WO2019151338A1

WO2019151338A1 - Tubular artificial organ

Info

Publication number: WO2019151338A1
Application number: PCT/JP2019/003213
Authority: WO
Inventors: 中山　泰秀; 武寺澤; 宏臣奥山; 勇一 ▲高▼間; 聡梅田; 勝平樋渡; 敬史山本; 修司福瀧; 井手　純一; 彩佳山本
Original assignee: 株式会社ジェイ・エム・エス; 国立研究開発法人国立循環器病研究センター; 国立大学法人大阪大学
Priority date: 2018-01-30
Filing date: 2019-01-30
Publication date: 2019-08-08
Also published as: JP2019129979A

Abstract

The purpose of the present invention is to provide a tubular artificial organ that has a predetermined strength to be able to retain a lumen without increasing the thickness of the cylinder wall, and that has excellent biocompatibility and growth. This tubular artificial organ 1A is provided with: a tubular tissue body 10 that is formed in an environment in which a biotissue material is present, and is configured with fibrous tissue; and a tubular reinforcement body 20A that is configured with a biodegradable material and is enclosed inside the tubular tissue body 10. The tubular tissue body 10 is formed in a tubular shape by implanting a mold inside an organism and the tubular reinforcement body 20A is preferably enclosed across the entire length. In addition, the tubular tissue body 10 is preferably configured to have a mesh shape by using a biodegradable material.

Description

Tubular artificial organ

The present invention relates to a high-strength tubular artificial organ that is excellent in biocompatibility and does not collapse the lumen, and a substrate used for the production thereof.

Regenerative medicine for transplanting artificial materials and artificial organs formed by cells and treatment of congenital diseases and regeneration of tissues and organs lost in diseases and accidents as tissue regeneration scaffold materials Many studies have been used.

Conventionally, a biological reaction called encapsulation is known as one of the self-defense functions of a living body. Encapsulation is a fibrous tissue composed mainly of fibroblasts and collagen produced by fibroblasts when, for example, a foreign body enters a deep position in the body and fibroblasts gather around the foreign body. This is a biological reaction that isolates foreign matter in the body by forming a capsule and covering the foreign matter.

As regenerative medical technology using this encapsulation, Patent Document 1 discloses that a core rod made of a non-absorbable and non-degradable material such as silicon resin or vinyl chloride resin is implanted in a living body for a certain period of time There has been proposed a technique for obtaining an artificial blood vessel composed of fibrous tissue by taking out an encapsulated core rod and removing the core rod. Since this artificial blood vessel is composed of only living tissue, it has excellent biocompatibility. In addition, since this artificial blood vessel is infiltrated from surrounding tissues after transplantation, self-organization proceeds, and the fibrous tissue is replaced by the recipient's vascular tissue. It also has the growth potential of being able to follow the increase.

By the way, since the artificial blood vessel described above is composed of fibrous tissue, it has poor shape retention and is difficult to anastomosis with the blood vessel. In order to solve this, Patent Document 2 proposes an artificial blood vessel in which an anastomosis with a blood vessel is facilitated by reinforcing both ends with a sponge-like thermoplastic resin in an artificial blood vessel obtained by utilizing encapsulation. ing.

Further, Patent Document 3 discloses that a cylindrical member and a core rod are embedded by implanting a mold composed of a cylindrical member having a slit and a core rod inserted into the cylindrical member under the skin of a living body. There has been proposed a technique for obtaining a tubular fibrous tissue body (tubular artificial organ) having an arbitrary thickness by infiltrating a fibrous tissue into a gap.

JP 2004-261260 A Japanese Patent No. 4484545 Japanese Unexamined Patent Publication No. 2017-1113051

As described above, since a tubular artificial organ composed of a fibrous tissue body has poor physical strength, reinforcement may be necessary by some means in order to retain the lumen. As described in Patent Document 2, it is difficult to hold the lumen outside the both ends only by reinforcing both ends of the artificial blood vessel. Moreover, the method of increasing the wall thickness of a pipe wall over the full length using the technique of patent document 3 is also considered. However, if the wall thickness is increased in order to obtain a predetermined strength capable of holding the lumen, it may be larger than the wall thickness of the tube wall of the patient's tubular organ, and may not be transplanted due to anastomosis mismatch. .

Therefore, the present invention provides a tubular artificial organ having a predetermined strength capable of holding a lumen without increasing the wall thickness of the tube wall and excellent in biocompatibility and growth, and the production of the tubular artificial organ. It aims at providing the base material used and the tubular reinforcement used in order to produce a tubular artificial organ.

The present invention includes a tubular tissue body that is formed in an environment where a biological tissue material exists and is composed of a fibrous tissue, and a tubular reinforcement body that is composed of a biodegradable material and is included in the tubular tissue body. The present invention relates to a tubular artificial organ provided.

Further, the tubular reinforcement body made of the biodegradable material has a mesh-like side surface and a through-hole so that the fibrous connective tissue infiltrates in vivo. In order to obtain a high-strength tubular artificial organ by integrating the connective tissue with the tubular reinforcing body, the mesh preferably has a large aperture ratio, and more preferably is formed in a mesh shape with biodegradable fibers.

Further, it is preferable that the tubular tissue body is formed into a tubular shape by implanting a template in a living body, and the tubular reinforcing body is included over the entire length.

Further, it is preferable that the lumen holding force in the circumferential direction of the tubular artificial organ is 2.0 [N · mm] or more.

Further, it is preferable that the tubular reinforcement body is restricted from contracting in the axial direction.

Further, the tubular reinforcing body is formed by braiding using a plurality of biodegradable wires, and the contraction in the axial direction is restricted by joining the intersecting portions of the biodegradable wires. preferable.

In addition, it is preferable that the tubular reinforcement body is formed by knit knitting using a biodegradable wire to restrict axial contraction.

The present invention also provides a base material for producing an artificial tubular organ by forming a connective tissue around the body by being embedded in a living body, and has a rod-shaped core material and a plurality of slits, and stores the core material. An outer cylinder, and a cylindrical mesh member disposed in a space between the core material and the outer cylinder, wherein the core material and the outer cylinder are made of a non-biodegradable material, and the mesh The member relates to a base material for producing a tubular artificial organ composed of a biodegradable material.

The present invention also relates to a tubular reinforcing body used for producing a tubular artificial organ by forming a connective tissue around it, and has a predetermined axial compressive strength and a predetermined radial strength, and is configured in a tubular shape A plurality of first structures and a second structure having an axial compressive strength smaller than the predetermined axial compressive strength, wherein the first structure is the second structure The present invention relates to a tubular reinforcing body connected through a body.

Further, the tubular reinforcing body includes three or more first structures including the two first structures disposed at one end and the other end, and the two first structures disposed adjacent to each other. It is preferable to provide two or more second structures disposed between the structures.

Moreover, it is preferable that the first structure is configured in a mesh shape with a wire.

Further, it is preferable that the second structure is constituted by a wire connecting the first structure.

In addition, the first structure is configured in a mesh shape with a wire, and the diameter of the wire constituting the second structure is smaller than the diameter of the wire constituting the first structure. Is preferred.

Further, the first structure is configured in a mesh shape with a wire, and the number of the wire constituting the second structure is smaller than the number of the wire constituting the first structure. Is preferred.

Moreover, it is preferable that the cross-sectional area of the second structure is smaller than the cross-sectional area of the first structure.

The tubular reinforcing body has a predetermined length in the axial direction and has a plurality of annular structures configured in a mesh shape with a wire, and a length corresponding to the entire length of the tubular reinforcing body in the axial direction. A plurality of annular structures that are arranged so as to overlap the outer side or the inner side of the tubular structure at predetermined intervals in the axial direction. The tubular structure is fixed to the tubular structure, and the first structure is constituted by a portion where the plurality of annular structures and the tubular structure are overlapped, and the second structure is the tubular structure. Among these, it is preferable that the plurality of annular structures are configured by portions that do not overlap.

