Linear tissue structure, device for forming tissue structure, and method for forming tissue structure

Abstract

The present disclosure addresses the problem of providing a linear tissue structure, a device for forming tissue structure and a method for forming tissue structure that enable smooth handling. A linear tissue structure (20) includes: a first outer surface (26B) which is an uneven surface extending in an extension direction of the linear tissue structure (20); and a flat second outer surface (20S) which extends in the extension direction of the linear tissue structure (20) and which is connected to the first outer surface (26B) via a ridge line. A recess (21A) sandwiched between protrusions (21T) adjacent to each other on the first outer surface (26B) has a mesh shape.

Description

Linear tissue structure, tissue structure forming device, and tissue structure forming method

[0001] The present disclosure relates to a linear tissue structure, a tissue structure forming device that is placed in an environment including a biological tissue to form the linear tissue structure, and a tissue structure forming method.

[0002] The self-defense function of a living body accumulates macrophages and the like around a foreign object that has invaded the living body. Macrophages adsorb to the surface of the foreign object and promote the production of collagen by fibroblasts through the production of TGF-β by monocytes. A foreign object that has invaded the living body is covered with connective tissue containing fibroblasts and collagen and is isolated in the living body.

[0003] One of the regenerative medical technologies for reviving lost tissues and organs is to replace a damaged linear tissue structure with a living body-derived linear tissue structure. One of the technologies for forming a living body-derived linear tissue structure is to place a tissue structure forming device, which is a foreign object, in a biological tissue and then utilize the self-defense function of the biological tissue to form a living body-derived linear tissue structure on the tissue structure forming device (see, for example, Patent Documents 1 and 2).

[0004] Examples of such tissue structure forming devices include two connective tissue forming surfaces facing each other. The two connective tissue forming surfaces delimit a hollow portion having various shapes such as a flat space, a cylindrical space, a valve-shaped space, etc. Cells such as fibroblasts that enter between the two connective tissue forming surfaces form a connective tissue body as a linear tissue structure so as to fill the space (see, for example, Patent Documents 3 to 7).

[0005] In regenerative medical technology for regenerating or repairing a target tissue, stem cells are important materials. On the other hand, embryonic stem cells that require ethical consideration and induced pluripotent stem cells that require the establishment of safety still do not have a firmly established basis for use in regenerative medical technology. On the other hand, although the number of pluripotent stem cells present in a living body is small, they have progressed from the development stage to the clinical stage. One of the technologies for accumulating pluripotent stem cells present in a living body is to place a tissue structure forming device, which is a foreign object, in a biological tissue and then accumulate the pluripotent stem cells in the biological tissue in the tissue structure forming device.

[0006] Examples of such tissue structure formation devices involve accumulating pluripotent stem cells within the hollow portion of the device. The tissue structure formation device comprises a frame surrounding the hollow portion. The frame divides an opening extending in the direction of the columnar members by two columnar members. The hollow portion enclosed by the frame communicates with the biological environment through the opening. The width of the opening and the depth of the hollow portion cause fibroblasts to fill the hollow portion with fibrous connective tissue, forming a recess in the fibrous connective tissue opposite the opening. Furthermore, the width of the opening and the depth of the hollow portion create a depression in the fibrous connective tissue opposite the opening, extending from the opening to the hollow portion. Pluripotent stem cells present in the living body accumulate in this depression. In this way, examples of tissue structure formation devices form a linear tissue structure in the hollow portion by accumulating pluripotent stem cells in the depression of the connective tissue (see, for example, Patent Document 8).

[0007] Japanese Unexamined Patent Publication No. 2004-261260 Japanese Unexamined Patent Publication No. 2007-312821 Japanese Unexamined Patent Publication No. 2014-030598 Japanese Unexamined Patent Publication No. 2017-169778 Japanese Unexamined Patent Publication No. 2021-129834 Japanese Unexamined Patent Publication No. 2021-13480 Japanese Patent Publication No. 6978142 Japanese Patent Publication No. 6813923

[0008] Regenerative medicine technologies using tissue structure formation devices are progressing from the development stage to the clinical stage. In the clinical stage, where large-scale trials are conducted to prove efficacy and safety, there is a strong desire for smoother handling of linear tissue structures.

[0009] The linear tissue structure for solving the above problems is a linear tissue structure formed in a tissue structure forming device. The tissue structure forming device is placed in an environment containing biological tissue, and cells entering the hollow part of the tissue structure forming device from the environment form the linear tissue structure in the hollow part. The hollow part is divided by a linear region having a mesh in each of two thin plate sections having a flat plate shape opposite to each other, and a partitioning member sandwiched between the thin plate sections, having a shape that borders the linear region when viewed from a viewpoint opposite to the thin plate sections. The linear tissue structure has a first outer surface extending in the direction of extension of the linear region and having irregularities peeled off from the mesh, and a second flat outer surface connected to the first outer surface and peeled off from the surface of the partitioning member.

[0010] According to the linear structure described above, the corner of the columnar linear structure is composed of a first outer surface which is an uneven surface and a second outer surface which is a flat surface. The corner, composed of two outer surfaces with different surface structures, assists in visually confirming the orientation of the linear structure. As a result, twisting and excessive bending in the linear structure can be easily identified and corrected, thus facilitating the handling of the linear structure.

[0011] In the above linear tissue structure, the linear tissue structure may be a tubular connective tissue having a polygonal cross-section. In the above linear tissue structure, the linear tissue structure may be a tubular connective tissue having circular or polygonal pores in cross-section.

[0012] A tissue structure forming apparatus for solving the above problems is a tissue structure forming apparatus that is placed in an environment containing biological tissue to form a linear tissue structure. The tissue structure forming apparatus comprises two thin plate sections having a flat plate shape, and a partitioning member sandwiched between the thin plate sections and configured to be separable from the thin plate sections. The thin plate sections have linear regions having a mesh composed of multiple through-holes, and when viewed from a viewpoint opposite to the thin plate sections, one of the linear regions overlaps with the other linear region. The partitioning member has a flat surface and, when viewed from a viewpoint opposite to the thin plate sections, has a shape that borders the linear regions. The linear regions in the two thin plate sections and the partitioning member divide the linear hollow portion for forming the linear tissue structure.

[0013] According to the above-described structure formation apparatus, a partition member having a flat surface and a linear region having a mesh form the corners of the linear structure. The corners, which reflect the flat surface and mesh, assist in visually confirming the orientation of the linear structure. As a result, twisting and excessive bending in the linear structure can be easily identified and corrected, thus facilitating smooth handling of the linear structure.

[0014] Furthermore, when a tissue structure forming device is left in the environment, the entire surface of the device is covered by external connective tissue when forming linear tissue structures in the hollow section. The external connective tissue covering the entire surface of the device is integral with the linear tissue structure through a penetration that connects the hollow section and the environment. Therefore, the removal of the linear tissue structure requires various procedures, such as removing the tissue structure forming device, peeling the external connective tissue from the device surface, and separating the linear tissue structure from the external connective tissue. In this respect, with the above-described tissue structure forming device, since the two thin plate sections are separated from the partition member, when removing the linear tissue structure, the external connective tissue formed on the device surface is also separated from the linear tissue structure in the hollow section along with the thin plate sections. Therefore, when the linear tissue structure is formed, the load required for peeling the external connective tissue and the load required for separating the linear tissue structure are reduced.

[0015] In the above-described apparatus for forming a structural framework, the thin plate portion may be configured to include a reinforcing region that does not have the through portion, and the reinforcing region may be configured to border the linear region. With this configuration, in the two thin plate portions, the reinforcing region borders the linear region, thus suppressing the reduction in mechanical strength of the thin plate portion due to the mesh.

[0016] In the above-described structure forming apparatus, the reinforcing region may have a beam structure extending from the edge of the thin plate portion to the center of the thin plate portion. A thin plate portion with a linear region is prone to bending and sagging from the edge of the thin plate portion towards the center. In this respect, a reinforcing region having a beam structure suppresses the sagging of the thin plate portion. This suppresses deformation of the thin plate portion caused by sagging before and during placement.

[0017] In the above-described apparatus for forming a microstructure, the linear region has multiple rings composed of a plurality of annular regions, and the reinforcing region bordering one annular region may be arranged to border a part of another annular region adjacent to that annular region. With this configuration, one reinforcing region borders two annular regions, thus simplifying the structure of the thin plate portion.

[0018] In the above-described structure forming apparatus, the thickness of the reinforcing region may be thicker than that of the linear region. With this structure forming apparatus, since the reinforcing region, which is thicker than the linear region, borders the linear region, the reduction in the mechanical strength of the thin plate portion itself is further suppressed. In the above-described structure forming apparatus, the thickness of the reinforcing region may be equal to that of the linear region.

