Linear textured structure, textured structure forming device, and textured structure forming method

Abstract

A linear textured structure, a textured structure forming device, and a textured structure forming method that enable smooth handling are provided. [Solution] A linear tissue structure formed by a tissue structure forming device 10, which is placed in an environment containing biological tissue, and forms a linear tissue structure in the hollow portion of the tissue structure forming device 10 by cells entering the hollow portion of the tissue structure forming device 10 from the environment, the hollow portion being separated by a linear region having a mesh among two thin plate portions 31 which are flat and facing each other, and a partitioning member 11 which has a shape that borders the linear region when viewed from a viewpoint facing the thin plate portions 31 and is sandwiched between the thin plate portions 31, the linear tissue structure having a columnar shape with two first outer surfaces having irregularities peeled off from the mesh of the two linear regions, and two flat second outer surfaces peeled off from the surface of the partitioning member 11.

Description

[Technical field]

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

[0002] The body's self-defense mechanism accumulates macrophages around foreign bodies that have invaded the body. Macrophages adhere to the surface of foreign bodies and promote collagen production by fibroblasts through the production of TGF-β by monocytes. Foreign bodies that have invaded the body are isolated within the body by being covered with connective tissue that contains fibroblasts and collagen.

[0003] One of the regenerative medical technologies, which is a medical technology that revives lost tissues and organs, replaces a damaged linear tissue structure with a linear tissue structure derived from a living body. One of the technologies for forming a linear tissue structure derived from a living body involves placing a tissue structure forming device, which is a foreign body, in living tissue, and then using the self-defense function of living tissue to have the tissue structure forming device form a linear tissue structure derived from a living body (see, for example, Patent Documents 1 and 2).

[0004] An example of such a tissue structure forming device includes two connective tissue forming surfaces facing each other. The two connective tissue forming surfaces separate a hollow portion having various shapes such as a flat space, a cylindrical space, a valve-shaped space, etc. Cells such as fibroblasts that invade 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] Stem cells are important materials for regenerating and repairing target tissues in regenerative medicine technology. On the other hand, the basis for using embryonic stem cells, which require ethical consideration, and induced pluripotent stem cells, which require safety confirmation, in regenerative medicine technology has not yet been established. On the other hand, pluripotent stem cells present in the body, although present in small numbers in living tissues, have passed through the development stage and are moving to the clinical stage. One technique for accumulating pluripotent stem cells present in the body involves placing a tissue structure formation device, which is a foreign body, in the living tissue, and then accumulating the pluripotent stem cells in the living tissue in the tissue structure formation device.

[0006] An example of such a tissue structure forming device accumulates pluripotent stem cells in a hollow part of the device. The tissue structure forming device includes a frame surrounding the hollow part. The frame defines an opening extending in the direction of extension of the columnar members by two columnar members. The hollow part surrounded by the frame communicates with the environment in the living body through the opening. The opening width and the depth of the hollow part cause fibroblasts to fill the hollow part with fibrous connective tissue so as to form a recess in the fibrous connective tissue at a site facing the opening. In addition, the opening width and the depth of the hollow part form a depression from the opening toward the hollow part in the fibrous connective tissue at a site facing the opening. The pluripotent stem cells present in the living body are accumulated in this depression. In this way, an example of a tissue structure forming device forms a linear tissue structure in the hollow part by accumulating pluripotent stem cells in the depression of the connective tissue body (see, for example, Patent Document 8). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] JP 2004-261260 A [Patent Document 2] JP 2007-312821 A [Patent Document 3] JP 2014-030598 A [Patent Document 4] JP 2017-169778 A [Patent Document 5] Patent Publication No. 2021-129834 [Patent Document 6] Patent Publication No. 2021-13480 [Patent Document 7] Patent No. 6978142 [Patent Document 8] Patent No. 6813923 Summary of the Invention [Problem to be solved by the invention]

[0008] Regenerative medicine technology using tissue structure formation devices has passed the development stage and is moving to the clinical stage. In the clinical stage, where large-scale tests are conducted to prove efficacy and safety, smooth handling of linear tissue structures is highly desired. [Means for solving the problem]

[0009] The linear tissue structure for solving the above problems is a linear tissue structure formed by a tissue structure forming device. The tissue structure forming device is placed in an environment containing biological tissue, and forms the linear tissue structure in the hollow portion of the tissue structure forming device by cells entering the hollow portion from the environment. The hollow portion is partitioned by a linear region having a mesh in each of two mutually opposing flat thin plate portions, and a partitioning member sandwiched between the thin plate portions and having a shape that borders the linear region when viewed from a viewpoint facing the thin plate portions, and the linear tissue structure has a first outer surface that extends in the extension direction of the linear region and has an unevenness peeled off from the mesh, and a flat second outer surface that is connected to the first outer surface and peeled off from the surface of the partitioning member.

