for pathological bile duct, and treatment can be achieved without leading to liver transplantation. Is possible.

Patent Document 1 discloses a cylindrical biological duct stent including a stent base material made of a bioabsorbable material and a porous body covering the outside and / or the inside of the stent base material. If such a biological duct stent is used, not only the original role of preventing the narrowing of the biological duct but also the porous body can serve as a scaffold for regeneration of the biological duct and achieve early healing. The excellent effect that can be demonstrated. The biological duct stent described in Patent Document 1 is extremely effective for treatment of stenosis of the biological duct and regeneration of the biological duct.
However, when the biological duct stent described in Patent Document 1 is used as a scaffold for regeneration of bile duct tissue, bile is entangled in the stent portion, and a bile plug is formed so that a good bile duct tissue is not regenerated, sometimes cholangitis Or enterocolitis may occur.
JP 2007-130179 A

An object of the present invention is to provide a regenerating material for bile duct tissue that can serve as a scaffold for regenerating bile duct tissue and can regenerate the bile duct at an early stage.

The present invention relates to a cylindrical body composed of a stent base material made of a bioabsorbable material and a porous body made of a bioabsorbable material covering the outside and / or the inside of the stent base material, and the inside of the cylindrical body The biliary tissue regenerating material is a biliary tissue regenerating material that is made of a tube having an outer diameter smaller than the inner diameter of the cylindrical body.
The present invention is described in detail below.

The present inventors use a cylindrical biological duct stent composed of a stent base material made of a bioabsorbable material described in Patent Document 1 and a porous body covering the outside and / or the inside of the stent base material. If so, the cause of the inhibition of bile duct tissue regeneration was investigated. As a result, it has been found that epithelial cells that have invaded the porous body may fall off due to excessive attachment of the bile plug to the stent base material, which prevents the regeneration of the bile duct. On the other hand, in order to regenerate epithelial tissue, components contained in bile are indispensable, and fresh bile must always be supplied to the porous body of the biological duct stent.
Therefore, as a result of further intensive studies, the present inventors have arranged a tube having an outer diameter smaller than the inner diameter of the cylindrical body inside the cylindrical body constituting the biological duct stent, thereby regenerating the bile duct tissue. Has been found to be significantly improved, and the present invention has been completed.

It is thought that the role of the tube is to control the flow of bile. In the absence of the tube, a large amount of bile flows inside the biological duct stent, and a bile plug is easily formed. By arranging the tube, bile can flow inside the tube, and a bile plug can be prevented from being formed inside the biological duct stent. On the other hand, when the outer diameter of the tube is made smaller than the inner diameter of the cylindrical body, a portion of bile flows between the tube and the cylindrical body, so that regeneration of the bile duct tissue is sufficiently possible.

A schematic diagram showing an example of the biliary tissue regeneration material of the present invention is shown in FIG. FIG. 1a shows the bile duct tissue regenerating material 1 viewed from the side, and FIG. 1b shows a cross-sectional view of the bile duct tissue regenerating material 1 taken along the broken line in FIG. 1a.
The biliary tissue regenerating material 1 includes a stent base material 2, a porous body 3, and a tube 4. The porous body 3 is located outside the stent base material 2 and is integrated with the stent base material 2 to form a cylindrical body 5. The tube 4 is disposed inside the cylindrical body 5. Since the outer diameter of the tube 4 is smaller than the inner diameter of the cylindrical body 5, a space is formed between the tube 4 and the cylindrical body 5.

The biliary tissue regeneration material of the present invention has a cylindrical body composed of a stent base material and a porous body.
The stent base material has a role of imparting strength to the biliary tissue regenerating material of the present invention and maintaining the inner diameter of the biliary tissue when transplanted.
When transplanted, the porous body has a role of cells that invade and proliferate from around and become a scaffold for regeneration of the bile duct.

The stent substrate is made of a bioabsorbable material. By being made of a bioabsorbable material, it is gradually decomposed after the operation and absorbed into the living body, and it is not necessary to take it out again after the healing, thereby reducing the burden on the patient.

The bioabsorbable material constituting the stent base material is not particularly limited, and is selected from the group consisting of glycolide, lactide (D-form, L-form, DL-form), caprolactone, dioxanone, ethylene glycol, and trimethylene carbonate. And a polymer obtained by polymerizing at least one monomer. Of these, a lactide-caprolactone copolymer and a glycolide-caprolactone copolymer are suitable because flexibility and degradability can be controlled.

The stent base material is not particularly limited as long as it has a strength that can maintain the inner diameter of the regenerated bile duct tissue and has elasticity that does not damage the regenerated bile duct tissue. Any configuration such as a knitted fabric, a woven fabric, and a braid may be used. Among these, a knitted fabric, a woven fabric, and a braid made of a bioabsorbable material that does not have an end portion of the fiber is preferable. The stent base material having such a configuration is flexible and is not easily crushed and has excellent shape retention.
In the present specification, “having no fiber end” means a single continuous fiber, such as a braided woven fabric, and the ends of the single fiber are joined together or plural This means that the ends of the fibers are eliminated by connecting the ends of the adjacent fibers together, and that the braided woven fabric is composed of one fiber.