[0019] In the above-described tissue structure forming apparatus, the partition member may further include a core extending linearly within the hollow portion, corresponding to the shape of the linear region. With this tissue structure forming apparatus, the above-described effects can be obtained when a tubular linear tissue structure is formed.

[0020] In the above-described apparatus for forming a microstructure, the thickness of the thin plate portion is 0.1 mm or more and 2.0 mm or less, the opening size of the through portion is 0.01 mm or more and 3.0 mm or less, and the opening occupancy rate of the through portion in the linear region may be 30% or more and 70% or less.

[0021] According to the above-described microstructure forming apparatus, when the thickness of the thin plate portion is 0.1 mm or more and 2.0 mm or less, and the opening occupancy rate is 30% or more and 70% or less, a hollow portion even more suitable for forming a linear microstructure is provided. Furthermore, if the thin plate portion has a reinforcing region, even if such a very thin thin plate portion has a linear region, the reduction in the mechanical strength of the thin plate portion is suppressed to the extent that the reinforcing region borders the linear region. In other words, the effect of the reinforcing region in suppressing the reduction in strength becomes even more pronounced.

[0022] In the above-described tissue structure forming apparatus, the distance between the two thin plate portions may be 0.5 mm or more and 5 mm or less. With this configuration, when a thin linear tissue structure is formed, the load required for peeling off the outer connective tissue and the load required for separating the linear tissue structure are reduced.

[0023] In the above-described tissue structure forming apparatus, the two thin plate portions may extend in a planar shape including one direction, and the two thin plate portions may constitute a housing member that can insert and remove the partitioning member between the thin plate portions along the one direction. With this configuration, the partitioning member can be inserted into the housing member and the partitioning member can be removed from the housing member, making the tissue structure forming apparatus required for forming linear tissue structures easy to handle.

[0024] A method for forming a tissue structure to solve the above problems is a method for forming a tissue structure in which a tissue structure forming device is placed in an environment containing living tissue and a linear tissue structure is formed inside the tissue structure forming device, wherein the tissue structure forming device is the tissue structure forming device described above.

[0025] The linear tissue structure, tissue structure forming apparatus, and tissue structure forming method of this disclosure facilitate the handling of the linear tissue structure.

[0026] Figure 1 is an exploded perspective view of a tissue structure forming apparatus in one embodiment. Figure 2 is a cross-sectional view of the tissue structure forming apparatus in one embodiment. Figure 3 is a perspective view of a linear tissue structure in one embodiment. Figure 4 is an enlarged cross-sectional view of a linear tissue structure in one embodiment. Figure 5 is a cross-sectional view showing the formation process of a linear tissue structure in one embodiment. Figure 6 is a cross-sectional view showing the formation process of a linear tissue structure in one embodiment. Figure 7 is a cross-sectional view showing the formation process of a linear tissue structure in one embodiment. Figure 8 is a cross-sectional view of a tissue structure forming apparatus in a modified example. Figure 9 is a perspective view of the tissue structure forming apparatus in a modified example. Figure 10 is a cross-sectional view of a linear tissue structure in a modified example.

[0027] The following describes the tissue structure forming apparatus 10, the linear tissue structure 20, and the tissue structure forming method. [Overview of the tissue structure forming apparatus] As shown in Figure 1, the tissue structure forming apparatus 10 comprises a partitioning member 11 and two thin plate portions 31 that sandwich the partitioning member 11. The partitioning member 11 is configured to be separable from the two thin plate portions 31. The tissue structure forming apparatus 10 is left in an environment containing biological tissue for a predetermined period of time. The period for which the tissue structure forming apparatus 10 is left is predetermined based on tests, etc., for forming the linear tissue structure 20.

[0028] The environment containing living tissue may be within a living organism containing living tissue. The living organism containing living tissue may be within the body of a disease model animal. The environment containing living tissue may be an in vitro culture system containing living tissue extracted from within a living organism. The environment containing living tissue may be an artificial environment constructed outside the living organism to mimic living tissue within a living organism. The living tissue may be ectodermous tissue, mesodermous tissue, or endodermous tissue. The living tissue may be tissue in which pluripotent stem cells 20M exist in a healthy state. The living tissue may be tissue in which pluripotent stem cells 20M necessary for tissue repair exist, such as in an injured or defective area. The living tissue may be subcutaneous tissue containing fibroblasts. The living tissue may be from a human or any other animal that can be a source of pluripotent stem cells 20M. The living organism containing living tissue may be within a human body or within the body of an organism other than a human. The organism other than a human may be a primate other than a human, such as a monkey or chimpanzee. Non-human organisms may include mammals such as dogs, cats, cows, pigs, horses, goats, sheep, rats, and mice, as well as birds, fish, and amphibians. The internal tissues may be subcutaneous tissue in the limbs, shoulders, back, abdomen, etc., or the abdominal cavity.

[0029] The thin plate portion 31 includes a linear region 36 that has a linear shape when viewed from a viewpoint facing the outer surface 31A of the thin plate portion 31. The linear region 36 is a region within the thin plate portion 31 that has a plurality of through portions 36H (see Figure 2). The linear region 36 has a mesh formed by the through portions 36H. Figure 1 shows an example in which the linear region 36 is a double annular region consisting of two annular regions.

[0030] The partitioning member 11 comprises an outer partitioning wall 12, an inner partitioning wall 13, and an intermediate partitioning wall 14. Viewed from a viewpoint opposite to the thin plate portion 31, the linear region 36 of one thin plate portion 31 is arranged to overlap with the linear region 36 of the other thin plate portion 31. The linear regions 36 in the two thin plate portions 31, the outer partitioning wall 12, the inner partitioning wall 13, and the intermediate partitioning wall 14 divide the curved hollow portion 30S (see Figure 2) for forming the linear structure 20.

[0031] When the tissue structure forming device 10 is placed in an environment containing biological tissue, cells and plasma proteins derived from the biological tissue enter the hollow section 30S from the environment through the perforation 36H of the thin plate section 31. Cells derived from the biological tissue that have entered the hollow section 30S use the inner surface 31B bordering the opening of the perforation 36H as a scaffold to grow loose fibrous tissue 22 (see Figure 5) and accumulate pluripotent stem cells 20M in the loose fibrous tissue 22. Fibroblasts and pluripotent stem cells 20M grow fibrous connective tissue 21 (see Figure 6) from the inner surface 31B bordering the opening of the perforation 36H toward the inside of the hollow section 30S. Fibroblasts and pluripotent stem cells 20M continue to enter and proliferate in the hollow section 30S, growing membranous loose fibrous tissue 22 further inward than the fibrous connective tissue 21, and further accumulating pluripotent stem cells 20M in the loose fibrous tissue 22. Then, the fibroblasts and pluripotent stem cells 20M of the loose fibrous tissue 22 grow fibrous connective tissue 21 (see Figures 3 and 4) to fill the entire hollow portion 30S.

[0032] In this way, the placement of the tissue structure forming device 10 for a predetermined period of time forms a linear tissue structure 20 composed of fibrous connective tissue 21 in the hollow portion 30S. The linear tissue structure 20, mainly composed of fibrous connective tissue 21, has high toughness. For this reason, the linear tissue structure 20, mainly composed of fibrous connective tissue 21, may be used in regenerative medicine, such as repairing the deterioration of connective tissue bodies that require specific lengths and thicknesses, such as blood vessels, tendons, and ligaments.

[0033] The linear tissue structure 20 formed by the tissue structure forming device 10 may include loose fibrous tissue 22. Cells derived from biological tissue that enter the hollow portion 30S grow the loose fibrous tissue 22 further inward than the fibrous connective tissue 21, and accumulate pluripotent stem cells 20M in the loose fibrous tissue 22. Removing the tissue structure forming device 10 from the environment during the period when the loose fibrous tissue 22 remains present results in the inclusion of the loose fibrous tissue 22 in the linear tissue structure 20. The cell population containing pluripotent stem cells 20M, or the pluripotent stem cells 20M, are accumulated in the loose fibrous tissue 22.

[0034] A linear tissue structure 20 containing accumulated pluripotent stem cells 20M may be attached to appropriate biological tissue or biological tissue exhibiting functional decline, such as loose fibrous tissue 22, without inducing differentiation. For example, a linear tissue structure 20 having a linear shape may be cut open to form a strip, and the strip-shaped linear tissue structure 20 may be attached to biological tissue. In this way, the cell population containing pluripotent stem cells 20M in the linear tissue structure 20, or the pluripotent stem cells 20M themselves, may be directly administered to appropriate biological tissue or biological tissue exhibiting functional decline. The linear tissue structure 20 containing accumulated pluripotent stem cells 20M may also be used as a strip formed by cutting open a tubular structure.