[0010] According to the linear tissue structure, the corner of the linear tissue structure having a columnar shape 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 visual confirmation of the posture of the linear tissue structure. As a result, it is easy to grasp and repair twists and excessive bends in the linear tissue structure, which facilitates the handling of the linear tissue structure.

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

[0012] The tissue structure forming device for solving the above problems is a tissue structure forming device that is placed in an environment containing biological tissue to form a linear tissue structure. The tissue structure forming device includes two flat thin plate parts and a partitioning member that is sandwiched between the thin plate parts and configured to be separable from the thin plate parts. The thin plate parts include linear regions having a mesh formed of a plurality of through-holes, and one of the linear regions overlaps with the other linear region when viewed from a viewpoint opposite the thin plate parts. The partitioning member has a flat surface and is shaped to border the linear region when viewed from a viewpoint opposite the thin plate parts. The linear regions in the two thin plate parts and the partitioning member separate a linear hollow portion for forming the linear tissue structure.

[0013] According to the tissue structure forming device, a partition member having a flat surface and a linear region having a mesh form a corner of the linear tissue structure. The corner reflecting the flat surface and the mesh assists in visually checking the posture of the linear tissue structure. As a result, twists and excessive bends in the linear tissue structure can be easily detected and repaired, which facilitates the handling of the linear tissue structure.

[0014] In addition, when the tissue structure forming device placed in the environment forms a linear tissue structure in the hollow portion, the entire device surface is covered with the external connective tissue. The external connective tissue covering the entire device surface is integrated with the linear tissue structure through a through-hole that communicates the hollow portion with the environment. For this reason, removal of the linear tissue structure requires various procedures such as removal of the tissue structure forming device, peeling of the external connective tissue from the device surface, and separation of the linear tissue structure from the external connective tissue. In this regard, according to the tissue structure forming device, since the two thin plate portions are separated from the partition member, the external connective tissue formed on the device surface is also separated from the linear tissue structure in the hollow portion together with the thin plate portions when removing the linear tissue structure. For this reason, when a linear tissue structure is formed, the load required for peeling of the external connective tissue and the load required for separation of the linear tissue structure are reduced.

[0015] In the tissue structure forming device, the thin plate portion may be provided with 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, so that a decrease in mechanical strength of the thin plate portions due to a mesh is also suppressed.

[0016] In the tissue structure forming device, the reinforcing region may have a beam structure extending from an edge of the thin plate portion to the center of the thin plate portion. A thin plate portion having a linear region is prone to bending so as to sag from the edge of the thin plate portion toward the center. In this regard, the reinforcing region having a beam structure suppresses the sagging of the thin plate portion. This suppresses deformation of the thin plate portion due to sagging before and during placement.

[0017] In the tissue structure forming device, the linear region may have a multiple ring shape composed of a plurality of annular regions, and the reinforcing region bordering one annular region may be disposed so as to border a part of the other annular region adjacent to the first annular region. With this configuration, one reinforcing region borders two annular regions, so that the configuration of the thin plate portion can be simplified.

[0018] In the tissue structure forming apparatus, the thickness of the reinforcing region may be greater than that of the linear region. According to this tissue structure forming apparatus, the reinforcing region is thicker than the linear region and borders the linear region, so that a decrease in mechanical strength of the thin plate portion itself is further suppressed. In the tissue structure forming apparatus, the thickness of the reinforcing region may be equal to that of the linear region.

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

[0020] In the above tissue structure forming device, the thickness of the thin plate portion may be 0.1 mm or more and 2.0 mm or less, the opening dimension of the through-hole may be 0.01 mm or more and 3.0 mm or less, and the opening occupancy rate of the through-hole in the linear region may be 30% or more and 70% or less.