The present invention also provides a tubular artificial organ comprising a tubular tissue body formed in an environment where a biological tissue material is present and composed of a fibrous tissue, and the above-described tubular reinforcement body included in the tubular tissue body. About.

According to the present invention, a tubular artificial organ having a predetermined strength capable of holding a lumen without increasing the wall thickness of the tube wall and excellent in biocompatibility and growth, and the production of the tubular artificial organ The base material used and the tubular reinforcement used for producing the tubular artificial organ can be obtained.

1 is a perspective view schematically showing a tubular artificial organ according to a first embodiment of the present invention. It is a side view which shows the tubular reinforcement body in 1st Embodiment. It is a disassembled perspective view which shows the casting_mold | template used for manufacture of a tubular artificial organ. It is a side view which shows the example of the tubular reinforcement body which concerns on 2nd Embodiment of this invention. It is a figure for demonstrating the measuring method of lumen retention force and Young's modulus (compression elastic modulus). 2 is a photograph of the tubular artificial organ of Example 1. It is the photograph of the tubular artificial organ of Example 2, and the photograph of the transplanted state. It is an observation photograph from the inside and the outside of the tissue 13 weeks after the transplantation in Example 2. 2 is an observation photograph of a tissue extracted after 13 weeks from transplantation in Example 2. FIG. It is the observation photograph at the time of the transplantation of the tubular artificial organ in the comparative example 1, and the observation photograph 25 days after the transplantation. It is a figure which shows typically the tubular reinforcement body which concerns on 3rd Embodiment of this invention. It is a figure which shows typically the other example of the tubular reinforcement body which concerns on 3rd Embodiment. It is a figure which shows typically the other example of the tubular reinforcement body which concerns on 3rd Embodiment. It is explanatory drawing about the method of reducing the axial compressive strength in a 2nd structure. It is a figure which shows typically the tubular reinforcement body which concerns on 4th Embodiment of this invention. It is explanatory drawing about the method of fixing the annular structure in the tubular reinforcement shown in FIG. 12 to a tubular structure. 3 is a tubular reinforcing body of Example 3. FIG. 4 is a tubular reinforcing body of Example 4. FIG. 10 is a tubular reinforcing body of Example 5. FIG. It is a figure for demonstrating the measuring method of lumen retention force and compressive strength. It is a graph which shows the measurement result of compressive strength.

In the present specification and claims, the term “tubular artificial organ” refers to a luminal organ or organ substitute such as trachea, esophagus, stomach, duodenum, small intestine, large intestine, bile duct, ureter, oviduct, and blood vessel. Are artificially produced and used for transplantation.

In addition, “biological tissue material” is a substance necessary for forming a desired biological tissue, for example, somatic cells (fibroblasts, smooth muscle cells, endothelial cells, etc.) and pluripotent stem cells. Human cells such as ES cells, iPS cells, etc., nutrients such as various proteins (collagen, elastin) and saccharides such as hyaluronic acid, and other in vivo organisms such as cell growth factors and cytokines that promote cell growth and differentiation And various physiologically active substances present in The “biological tissue material” includes materials derived from mammals such as humans, dogs, cows, pigs, goats and sheep, birds, fish and other animals, or artificial materials equivalent thereto.

In addition, the “living body” in which the template is implanted refers to the living body (eg, extremities, shoulders) of animals (mammals such as humans, dogs, cows, pigs, goats, sheep, birds, fish, and other animals). , Subcutaneous in the back or abdomen, or embedding in the abdominal cavity).

Further, “fibrous tissue” refers to a fibrous tissue mainly composed of collagen produced by fibroblasts, which is formed by encapsulation of a foreign substance in a living body.

In addition, “encapsulation” means that fibroblasts gather around a foreign substance in a living body, and a fibrous tissue body mainly composed of fibroblasts and collagen produced by fibroblasts covers the foreign substance in the living body. A biological reaction that isolates foreign matter.
Using this encapsulation, molds of a predetermined shape made of non-absorbable and non-degradable materials such as silicon resin, vinyl chloride resin, and stainless steel are embedded in a living body that maintains sterility for a certain period of time. By implanting and removing the encapsulated template and removing the template, a fibrous tissue (connective tissue) formed in a predetermined shape can be obtained. Hereinafter, such a tissue shaping technique is referred to as “in vivo tissue shaping technique”. Biological tissue formation can form a fibrous tissue as an artificial organ in a living body in which aseptic conditions are maintained and supply of nutrients and oxygen is ensured. In addition, when a fibrous tissue is formed in the body, immune rejection does not occur, and thus an artificial organ with high biocompatibility can be obtained.

On the other hand, when forming a fibrous tissue by culturing in an in vitro artificial environment, a series of cell manipulations (for example, cell collection, separation, differentiation, proliferation, seeding on a scaffold, mechanical load, etc. as necessary) Engraftment under appropriate conditions, etc.) must be performed under aseptic conditions, which is more laborious and costly than in the case of in vivo histogenesis.
Therefore, in each embodiment described below, an artificial organ formed by using in vivo tissue forming technique and a tubular reinforcing body used for producing the artificial organ will be described. The tubular reinforcing body of the present invention is arranged in the above-described mold, and is encapsulated over the entire length of the tubular artificial organ by forming a fibrous tissue (connective tissue) around by encapsulation. It gives desired mechanical properties to a tubular artificial organ.

Hereinafter, each embodiment of the present invention will be described with reference to the drawings.

<First Embodiment>
A tubular artificial organ 1A according to the first embodiment will be described with reference to FIGS.
As shown in FIG. 1, the tubular artificial organ 1A includes a tubular tissue body 10 and a tubular reinforcing body 20A.

The tubular tissue body 10 is composed of a fibrous tissue mainly made of collagen and is formed into a cylindrical shape. This fibrous tissue is formed with a template (base material) having a predetermined shape in a living body by using a biopsy technique. By embedding, a shape corresponding to the mold is formed. The configuration of the mold will be described in detail later.

The tubular reinforcing body 20A is formed in the same cylindrical shape as the tubular tissue body 10, and is provided so as to be included in the tube wall of the tubular tissue body 10 (see FIG. 1). The tubular reinforcing body 20A has a predetermined strength enough to hold the lumen so that the lumen of the tubular tissue body 10 is not crushed by external pressure or negative pressure.

As shown in FIG. 2, the tubular reinforcing body 20 A has a mesh shape (mesh shape), and the fibrous tissue of the tubular tissue body 10 can enter the mesh structure. Therefore, the tubular tissue body 10 and the tubular reinforcing body 20A can be brought into close contact with each other, and the strength can be imparted to the tubular tissue body 10.

Further, since the tubular reinforcing body 20A is composed of a biodegradable material that is decomposed and absorbed in the body, it is difficult for the tubular reinforcing body to remain as a foreign substance in the body after the tubular artificial organ 1A has been transplanted and a predetermined period has elapsed. Therefore, adverse effects such as inhibiting tissue regeneration are reduced, and the growth of the tubular artificial organ 1A is not hindered.
Here, the predetermined period is a period until the fibrous tissue constituting the tubular tissue body 10 is replaced with the self tissue and the tissue regeneration is completed, and the tissue regeneration is completed as a material of the tubular reinforcing body 20A. Until then, a biodegradable material that is slow to decompose and absorb in the body is preferable so as to maintain the function as a reinforcing body. As an example, when the tubular artificial organ 1A is transplanted into the trachea, it is preferable that the shape is maintained for 6 to 12 months after the transplantation, and then slowly decomposed and absorbed. The period from 6 to 12 months after transplantation is a period necessary for tissue formation with a slow regeneration rate such as cartilage constituting the trachea, and then slowly decomposes and absorbs to suppress the occurrence of excessive inflammation. be able to.