[0035] The linear tissue structure 20, the cell population containing pluripotent stem cells 20M, and the pluripotent stem cells 20M may be administered to living tissue or the like after being induced to differentiate into target cells outside of living tissue. The linear tissue structure 20, the cell population containing pluripotent stem cells 20M, or the pluripotent stem cells 20M may be administered at a desired time after cryopreservation. The pluripotent stem cells 20M may also be isolated from the loose fibrous tissue 22. The isolation of the pluripotent stem cells 20M may be performed using enzymatic treatment of the tissue structure forming device 10 removed from an environment containing living tissue. The isolation of the pluripotent stem cells 20M may also be performed using filtration using a membrane filter or mesh filter. The pluripotent stem cells 20M isolated from the loose fibrous tissue 22 may or may not be cultured and proliferated. The cell population containing pluripotent stem cells 20M partially purified from the loose fibrous tissue 22 may or may not be cultured and proliferated.

[0036] The linear tissue structure 20, the cell population containing pluripotent stem cells 20M, or the pluripotent stem cells 20M may be administered to the disease site and used in regenerative medicine for purposes such as tissue repair, tissue regeneration, repair of tissue or organ damage, and repair of impaired tissue or organ function. The linear tissue structure 20, the cell population containing pluripotent stem cells 20M, or the pluripotent stem cells 20M may be used for tissue construction or cell differentiation in an in vitro culture system. The linear tissue structure 20, the cell population containing pluripotent stem cells 20M, or the pluripotent stem cells 20M may be used for tissue construction or cell differentiation in an ex vivo system.

[0037] The linear tissue structure 20 may be used as a fluid obtained by grinding fibrous connective tissue 21 and loose fibrous tissue 22. The linear tissue structure 20 may also be used as a fluid obtained by grinding only loose fibrous tissue 22. The fluidized linear tissue structure 20 may be administered to the disease site by injection or other means.

[0038] [Configuration of the thin plate portion 31] Returning to Figure 1, the thin plate portion 31 has an elliptical plate shape, which is an example of a flat plate shape. The thin plate portion 31 may also have a circular plate shape or a polygonal plate shape. The thin plate portion 31 may have an irregular shape when viewed from the direction opposite to the outer surface 31A of the thin plate portion 31, or it may have a shape with rounded corners.

[0039] The constituent material of the thin plate portion 31 is biocompatible. The constituent material of the thin plate portion 31 may be a metallic material such as stainless steel, titanium, titanium-nickel alloy, or cobalt-chromium alloy, or a synthetic resin such as silicon resin, polymethylpentene resin, polytetrafluoroethylene resin, polypropylene resin, polyethylene resin, PEEK, acrylic resin, nylon, polycarbonate resin, or polysulfone resin. The constituent material of the thin plate portion 31 may also be a laminate of a metallic material and a synthetic resin.

[0040] The inner surface 31B of the thin plate portion 31 may have softness and a water contact angle to promote the formation of fibrous connective tissue 21. Promoting the formation of fibrous connective tissue 21 stabilizes the support of the loose fibrous tissue 22 by the fibrous connective tissue 21, making it easier to handle the loose fibrous tissue 22 in the linear structure 20. When promoting the formation of fibrous connective tissue 21 is required, the constituent material of the inner surface 31B of the thin plate portion 31 is preferably one selected from the group consisting of polymethylpentene resin, polyfluoroethylene resin, polypropylene resin, polyethylene resin, silicone resin, or a mixed resin of these with other resin components.

[0041] The thin plate portion 31 comprises two linear regions 36. The number of linear regions 36 may be one or three or more. The linear region 36 is a strip-shaped region within the thin plate portion 31 that has a through portion 36H. When viewed from a viewpoint facing the outer surface 31A of the thin plate portion 31, the linear region 36 has an elliptical annular shape. The linear region 36 may also have an annular shape, a wavy shape, or a bent shape. When viewed from a viewpoint facing the outer surface 31A of the thin plate portion 31, the linear region 36 may have a straight shape in part.

[0042] The loop that the linear region 36 has has an open-loop shape in which a part of the loop is interrupted in the circumferential direction of the linear region 36. Both ends of the linear region 36 are integrated with one connecting and reinforcing region 35. The connecting and reinforcing region 35 has a thick belt-like shape that extends along the major axis in the thin plate portion 31 and does not have a through portion 36H.

[0043] The connecting and reinforcing region 35 mechanically reinforces both ends of the linear region 36 to suppress bending of the linear region 36 during the retention period. The connecting and reinforcing region 35 may function as an operating portion for sliding or peeling off the thin plate portion 31 with respect to the partitioning member 11 when separating the thin plate portion 31 from the partitioning member 11. Note that the thin plate portion 31 may omit the connecting and reinforcing region 35.

[0044] The loop that the linear region 36 has may have a closed-loop shape that is continuous throughout the circumferential direction. The linear region 36 may have a multi-loop shape or a concentric shape having the same center. One linear region 36 may have a shape obtained by translating another linear region 36 along the outer surface 31A of the thin plate portion 31, or may have a shape obtained by rotating another linear region 36.

[0045] The multi-loop shape that the linear region 36 has may have a single spiral shape interrupted by the connecting and reinforcing region 35. The multi-loop shape that the linear region 36 has may have a single spiral shape in which the connecting and reinforcing region 35 is omitted. The linear regions 36 that the thin plate portion 31 has may each have a separate spiral shape. One linear region 36 may have a shape different from that of another linear region 36. One linear region 36 may have a length different from that of another linear region 36 or a line width different from that of another linear region 36.

[0046] The through-hole 36H is a circular hole that penetrates from the outer surface 31A to the inner surface 31B of the thin plate portion 31. The outer surface 31A of the thin plate portion 31 is in contact with the environment where the tissue structure forming device 10 is placed. The through-holes 36H are scattered throughout the linear region 36. The openings of the through-holes 36H are circular in shape on the outer surface 31A of the thin plate portion 31 and on the inner surface 31B of the thin plate portion 31, and are scattered throughout the linear region 36. The through-holes 36H are arranged at equal intervals in the direction in which the linear region 36 extends and in the direction intersecting with that direction, respectively.

[0047] The through-hole 36H is not limited to a circular hole, and may be an elliptical hole, a polygonal hole, a linear hole, or an irregular hole. The openings of the through-holes 36H may have an elliptical shape, a polygonal shape, or a linear shape on the outer surface 31A of the thin plate portion 31 and on the inner surface 31B of the thin plate portion 31. The openings of the through-holes 36H may have a curved shape such as a C shape, an L shape, or an M shape, a branched linear shape such as an E shape, an H shape, or a Y shape, or an irregular shape. The thin plate portion 31 may have a combination of a plurality of different shapes or a combination of different sizes as the openings of the through-holes 36H. When the peeling of the fibrous connective tissue 21 requires smoothing, the inner surface of the hole of the through-hole 36H is preferably a curved surface, and the through-hole 36H is preferably a circular hole.

[0048] The openings of the through-holes 36H may be regularly arranged or disorderly arranged in the linear region 36. When the thickness H20 of the fibrous connective tissue 21 is required to be uniform within a predetermined range or the distribution of the pluripotent stem cells 20M is required to be uniform within a predetermined range, a regular arrangement in the linear region 36 is preferable for the openings of the through-holes 36H.

[0049] The opening dimensions of the through-hole 36H are the dimensions of the opening of the through-hole 36H on the inner surface 31B of the thin plate portion 31. The dimensions of the opening of the through-hole 36H on the inner surface 31B of the thin plate portion 31 are equal to the dimensions of the opening of the through-hole 36H on the outer surface 31A of the thin plate portion 31. The opening dimensions of the through-hole 36H are large enough to allow cells in biological tissue to pass through the through-hole 36H. The minimum opening dimension through which cells in biological tissue can pass is approximately 0.01 mm. If the through-hole 36H is a circular hole, the opening dimensions of the through-hole 36H are the diameter of the circular hole. If the through-hole 36H is an elliptical hole, the opening dimensions of the through-hole 36H are the major axis of the elliptical hole. If the opening of the through-hole 36H is polygonal, or if the opening of the through-hole 36H is of an irregular shape, the opening dimensions are the diameter of the circle circumscribing the opening. The opening size of the through-hole 36H may be 0.3 mm or more and 3.0 mm or less. The through-hole 36H is also used to reduce the pressure in the hollow section 30S when the tissue structure forming device 10 is placed.

