JP2016136984A - Tubular tissue body forming substrate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tubular tissue body forming substrate that is capable of forming a tubular connective tissue body with a reinforced end without providing foreign matter.SOLUTION: A rod-like substrate body 3 is provided. An end reinforcement substrate 5 is provided. The end reinforcement substrate 5 is radially opposed to an outer circumferential surface of the end of the substrate body 3. A tissue forming space is constituted between the outer circumferential surface of the end of the substrate body 3 and the end reinforcement substrate 4. A tubular tissue body forming substrate 1 is installed in the existing environment of a bio-tissue material, and a tubular connective tissue body is formed on the substrate surface. An interval between the outer circumferential surface of the substrate body 3 and the end reinforcement base material 5 is properly set, and the end of the tubular tissue body is formed in a desired thickness. The end of the tubular tissue body is formed from the inside and outside, and the connective tissue is formed in uniform density. The end of the tubular tissue body is formed thick and in the uniform density, and thereby is reinforced.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a tubular tissue-forming base material that is installed in an environment in which a biological tissue material exists to form a tubular connective tissue body on the surface of the base material.

  There have been many studies on regenerative medicine in which cells, tissues, and organs lost due to illness and accidents are revived by artificial materials and cells.

  Normally, the body has a self-defense function, and when a foreign object such as a thorn enters a shallow position in the body, it tries to push it out of the body. In addition, when a foreign object enters a deep position in the body, fibroblasts gradually gather around it to form a connective tissue capsule mainly composed of fibroblasts and collagen to cover the foreign object It is known to isolate foreign substances in the body. As a technique for forming a living body-derived tissue from living cells using the latter self-defense reaction, a plurality of techniques for forming a connective tissue body by embedding a base material as a foreign substance in the living body have been reported (patent) References 1-3).

  Furthermore, Patent Document 4 is composed of a tissue that is formed so as to cover an artificial object embedded in a living body, and is provided with a sponge-like cylindrical shape-retaining member at both ends thereof so that it can be kept in a cylindrical shape, and can easily be a blood vessel. An artificial blood vessel that can be sutured to the skin is disclosed.

JP 2007-312821 A JP 2008-237896 A JP 2010-094476 A JP 2006-141681 A (paragraph 0017)

  However, the artificial blood vessel described in Patent Document 4 is not only formed of a living tissue, but also provided with a shape-retaining member that is a foreign substance at both ends thereof. It is more desirable to reinforce the stitched end.

  An object of the present invention is to provide a tubular tissue body-forming substrate capable of forming a tubular connective tissue body with reinforced ends without providing foreign matter.

  In order to achieve the above object, the tubular tissue body-forming substrate according to the present invention is capable of forming a tubular connective tissue body on the surface of a substrate by being installed in an environment where a biological tissue material is present. A base body and an end reinforcing base capable of reinforcing the end of the connective tissue body, and the end reinforcing base and the outer peripheral surface of the end of the base body and the radial direction across the tissue formation space It is the one that faced.

  According to the above configuration, since the end reinforcing base is opposed to the outer peripheral surface of the end of the base body in the radial direction across the tissue forming space, the end of the tubular tissue body is appropriately set. Can be formed to a desired thickness.

  In addition, since the end of the tubular tissue body is formed between the base body and the end reinforcing base material, the end of the tubular tissue body is formed from the inside and outside, and the connective tissue is formed with a thick and uniform density. can do. That is, when the connective tissue is simply formed only from the inside by the base body, the distance from the outer surface of the connective tissue to the base material surface becomes long, so that it is difficult to form a thick connective tissue and the density tends to be uneven. On the other hand, by forming the connective tissue from inside and outside, it is possible to shorten the distance to the part farthest from the surface of the base material and form a thick and uniform connective tissue.

  Accordingly, the connective tissue constituting the end portion of the tubular tissue body can be strengthened without providing a foreign body such as an artificial object in the tubular tissue body, and a tubular tissue body that can be easily sutured to a transplant site is formed. Can do.

  Here, the “connective tissue” usually refers to a tissue mainly composed of collagen and formed in a living body. In the description of the present specification and claims, This is a concept including a tissue corresponding to a connective tissue formed in a living body when the tissue is formed in an environment outside the living body.

  The “biological tissue material” is a substance necessary for forming a desired biological tissue, such as fibroblasts, smooth muscle cells, endothelial cells, stem cells, ES cells, iPS cells, etc. Examples include animal cells, various proteins (collagen, elastin), saccharides such as hyaluronic acid, and other physiologically active substances existing in the body such as cell growth factors and cytokines. 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 “environment where biological tissue material exists” refers to the living body (for example, limbs, shoulders) Or an artificial environment containing a biological tissue material outside the living body of an animal).