[0021] According to the above-mentioned tissue structure forming device, 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 more suitable for forming a linear tissue structure is provided. Note that when the thin plate portion includes a reinforcing region, even if such a very thin thin plate portion has a linear region, the mechanical strength reduction of the thin plate portion is suppressed to the extent that the reinforcing region borders the linear region. In other words, the effect of suppressing the strength reduction by the reinforcing region becomes even more remarkable.

[0022] In the tissue structure forming device, 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 external connective tissue and the load required for separating the linear tissue structure are reduced.

[0023] In the tissue structure forming device, the two thin plate portions may extend in a plane including one direction, and the two thin plate portions may form a housing member that houses the partition member insertably and removably between the thin plate portions along the one direction. With this configuration, the partition member can be inserted into the housing member and removed from the housing member, making it easy to handle the tissue structure forming device required to form a linear tissue structure.

[0024] A tissue structure formation method for solving the above problems is a method for forming a tissue structure, in which a tissue structure formation device is placed in an environment containing biological tissue and a linear tissue structure is formed in the tissue structure formation device, wherein the tissue structure formation device is the tissue structure formation device described above. Effect of the Invention

[0025] According to the linear textured structure, textured structure forming apparatus, and textured structure forming method of the present disclosure, the linear textured structure can be handled smoothly. [Brief description of the drawings]

[0026] [Figure 1] FIG. 1 is an exploded perspective view of a tissue structure forming device according to one embodiment. [Diagram 2] FIG. 2 is a cross-sectional view of a tissue structure forming device according to one embodiment. [Diagram 3] FIG. 3 is a perspective view of a linear texture structure according to one embodiment. [Figure 4] FIG. 4 is an enlarged cross-sectional view of a linear texture structure according to one embodiment. [Diagram 5] FIG. 5 is a cross-sectional view showing a process of forming a linear texture structure in one embodiment. [Figure 6] FIG. 6 is a cross-sectional view showing a process for forming a linear texture structure in one embodiment. [Figure 7] FIG. 7 is a cross-sectional view showing a process of forming a linear texture structure in one embodiment. [Figure 8] FIG. 8 is a cross-sectional view of a tissue structure forming device according to a modified example. [Figure 9] FIG. 9 is a perspective view of a tissue structure forming device in a modified example. [Figure 10] FIG. 10 is a cross-sectional view of a linear texture structure in a modified example. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The tissue structure forming apparatus 10, the linear tissue structure 20, and the tissue structure forming method will be described below. [Outline of the tissue structure formation device] As shown in Fig. 1, the tissue structure forming device 10 includes 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 device 10 is placed in an environment containing biological tissue for a predetermined period of time. The period for which the tissue structure forming device 10 is placed is set in advance based on tests for forming a linear tissue structure 20, etc.

[0028] The environment including the biological tissue may be an in vivo environment including biological tissue. The in vivo environment including biological tissue may be the inside of a disease model animal. The environment including biological tissue may be an in vitro culture system including biological tissue taken out of a living body. The environment including biological tissue may be an artificial environment constructed outside the living body by imitating biological tissue in a living body. The biological tissue may be an ectodermal tissue, a mesodermal tissue, or an endodermal tissue. The biological tissue may be a tissue in which the pluripotent stem cells 20M exist in a healthy state. The biological tissue may be a tissue in which the pluripotent stem cells 20M required for tissue repair exist, such as an injured part or a defective part. The biological tissue may be a subcutaneous tissue including fibroblasts. The biological tissue may be that of a human or any animal other than a human that may be a source of obtaining the pluripotent stem cells 20M. The in vivo environment including biological tissue may be the inside of a human body or the inside of a non-human organism. The non-human organism may be a non-human primate such as a monkey or a chimpanzee. The non-human organism may be a mammal such as a dog, cat, cow, pig, horse, goat, sheep, rat, or mouse, or may be a bird, fish, or amphibian. The inside of a living body containing a biological tissue may be subcutaneously in the limbs, shoulder, back, or abdomen, or may be the abdominal cavity.

[0029] The thin plate portion 31 has a linear region 36 having 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 in the thin plate portion 31 that has a plurality of through-holes 36H (see FIG. 2). The linear region 36 has a mesh formed by the through-holes 36H. FIG. 1 shows an example in which the linear region 36 is a double annular region made up of two annular regions.