[0050] When the tissue structure forming device 10 is placed in an environment containing biological tissue, the inner surface 31B of the thin plate portion 31 has a size that functions as a scaffold for cells derived from biological tissue. The spacing between the perforations on the inner surface 31B of the thin plate portion 31 is the shortest length on the inner surface 31B between adjacent perforations 36H. The spacing between the perforations on the inner surface 31B has a size that allows the inner surface 31B, which is a plane between adjacent perforations 36H, to function as a scaffold for cells and the like in biological tissue. The spacing between the perforations on the inner surface 31B of the thin plate portion 31 may be 0.3 mm or more and 5.0 mm or less.

[0051] The density of openings on the inner surface 31B of the thin plate portion 31 is such that the intrusion of cells derived from biological tissue is not inhibited by the fibrous connective tissue 21. The density of openings on the inner surface 31B of the thin plate portion 31 is such that the fibrous connective tissue 21 forms a membrane-like structure. The opening occupancy rate on the inner surface 31B of the thin plate portion 31 is the ratio of the total area occupied by the openings of the through portion 36H within a unit area to the unit area of ​​the inner surface 31B of the thin plate portion 31. The opening occupancy rate on the inner surface 31B of the thin plate portion 31 may be 30% or more and 70% or less.

[0052] The thin plate portion 31 includes a reinforcing region bordering the linear region 36. The reinforcing region does not have a through portion 36H. The reinforcing region consists of an outer edge reinforcing region 32, an inner edge reinforcing region 33, an intermediate reinforcing region 34, and a connecting reinforcing region 35.

[0053] The outer edge reinforcement region 32, the intermediate reinforcement region 34, and the connecting reinforcement region 35 border a single linear region 36. The linear region 36 bordered by the outer edge reinforcement region 32, the intermediate reinforcement region 34, and the connecting reinforcement region 35 has deflection and other deformations suppressed throughout the linear region 36 during the implantation period by the mechanical reinforcement of the outer edge reinforcement region 32, the intermediate reinforcement region 34, and the connecting reinforcement region 35.

[0054] The intermediate reinforcement region 34, the inner edge reinforcement region 33, and the connecting reinforcement region 35 border other linear regions 36. The intermediate reinforcement region 34 borders one linear region 36 and also borders a portion of another linear region 36 adjacent to that linear region 36. The linear region 36 bordered by the intermediate reinforcement region 34, the inner edge reinforcement region 33, and the connecting reinforcement region 35 also has deflection and other deformations suppressed throughout the linear region 36 during the implantation period by the mechanical reinforcement of the intermediate reinforcement region 34, the inner edge reinforcement region 33, and the connecting reinforcement region 35.

[0055] The reinforcing region has a shape similar to the shape of the linear region 36. If the linear region 36 has an open annular shape, the reinforcing region may have a single linear shape that borders the entire linear region 36. If the linear region 36 has a closed annular shape, the reinforcing region may have a double closed annular shape that is separately connected to the outer and inner edges of the linear region 36. If the linear region 36 has a spiral shape, the reinforcing region may have a single linear shape that borders the entire linear region 36.

[0056] In the width direction perpendicular to the direction in which the linear region 36 extends, the width of the reinforcing region may be smaller than or equal to the line width of the linear region 36. The width of the reinforcing region is appropriately selected within the range in which the shape of the linear region 36 is stable. For example, a thin plate portion 31 having a linear region 36 is prone to bending due to its own weight, causing the center of the thin plate portion 31 to sag. The inner edge reinforcing region 33 and the connecting reinforcing region 35 have a wider band shape than the outer edge reinforcing region 32 and the intermediate reinforcing region 34, which suppresses shape changes that would cause the center of the thin plate portion 31 to sag due to the beam structure extending from the edge to the center of the thin plate portion 31.

[0057] On the outer surface 31A of the thin plate portion 31, the mesh portion that separates the opening of the through portion 36H within the linear region 36, and the reinforcement region are continuous flat surfaces. The tissue structure forming device 10, which is placed in the environment, forms external connective tissue on the outer surface 31A of the thin plate portion 31. The external connective tissue covers the linear region 36 and the reinforcement region. When removing the linear tissue structure 20, the external connective tissue formed on the outer surface 31A is peeled off from the outer surface 31A using a peeler or the like, and separated from the linear tissue structure 20. The fact that the mesh portion that separates the opening of the through portion 36H and the reinforcement region are flat surfaces facilitates the peeling of this external connective tissue from the outer surface 31A.

[0058] The thin plate portion 31 has a thickness that allows cells and other organisms to pass from the environment containing biological tissue into the hollow portion 30S. The thickness of the linear region 36 is equal to the thickness of the auxiliary region. The thickness of the thin plate portion 31 is the depth of the through portion 36H. The thickness of the thin plate portion 31 is large enough to suppress the deformation of the thin plate portion 31 within the biological tissue. The thickness of the thin plate portion 31 is approximately equal within the area where the through portion 36H is located. The thickness of the thin plate portion 31 is large enough to allow cells and other organisms within the biological tissue to enter the hollow portion 30S. The thickness of the thin plate portion 31 may be 0.1 mm or more and 2.0 mm or less.

[0059] [Configuration of Partition Member 11] The partition member 11 includes a partition wall. The partition wall has a shape similar to the reinforcing region so as to be in contact with the reinforcing region of the thin plate portion 31. The thickness direction of the partition member 11 is the direction in which the two thin plate portions 31 and the partition member 11 are aligned. The shape similar to the reinforcing region is the shape obtained by projecting the reinforcing region in the thickness direction, and is a shape that overlaps with the reinforcing region in the thickness direction. The linear regions 36 of the two thin plate portions 31 and the partition wall separate a curved hollow portion 30S for forming the linear structure 20 between the two thin plate portions 31 by the partition wall being in contact with the reinforcing region.

[0060] The constituent material of the partition member 11 is biocompatible. The constituent material of the partition member 11 may be a metallic material such as stainless steel, titanium, titanium-nickel alloy, or cobalt-chromium alloy, or a synthetic resin such as silicon resin, polymethylpentene resin, polytetrafluoroethylene resin, polypropylene resin, polyethylene resin, PEEK, acrylic resin, nylon, polycarbonate resin, or polysulfone resin. The constituent material of the partition member 11 may also be a laminate of a metallic material and a synthetic resin.

[0061] The surface of the partition member 11 may have softness and a water contact angle to promote the formation of fibrous connective tissue 21. Promoting the formation of fibrous connective tissue 21 stabilizes the support of the loose fibrous tissue 22 by the fibrous connective tissue 21, making it easier to handle the loose fibrous tissue 22 in the linear structure 20. When promoting the formation of fibrous connective tissue 21 is required, the constituent material of the inner surface 31B of the thin plate portion 31 is preferably one selected from the group consisting of polymethylpentene resin, polyfluoroethylene resin, polypropylene resin, polyethylene resin, silicone resin, or a mixed resin of these with other resin components.

[0062] The surface 11A of the partitioning member 11 is configured to allow the removal of the linear structure 20. The surface 11A of the partitioning member 11 may also be a flat surface that facilitates the removal of the linear structure 20.

[0063] The partition member 11 may include an outer partition wall 12, an inner partition wall 13, an intermediate partition wall 14, and a connecting wall 15 as partition walls. The partition member 11 may further include two cores 16. The connecting wall 15 has a strip shape corresponding to the connecting reinforcement region 35 so as to be in contact with the entire connecting reinforcement region 35 on the inner surface 31B of the thin plate portion 31.

[0064] The outer partition wall 12, inner partition wall 13, intermediate partition wall 14, and connecting wall 15 have equal wall heights to each other so as to ensure uniform spacing between the two thin plate sections 31. The wall heights of the outer partition wall 12, inner partition wall 13, intermediate partition wall 14, and connecting wall 15 may be between 0.5 mm and 5 mm. The thickness of the core 16 is thinner than the wall heights of the outer partition wall 12, inner partition wall 13, intermediate partition wall 14, and connecting wall 15.

[0065] The outer partition wall 12 has an elliptical ring shape similar to the outer edge reinforcement region 32 so as to be in contact with the entire outer edge reinforcement region 32 on the inner surface 31B of the thin plate portion 31. Both ends of the outer partition wall 12 may be integral with the connecting wall 15, or they may be supported by the connecting wall 15 through fitting with the connecting wall 15 or the like. The side surface of the outer partition wall 12 facing the core 16 may be straight in a cross section perpendicular to the extending direction of the outer partition wall 12, or it may be a concave curved surface that is recessed away from the core 16, or it may be a concave broken line that is recessed away from the core 16.

[0066] The inner partition wall 13 has an elliptical ring shape similar to the inner edge reinforcement region 33 so as to be in contact with the entire inner edge reinforcement region 33 on the inner surface 31B of the thin plate portion 31. The inner partition wall 13 may be integral with the connecting wall 15, or it may be supported by the connecting wall 15 through fitting with the connecting wall 15 or the like. The side surface of the inner partition wall 13 facing the core 16 may be straight in a cross section perpendicular to the extending direction of the inner partition wall 13, or it may be a concave curved surface that is recessed away from the core 16, or it may be a concave broken line that is recessed away from the core 16.