  Furthermore, the end portion reinforcing base material may be formed integrally with the base body body, but may be formed separately from the base body body and attached to the end portion of the base body body.

  That is, the present invention is an end reinforcing base material capable of reinforcing the end of a tubular connective tissue body formed on the outer peripheral surface of a rod-shaped base body body installed in an environment where a biological tissue material exists, By attaching to the end portion of the material main body, an end reinforcing base material for a tubular tissue body is provided that is opposed to the outer peripheral surface of the end portion of the base material main body in the radial direction across the tissue forming space.

  According to this configuration, the tubular tissue-forming substrate can be configured by mounting the end portion reinforcing substrate on the end of the substrate body. As a result, a tubular tissue body-forming substrate having a desired length can be configured simply by setting the substrate body to which the end portion reinforcing substrate is mounted to a desired length, and the tubular tissue having various lengths. About a body formation base material, the end part reinforcement base material can be made common and manufacture as the whole tubular structure body formation base material can be made easy.

  Furthermore, you may make it form the intrusion port which connects a structure | tissue formation space and the base-material exterior to a radial direction in an edge part reinforcement base material.

  According to this configuration, since the tissue formation space and the outside of the base material are communicated in the radial direction by the intrusion opening, only the gap between the end of the end portion reinforcing base material and the base material body, that is, the end opening of the tissue formation space. Instead, in addition to the opening at the end of the tissue formation space, the connective tissue can be invaded from the intrusion port or only from the intrusion port. Thereby, the time required to form the connective tissue body in the tissue formation space can be shortened.

  Furthermore, the entrance may be a slit parallel to the central axis of the base body.

  According to this configuration, the connective tissue formed in the slit functions as a reinforcing portion that reinforces the end of the tubular tissue body by forming a protrusion that protrudes from the end of the tubular tissue body to the outer peripheral side. The protrusions are formed parallel to the central axis of the tubular tissue body to prevent twisting of the tubular tissue body due to the force acting on the protrusions.

  In the description of the present specification and claims, the slit means a slit having a slit length larger than twice the slit width, and more preferably a slit length larger than three times the slit width. The slit is set to a slit width that allows the connective tissue to easily enter, and is set to a slit length that is twice or more, preferably three times or more. The upper limit of the slit length is determined by the strength.

  The slit is long enough compared to the slit width, so the slit width is set narrow, and the remaining part of the end reinforcement base is secured, and the bond formed at the peripheral edge It is possible to prevent the slit from being closed early by the tissue, and the connective tissue can easily enter the tissue forming space.

  In other words, instead of the slit, it is also possible to form, for example, a circular small hole in the end reinforcing base material, but in this case, the circular hole is closed from all directions by the connective tissue itself formed in the peripheral portion, There is a risk of inhibiting the invasion of connective tissue into the tissue formation space. In contrast, a slit having a sufficiently long slit length is not blocked from all directions by the connective tissue formed at the peripheral edge thereof, and can prevent the entire slit from being blocked at an early stage. .

  Furthermore, you may make it form an entrance in the shape which reaches the edge of the base-material main body center side among edge part reinforcement base materials.

  According to this configuration, since the intrusion port reaches the edge on the center side of the base material body, the connective tissue is formed without destroying the connective tissue formed in the intrusion port when removing the end reinforcing base material from the base material body. Can be removed from the edge opening of the intrusion opening, and the end reinforcing base can be removed from the base body.

  Furthermore, it is good also considering the edge part reinforcement base material in the outer end side as an outer fitting part formed in the edge part of a base-material main body, and making it a cap shape which can be attached or detached to the edge part of a base-material main body.

  According to this configuration, the end reinforcing base can be easily attached to and detached from the base body simply by externally fitting the outer fitting part to the end of the base body, and the tubular tissue body is attached to the base surface. After the formation, the end reinforcing base can be removed from the base body to facilitate the removal of the tubular tissue body.

  In addition, the present invention provides a tubular tissue body in which the end portion is reinforced to facilitate sutures to a transplant site. That is, the present invention is a tubular connective tissue body formed on the outer peripheral surface of a base material installed in an environment where a biological tissue material exists, and the end connective tissue is strengthened more than the central portion. A featured tubular tissue is provided.