As an example of a method of forming the tubular reinforcing body 20A, a method of forming by braiding using a plurality of biodegradable wires 21 as shown in FIG. By appropriately changing the type, diameter and knitting pitch P of the biodegradable wire 21, the strength of the tubular reinforcing body 20 A and the decomposition rate in the living body can be adjusted. Here, the knitting pitch P represents the size of the mesh in the axial direction, that is, the distance between the intersections formed by the intersection of the biodegradable wires 21 as shown in FIG.

As the biodegradable material, polyester excellent in biocompatibility is preferable, and polylactic acid, polyglycolic acid, poly (ε-caprolactone), polydioxanone (polymer of trimethylene carbonate) or a copolymer thereof should be used. Can do. A fiber made of these materials can be used as the biodegradable wire 21.

In addition, these biodegradable materials have physiological activities such as growth factors and anti-inflammatory agents for the purpose of promoting tissue regeneration and suppressing inflammatory reactions after being implanted as an artificial organ. You may impregnate the medicine which has. Examples of growth factors include platelet-derived growth factor (PDGF), transforming growth factor-α (TGF-α), transforming growth factor-β (TGF-β), insulin-like growth factor (IGF), colony stimulating factor (CSF). ), Fibroblast growth factor (FGF), epidermal growth factor (EGF), insulin, platelet-derived wound healing factor (PDWHF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), hepatocyte growth factor (HGF) and bone morphogenetic protein (BMP).
Examples of anti-inflammatory agents include cortisol, dexamethasone, betamethasone, prednisolone, triamcinolone, acetylsalicylic acid, etenzamide, diflunisal, loxobrofen, ibuprofen, indomethacin, diclofenac, meloxicam, ferden, and acetaminophen.

Next, with reference to FIG. 3, a method for producing the tubular artificial organ 1A by the biopsy will be described.

A mold 100 shown in FIG. 3 includes a silicon resin core rod 110 having a predetermined outer diameter and a stainless steel cylinder 120 as an outer cylinder having a predetermined inner diameter and provided with the core rod 110 fixed inside. Is done. The stainless steel cylinder 120 includes a main body portion 121 and a lid portion 122, and a plurality of slits are provided in the main body portion 121 so that a living tissue material can enter the gap between the core rod 110 and the cylinder 120. 123 is formed.
With the tubular reinforcing body 20A disposed between the core rod 110 and the cylinder 120, the mold 100 is implanted in a living body such as subcutaneous or abdominal cavity for a predetermined period of about 1 to 2 months.
While the mold 100 is implanted in the living body, a fibrous tissue by encapsulation is formed in the gap between the core rod 110 and the cylinder 120 from the slit 123 formed in the cylinder 120. At this time, the fibrous tissue fills the gap between the core rod 110 and the cylinder 120 in a state of entering the network structure of the tubular reinforcing body 20A.
After elapse of a predetermined period, the mold 100 is taken out from the living body, and the core rod 110 and the cylinder 120 are removed, whereby the tubular tissue body 10 having the outer diameter as the inner diameter of the cylinder 120 and the inner diameter as the outer diameter of the core rod 110 is obtained. A tubular artificial organ 1A in which a tubular reinforcement body 20A is included in the tube wall can be obtained. That is, in this embodiment, the tubular artificial organ 1A is manufactured using the core rod 110, the cylinder 120, and the tubular reinforcing body 20A disposed in the space between the core rod 110 and the cylinder 120 as a base material. .

In the tubular artificial organ 1A according to the first embodiment described above, the fibrous tissue constituting the tubular tissue body 10 becomes a scaffold for engraftment of cells in the body after transplantation, and gradually replaces the self tissue. Therefore, when applied to an organ in the middle of growth, it has the growth ability of being able to follow the increase in tube diameter. In addition, the lumen can be maintained even when applied to a tubular organ in which negative pressure or external pressure is applied in the radial direction.

The tubular artificial organ 1A according to the first embodiment has the following effects.

(1) A tubular artificial organ 1A is composed of a tubular tissue body 10 composed of a fibrous tissue formed using a template 100 having a predetermined shape in an environment where a biological tissue material exists, and a biodegradable wire 21. And a tubular reinforcement body 20 A configured and enclosed in the tubular tissue body 10. Accordingly, the tubular artificial organ 1A can be formed to have a predetermined strength capable of holding the lumen without increasing the wall thickness of the tube wall of the tubular tissue body 10. Therefore, for example, the tubular artificial organ 1A can be applied to various tubular organs, such as a blood vessel having a thin tube wall, regardless of the thickness of the tube wall. Further, the tubular tissue body 10 is composed of a fibrous tissue having high biocompatibility and growth, and the tubular reinforcing body 20A is decomposed and absorbed after transplantation so that the growth of the tubular tissue body 10 is not hindered. 1A has high biocompatibility and growth. Therefore, application to organ transplantation in children can be expected.

(2) Since the fibrous tissue of the tubular tissue body 10 can enter the network structure of the tubular reinforcement body 20A by configuring the tubular reinforcement body 20A in a mesh shape, the tubular tissue body 10 and the tubular reinforcement body 20A And can be integrated.

<Second Embodiment>
A tubular artificial organ 1B according to the second embodiment will be described with reference to FIG. The tubular artificial organ 1B of the second embodiment is different from that of the first embodiment in the configuration of the tubular reinforcing body 20B. In the description of the second embodiment, the same components are denoted by the same reference numerals, and the description thereof is omitted or simplified.

The tubular artificial organ 1B includes a tubular tissue body 10 and a tubular reinforcing body 20B.
As in the case of the first embodiment, the tubular reinforcing body 20B is formed in a mesh shape with a biodegradable material, is formed in a cylindrical shape substantially equivalent to the tubular tissue body 10, and is provided on the tube wall of the tubular tissue body 10. And having a predetermined strength capable of holding the lumen of the tubular tissue body 10. The tubular reinforcement body 20B according to the second embodiment is different from the tubular reinforcement body 20A according to the first embodiment in that axial contraction is restricted.

FIG. 4 shows

tubular reinforcements

201B, 202B, and 203B, which are structural examples of the tubular reinforcement 20B in which axial contraction is restricted.

A tubular reinforcing body 201B shown in FIG. 4A is formed into a mesh-like cylindrical shape by braiding using a plurality of biodegradable wire rods 21, and the intersecting portion between the biodegradable wire rods 21 is super-long. A plurality of joints 23 joined by sonic welding are provided. Since the biodegradable wires 21 are joined at the joint 23, contraction in the axial direction of the tubular reinforcement 201B is restricted. In addition, about the joining method, you may use heat welding, an adhesive agent, etc. other than ultrasonic welding.

The tubular reinforcing body 202B shown in FIG. 4 (b) is formed into a mesh-like cylindrical shape by knit-knitting (also called Lilian knitting) one biodegradable wire 21. By making the tubular reinforcing body 202B into a structure in which a plurality of loops are connected by knitting, strength can be imparted against compression in the axial direction. Therefore, contraction in the axial direction of the tubular reinforcement 202B is restricted. The knit knitting represents an operation of forming one stitch by a single threading operation on a knitting needle.

The tubular reinforcing body 203B shown in FIG. 4 (c) is formed by cutting an axially contractible cylinder made of a biodegradable material so as to have a network structure by laser or water flow. The Therefore, the axial contraction of the tubular reinforcing body 203B is restricted. As the biodegradable material, the aforementioned biodegradable material can be used.

In addition to the example illustrated in FIG. 4, a tubular reinforcement body 20 B having a network structure and restricted in axial contraction may be manufactured by injection molding a thermoplastic biodegradable resin.