[0067] The intermediate partition wall 14 has an elliptical ring shape similar to the intermediate reinforcement region 34 so as to be in contact with the entire intermediate reinforcement region 34 on the inner surface 31B of the thin plate portion 31. Both ends of the intermediate partition wall 14 may be integral with the connecting wall 15, or they may be supported by the connecting wall 15 through fitting with the connecting wall 15 or the like. The side surface of the intermediate partition wall 14 facing the core 16 may be straight in a cross section perpendicular to the extending direction of the intermediate partition wall 14, or it may be a concave curved surface that is recessed away from the core 16, or it may be a concave broken line that is recessed away from the core 16.

[0068] The core 16 has a columnar shape extending in one direction. The direction in which the core 16 extends is parallel to the outer partition wall 12, the inner partition wall 13, and the intermediate partition wall 14. One core 16 is positioned between the outer partition wall 12 and the intermediate partition wall 14. One core 16 is spaced equally apart from the outer partition wall 12 and the intermediate partition wall 14. Another core 16 is positioned between the inner partition wall 13 and the intermediate partition wall 14. Another core 16 is spaced equally apart from the inner partition wall 13 and the intermediate partition wall 14. The core 16 is supported by the connecting wall 15 in a manner that allows it to be separated from the connecting wall 15, such as by fitting with the connecting wall 15. The core 16 may have a polygonal shape, a rectangular shape, a hexagonal shape, or an octagonal shape in a cross section perpendicular to the direction in which the core 16 extends. The core 16 may have a shape in which some of the line segments of the polygon are curved in a cross section perpendicular to the direction of extension of the core 16.

[0069] As shown in Figure 2, the two thin plate sections 31 are in contact with the outer partition wall 12 and the intermediate partition wall 14. The two thin plate sections 31 are in contact with the inner partition wall 13 and the intermediate partition wall 14. The two thin plate sections 31, the outer partition wall 12, and the intermediate partition wall 14 divide a hollow section 30S that houses one core 16. The distance between the thin plate section 31 and the core 16 is approximately equal to the distance between the outer partition wall 12 and the core 16, and the distance between the intermediate partition wall 14 and the core 16. The hollow section 30S that houses one core 16 is a tubular space that extends in an annular shape.

[0070] The two thin plate sections 31, the inner partition wall 13, and the intermediate partition wall 14 separate the hollow section 30S that accommodates the other core 16. The distance between the thin plate section 31 and the core 16 is approximately equal to the distance between the inner partition wall 13 and the core 16. The hollow section 30S that accommodates the other core 16 is also a tubular space extending in an annular shape. The partition member 11 may omit the other core 16, or the cross-sectional shape and cross-sectional area may differ between one core 16 and the other core 16.

[0071] The depth of the hollow section 30S is the dimension along the thickness direction of the hollow section 30S, and is the hollow depth. The hollow depth is the depth of the hollow section 30S along the depth direction of the through section 36H. The depth direction of the through section 36H is the thickness direction of the partition member 11 around the through section 36H. If a structure such as a core 16 exists in the hollow section 30S, the hollow depth is the distance between the inner surface 31B and the structure in the depth direction of the through section 36H. If no structure exists in the hollow section 30S, the hollow depth is the distance between one thin plate section 31 and another thin plate section 31. The hollow depth may be 0.5 mm or more and 10 mm or less.

[0072] When the linear tissue structure 20 is composed of fibrous connective tissue 21, the hollow depth is equal to the required thickness and wall thickness of the linear tissue structure 20. Furthermore, when pluripotent stem cells 20M are to be accumulated in the loose fibrous tissue 22, the hollow depth should be sufficiently large. That is, the hollow depth promotes the invasion of pluripotent stem cells 20M during the growth process of the fibrous connective tissue 21, making it easier for the loose fibrous tissue 22 to form than for the fibrous connective tissue 21 to form.

[0073] Collagen production in the tissue structure forming apparatus 10 can occur in competition between the outer surface 31A of the thin plate portion 31 and within the hollow portion 30S. Even if the structure has equal opening occupancy rates, if the number of openings is small and the size of the openings is large, the outer surface 31A of the thin plate portion 31 is more likely to be recognized as a foreign object due to the excessively large spacing between the penetration portions, and the outer surface 31A of the thin plate portion 31 is more likely to be covered with connective tissue. As a result, the openings of the penetration portions 36H are more likely to be closed with connective tissue before the linear tissue structure 20 is formed in the hollow portion 30S. Alternatively, pluripotent stem cells 20M such as plasma proteins, fibroblasts, vascular endothelial cells, and mesenchymal cells may have difficulty entering the hollow portion 30S, delaying the formation of fibrous connective tissue 21 and loose fibrous tissue 22.

[0074] In contrast, when the above-mentioned dimensional range is met, the number of through-holes 36H is moderately large, and the opening dimensions are moderately small. Therefore, on the outer surface 31A of the thin plate portion 31, the openings of the through-holes 36H are less likely to be covered with collagen due to the smaller spacing between the through-holes. Furthermore, on the inner surface 31B of the partition member 11, there are enough starting points for the formation of fibrous connective tissue 21 to form a membrane-like structure.

[0075] The accumulation of pluripotent stem cells 20M is achieved by the invasion of pluripotent stem cells 20M from the biological tissue into the hollow section 30S, and by the proliferation of the invaded pluripotent stem cells 20M within the hollow section 30S. The invasion of pluripotent stem cells 20M is promoted by the fact that the perforation section 36H remains open for most of the predetermined implantation period, and that the space for the formation of loose fibrous tissue 22 continues to exist within the hollow section 30S. Within the dimensional range described above, if the hollow depth is 2.0 mm or more, the growth of loose fibrous tissue 22 can be promoted more than the growth of fibrous connective tissue 21. Furthermore, the invasion of fibroblasts and pluripotent stem cells 20M can be promoted to the extent that large recesses or holes opposite the opening of the perforation section 36H are not formed in the fibrous connective tissue 21. As a result, membranous fibrous connective tissue 21 is more easily formed, and as the growth of fibrous connective tissue 21 is promoted, pluripotent stem cells 20M tend to accumulate more inward than the fibrous connective tissue 21. In particular, when the environment containing biological tissue is within the body of a disease model animal, the growth of fibrous connective tissue 21 tends to be slower, which increases the likelihood of accumulating pluripotent stem cells 20M.

[0076] If the plate thickness of the thin plate portion 31 is 2.0 mm or less, and the opening dimension of the through portion 36H is 0.3 mm or more, then even if the through portion 36H is slightly narrowed by the fibrous connective tissue 21, cells and other organisms in the biological tissue can enter the hollow portion 30S. Because the through portion 36H is less likely to be blocked by the fibrous connective tissue 21, the fibrous connective tissue 21 can grow easily, and pluripotent stem cells 20M can easily accumulate in the loose fibrous tissue 22.

[0077] When the plate thickness of the thin plate portion 31 is 2.0 mm or less, and the opening dimension of the through portion 36H is 3.0 mm or less, large recesses or holes are less likely to form in the fibrous connective tissue 21 in the area facing the through portion 36H. Suppressing the formation of large recesses in the fibrous connective tissue 21 suppresses the formation of localized weak areas in the fibrous connective tissue 21, making it easier to handle in the linear tissue structure 20.

[0078] When the plate thickness of the thin plate portion 31 is 0.1 mm or more, the opening dimension of the through portion 36H is 3.0 mm or less, and the opening occupancy rate is 70% or less, the mechanical strength of the thin plate portion 31 is easily obtained. For this reason, the deformation of the thin plate portion 31 is easily suppressed within the biological tissue.

[0079] When the spacing between penetrations is 0.5 mm or more, the fibrous connective tissue 21 tends to grow using the inner surface 31B as a scaffold. When the spacing between penetrations is 5.0 mm or less, the fibrous connective tissue 21 growing around the opening of one penetration 36H tends to connect with the fibrous connective tissue 21 growing around the openings of other penetrations 36H. The connection of the peripheries of the openings of the penetrations 36H in the fibrous connective tissue 21 suppresses the formation of localized weak areas in the fibrous connective tissue 21, making it easier to handle in the linear tissue structure 20. Furthermore, when the opening occupancy rate is between 30% and 70%, the fibrous connective tissue 21 tends to spread in a membrane-like manner across the entire inner surface 31B.