The fiber made of the bioabsorbable material is not particularly limited, and examples thereof include monofilament yarn, multifilament yarn, twisted yarn, braid and the like. Of these, monofilament yarn is preferred.
The diameter of the fiber made of the bioabsorbable material is preferably 0.1 to 0.8 mm.

The fibers made of the bioabsorbable material are preferably oriented and crystallized by stretching. As the degree of crystallization, it is preferable that about 40 to 60% of crystals are contained in the fiber. Such oriented and crystallized fibers can be produced, for example, by stretching the fibers about 5 to 10 times.

The cross section of the fiber made of the bioabsorbable material is not particularly limited, and for example, a circle, an ellipse, or other irregular shapes (for example, a star shape) can be used. The fiber made of the bioabsorbable material may be subjected to a hydrophilic treatment on the surface by plasma discharge, electron beam treatment, corona discharge, ultraviolet irradiation, ozone treatment or the like.

In order to improve the fixing force, for example, the stent base material may be configured in advance so that the diameters at both ends of the stent are larger than those of other portions.

The porous body is not particularly limited, but is made of collagen, gelatin, a copolymer of lactide and caprolactone, a copolymer of glycolide and caprolactone, etc. because of its high flexibility and excellent affinity with cells. Sponges, nonwoven fabrics and the like are suitable.
When collagen or gelatin is used, conventionally known crosslinking such as thermal crosslinking, ultraviolet crosslinking, glutaraldehyde crosslinking, and water-soluble carbodiimide crosslinking may be performed for the purpose of adjusting bioabsorbability.

The porous body may be reinforced with a fiber structure such as a knitted fabric, a woven fabric, or a nonwoven fabric made of a bioabsorbable material.
Although it does not specifically limit as a fiber structure which consists of the said bioabsorbable material, For example, it selects from the group which consists of glycolide, lactide (D body, L body, DL body), caprolactone, dioxanone, ethylene glycol, and trimethylene carbonate. What consists of a polymer formed by polymerizing at least one monomer is preferred.

The method for producing the porous body is not particularly limited, and examples thereof include conventionally known methods such as freeze-drying a solution in which the bioabsorbable material is dissolved. In addition, the method for reinforcing with a fiber structure made of a bioabsorbable material is not particularly limited. The method etc. which bond the porous body and fiber structure which were prepared separately are mentioned.

Although it does not specifically limit as thickness of the said porous body, A preferable minimum is 0.15 mm and a preferable upper limit is 5 mm. If the thickness of the porous body is less than 0.15 mm, it may not function as a three-dimensional scaffold for cells, and if it exceeds 5 mm, the lumen may not be retained.

The porous body may contain a growth factor for the purpose of promoting regeneration of the bile duct. For the same purpose, cells may be seeded in advance and not cultured, or may be used after culturing.
Although it does not specifically limit as said growth factor, For example, basic fibroblast growth factor (bFGF) etc. are mentioned.
The cells are appropriately selected depending on the application site of the biological duct stent of the present invention, and examples thereof include autologous bone marrow cells, fibroblasts, keratinocytes, mucosal epithelial cells, and endothelial cells.

In the cylindrical body, the outside and / or the inside of the stent base material is covered with the porous body.
The method for producing the cylindrical body is not particularly limited. For example, the surface of the stent base material is coated with a porous body formed into a sheet shape, and the ends are bonded or stitched. A method of directly coating a cylindrically shaped porous body on the surface of a material, a method of inserting a stent base material into a cylindrically shaped porous body, and a bioresorbability that uses the stent base material as a raw material for the porous body Examples include a method of dipping in a solution in which the material is dissolved, air drying, or freeze drying.

The cylindrical body preferably has an outer diameter of about 3 to 20 mm for the purpose of regeneration of bile duct tissue.

In the bile duct tissue regenerating material of the present invention, a tube is further arranged inside the cylindrical body. The tube controls the flow of bile, maintains its shape, and has a role in anti-kinking.

Although it does not specifically limit as an internal diameter of the said tube, A preferable minimum is 1 mm. If it is less than 1 mm, bile cannot sufficiently flow through the tube, and the effects of the present invention may not be exhibited.

The outer diameter of the tube is smaller than the inner diameter of the cylindrical body.
Although it does not specifically limit as a ratio of the outer diameter of the said tube with respect to the internal diameter of the said cylindrical body, A preferable minimum is 10% and a preferable upper limit is 80%. If the ratio of the outer diameter of the tube to the inner diameter of the cylindrical body is less than 10%, most bile flows so as to be in contact with the cylindrical body, so that the occurrence of bile plugs may not be prevented, If it exceeds 80%, most of the bile flows only inside the tube, and the necessary bile cannot contact the porous body that serves as a scaffold for the regeneration of the bile duct tissue, which may prevent the regeneration of the bile duct tissue. is there. A more preferable lower limit of the ratio of the outer diameter of the tube to the inner diameter of the cylindrical body is 15%, and a more preferable upper limit is 75%.