Since the tubular artificial organ 1B described above is restricted from contraction in the axial direction, it is preferably applied to transplantation of a tubular organ such as a trachea in which external pressure is applied in the axial direction.

The tubular artificial organ 1B according to the second embodiment has the following effects in addition to the effects (1) and (2) described above.
(3) The tubular artificial organ 1B includes the tubular reinforcing body 20B in which axial contraction is restricted. Thereby, since it can control that tubular artificial organ 1B contracts in the direction of an axis, a lumen can be maintained better.

(4) The tubular reinforcing body 201B is formed by braiding using a plurality of biodegradable wire rods 21 and includes a plurality of joint portions 23 in which crossing portions of the biodegradable wire rods 21 are joined. . Thereby, since shrinkage | contraction of the axial direction of the tubular reinforcement body 201B can be controlled suitably, shrinkage | contraction of the axial direction of the tubular artificial organ 1B can be controlled suitably.

(5) The tubular reinforcement 202B is formed by knit knitting using the biodegradable wire 21, so that axial shrinkage is restricted. Thereby, contraction of the axial direction of the tubular artificial organ 1B can be regulated.

<Example>
Next, an example in which the configuration of the tubular artificial organ according to each embodiment of the present invention is applied to a beagle dog with an artificial trachea that requires higher strength than an artificial blood vessel or the like will be described in detail.

Table 1 shows the configurations of the tubular reinforcing bodies of Examples 1 to 5.

(Configuration of tubular reinforcement)
With reference to Table 1, the configuration of the tubular reinforcements of Examples 1 to 5 will be described.
As the biodegradable wire 21, a monofilament formed by spinning and drawing poly L-lactic acid (weight average molecular weight 450,000, melting point 195 ° C.) was used, and each of them had a cylindrical shape with an inner diameter of 15 mm and a length of 40 mm. Tubular reinforcements of Examples 1 to 5 were produced. The diameter of the biodegradable wire 21 is 0.3 mm in Examples 1 to 4, and 0.4 mm only in Example 5.
The tubular reinforcing bodies shown in Examples 1 and 2 are formed by braiding a plurality of biodegradable wire rods 21, and an implementation corresponding to the configuration of the tubular reinforcing body 20A according to the first embodiment. It is an example (refer FIG. 2). The tubular reinforcing bodies shown in Examples 3 to 5 are formed so that axial contraction is restricted, and the configuration of the tubular reinforcing body 20B according to the second embodiment (Example 3 is shown in FIG. The configuration of the tubular reinforcing body 201B shown in a), Examples 4 and 5 are examples corresponding to the configuration of the tubular reinforcing body 202B shown in FIG. 4B.

(Measurement method of strength)
The physical properties of the tubular reinforcement were evaluated by “Young's modulus (compression elastic modulus)” as “luminal retention strength” which is an index of strength in the radial direction and strength in the long axis direction. A compression tester (Autograph AG-X Plus, manufactured by Shimadzu Corporation) was used to measure these physical properties.
As shown in FIG. 5 (a), the lumen holding force is measured by placing the tubular reinforcement on a jig J (adjusted to the length of the tubular reinforcement) that regulates the movement in the axial direction. The compression strength was measured by pressing from above with the pusher PL until the outer diameter reached 30%. The lumen holding force [N · mm] is determined by compressive strength [N] × (diameter of tubular reinforcement) ² [mm ² ] / axial length [mm] of the tubular reinforcement.
Further, as shown in FIG. 5 (b), the axial Young's modulus is determined by placing the tubular reinforcement body vertically and pressing the tubular reinforcement body from above with a pusher PL until the length reaches 90%. The compressive strength was measured. The maximum spring constant [N / mm] was determined from the slope of the obtained stress-strain curve in the 0-10% strain region. The Young's modulus E (MPa) is obtained by E = spring constant [N / mm] × initial length [mm] / cross-sectional area [mm ² ] of the tubular reinforcement.

(Measurement result of strength)
The results of measuring the lumen holding force and compression elastic modulus of the tubular reinforcements of Examples 1 to 5 and the lumen holding force of the tubular artificial organ of Comparative Example 1 will be described in detail.

As shown in Table 1, each of the tubular reinforcing bodies of Examples 1 to 5 had a lumen holding force of 2.0 [N · mm] or more.
Regarding the lumen holding force, the braiding method is the same braiding, and when Example 1 having a large knitting pitch is compared with Example 2 having a small knitting pitch, Example 2 has a larger lumen holding force. Therefore, it was confirmed that the lumen retention force can be increased by reducing the knitting pitch.
Example 2 in which the knitting method is the same, the knitting pitch is the same, and the intersecting portion of the biodegradable wire 21 is not joined, and the joined Example 3 in the axial compression elastic modulus. When compared, Example 3 had a larger Young's modulus. Therefore, it was confirmed that the Young's modulus can be increased by joining the intersecting portions of the biodegradable wire rods 21 to restrict axial contraction. In addition, when Example 3 and Example 4 having different means for restricting axial contraction are compared, Example 3 in which a tubular reinforcing body is formed by braiding and the intersecting portion of the biodegradable wire 21 is joined. In comparison, it was confirmed that Example 4 formed by knit knitting can greatly improve the Young's modulus.
Further, when Example 4 and Example 5 in which the knitting method is the same knitting and only the diameter of the biodegradable wire 21 is compared, the lumen of the biodegradable wire 21 is increased by increasing the diameter. It was confirmed that the holding force and Young's modulus can be improved.

(Mold structure)
As a mold, a round rod-shaped core rod 110 made of silicon resin having an outer diameter of 15 mm and a length of 40 mm, and a stainless steel cylinder 120 having a main body portion 121 having a plurality of slits 123 and an inner diameter of 17 mm and a lid portion 122, and (See FIG. 3).

(Production of tubular artificial organs)
The tubular reinforcing body 20A of Example 1 manufactured under the conditions shown in Table 1 was inserted into the mold 100 described above.
The template 100 obtained in this way was implanted under the back of a beagle dog to perform in vivo tissue formation. In implanting the mold 100, the beagle dog was anesthetized by a general procedure, then the disinfected skin was incised about 30 mm, the sterilized mold 100 was placed subcutaneously, and the skin was sutured. After the implantation operation, water was freely given, food was given according to body weight, and beagle dogs were raised in a normal environment.
Two months after the implantation of the mold 100, the encapsulated mold 100 was removed under anesthesia, the mold 100 was removed, and the cylindrical shape of Example 1 having an inner diameter of 15 mm, an outer diameter of 17 mm, and a length of 40 mm was obtained. A tubular artificial organ 1A was obtained (see FIG. 6). The lumen holding force of the tubular artificial organ 1A was measured and found to be 2.5 N · mm. From this result, it was shown that the lumen holding force of the tubular artificial organ 1A is larger than at least 2.1 N · mm of the tubular reinforcing body 20A. The obtained tubular artificial organ 1A was decellularized by being immersed in ethanol for 24 hours or more at room temperature before transplantation.

Moreover, the tubular artificial organ 1A of Example 2 provided with the tubular reinforcement body 20A of Example 2 was obtained by the same method as Example 1 (see FIG. 7A). The obtained tubular artificial organ 1A was decellularized by being immersed in ethanol for 24 hours or more at room temperature before transplantation.

Further, using the mold 100 described above, a tubular artificial organ 300 of Comparative Example 1 having no tubular reinforcement was obtained by the same method as in Examples 1 and 2 except that the tubular reinforcement was not inserted. When the lumen holding force of the tubular artificial organ 300 was measured, it was 0.1 N · mm, which was lower than the lumen holding force of the tubular artificial organ 1A of Example 1.