[0080] The implantation period for the tissue structure forming device 10 is preferably a short period of about four weeks from the start of implantation, after the inflammation caused by the incision required for implantation of the tissue structure forming device 10 has subsided. On the other hand, when the environment containing living tissue is the inside of a disease model animal, the growth of fibrous connective tissue 21 tends to be slower than in a healthy state. When the plate thickness of the thin plate portion 31 is 2.0 mm or less, and the opening dimension of the penetrating portion 36H is 3.0 mm or less, even in such an environment, large depressions or holes are less likely to form in the fibrous connective tissue 21 in the area facing the penetrating portion 36H after the implantation period has elapsed. Also, when the opening occupancy rate is 30% to 70%, the fibrous connective tissue 21 tends to spread in a membrane-like manner over the entire inner surface 31B. Furthermore, the penetrating portion 36H is less likely to be blocked by the fibrous connective tissue 21.

[0081] Furthermore, when the hollow depth is 2 mm or more, the embedding of the hollow portion 30S into the fibrous connective tissue 21 is significantly suppressed during a suitable implantation period, making it easier to obtain loose fibrous tissue 22 with sufficient thickness and pluripotent stem cells 20M that accumulate in the loose fibrous tissue 22. In particular, when the environment containing living tissue is the in vivo environment of a disease model animal, the growth of fibrous connective tissue 21 tends to be slower, thus increasing the likelihood of accumulating pluripotent stem cells 20M.

[0082] [Linear Structure 20] As shown in Figure 3, an example of the linear structure 20 is a linear structure having a curved tubular shape. The linear structure 20 may have a polygonal tubular shape with a polygonal cross-section. The cross-sectional shape of the linear structure 20 may be a shape in which some of the line segments of the polygon are curved. The cross-sectional shape of the linear structure 20 may be rectangular, hexagonal, or octagonal.

[0083] The linear structure 20 includes an annular hollow section 20V from which the core 16 has been removed. The annular hollow section 20V may be a hole with a polygonal cross-section. The cross-sectional shape of the annular hollow section 20V may be a shape in which some of the line segments of the polygon are curved. The cross-sectional shape of the annular hollow section 20V may be rectangular, hexagonal, or octagonal. The linear structure 20 may also have a columnar shape with the annular hollow section 20V omitted.

[0084] The outer surface of the linear structure 20 has corners 20C along the direction in which the linear structure 20 extends. The corners 20C of the linear structure 20 are formed by the contact points between the thin plate portion 31 and the outer partition wall 12, the contact points between the thin plate portion 31 and the intermediate partition wall 14, and the contact points between the thin plate portion 31 and the inner partition wall 13. The corners 20C extending in one direction in the linear structure 20 make it easier to visually check whether the linear structure 20 is twisted or excessively bent when using the linear structure 20.

[0085] The linear structure 20 has an inner surface 26A. The inner surface 26A is a flat surface that reflects the surface shape of the core 16. The linear structure 20 comprises a first outer surface 26B and a second outer surface 20S. The first outer surface 26B is an uneven surface peeled off from the inner surface 31B of the thin plate portion 31. The first outer surface 26B has irregularities that reflect the mesh shape of the linear region 36. The second outer surface 20S is a flat surface peeled off from the partition member 11. The second outer surface 20S may have a surface roughness Ra that is sufficiently smaller than the surface roughness Ra of the first outer surface 26B, or it may have a surface roughness Ra of 1 μm or less. The second outer surface 20S may be peeled off from the outer partition wall 12, from the intermediate partition wall 14, or from the inner partition wall 13.

[0086] The corners 20C of the linear structure 20 include the ridge line between the first outer surface 26B and the second outer surface 20S. The corners 20C are formed from the first outer surface 26B, which is an uneven surface, and the second outer surface 20S, which is a flat surface. This makes it easier to visually confirm whether or not the corners 20C are present. Furthermore, it makes it easier to visually confirm whether or not the linear structure 20 is twisted, and whether or not the linear structure 20 is excessively bent.

[0087] As shown in Figure 4, the linear structure 20 comprises fibrous connective tissue 21. The fibrous connective tissue 21 comprises a first outer surface 26B that has been peeled off from the inner surface 31B of the thin plate portion 31. The first outer surface 26B has a projection 21T that reflects the shape of the through portion 36H, and a recess 21A sandwiched between the projections 21T. The width 20W of the projection 21T corresponds to the opening dimension of the through portion 36H.

[0088] The fibrous connective tissue 21 has a higher fiber density than the loose fibrous tissue 22 and contains fewer cells than the loose fibrous tissue 22. The fibrous connective tissue 21 contains collagen fibers such as fibrous collagen and fibroblasts. The fibrous connective tissue 21 may also contain collagen fiber bundles. The collagen fibers of the fibrous connective tissue 21 preferably contain type I collagen. The ratio of type I collagen to the total collagen contained in the fibrous connective tissue 21 may be 65% by weight or more and 90% by weight or less. The ratio of type I collagen to the total collagen contained in the fibrous connective tissue 21 is higher than the ratio of type I collagen to the total collagen contained in the loose fibrous tissue 22.

[0089] If the linear tissue structure 20 includes loose fibrous tissue 22, the loose fibrous tissue 22 is formed over the entire side surface of the fibrous connective tissue 21 opposite to the first outer surface 26B. During the predetermined implantation period, the tissue structure forming device 10 forms fibrous connective tissue 21 in the hollow portion 30S, and also forms membranous loose fibrous tissue 22 supported by the fibrous connective tissue 21. A cell population including pluripotent stem cells 20M, or the pluripotent stem cells 20M, accumulates in the loose fibrous tissue 22.

[0090] The thickness H20 of the fibrous connective tissue 21 may be 0.05 mm or more. When the thickness H20 of the fibrous connective tissue 21 is 0.05 mm or more, the strength of the fibrous connective tissue 21 is ensured, making it easy to handle the linear tissue structure 20. If the linear tissue structure 20 does not contain loose fibrous tissue 22, the thickness H20 of the fibrous connective tissue 21 is approximately equal to the hollow depth, for example, 0.5 mm or more and 10 mm or less. If the linear tissue structure 20 contains loose fibrous tissue 22, if the thickness H20 of the fibrous connective tissue 21 is 0.05 mm or more and 0.5 mm or less, a space for accumulating pluripotent stem cells 20M is easily secured within the hollow portion 30S.

[0091] The thickness HT of the projection 21T is less than or equal to the depth of the penetration 36H. The fibrous connective tissue 21 may omit the projection 21T. The fibrous connective tissue 21 may have capillaries 24 in the area corresponding to the penetration 36H. The capillaries 24 are newly formed in the hollow portion 30S through the penetration 36H during the formation of the linear tissue structure 20. If the linear tissue structure 20 includes loose fibrous tissue 22, the capillaries 24 may reach the loose fibrous tissue 22.

[0092] The loose fibrous tissue 22 has a lower fiber density than the fibrous connective tissue 21 and contains more cells scattered within its fibers than the fibrous connective tissue 21. The loose fibrous tissue 22 contains fibroblasts, collagen fibers such as fibrous collagen, vascular endothelial cells, fibrin, and pluripotent stem cells 20M such as mesenchymal cells. The loose fibrous tissue 22 may contain type III collagen or fibrous collagen other than type III collagen. The type III collagen content in the loose fibrous tissue 22 is higher than the type III collagen content in the fibrous connective tissue 21.

[0093] The pluripotent stem cells 20M contained in the loose fibrous tissue 22 express pluripotent stem cell markers. The pluripotent stem cells 20M may express at least one pluripotent stem cell marker, or at least one mesenchymal stem cell marker. The pluripotent stem cells 20M contained in the loose fibrous tissue 22 may also contain mesenchymal stem cells.

[0094] The pluripotent stem cells 20M contained in the loose fibrous tissue 22 may express both the pluripotent stem cell marker SSEA3 and the pluripotent stem cell marker SSEA4.

[0095] Pluripotent stem cells 20M contained in the loose fibrous tissue 22 may express both the mesenchymal stem cell marker CD90 and the mesenchymal stem cell marker CD105. Pluripotent stem cells 20M contained in the loose fibrous tissue 22 may express either the mesenchymal stem cell marker CD90 or the mesenchymal stem cell marker CD105. Pluripotent stem cells 20M contained in the loose fibrous tissue 22 may express both the mesenchymal stem cell marker CD90 and the pluripotent stem cell marker SSEA3.

[0096] The loose fibrous tissue 22 may contain stem cells expressing the mesenchymal stem cell marker CD105, and stem cells expressing both the mesenchymal stem cell marker CD105 and the pluripotent stem cell marker SSEA3.