[0030] The partition member 11 includes an outer partition wall 12, an inner partition wall 13, and an intermediate partition wall 14. When viewed from a viewpoint facing the thin plate portions 31, a linear region 36 of one thin plate portion 31 is arranged to overlap a linear region 36 of the other thin plate portion 31. The linear regions 36, the outer partition wall 12, the inner partition wall 13, and the intermediate partition wall 14 in the two thin plate portions 31 define a curved hollow portion 30S (see FIG. 2) for forming the linear texture 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 portion 30S from the environment through the penetration portion 36H of the thin plate portion 31. The cells derived from the biological tissue that have entered the hollow portion 30S use the inner surface 31B bordering the opening of the penetration portion 36H as a scaffold to grow a sparse fibrous tissue 22 (see FIG. 5) and accumulate pluripotent stem cells 20M in the sparse fibrous tissue 22. The fibroblasts and pluripotent stem cells 20M grow a fibrous connective tissue 21 (see FIG. 6) from the inner surface 31B bordering the opening of the penetration portion 36H toward the inside of the hollow portion 30S. The fibroblasts and pluripotent stem cells 20M continue to enter and grow in the hollow portion 30S, growing a membranous sparse fibrous tissue 22 further inward than the fibrous connective tissue 21 and further accumulating the pluripotent stem cells 20M in the sparse fibrous tissue 22. Then, the fibroblasts and pluripotent stem cells 20M in the loose fibrous tissue 22 grow fibrous connective tissue 21 (see FIGS. 3 and 4) so ​​as to fill the entire hollow portion 30S.

[0032] In this manner, placement of the tissue structure forming device 10 for a predetermined placement period 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 reduced function of connective tissues that require length and thickness, such as blood vessels, tendons, and ligaments.

[0033] The linear tissue structure 20 formed by the tissue structure forming apparatus 10 may include sparse fibrous tissue 22. Cells derived from biological tissue that have entered the hollow portion 30S grow the sparse fibrous tissue 22 further inward than the fibrous connective tissue 21, and accumulate pluripotent stem cells 20M in the sparse fibrous tissue 22. Removing the tissue structure forming apparatus 10 from the environment while the sparse fibrous tissue 22 remains causes the linear tissue structure 20 to include the sparse fibrous tissue 22. A cell population including the pluripotent stem cells 20M, or the pluripotent stem cells 20M, are accumulated in the sparse fibrous tissue 22.

[0034] The linear tissue structure 20 in which the pluripotent stem cells 20M have been accumulated may be attached to an appropriate biological tissue or a biological tissue having a decreased function, without inducing differentiation, so that the loose fibrous tissue 22 is brought into contact with the appropriate biological tissue or a biological tissue having a decreased function. For example, the linear tissue structure 20 having a linear shape is cut open to form a strip, and the strip-shaped linear tissue structure 20 is attached to the biological tissue. In this manner, the cell population containing the pluripotent stem cells 20M in the linear tissue structure 20, or the pluripotent stem cells 20M, may be directly administered to an appropriate biological tissue or a biological tissue having a decreased function. The linear tissue structure 20 in which the pluripotent stem cells 20M have been accumulated may be used as a strip formed by cutting open a tubular body.

[0035] The linear tissue structure 20, the cell population containing the pluripotent stem cells 20M, and the pluripotent stem cells 20M may be induced to differentiate into target cells outside of a living tissue and then administered to a living tissue or the like. The linear tissue structure 20, the cell population containing the 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 sparse fibrous tissue 22. The isolation of the pluripotent stem cells 20M may be performed by enzyme treatment of the tissue structure forming device 10 taken out from the environment containing the living tissue. The isolation of the pluripotent stem cells 20M may be performed by filtration using a membrane filter, a mesh filter, or the like. The pluripotent stem cells 20M isolated from the sparse fibrous tissue 22 may be cultured and expanded, or may not be cultured and expanded. The cell population containing the pluripotent stem cells 20M partially purified from the sparse fibrous tissue 22 may be cultured and expanded, or may not be cultured and expanded.