(Tracheal transplantation test for tubular artificial organs)
The results of a test of transplanting the tubular artificial organs of Examples 1 and 2 and Comparative Example 1 into the trachea of a beagle dog will be described.

First, the contents of the tracheal transplantation test of the tubular artificial organ 1A of Example 1 and the course after the transplantation will be described in detail.
Under general anesthesia, 1 cm of the trachea of the beagle dog was excised, and the tubular artificial organ 1A of Example 1 cut to 1 cm length was connected by end-to-end anastomosis. After transplantation, the animals were reared in the usual manner. No abnormal findings were observed during the breeding, and the respiratory condition was good.
As a result of observing the trachea of the transplanted portion with an endoscope 19 weeks after the transplantation, the patency of the lumen was maintained, but the lumen diameter was 5.5 mm. Therefore, the balloon catheter was expanded with a balloon catheter having an outer diameter of 15 mm. At the same time, spraying of 1 to 2 mL of 0.1% Linderon (steroid) was performed.
As a result of observation with an endoscope again at 24 weeks after transplantation, the patency of the lumen was maintained as in the previous observation, but the lumen diameter was 6.5 mm. In addition to expansion, spraying of 1 mL to 2 mL of 0.1% Linderone (steroid) was performed.
As a result of endoscopy at the 25th and 27th weeks after transplantation, the lumen diameter of the trachea was maintained at 7 mm, and the patency was maintained.

Next, the contents of the tracheal transplantation test of the tubular artificial organ 1A of Example 2 and the course after the transplantation will be described in detail.
Under general anesthesia, 2 cm of the trachea of the beagle dog was excised, and the tubular artificial organ 1A of Example 2 cut to a length of 2 cm was connected by end-to-end anastomosis (see FIG. 7B). After transplantation, the animals were reared in the usual manner.
Four weeks after transplantation, the lumen diameter of the trachea in the transplanted portion was narrowed to 5 mm, and therefore, the balloon catheter was expanded with a balloon catheter having an outer diameter of 10 mm.
Thereafter, expansion was performed with a 15 mm balloon catheter at 5, 6, and 7 weeks, and spraying of 1 mL to 2 mL of 0.1% Linderon (steroid) was performed.
Since the lumen diameter of the trachea in the transplanted portion was stable from about 8 weeks, the balloon catheter was not expanded and the steroid agent was not sprayed thereafter. It is thought that the self-organization of the tubular artificial organ 1A transplanted at 8 weeks progressed and the strength was stabilized. No other abnormal findings were observed during the breeding, and the respiratory condition was good.
The results of euthanizing 13 weeks after transplantation and observing the transplanted tubular artificial organ 1A with an endoscope are shown in FIG. 8 (a), and the results of observation with the trachea exposed through incision are shown in FIG. 8 (b). ). Further, in order to observe the anastomosis from the inside, FIG. 9A shows a photograph of a state in which a trachea including the tubular artificial organ 1A is incised, and FIG. 9B shows an enlarged photograph of FIG. 9A. .
The tubular artificial organ 1A was engrafted in the living trachea, and there was no abnormality in the anastomosis as shown in FIGS. 8 (a) and 8 (b). Further, the lumen diameter of the transplanted portion indicated by the arrow in FIG. 8A was 10 mm, and the lumen structure was maintained. Further, as shown in FIGS. 9A and 9B, a white tracheal mucosa was formed on the inner surface of the lumen, and reconstruction of the tracheal tissue was proceeding.

Finally, the contents of the tracheal transplantation test of the tubular artificial organ 300 of Comparative Example 1 and the course after the transplantation will be described in detail.
Under general anesthesia, 1 cm of the trachea of the beagle dog was excised, and the tubular artificial organ 300 of Comparative Example 1 cut to 1 cm length as shown in FIG. After transplantation, the animals were reared in the usual manner.
After transplantation, there was no abnormality in the health condition, but he died suddenly on the 25th day. As a result of necropsy, the transplanted tissue was crushed toward the lumen as shown in FIG. Thus, it was shown that the tubular artificial organ 300 that does not have the tubular reinforcement has a small lumen holding force and does not have a sufficient function as an artificial trachea.

The preferred embodiments and examples of the tubular artificial organ of the present invention have been described above, but the present invention is not limited to the above-described embodiments and examples, and can be modified as appropriate.
The present embodiment is a technique for forming a tubular tissue body that encloses a tubular biodegradable material by in vivo tissue formation. This technology can design all sizes and shapes, and enables tissue formation according to the physique and lesion. In addition to its high affinity with the living body, it has a mechanically high lumen retention, so it can also be used as an organ regeneration scaffold for organs that apply negative pressure during inspiration, such as the trachea, and for the esophagus and diaphragm. it can. After implantation, cells infiltrate from surrounding tissues and self-organization (tissue regeneration) progresses. Finally, a biodegradable skeleton is decomposed and absorbed to form a normal tissue body and have growth potential. It becomes. Therefore, it can also be used in children who need organ growth after transplantation.
In the above-described embodiments, the case where the present invention is applied to the trachea as an example of a tubular artificial organ has been described. It may be applied to organs.

<Third Embodiment>
Next, a tubular reinforcing body 1C according to a third embodiment of the present invention will be described with reference to FIGS. 11A to 11C.
As shown in FIG. 1A, the tubular reinforcing body 20C is formed in a cylindrical shape and includes a plurality of first structures 101 and second structures 201C. The plurality of first structures 101 are connected via the second structure 201C.
The tubular reinforcing body 20C is configured to have a predetermined radial strength enough to hold the lumen so that the lumen of the tubular artificial organ is not crushed by external pressure or negative pressure. It is configured to have a predetermined compressive strength so as to maintain shape retention without contracting more than necessary in the axial direction even when external pressure is applied.

The first structure 101 is formed in a tubular shape, and in the first embodiment, the first structure 101 is formed by an annular structure 15 having a predetermined length in the axial direction. The first structure 101 has predetermined compressive strength and radial strength necessary for a tubular artificial organ. Further, as shown in FIG. 11A, the first structure 101 is configured in a mesh shape (mesh shape), and when forming a tubular artificial organ, the fibrous tissue (connective tissue) has a mesh structure. I can get in. Therefore, the tubular reinforcing body 20C can be brought into close contact with and integrated with the tubular artificial organ, and strength can be imparted to the tubular artificial organ.

The first structure 101 is configured in a mesh shape with a wire, for example. As an example of a method of forming the first structure 101, a method of forming a plurality of wires 111 by braiding may be used. By appropriately changing the type, diameter, and knitting pitch P of the wire 111, the strength of the first structure 101 can be adjusted. Here, the knitting pitch P represents the size of the mesh in the axial direction, that is, the distance between the intersections formed by the intersection of the wires 111, as shown in FIG. 11A.
In addition, by joining the intersections of the wires 111 by ultrasonic welding or an adhesive, the axial contraction of the first structure 101 can be restricted, and the compressive strength in the axial direction can be improved. Directional strength can also be improved.

The second structure 201C has an axial compressive strength smaller than a predetermined axial compressive strength of the first structure 101, and imparts flexibility and axial flexibility to the tubular reinforcing body 20C. belongs to. The second structure 201 C is configured by a wire 211 that is disposed between the plurality of first structures 101 and connects the first structures 101.
The second structure 201C may connect the first structures 101 with at least one wire 211 as shown in FIG. 11A. Further, a plurality of wires 211 may be connected in a ring shape, as in the second structure 201D in the tubular reinforcement 20D shown in FIG. 11B and the second structure 201E in the tubular reinforcement 20E shown in FIG. 11C.
Further, the joining of the wire 111 constituting the first structure 101 and the wire 211 constituting the second structure is performed by ultrasonic welding or an adhesive. Moreover, as shown in FIG. 11B, when the wires 211 cross each other, the crossing portion is joined by ultrasonic welding or an adhesive, thereby improving the axial compressive strength as in the case of the first structure 101. The radial strength can also be improved. However, the

second structures

201C, 201D, and 201D are configured so that the compressive strength in the axial direction of the

second structures

201C, 201D, and 201D is smaller than the strength of the first structure 101.