  Since the tubular tissue body of the present invention reinforces the end portion that is sutured to the transplant site, it can be suitably used as an artificial blood vessel that receives a relatively high internal pressure.

  In addition, as long as the tubular tissue body of this invention is a tubular tissue body, you may use for anything, such as a digestive tract and a trachea besides a blood vessel. In addition, the tubular tissue body of the present invention may be any of autotransplantation, allotransplantation, and xenotransplantation for the transplant recipient, but autotransplantation or allotransplantation is preferable from the viewpoint of avoiding rejection. Furthermore, in the case of xenotransplantation, it is preferable to perform an immunogen removal treatment such as a known decellularization treatment in order to avoid rejection.

  As described above, according to the present invention, the end reinforcing base material is provided so as to face the outer peripheral surface of the end portion of the rod-shaped base material body in the radial direction across the tissue forming space. While forming to a desired thickness, the connective tissue can be formed to a uniform density. Accordingly, the end of the tubular connective tissue body can be reinforced while forming a tubular connective tissue body without providing a foreign object such as an artificial object, and the tubular tissue body can be easily sutured to the transplant site.

The perspective view of the edge part of the tubular structure | tissue formation base material which concerns on this invention Perspective view of end of tubular tissue body The figure which shows a mode that a tubular tissue body is formed A figure showing how an artificial blood vessel is transplanted

  Hereinafter, the form for implementing the tubular structure | tissue formation base material which concerns on this invention is demonstrated using drawing.

  As shown in FIG. 1, a tubular tissue body-forming substrate 1 is installed in an environment in which a biological tissue material exists, and forms a tubular tissue body 2 that is a tubular connective tissue body on the surface of the substrate. A rod-shaped base body 3 and an end reinforcing base 5 for reinforcing the end 4 of the tubular tissue body 2, and the end reinforcing base 5 is formed on the basis of the tissue forming space 6. This is opposed to the outer peripheral surface of the end of the material body 3 in the radial direction.

  The base body 3 is shaped like a rod having a circular cross section made of, for example, a silicone resin, and is placed in an environment where a biological tissue material exists, and the connective tissue 7 is formed on the outer peripheral surface, thereby forming the tubular tissue body 2. It has become.

  The end portion reinforcing base material 5 is, for example, a cap made of acrylic resin, and has a tapered shape and a ring shape that can be externally fitted to the end portion of the base material body 3 on the outer end side of the tubular portion 8 that forms a tubular shape as a whole. It is set as the structure which formed the external fitting part 9, and can be attached or detached to the edge part of the base-material main body 3. FIG. By attaching the end portion reinforcing base material 5 to the end portion of the base body 3, the cylindrical portion 8 faces the outer peripheral surface of the end portion of the base body 3 in the radial direction with the tissue forming space 6 interposed therebetween.

  The cylindrical portion 8 is formed with a slit 10 having a shape that is parallel to the central axis of the substrate body 3 and reaches the edge of the substrate body center side. The slit 10 connects the tissue forming space 6 and the outside of the substrate. It communicates in the radial direction and functions as an entry port for allowing the connective tissue 7 to enter the tissue formation space 6.

  In addition, the material of the tubular tissue body forming substrate 1 has a strength (hardness) that does not greatly deform when implanted in a living body, has chemical stability, and is resistant to a load such as sterilization. There are preferable resins that have no or little eluate stimulating the living body, and examples thereof include, but are not limited to, silicone resins and acrylic resins as described above.

  As shown in FIG. 2, the tubular tissue body 2 produced using the tubular tissue body-forming substrate 1 is used as, for example, an artificial blood vessel, and the end 4 that is sutured to the transplant site is In addition to being thicker than the central portion, the plurality of protrusions 11 are formed in parallel to the central axis, and are strengthened more than the central portion.

  Next, a method for producing the tubular tissue body 2 using the tubular tissue body-forming substrate 1 as described above will be described.

  As shown in FIG. 3, this production method includes an “installation step” in which the tubular tissue body-forming substrate 1 is placed in an environment where biological tissue material exists, and a connective tissue 7 is disposed around the tubular tissue body-forming substrate 1. A “forming step” for injecting the connective tissue 7 into the tissue forming space 6 while forming, a “extracting step” for taking out the tubular tissue forming substrate 1 from the environment, and the connective tissue 7 from the tubular tissue forming substrate 1. It consists of a “separation step” of peeling and taking out as a tubular tissue body 2.