[0036] The linear tissue structure 20, the cell population containing the pluripotent stem cells 20M, or the pluripotent stem cells 20M may be administered to a disease site and used in regenerative medicine such as tissue repair, tissue regeneration, repair of tissue or organ damage, and repair of reduced function of tissue or organ. The linear tissue structure 20, the cell population containing the 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 the 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 the fibrous connective tissue 21 and the loose fibrous tissue 22. The linear tissue structure 20 may be used as a fluid obtained by grinding only the loose fibrous tissue 22. The fluidized linear tissue structure 20 may be administered to the diseased site by injection or the like.

[0038] [Configuration of thin plate portion 31] Returning to Fig. 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 have a circular plate shape or a polygonal plate shape. The thin plate portion 31 may have an irregular shape when viewed from a direction facing the outer surface 31A of the thin plate portion 31, or may have a shape with rounded corners.

[0039] The constituent material of the thin plate portion 31 is compatible with biological tissues. The constituent material of the thin plate portion 31 may be a metal material such as stainless steel, titanium, a titanium-nickel alloy, or a cobalt-chromium alloy, or a synthetic resin such as a silicon resin, a polymethylpentene resin, a polytetrafluoroethylene resin, a polypropylene resin, a polyethylene resin, PEEK, an acrylic resin, a nylon, a polycarbonate resin, or a polysulfone resin. The constituent material of the thin plate portion 31 may be a laminate of a metal 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 tissue structure 20. When promotion of 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 any one selected from the group consisting of polymethylpentene resins, polyfluoroethylene resins, polypropylene resins, polyethylene resins, silicone resins, and mixed resins of these resins with other resin components.

[0041] The thin plate portion 31 has two linear regions 36. The number of linear regions 36 may be one or may be three or more. The linear region 36 is a region in the thin plate portion 31 having a band shape with 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 ring shape. The linear region 36 may have a circular ring shape, a wavy line shape, or a broken line shape. When viewed from a viewpoint facing the outer surface 31A of the thin plate portion 31, the linear region 36 may have a linear shape in part.

[0042] The ring shape of the linear region 36 has an open ring shape in which a part of the ring is interrupted in the circumferential direction of the linear region 36. Both ends of the linear region 36 are integral with one connecting reinforcement region 35. The connecting reinforcement region 35 is a region that has a thick band shape extending along the major axis in the thin plate portion 31 and does not have a through portion 36H.

[0043] The connecting reinforcement region 35 mechanically reinforces both ends of the linear region 36 to suppress bending of the linear region 36 during the placement period. The connecting reinforcement region 35 may function as an operating portion for sliding or peeling off the thin plate portion 31 relative to the partition member 11 when separating the thin plate portion 31 from the partition member 11. The connecting reinforcement region 35 may be omitted from the thin plate portion 31.

[0044] The ring shape of the linear region 36 may be a closed ring shape that continues over the entire circumferential direction. The linear region 36 may have multiple rings or may have a concentric shape with 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 multiple annular shapes of the linear region 36 may have one spiral shape interrupted by the connecting reinforcement region 35. The multiple annular shapes of the linear region 36 may have one spiral shape with the connecting reinforcement region 35 omitted. The linear regions 36 of the thin plate portion 31 may have different spiral shapes for each linear region 36. One linear region 36 may have a different shape from the other linear regions 36. One linear region 36 may have a different length from the other linear regions 36, or may have a different line width from the other linear regions 36.

[0046] The through-holes 36H are circular holes penetrating 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 contacts the environment in which 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 have a circular 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 disposed at equal intervals in the extension direction of the linear region 36 and in a direction intersecting said direction.

[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 opening of the through-hole 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 the inner surface 31B of the thin plate portion 31. The opening of the through-hole 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 may have an irregular shape. The thin plate portion 31 may have a combination of a plurality of mutually different shapes as the opening of the through-hole 36H, or a combination of mutually different sizes. When smooth peeling of the fibrous connective tissue 21 is required, 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 penetrating parts 36H may be regularly or randomly 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 when the distribution of the pluripotent stem cells 20M is required to be uniform within a predetermined range, it is preferable that the openings of the penetrating parts 36H are regularly arranged within the linear region 36.