Further, the ratio of the length of the second structural body to the axial length of the tubular reinforcing body is, for example, in the range of 5% to 50% when the tubular artificial organ is used as an artificial trachea. Preferably, it is about 10%. This is because the structure in the axial direction of the trachea is about 90% for high-strength cartilage and about 10% for low-strength ligaments. By making the structure similar to the trachea, the mechanical properties similar to those of the trachea are tubular. This is because it can be applied to the reinforcing body.

As materials for the wire 111 and the wire 211, various plastic materials such as polypropylene, polyethylene, polyethylene terephthalate, and the like can be used. Among them, the material of the wire 111 and the wire 211 is preferably a polyester excellent in biocompatibility, such as polylactic acid, polyglycolic acid, poly (ε-caprolactone), polydioxanone (trimethylene carbonate polymer), and respective monomers and copolymers. Etc. can be used. And the fiber which consists of these materials can be used as the wire 111 and the wire 211. FIG.

These materials also contain physiologically active agents such as growth factors and anti-inflammatory agents for the purpose of promoting tissue regeneration after implantation as an artificial organ or suppressing inflammatory reactions. You may invade. Examples of growth factors include platelet-derived growth factor (PDGF), transforming growth factor-α (TGF-α), transforming growth factor-β (TGF-β), insulin-like growth factor (IGF), colony stimulating factor (CSF). ), Fibroblast growth factor (FGF), epidermal growth factor (EGF), insulin, platelet-derived wound healing factor (PDWHF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), hepatocyte growth factor (HGF) and bone morphogenetic protein (BMP).
Examples of anti-inflammatory agents include cortisol, dexamethasone, betamethasone, prednisolone, triamcinolone, acetylsalicylic acid, etenzamide, diflunisal, loxobrofen, ibuprofen, indomethacin, diclofenac, meloxicam, ferden, and acetaminophen. In addition, since the encapsulation is performed using a rejection reaction and an inflammatory reaction in the body, it is preferable that these anti-inflammatory agents are not released slowly at the encapsulation stage.

In the first embodiment, a method of forming a first structural body 101 by braiding the wire 111 and connecting the second

structural bodies

201C, 201D, or 201E made of the wire 211 to obtain a tubular reinforcing body. Although shown, it is not limited to this. If the relationship between the compressive strengths in the axial direction between the first structure and the second structure is satisfied, the tubular reinforcing body is produced by a method such as cutting, injection molding, laser processing, or lamination molding using a 3D printer. May be. Moreover, as a material of the tubular reinforcing body, in addition to the plastic materials such as polyester and polylactic acid mentioned above, stainless steel and titanium excellent in biocompatibility, or metal materials such as magnesium having biodegradability may be used. Good.

A method of making the second structure 201 weaker than the first structure 101 with respect to the compressive strength in the axial direction will be described with reference to FIG.
In order to weaken the compressive strength in the axial direction of the second structure 201, the diameter of the wire 211 of the second structure 201 is made smaller than the diameter of the wire 111 of the first structure 101 (FIG. 12 ( a) and (b)), a method of making the wall thickness of the second structure 201 thinner than the wall thickness of the first structure 101 (see FIG. 12C), and the like are conceivable. That is, when the first structure body 101 and the second structure body 201 are made of the same material, the radial cross-sectional area of the second structure body 201 is larger than the cross-sectional area of the first structure body 101 in the longitudinal direction. By making it smaller, the compressive strength in the axial direction of the second structure 201 can be made weaker than the compressive strength in the axial direction of the first structure 101.
When adjusting the diameter of the wire rod, the wire rods having different diameters are joined to each other as shown in FIG. 12A, or the wire rod is stretched as shown in FIG. 12B. be able to. Further, in the case of a metal wire, the diameter of the wire can be reduced by cutting.

Further, in the case where the diameters of the wire members constituting the first structure body 101 and the second structure body 201 are the same, the second structure body has a second number greater than the number of the wire members 111 constituting the first structure body 101. By reducing the number of the wires 211 constituting the structure 201, the compressive strength in the axial direction of the second structure 201 can be weakened. Further, the axial strength of the second structure 201 may be reduced by combining the method of making the diameter of the wire 211 of the second structure 201 thinner than that of the first structure 101. Good. Further, by making the materials of the wire 11 constituting the first structure 101 and the wire 211 constituting the second structure 201 different, the compressive strength in the axial direction of the second structure 201 can be weakened. .

In the third embodiment, as an example of the tubular reinforcing body, an example constituted by three first structures and two second structures is shown, but the present invention is not limited to this. The tubular reinforcement may be constituted by at least two first structures and at least one second structure. If the tubular reinforcing bodies have the same length ratio in the axial direction, the bending performance can be improved by being constituted by a large number of first structures and second structures. Further, when the tubular reinforcing body is configured using the plurality of first structures and the plurality of second structures, the physical properties of the plurality of first structures and the physical properties of the plurality of second structures are different. It may be allowed. For example, when two first structures are used, one first structure may have a length of 10 mm, and the other first structure may have a length of 8 mm.

The tubular reinforcement bodies 20C to 20E according to the third embodiment have the following effects.

(6) A tubular reinforcing body 20C (20D, 20E) used for producing a tubular artificial organ by forming a connective tissue around it has a predetermined compressive strength and a predetermined radial strength, and is configured in a tubular shape. A plurality of first structures 101 and second structures 201C (201D, 201E) having a compressive strength smaller than a predetermined compressive strength of the first structures 101, The structure body 101 is connected via the second structure body 201C (201D, 201E). As a result, the first structure 101 imparts shape retention and lumen retention to the tubular artificial organ, while the second structure 201C (201D, 201E) provides flexibility and axial flexibility. A tubular reinforcement that can be applied to an organ can be obtained.

(7) The ratio of the length of the second structural body 201C (201D, 201E) to the axial length of the tubular reinforcing body 20C (20D, 20E) is 5% or more and 50% or less. Thereby, when using a tubular artificial organ as an artificial trachea, the same mechanical characteristics as the trachea can be imparted to the tubular reinforcement.

(8) The first structure 101 is constituted by a plurality of braided wires 111, and the diameter of the wire 211 constituting the second structure 201 is made smaller than the diameter of the wire 111. did. Thereby, the compressive strength in the axial direction of the second structure 201 can be made weaker than the compressive strength in the axial direction of the first structure 101.

(9) The first structure 101 is configured by a predetermined number of the plurality of wires 111, and the number of the wires 211 that configure the second structure 201 is the number of the wires that configure the first structure 101. The number was less than 111. Thereby, the compressive strength in the axial direction of the second structure 201 can be made weaker than the compressive strength in the axial direction of the first structure 101.

<Fourth embodiment>
With reference to FIG.13 and FIG.14, the tubular reinforcement body 20F which concerns on 4th Embodiment is demonstrated. The tubular reinforcing body 20F of the fourth embodiment is different from that of the third embodiment in the configuration of the first structure and the second structure. In the description of the fourth embodiment, the same constituent elements are denoted by the same reference numerals, and the description thereof is omitted or simplified.

As shown in FIG. 13, the tubular reinforcement body 20F is formed in a cylindrical shape as in the case of the third embodiment, and has a length corresponding to the total axial length of the plurality of annular structures 15 and the tubular reinforcement body 20F. And a tubular structure 30 having the structure.
As an example, the plurality of annular structures 15 are arranged so as to overlap the outside of the tubular structure 30 with a predetermined interval in the axial direction, and are fixed to the tubular structure 30. The plurality of annular structures 15 may be arranged so as to overlap the inside of the tubular structure 30.