<Installation process>
The outer fitting part 9 is fitted on the end of the base body 3, the end reinforcing base 5 is attached to the end of the base body 3, and the cylindrical part 8 of the end reinforcing base 5 is attached to the base body. The tissue formation space 6 is configured between the outer peripheral surface of the base body 3 and the cylindrical portion 8 so as to face the outer peripheral surface of the end portion 3 in the radial direction (FIG. 3A).

  Next, the tubular tissue body-forming substrate 1 is placed in an environment where the biological tissue material exists. Examples of the environment in which the biological tissue material is present include the inside of an animal's living body (for example, implantation in the skin or the abdominal cavity) or an artificial environment such as a solution in which the biological tissue material floats outside the animal's body. As biological tissue materials, materials derived from other mammals such as humans, dogs, cows, pigs, goats, rabbits, sheep, birds, fish, other animals, or artificial materials can also be used.

  When the tubular tissue body-forming substrate 1 is implanted in an animal, it is performed with a minimum of incision under sufficient anesthesia, and the wound is sutured after implantation. As an implantation site | part of the tubular tissue body formation base material 1, for example, the abdominal cavity which has the volume which receives the tubular tissue body formation base material 1, or subcutaneous, such as an extremity part, a shoulder part or a back part, an abdominal part, is preferable. In addition, it is preferable that the implantation is performed by a minimally invasive method and the spirit of animal welfare is respected, and is performed with a minimum of incision under sufficient anesthesia.

  In addition, when the tubular tissue body-forming substrate 1 is placed in an environment in which a biological tissue material is present, cell culture may be performed according to a known method in a clean environment with various culture conditions.

<Formation process>
After a predetermined time has elapsed after the installation step, connective tissue 7 is formed around the tubular tissue body-forming substrate 1, and connective tissue 7 enters the tissue formation space 6 from the slit 10 and the end opening 12. Then, the connective tissue 7 is formed on the substrate surface (FIG. 3B). In this formation step, the connective tissue 7 is formed in the tissue formation space 6 in a relatively short time by the amount of the connective tissue 7 entering from the slit 10 having a sufficient area. The connective tissue 7 is composed of an extracellular matrix such as fibroblasts and collagen.

<Removal process>
After the connective tissue 7 is sufficiently formed on the surface of the base material through a formation process for a predetermined time, an extraction step of taking out the tubular tissue body-forming base material 1 from the environment where the biological tissue material exists is performed.

<Separation process>
The connective tissue 7 formed on the outer surface is removed from the end portion reinforcing base material 5 of the tubular tissue-forming base material 1 that has undergone the extraction step (FIG. 3C), and the end portion from the end portion of the base body 3 is removed. The reinforcing base material 5 is extracted. At this time, since the slit 10 has a shape that is parallel to the central axis of the substrate body 3 and reaches the edge of the substrate body center side, the connective tissue 7 as the protrusion 11 formed inside the slit 10 is destroyed. Without doing so, the end portion reinforcing base material 5 can be extracted.

  Thereafter, the connective tissue 7 is peeled off from the outer peripheral surface of the base body 3 to obtain the tubular tissue body 2 in which the end 4 is thickened and a plurality of protrusions 11 are formed on the end 4. (FIG. 3D).

  In addition, when the produced tubular connective tissue 2 is transplanted xenogeneically, it is preferable to perform an immunogen removal process such as a decellularization process, a dehydration process, and a fixing process in order to prevent rejection after transplantation. Examples of decellularization include ultrasonic treatment, surfactant treatment, and enzyme treatment such as collagenase to elute and wash the extracellular matrix. Dehydration methods include methanol, ethanol, isopropyl alcohol, etc. There is a method of washing with a water-soluble organic solvent, and as a method of fixing, there is a method of treating with an aldehyde compound such as glutaraldehyde or formaldehyde.

  According to the above configuration, the cap-shaped end reinforcing base 5 is attached to the end of the base body 3, and the tissue forming space 6 is configured between the end outer peripheral surface of the base body 3 and the cylindrical portion 8. doing. Accordingly, the connective tissue 7 constituting the end portion 4 of the tubular tissue body 2 can be formed from the inside and outside thereof, and can be set to a thick and uniform density. Part 4 can be strengthened.

  Here, as an example, characteristics such as strength of the tubular tissue body 2 formed by embedding the tubular tissue body forming substrate 1 under the skin of a beagle dog will be described.