[0097] The loose fibrous tissue 22 may contain stem cells with high angiogenic potential. The loose fibrous tissue 22 may contain stem cells expressing the growth factor marker VEGF, or stem cells expressing both the growth factor marker VEGF and the pluripotency stem cell marker SSEA3, as stem cells with high angiogenic potential. The loose fibrous tissue 22 may also contain stem cells expressing the growth factor marker HGF.

[0098] The ratio of the total number of pluripotent stem cells 20M contained in the loose fibrous tissue 22 to the total number of cells contained in the loose fibrous tissue 22 is the stem cell ratio. The stem cell ratio can be calculated by taking the number of cells recovered from the degraded tissue when the loose fibrous tissue 22 is treated in a 0.25% collagenase type I solution at 37°C for 1.5 hours, and using that as the total number of cells. The stem cell ratio can also be calculated by taking the number of cells expressing at least one selected from the group consisting of mesenchymal stem cell marker CD90, mesenchymal stem cell marker CD105, pluripotent stem cell marker SSEA3, and pluripotent stem cell marker SSEA4 as the number of pluripotent stem cells. The stem cell ratio of the loose fibrous tissue 22 is 5% or more, preferably 10% or more, more preferably 20% or more, and even more preferably 30% or more. The stem cell ratio of the loose fibrous tissue 22 may be 60% or less, 50% or less, 40% or less, or 30% or less.

[0099] The ratio of the number of mesenchymal interstitial cells in the loose fibrous tissue 22 to the number of pluripotent stem cells in the loose fibrous tissue 22 is the mesenchymal stem cell ratio. The mesenchymal stem cell ratio can be calculated by determining the number of mesenchymal stem cells based on the number of cells expressing the mesenchymal stem cell marker CD90 or the mesenchymal stem cell marker CD105. The mesenchymal stem cell ratio can also be calculated by determining the number of pluripotent stem cells based on the number of cells expressing the mesenchymal stem cell marker CD90, the mesenchymal stem cell marker CD105, the pluripotent stem cell marker SSEA3, or the pluripotent stem cell marker SSEA4. The mesenchymal stem cell ratio may be 5% or more, or 10% or more. The mesenchymal stem cell ratio may be 60% or less, or 50% or less.

[0100] [Method for forming tissue structures] As shown in Figure 5, when the tissue structure forming device 10 is placed in an environment containing living tissue, liquid components 20L such as extracellular matrix derived from living tissue enter the hollow portion 30S through the penetrating portion 36H of the linear region 36. The hollow portion 30S of the tissue structure forming device 10 is filled with liquid components 20L derived from living tissue. When the hollow portion 30S of the tissue structure forming device 10 is filled with liquid components 20L, cells such as pluripotent stem cells 20M and fibroblasts derived from living tissue enter the hollow portion 30S through the penetrating portion 36H. The fibroblasts that have entered the hollow portion 30S begin to form loose fibrous tissue 22 in the linear region 36, using the inner surface 31B bordering the opening of the penetrating portion 36H as a scaffold, extending inward from the inner surface 31B into the hollow portion 30S.

[0101] As shown in Figure 6, the loose fibrous tissue 22 formed using the inner surface 31B of the linear region 36 as a scaffold promotes the production of collagen and other substances by cells accumulated in the loose fibrous tissue 22 at the inner surface 31B, which is easily recognized as a foreign body. As a result, the loose fibrous tissue 22 formed using the inner surface 31B as a scaffold grows denser fibrous connective tissue 21 from the inner surface 31B toward the hollow portion 30S, starting from the opening edge of the penetrating portion 36H.

[0102] The interior of the hollow section 30S, which is more easily recognized as a foreign object than the exterior, further promotes the invasion of fibroblasts and pluripotent stem cells 20M. The fibroblasts and pluripotent stem cells 20M that continue to invade the hollow section 30S form loose fibrous tissue 22 inside the fibrous connective tissue 21 during the growth process of the fibrous connective tissue 21. The pluripotent stem cells 20M that invade the hollow section 30S continue to accumulate in the loose fibrous tissue 22.

[0103] As shown in Figure 7, fibroblasts and pluripotent stem cells 20M that continue to penetrate the hollow portion 30S form membranous fibrous connective tissue 21 that spreads throughout the entire linear region 36, connecting the opening edges of the penetrating portion 36H with fibrous connective tissue 21. The fibroblasts and pluripotent stem cells 20M that continue to penetrate the hollow portion 30S form membranous loose fibrous tissue 22 and capillaries 24, following the spread of the fibrous connective tissue 21.

[0104] The inside of the hollow section 30S, which is more easily recognized as a foreign object than the outside of the hollow section 30S, continues to accumulate pluripotent stem cells 20M in the loose fibrous tissue 22 even while the fibrous connective tissue 21 is forming in a membrane-like manner. The pluripotent stem cells 20M accumulated in the loose fibrous tissue 22 proliferate within the loose fibrous tissue 22. As a result, cells derived from biological tissue that enter the hollow section 30S cause the membrane-like loose fibrous tissue 22 to grow further inside than the membrane-like fibrous connective tissue 21, and also cause a large number of pluripotent stem cells 20M to accumulate in the loose fibrous tissue 22.

[0105] If the linear tissue structure 20 comprises fibrous connective tissue 21 and loose fibrous tissue 22, the tissue structure forming apparatus 10 is removed from the environment containing biological tissue before the fibrous connective tissue 21 completely fills the hollow portion 30S. If the linear tissue structure 20 is composed of fibrous connective tissue 21, the tissue structure forming apparatus 10 is removed from the environment containing biological tissue after a period of time has passed during which the fibrous connective tissue 21 completely fills the hollow portion 30S.

[0106] When the tissue structure forming device 10 is removed from the environment, the connective tissue formed on the outer surface 31A of the thin plate portion 31 is first peeled off. In peeling with a peeler, peeling is repeated at various parts of the surface of the tissue structure forming device 10, with the peeling depending on the skill of the operator. At this time, because the thin plate portion 31 is flat, the peeling of the external connective tissue proceeds smoothly.

[0107] Next, the tissue structure forming apparatus 10, from which the connective tissue has been removed, has the thin plate portion 31 separated from the partition member 11. The separation of the thin plate portion 31 may be done by sliding the thin plate portion 31 relative to the partition member 11 along the surface direction of the thin plate portion 31, or by peeling the thin plate portion 31 away from the partition member 11. Then, the partition member 11 separated from the thin plate portion 31 has the linear tissue structure 20 covering the core 16 and the core 16 removed from the connecting wall 15. The linear tissue structure 20 removed from the hollow portion 30S has the core 16 removed.

[0108] As described above, the following effects can be obtained according to the above embodiment: (1) The corner portion 20C of the linear structure 20 is composed of a first outer surface 26B which is an uneven surface and a second outer surface 20S which is a flat surface. The corner portion 20C, composed of surfaces with different surface structures, helps in visually confirming the orientation of the linear structure 20. As a result, twisting and excessive bending within the linear structure 20 can be easily grasped and corrected, thus facilitating the handling of the linear structure 20.

[0109] (2) When the hollow portion 30S is divided in a curved shape, such as a multiple ring or spiral, the environment required for implantation can be reduced compared to when the hollow portion 30S is divided in a straight line. On the other hand, when the surface of the tissue structure forming device 10 has an inner cylindrical surface with an annular shape and an outer cylindrical surface with an annular shape, a narrow annular recess is formed on the surface of the tissue structure forming device 10 between the inner cylindrical surface and the outer cylindrical surface. The narrow recess on the surface of the device requires troublesome procedures such as peeling off the external connective tissue or separating the external connective tissue from the tissue structure.

[0110] In this respect, since the thin plate portion 31 has a flat shape, the surface of the device, which corresponds to the surface shape of the thin plate portion 31, is configured to be almost flat. For this reason, even if the linear hollow portions 30S are adjacent to each other, no narrow recesses are formed on the surface of the device.

[0111] (3) Since the two thin plate portions 31 are separated from the partition member 11, when the linear structure 20 is removed, the external connective tissue remaining on the outer surface 31A of the thin plate portion 31 is separated from the linear structure 20 of the hollow portion 30S together with the thin plate portion 31. As a result, when the curved linear structure 20 is formed, the load required for peeling off the external connective tissue and the load required for separating the linear structure 20 are reduced.

[0112] (4) In the two thin plate sections 31, the outer edge reinforcement region 32, the inner edge reinforcement region 33, and the intermediate reinforcement region 34 border the linear region 36, thus suppressing a decrease in the mechanical strength of the thin plate section 31 itself due to the presence of a mesh. Furthermore, when the partition member 11 is equipped with a core 16, the effects similar to those described in (1) to (3) above can be obtained when forming the tubular linear structure 20.

[0113] (5) When the connecting reinforcement region 35 and the inner edge reinforcement region 33 constitute a beam structure, the sagging of the thin plate portion 31 is suppressed. This suppresses deformation of the thin plate portion 31 caused by sagging before and during the installation period.