The tubular structure 30 can be formed by braiding using a plurality of wires 311 in the same manner as the annular structure 15, and includes methods such as cutting, injection molding, laser processing, and lamination molding using a 3D printer. You may produce by. Moreover, as a raw material of the tubular structure 30, a metal material such as stainless steel or titanium excellent in biocompatibility may be used in addition to the plastic materials such as polyester and polylactic acid mentioned above.
As shown in FIG. 13, in the tubular structure 30, a portion that overlaps the annular structure 15 is a first tubular structure portion 32, and a portion that does not overlap is a second tubular structure portion 33.

An example of a method for fixing the annular structure 15 to the tubular structure 30 will be described with reference to FIG.
As shown in FIG. 14, the thin wire 411 is wound and fixed so as to be looped at a portion where the crossing portions of the wire rods of the annular structure 15 and the first tubular structure portion 32 overlap each other. In addition, the portions where the intersecting portions of the wires overlap each other may be joined by ultrasonic welding or an adhesive. Moreover, in 4th Embodiment, although the case where the knitting pitch P in the cyclic structure 15 and the tubular structure 30 became the same was shown, when the knitting pitch P differs, the crossing parts of the wire arrange | positioned in the vicinity are mutually. Fix it with.

In the fourth embodiment, the first structure 101F is constituted by the annular structure 15 and the first tubular structure portion 32, and the second structure 201F is constituted by the second tubular structure portion 33. Since the tubular structure 30 has a length corresponding to the entire axial length of the tubular reinforcement body 20F, when the tubular artificial organ returns to its original shape by receiving an external force that bends, it is compared with the configuration of the fourth embodiment. Thus, the first structural body 101F can return to its original shape without being displaced from the axial center of the tubular reinforcing body 20F.

According to the tubular reinforcing body 20F according to the fourth embodiment, in addition to the effects (6) to (9) described above, the following effects can be obtained.
(10) The tubular reinforcement body 20F has a predetermined length in the axial direction, and corresponds to the total length of the plurality of annular structures 15 formed by braiding using the plurality of wires 111, and the tubular reinforcement body 20F. A tubular structure 30 having a length and formed by braiding using a plurality of wires 311, and the plurality of annular structures 15 are tubular structures with predetermined intervals in the axial direction. The first tubular structure portion is arranged so as to overlap the outer side or the inner side of 30 and fixed to the tubular structure 30, and the first structure 101 F is formed by overlapping the plurality of annular structures 15 and the tubular structure 30. 32, and the second structure 201 F is configured by the second tubular structure portion 33 that does not overlap the plurality of annular structures 15 in the tubular structure 30. Thereby, since the tubular structure 30 has a length corresponding to the entire axial length of the tubular reinforcing body 20F, when the tubular artificial organ returns to its original shape by receiving an external force that causes the tubular artificial organ to bend, the tubular structure 30 of FIG. Compared to the configuration, the first structural body 101F can return to the original shape without being displaced from the axial center of the tubular reinforcing body 20F.

Next, an example in which the configuration of the tubular reinforcement body according to the third and fourth embodiments of the present invention is applied will be described in detail.

(Configuration of tubular reinforcement)
With reference to FIGS. 15 to 17, the configurations of the tubular reinforcing bodies of Examples 1 to 3 will be described.
<Example 3>
A tubular reinforcing body 20D was produced as an example corresponding to the tubular reinforcing body 20D shown in FIG. 11B described in the third embodiment.
Using a monofilament (hereinafter referred to as PLA fiber) formed by spinning and drawing poly L-lactic acid (weight average molecular weight 450,000, melting point 195 ° C.) as a wire, a tube as shown in the schematic diagram of FIG. A tubular reinforcing body 20D of Example 3 having a cylindrical shape with a diameter of 15 mm and a length of 40 mm was produced. The diameter of the wire 111 in the first structure 101 is 0.5 mm, and the diameter of the wire 211 in the second structure 201D is 0.2 mm. The number of wire rods knitted in a spiral shape (number of knitting) is 16 in total, 8 each for right-handed and left-handed. The total number (number of stages) of lattices formed in one row in the axial direction is preferably about 6 to 10 in total for the first structural body 101, and in Example 3, it was set to 8.
The tubular reinforcing body 20D of the third embodiment is formed by joining a wire rod having a diameter of 0.5 mm and a wire rod having a diameter of 0.2 mm, and second structures 201D are provided at three locations. The length of each second structure 201D is preferably about 1 to 2 mm.
When the tubular reinforcing body 20D of Example 3 produced in this way was bent, it had sufficient flexibility.

<Example 4>
A tubular reinforcing body 20C was produced as an example corresponding to the structure of the tubular reinforcing body 20C shown in FIG. 11A described in the third embodiment.
As a wire rod, a PLA fiber with a diameter of 0.5 mm is used, and there are a total of 16 right-handed and left-handed eight each, a tube diameter of 15 mm, a length of 8 mm, and a number of grids (number of stages) of 2 Four structural bodies were produced, and the annular structural bodies 15 were joined and joined by ultrasonic welding with the wire material 211 having the same diameter and the same material to produce a tubular reinforcing body 20C as shown in FIG. All the intersecting portions of the wire 111 constituting the annular structure 15 in Example 4 were fixed. In this way, a tubular reinforcing body having an axial length of 36 mm was obtained.
When the tubular reinforcing body 20C of Example 4 produced in this way was bent, it had sufficient flexibility.

<Example 5>
A tubular reinforcing body 20F was produced as an example corresponding to the structure of the tubular reinforcing body 20F shown in FIG. 13 described in the fourth embodiment.
As a wire rod, a PLA fiber having a diameter of 0.5 mm is used. The right-handed and left-handed eight are each 16 in total, the tube diameter is 16 mm, the length is 10 mm, and the number of lattices (stages) is 2 Four structures 15 were produced. Further, one tubular structure 30 having a tube diameter of 15 mm and a length of 37.5 mm was produced using a PLA fiber having a diameter of 0.2 mm. All the intersecting portions of the wires constituting the annular structure 15 and the tubular structure 30 were fixed. As shown in FIG. 17, the annular structure 15 is fixed on the tubular structure 30 with a space of 1.25 mm. In the fixing method, a thin wire rod 411 of a PLA fiber having a diameter of 0.2 mm is inserted in the circumferential direction, and around the point where the crossing portions of the wire rods of the annular structure 15 and the tubular structure 30 overlap each other. The aforementioned thin wire 411 was wound and fixed so as to loop (see FIG. 14). As a result, a tubular reinforcing body having a total length of 37.5 mm was obtained.
When the tubular reinforcing body 20F of Example 5 produced in this way was bent, it had sufficient flexibility.

(Measurement of strength)
The results of measuring the lumen holding force and compressive strength of the tubular reinforcing body 20F of Example 5 will be described in detail.

The physical properties of the tubular reinforcing body 20F were evaluated by “lumen retention force” that is an index of strength in the radial direction and “Young's modulus (compression elastic modulus)” that is an index of compressive strength in the axial direction. A compression tester (Autograph AG-X Plus, manufactured by Shimadzu Corporation) was used to measure these physical properties.
As shown in FIG. 18A, the lumen holding force is measured by placing the tubular reinforcing body 20F on a jig J (adjusted to the length of the tubular reinforcing body 20F) that restricts the movement in the axial direction. The body 20F was pressed from above with a pusher PL until the outer diameter became 25%, and the compressive strength was measured. The lumen retention force [N · mm] is obtained by compressive strength [N] × (diameter of tubular reinforcing body) ² [mm ² ] / axial length [mm] of the tubular reinforcing body 20F.
Further, as shown in FIG. 18 (b), the axial Young's modulus is determined by pressing the tubular reinforcement body 20F vertically from the top until the length reaches a predetermined value (for example, 80% to 90%). It calculated by pressing with PL and measuring compressive strength. The maximum spring constant [N / mm] was determined from the slope of the obtained stress-strain curve in the strain range of 0% to 20%. The Young's modulus E (MPa) is obtained by E = spring constant [N / mm] × initial length [mm] / cross-sectional area [mm ² ] of the tubular reinforcement.