  The cross-sectional dimensions of the used tubular tissue-forming substrate 1 are as follows: the outer diameter of the substrate body 3 is 5 mm, the inner diameter of the cylindrical portion 8 of the end portion reinforcing substrate 5 is 7 mm, and the thickness of the tissue-forming space 6 is 1 mm. is there. The tubular tissue body-forming substrate 1 was placed under the skin of a beagle dog. After 5 weeks, the tubular tissue body-forming substrate 1 was taken out to obtain a tubular tissue body 2. Furthermore, the tubular tissue body 2 was cut in the length direction to form a sheet, which was cut into a length of 10 mm, and each characteristic was measured.

  When the cross-sectional dimension of the tubular tissue body 2 was measured, the inner diameter was 5 mm which is the same as the outer diameter of the base body 3 over the entire length, and the thickness was 100 to 200 μm at the central portion and 400 to 400 at the end portion 4. It was 600 μm.

  Further, when the elastic modulus and the breaking load were measured, the elastic modulus was 2092 ± 597 kPa at the center and 4695 ± 721 kPa at the end 4, and the breaking load was 335.4 ± 98.7 g at the center. 4 was 762.2 ± 271.6 g. Note that the number of samples is three for each of the central portion and the end portion 4.

  In this way, by using the tubular tissue-forming base material 1 and attaching the cap-shaped end portion reinforcing base material 5 to the end portion of the base material body 3, the thickness of the end portion 4 of the tubular tissue body 2 is reduced. While increasing the thickness, the elastic modulus and breaking load of the end portion 4 could be doubled or more than in the central portion, and the end portion 4 of the tubular tissue body 2 could be strengthened.

  In addition, this invention is not limited to said embodiment, A change can be suitably added within the scope of the present invention. For example, instead of forming a tubular tissue body 2 by providing a “removal step” for taking out the tubular tissue body forming substrate 1 from the environment, as shown in FIG. Alternatively, it may be formed directly.

  Specifically, first, the tubular tissue body forming substrate 1 is embedded in the body of the patient near the damaged site 14 of the blood vessel 13 (FIG. 4A). This state is maintained until a predetermined period elapses, and after the connective tissue is formed on the surface of the base material, the tubular tissue body forming base material 1 is taken out from the patient's body while peeling the connective tissue, thereby A tubular tissue body 2 as an artificial blood vessel having an enhanced end 4 is formed near the damaged site 14 (FIG. 4B). Of the tubular tissue body 2 formed in the patient's body, only the end 4 is moved without moving the central part, and the blood vessel 13 is sutured across the damaged part 14 and the damaged part 14 is removed. As a result, the artificial blood vessel is transplanted into the blood vessel 13 (FIG. 4C).

DESCRIPTION OF SYMBOLS 1 Tubular structure | tissue formation base material 2 Tubular structure | tissue 3 Base material body 4 End part 5 End part reinforcement base material 6 Tissue formation space 7 Connective tissue 8 Tube part 9 Outer fitting part 10 Slit 11 Projection 12 End part opening 13 Blood vessel 14 Damaged part

Claims (8)

  A base material that can be installed in an environment where biological tissue material exists to form a tubular connective tissue body on the surface of the base material, and is a rod-shaped base body body and an end portion capable of reinforcing the end of the connective tissue body A tubular tissue-forming base material, comprising: a reinforcing base material, wherein the end reinforcing base material faces the outer peripheral surface of the end portion of the base material body in the radial direction across the tissue forming space.   An end-reinforcing base material capable of reinforcing an end of a tubular connective tissue formed on an outer peripheral surface of a rod-shaped base body installed in an environment in which a biological tissue material exists, the end of the base body An end-reinforcing base material for a tubular tissue body, wherein the end-reinforcing base material for a tubular tissue body is opposed to the outer peripheral surface of the end portion of the base body main body in a radial direction across the tissue forming space.   The end reinforcing base material according to claim 2, wherein an intrusion opening for communicating the tissue forming space and the outside of the base material in a radial direction is formed.   The end reinforcing base material according to claim 3, wherein the intrusion opening is a slit parallel to the central axis of the base body.   5. The end reinforcing base material according to claim 3, wherein the intrusion port is formed in a shape reaching an end edge of the end portion reinforcing base material on the center side of the base body main body.   The outer end portion is formed with an outer fitting portion that is fitted to the end portion of the base body, and the cap portion is detachable from the end portion of the base body. The edge part reinforcement base material in any one.   A tubular connective tissue formed on the outer peripheral surface of a base material placed in an environment where a biological tissue material exists, wherein the connective tissue at the end is strengthened more than the central portion. .   The tubular tissue body according to claim 7, wherein the tubular tissue body is used as an artificial blood vessel.

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