The tube is preferably made of a bioabsorbable material in the same manner as the stent base material and the porous body. However, since it is considered that the bile duct tissue is spontaneously dropped and discharged from the digestive organs to the outside of the body, there is no problem even if it is made of a non-absorbable material in vivo.

The method of fixing the tube is not particularly limited. For example, a method of fixing the stent base material using a thread or the like at one end of the tube, a method of partially suturing one end of the tube and tissue, For example, a method of joining one tip to the tip of the stent can be used.

ADVANTAGE OF THE INVENTION According to this invention, the bile duct tissue regeneration material which can become a scaffold of a bile duct tissue reproduction | regeneration and can reproduce a bile duct at an early stage can be provided.

Hereinafter, embodiments of the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

Example 1
(1) Production of porous body A flat knitted fabric was produced by knitting a polyglycolide yarn having a fiber diameter of 140 denier into a cylindrical shape. This was attached to a fluororesin rod having an outer diameter of 8 mm.
After preparing a 4% by weight dioxane solution of L-lactide-ε-caprolactone copolymer (molar ratio 50:50) and immersing a rod with a flat knitted fabric in this solution, it was frozen at −80 ° C., Lyophilized at −40 ° C. to 40 ° C. for 12 hours.
Subsequently, the obtained composite was removed from the fluororesin rod while being inverted, and then attached to the rod again so that the porous body side was in contact with the rod. This was immersed in a 4% by weight dioxane solution of L-lactide-ε-caprolactone copolymer (molar ratio 50:50), frozen at −80 ° C., freeze-dried at −40 ° C. to 40 ° C. for 12 hours, A cylindrical porous body having a sandwich structure reinforced with a polyglycolide knitted fabric was obtained. The total thickness of the porous body was about 0.7 mm on both sides.

(2) Preparation of stent substrate A stent substrate was prepared using a monofilament yarn made of glycolide-caprolactone copolymer (molar ratio 75:25) having a diameter of 0.3 mm.
As a manufacturing method, a polystyrene tube having a diameter of 5 mm was cut into a certain length, and eight pins were set on the circumferences of both ends thereof. At that time, the pin on one end was placed in the middle of the pin on the opposite side. The monofilament yarn was spirally wound around the tube and turned back with the opposite pin. Also, when crossing halfway, we knit so that the vertical relationship between the adjacent intersections and the fibers alternately changed. When the knitting to the starting point was completed, both ends of the fiber were partially overlapped and knitted to join and fix. Then, it heated at 80 degreeC under vacuum for 3 hours, and heat-set to the cylindrical shape, and obtained the stent base material.

(3) Preparation of cylindrical body The obtained porous body was covered with the stent base material, and the cylindrical body was obtained. The obtained cylindrical body had an inner diameter of 5 mm and an outer diameter of 8 mm.
A silicone tube having an inner diameter of 1.5 mm and an outer diameter of 2 mm was inserted inside the cylindrical body to obtain a bile duct tissue regenerating material.

(Comparative Example 1)
A biliary tissue regenerating material was obtained in the same manner as in Example 1 except that no silicone tube was inserted.

(Evaluation)
Part of the bile duct of the pig was excised and replaced with the bile duct tissue regeneration material obtained in Example 1 and Comparative Example 1 when the liver bile duct and the intestine were anastomosed.
Three months after the operation, sacrifice was performed, and the replaced tissue was collected.
FIGS. 2 and 3 show HE-stained images of tissues regenerated using the bile duct tissue regenerating material of Example 1 and Comparative Example 1. FIG.

From FIG. 2, when anastomosis between the liver bile duct and the intestine was performed using the bile duct tissue regeneration material of Example 1, regeneration of a clean bile duct epithelium was confirmed in the replaced part 3 months after the operation.
From FIG. 3, when the anastomosis between the bile duct of the liver and the intestine was performed using the bile duct tissue regenerating material of Comparative Example 1, the bile duct epithelium was regenerated in the replaced part 3 months after the operation, but it should be engrafted. It turns out that it has been peeled off.

ADVANTAGE OF THE INVENTION According to this invention, the bile duct tissue regeneration material which can become a scaffold of a bile duct tissue reproduction | regeneration and can reproduce a bile duct at an early stage can be provided.

It is a schematic diagram which shows an example of the bile duct tissue regeneration material of this invention. 3 is a HE-stained image of the tissue at the anastomosis when anastomosis is performed using the bile duct tissue regenerating material of Example 1. FIG. 3 is an HE-stained image of an anastomotic tissue when anastomosis is performed using the bile duct tissue regeneration material of Comparative Example 1. FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Bile duct tissue regeneration material 2 Stent base material 3 Porous body 4 Tube 5 Tubular body

Claims (2)

A cylindrical body composed of a stent base material made of a bioabsorbable material and a porous body made of a bioabsorbable material covering the outside and / or the inside of the stent base material, and disposed inside the cylindrical body The bile duct tissue regenerating material is characterized by comprising a tube having an outer diameter smaller than the inner diameter of the cylindrical body. The bile duct tissue regenerating material according to claim 1, wherein the ratio of the outer diameter of the tube to the inner diameter of the cylindrical body is 10 to 80%.