The measurement results of lumen holding force for the trachea of the beagle dog and the tubular reinforcing body 20F of Example 5 are shown in Table 2, and the measurement result of the compressive strength in the axial direction is shown in FIG. In addition, about the compressive strength of the axial direction, the two tubular reinforcement bodies 20F were produced on the conditions demonstrated in Example 5, and were measured.

As shown in Table 2, the lumen retention force of the trachea of the beagle dog was 6.13 [N · mm], whereas the tubular reinforcing body 20F of Example 5 was 6.00 [N · mm]. It was confirmed that it has the same lumen retention force. Therefore, it is considered that the tubular reinforcing body of the present invention has sufficient radial strength to hold the lumen.

As a result of measuring the axial Young's modulus from the inclination of the compressive strength in the axial direction in the graph shown in FIG. 19, the Young's modulus in the axial direction of the trachea of a beagle dog is 0.375 [N in a low strain region up to 10% compression. / Mm] and 3.5 [N / mm] in the high strain region of 10% or more compression. The elasticity changes in the middle of this. First, the soft part (ligament) of the trachea is compressed in the low strain region, and then the hard part (cartilage) of the trachea is compressed and the Young's modulus increases in the high strain region. it is conceivable that.
On the other hand, as a result of measuring the two tubular reinforcing materials of Example 5 in the same manner, the average was 0.28 [N / mm] in the low strain region, and 3.9 [N / mm] in the high strain region. Compared with the results of the trachea of the beagle dog, the values were close to each other. Similar to the trachea of the beagle dog, a behavior in which the Young's modulus changed in a region where the strain was 10% or more was observed. Therefore, it is considered that the tubular reinforcing body of the present invention has the same flexibility as the beagle's trachea in the axial direction.
Thus, according to this embodiment, when the tubular reinforcing body 20C (20D, 20E, 20F) is compressed in the axial direction, the compressive strength can be changed in the low strain region and the high strain region. Thereby, the axial compression characteristic of the tubular reinforcing body 20C (20D, 20E, 20F) can be approximated to the compression characteristic of the trachea.

The preferred embodiments and examples of the tubular reinforcing body of the present invention have been described above, but the present invention is not limited to the above-described embodiments and examples, and can be modified as appropriate.
In the above-described embodiments, the case where the present invention is applied to the trachea as an example of a tubular artificial organ has been described. It may be applied to organs.
In each of the above-described embodiments and examples, the example in which the intersecting portions of the wire members constituting the first structure and the second structure are joined is shown. You don't have to.
In the first embodiment described above, the wire constituting the second structural body is shorter than the total length in the axial direction of the tubular reinforcement body. However, it is about the same as the total length in the axial direction of the tubular reinforcement body. It is good also as a structure which connects a 1st structure body with the 1 or several wire which has the length of.

DESCRIPTION OF SYMBOLS 1A, 1B Tubular artificial organ 10 Tubular structure |

tissue

20A, 20B Tubular reinforcement 21 Biodegradable wire 100 Mold 110 Core rod 120 Cylinder 121 Body part 122 Cover part 123 Slit J Jig P P Knitting

pitch PL Presser

20C, 20D, 20E , 20F Tubular reinforcement 15 Ring structure 101,

101D First structure

201, 201C, 201D, 201E, 201F Second structure 30 Tubular structure J Jig P P Knitting pitch PL Pusher

Claims

A tubular tissue body formed in an environment in which a biological tissue material exists and composed of fibrous tissue;
A tubular prosthesis comprising a tubular reinforcement body made of a biodegradable material and enclosed in the tubular tissue body.
The tubular artificial organ according to claim 1, wherein the tubular tissue body is formed into a tubular shape by implanting a template in a living body, and the tubular reinforcing body is included over the entire length.
The tubular artificial organ according to claim 1 or 2, wherein a lumen holding force in a circumferential direction of the tubular artificial organ is 2.0 [N · mm] or more.
The tubular artificial organ according to any one of claims 1 to 3, wherein the tubular reinforcing body is configured in a mesh shape with a biodegradable material.
The tubular artificial organ according to any one of claims 1 to 4, wherein the tubular reinforcing body is restricted from contraction in an axial direction.
The tubular reinforcement is formed by braiding using a plurality of biodegradable wires,
The tubular artificial organ according to claim 5, wherein contraction in the axial direction is regulated by joining crossing portions of the biodegradable wires.
6. The tubular artificial organ according to claim 5, wherein the tubular reinforcement body is formed by knit knitting using a biodegradable wire rod, whereby axial contraction is restricted.
A base material for producing an artificial tubular organ by forming a connective tissue around it by being embedded in a living body,
A rod-shaped core material;
An outer cylinder having a plurality of slits and storing the core material;
A cylindrical mesh member disposed in a space between the core material and the outer cylinder,
The core material and the outer cylinder are made of a non-biodegradable material,
The mesh member is a base material for producing a tubular artificial organ composed of a biodegradable material.
A tubular reinforcing body used for producing a tubular artificial organ by forming a connective tissue around it,
A plurality of first structures having a predetermined axial compressive strength and a predetermined radial strength and configured in a tubular shape;
A second structure having an axial compressive strength less than the predetermined axial compressive strength;
With
The first structural body is a tubular reinforcing body connected via the second structural body.
Three or more first structures including two first structures disposed at one end and the other end, and two first structures disposed adjacent to each other. The tubular reinforcement body according to claim 9, further comprising two or more second structures.
The tubular reinforcing body according to claim 9 or 10, wherein the first structure is configured in a mesh shape with a wire.
The tubular reinforcing body according to any one of claims 9 to 11, wherein the second structural body is formed of a wire rod that connects the first structural bodies.
The first structure is configured in a mesh shape with a wire,
The tubular reinforcing body according to claim 12, wherein a diameter of the wire constituting the second structure is smaller than a diameter of the wire constituting the first structure.
The first structure is configured in a mesh shape with a wire,
The tubular reinforcing body according to claim 12 or 13, wherein the number of the wires constituting the second structure is smaller than the number of the wires constituting the first structure.
The tubular reinforcing body according to claim 9 or 10, wherein a cross-sectional area of the second structure is smaller than a cross-sectional area of the first structure.
The tubular reinforcement is
A plurality of annular structures having a predetermined length in the axial direction and configured in a mesh shape with a wire;
A tubular structure having a length corresponding to the entire length of the tubular reinforcing body in the axial direction and configured in a mesh shape with a wire;
The plurality of annular structures are arranged so as to overlap the outer side or the inner side of the tubular structure with a predetermined interval in the axial direction, and are fixed to the tubular structure,
The first structure is constituted by a portion where the plurality of annular structures and the tubular structure are overlapped,
The tubular reinforcing body according to any one of claims 9 to 14, wherein the second structure is configured by a portion of the tubular structure that does not overlap the plurality of annular structures.
A tubular tissue body formed in an environment in which a biological tissue material exists and composed of fibrous tissue;
A tubular artificial organ comprising: the tubular reinforcing body according to any one of claims 9 to 16 enclosed in the tubular tissue body.
The tubular artificial organ according to claim 17, wherein the tubular tissue body is formed into a tubular shape by implanting a template in a living body, and the tubular reinforcing body is included over the entire length.