[0114] (6) When the plate thickness of the thin plate portion 31 is 0.1 mm or more and 2.0 mm or less, and the opening occupancy rate is 30% or more and 70% or less, a hollow portion 30S more suitable for forming the linear structure 20 is provided. Even if such a very thin thin plate portion 31 has a linear region 36, the mechanical strength reduction of the thin plate portion 31 is suppressed to the extent that the reinforcing region borders the linear region 36. In other words, the effect of the reinforcing region in suppressing strength reduction becomes even more pronounced.

[0115] (7) Because the inner surface 31B of the thin plate portion 31, the side surface of the inner partition wall 13, and the side surface of the intermediate partition wall 14 are flat surfaces, or because the outer surface of the core 16 is flat, the linear structure 20 can be removed from the hollow portion 30S smoothly.

[0116] (8) When the distance between the two thin plate portions 31 is 0.5 mm or more and 5 mm or less, a thin linear structure 20 is formed having a diameter of 0.5 mm or more and 5 mm or less. When the thin linear structure 20 is formed, the effects described in (1) to (7) above are obtained.

[0117] The above embodiment may be modified as follows: [Thin plate portion 31] As shown in Figure 8, the thickness 30T of the outer edge reinforcement region 32, the inner edge reinforcement region 33, and the intermediate reinforcement region 34 may be thicker than the linear region 36. Since the reinforcement region, which is thicker than the linear region 36, borders the linear region 36, the reduction in the mechanical strength of the thin plate portion 31 itself is further suppressed. In this case, the outer surface 31A of the thin plate portion 31 may have a step 36D at the edge of the linear region 36 due to the difference between the plate thickness of the linear region 36 and the plate thickness of the reinforcement region. The step 36D may be placed on the outer surface 31A of the thin plate portion 31, or on the inner surface 31B of the thin plate portion 31. If the step 36D is greater than 0.5 mm, it is preferable that the step 36D be placed on the inner surface 31B of the thin plate portion 31 in order to obtain flatness on the outer surface 31A of the thin plate portion 31.

[0118] - The linear region 36 in which the mesh is arranged in a curved shape may also be a region in which the mesh is arranged in a straight line. That is, the thin plate portion 31 may be straight, or a combination of curved and straight. At least one of the curved, straight, and combination thereof is linear. The thin plate portion 31 may include this linear region 36 in which the mesh is arranged in a straight line.

[0119] As shown in Figure 9, the thin plate portion 31 may omit the inner edge reinforcement region 33 and the intermediate reinforcement region 34. The thin plate portion 31 may also omit the connecting reinforcement region 35 or the outer edge reinforcement region 32. The thin plate portion 31 may also have a through portion 36H extending throughout its entire length.

[0120] [Accommodation Member] Furthermore, the two thin plate sections 31 may constitute a single accommodation member. For example, as shown in Figure 9, two thin plate sections 31 having an elliptical flat plate shape are connected so as to face each other with a gap corresponding to the wall height of the partition member 11. In this case, both ends in the minor axis direction and one end in the major axis direction of one thin plate section 31 may be connected to both ends in the minor axis direction and one end in the major axis direction of the other thin plate section 31 by a connecting member 51. The connecting member 51 may include a strip-shaped portion extending in a cross shape in the minor axis direction and the major axis direction of the thin plate section 31, and a hook positioned at the end of the strip-shaped portion. The connecting member 51 may have its strip-shaped portion facing one thin plate section 31 (the thin plate section 31 on the back side of the paper in Figure 9), and the hook may be attached to the other thin plate section 31 (the thin plate section 31 on the front side of the paper in Figure 9). Alternatively, the connecting member 51 may be composed of a plurality of clips having a U-shaped cross-section.

[0121] As a result, the two thin plate portions 31 constitute a single housing member. The partition member 11 is then inserted between the two thin plate portions 31 from the other end in the long axis direction of the thin plate portion 31. Conversely, the partition member 11 is withdrawn from between the two thin plate portions 31 from the other end in the long axis direction of the thin plate portion 31. In other words, the housing member comprising the two thin plate portions 31 is configured to allow the partition member 11 to be inserted and removed.

[0122] According to this modified example, the partition member 11 can be inserted into the housing member and removed from the housing member, making it easier to handle the structure forming apparatus 10 required for forming the linear structure 20. Furthermore, the insertion and removal of the partition member 11 into and out of the gap between the two thin plate portions 31 is not limited to translation of the partition member 11 on the expanding surface of the thin plate portion 31, but may also be done by rotation of the partition member 11.

[0123] [Linear structure] As shown in Figure 10, the annular hollow portion 20V of the linear structure 20 may be a circular hole. That is, the linear structure 20 may be a tubular body having a rectangular outer cross-section and a hole with a circular cross-section.

[0124] 10...Tissue structure forming device 11...Partition member 12...Outer partition wall 13...Inner partition wall 14...Intermediate partition wall 15...Connecting wall 16...Core 20...Linear tissue structure 20C...Corner 20V...Annular hollow section 26A...Inner surface of cylinder 26B...First outer surface 20S...Second outer surface 21...Fibrous connective tissue 21A...Depression 22...Loose fibrous tissue 23...Pluripotent stem cells 24...Capillaries 31...Thin plate section 30S...Hollow section 32...Outer edge reinforcement region 33...Inner edge reinforcement region 34...Intermediate reinforcement region 35...Connecting reinforcement region 36...Linear region 36H...Penetration section

Claims

1. A linear structure comprising: a first outer surface which is an uneven surface extending in the direction of extension of the linear structure; and a second flat outer surface which extends in the direction of extension and is connected to the first outer surface via a ridge, wherein the depressions sandwiched between adjacent protrusions on the first outer surface are in a mesh-like pattern.

2. The linear tissue structure according to claim 1, wherein the linear tissue structure is a tubular connective tissue having a polygonal cross-section.

3. The linear tissue structure according to claim 2, wherein the linear tissue structure is a tubular connective tissue having pores with a circular or polygonal cross-section.

4. A tissue structure forming apparatus for being placed in an environment containing biological tissue to form a linear tissue structure, comprising: two thin plate portions having a flat plate shape; and a partition member sandwiched between the thin plate portions and configured to be separable from the thin plate portions, wherein each thin plate portion has a linear region having a mesh composed of a plurality of through portions, and when viewed from a viewpoint opposite to the thin plate portion, one of the linear regions overlaps with the other linear region; the partition member has a flat surface and, when viewed from a viewpoint opposite to the thin plate portion, has a shape that borders the linear region; and the linear regions in the two thin plate portions and the partition member divide a linear hollow portion for forming the linear tissue structure.

5. The apparatus for forming a tissue structure according to claim 4, wherein the thin plate portion includes a reinforcing region that does not have the through portion, and the reinforcing region borders the linear region.

6. The apparatus for forming a structural body according to claim 5, wherein the reinforcing region has a beam structure extending from the edge of the thin plate portion to the center of the thin plate portion.

7. The apparatus for forming a tissue structure according to claim 5 or 6, wherein the linear region has multiple rings composed of a plurality of annular regions, and the reinforcing region bordering one of the annular regions is arranged to border a portion of another annular region adjacent to that annular region.

8. The apparatus for forming a tissue structure according to claim 5 or 6, wherein the thickness of the reinforcement region is equal to the thickness of the linear region.

9. The apparatus for forming a tissue structure according to claim 5 or 6, wherein the thickness of the reinforcement region is greater than that of the linear region.

10. The apparatus for forming a tissue structure according to any one of claims 4 to 6, wherein the partition member further comprises a core extending linearly within the hollow portion, the core having a shape corresponding to the linear region.

11. The apparatus for forming a microstructure according to any one of claims 4 to 6, wherein the thickness of the thin plate portion is 0.1 mm or more and 2.0 mm or less, the opening dimension of the through portion is 0.01 mm or more and 3.0 mm or less, and the opening occupancy rate of the through portion in the linear region is 30% or more and 70% or less.

12. The apparatus for forming a tissue structure according to any one of claims 4 to 6, wherein the distance between the two thin plate portions is 0.5 mm or more and 5 mm or less.

13. The apparatus for forming a tissue structure according to any one of claims 4 to 6, wherein the two thin plate portions extend in a planar shape including one direction, and the two thin plate portions constitute a housing member that allows the partitioning member to be inserted and removed between the thin plate portions along the one direction.

14. A method for forming a tissue structure, comprising placing a tissue structure forming device in an environment containing non-human biological tissue and forming the linear tissue structure within the tissue structure forming device, wherein the tissue structure forming device is the tissue structure forming device described in any one of claims 4 to 6.

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