[0049] The opening dimension of the through portion 36H is the dimension of the opening of the through portion 36H on the inner surface 31B of the thin plate portion 31. The opening dimension of the through portion 36H on the inner surface 31B of the thin plate portion 31 is equal to the opening dimension of the through portion 36H on the outer surface 31A of the thin plate portion 31. The opening dimension of the through portion 36H is large enough to allow cells in the biological tissue to pass through the through portion 36H. The minimum opening dimension through which cells in the biological tissue can pass is about 0.01 mm. When the through portion 36H is a circular hole, the opening dimension of the through portion 36H is the diameter of the circular hole. When the through portion 36H is an elliptical hole, the opening dimension of the through portion 36H is the major axis of the elliptical hole. When the opening of the through portion 36H is a polygon, or when the opening of the through portion 36H is an irregular shape, the opening dimension is the diameter of a circle circumscribing the opening. The opening dimension of the penetrating part 36H may be 0.3 mm or more and 3.0 mm or less. The penetrating part 36H is also used to reduce the pressure in the hollow part 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 the biological tissue. The interval between the penetration parts on the inner surface 31B of the thin plate portion 31 is the shortest length on the inner surface 31B between the adjacent penetration parts 36H. The interval between the penetration parts on the inner surface 31B is a size that allows the inner surface 31B, which is a plane between the adjacent penetration parts 36H, to function as a scaffold for cells and the like in the biological tissue. The interval between the penetration parts 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 the openings on the inner surface 31B of the thin plate portion 31 is large enough that the infiltration of cells derived from biological tissue is not inhibited by the fibrous connective tissue 21. The density of the openings on the inner surface 31B of the thin plate portion 31 is large enough that the fibrous connective tissue 21 forms a membrane. 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 portions 36H to the unit area on 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 has a reinforcing region that borders the linear region 36. The reinforcing region does not have a through portion 36H. The reinforcing region is composed 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 one linear region 36. The mechanical reinforcement of the outer edge reinforcement region 32, the intermediate reinforcement region 34, and the connecting reinforcement region 35 prevents flexure and the like over the entire linear region 36 during the placement period.

[0054] The intermediate reinforcement region 34, the inner edge reinforcement region 33, and the connecting reinforcement region 35 border the other linear regions 36. The intermediate reinforcement region 34 borders one linear region 36, and also borders a part of the other linear region 36 adjacent to the 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 is also prevented from bending or the like during the placement period over the entire linear region 36 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 that conforms to the shape of the linear region 36. When 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. When the linear region 36 has a closed annular shape, the reinforcing region may have double closed annular shapes that are separately connected to the outer edge and the inner edge of the linear region 36. When 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 region width of the reinforcement region may be smaller than the line width of the linear region 36 or may be equal to or larger than the line width of the linear region 36. The region width of the reinforcement region is appropriately selected within a range in which the shape of the linear region 36 is stable. For example, the thin plate portion 31 having the linear region 36 is likely to bend so that the center of the thin plate portion 31 sags due to its own weight. The inner edge reinforcement region 33 and the connecting reinforcement region 35 have a belt shape thicker than the outer edge reinforcement region 32 and the intermediate reinforcement region 34, and this suppresses shape changes such as sagging at the center of the thin plate portion 31 due to a 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 in the linear region 36 and the reinforced region are continuous flat surfaces. The tissue structure forming device 10 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 reinforced 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 dissector 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 reinforced region are flat surfaces facilitates peeling off such external connective tissue from the outer surface 31A.

[0058] The thin plate portion 31 has a thickness that allows cells and the like to pass from an environment including biological tissue to 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 penetration portion 36H. The thickness of the thin plate portion 31 has a size that suppresses deformation of the thin plate portion 31 in the biological tissue. The thickness of the thin plate portion 31 has a substantially uniform size in the range where the penetration portion 36H is arranged. The thickness of the thin plate portion 31 has a size that allows cells and the like in 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 equivalent to the reinforcement region so as to contact the reinforcement 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 arranged. The shape equivalent to the reinforcement region is a shape obtained by projecting the reinforcement region in the thickness direction, and is a shape that overlaps with the reinforcement region in the thickness direction. The linear regions 36 of each of the two thin plate portions 31 and the partition wall separate a curved hollow portion 30S for forming the linear texture structure 20 between the two thin plate portions 31 by the partition wall contacting the reinforcement region.

[0060] The constituent material of the partition member 11 is compatible with biological tissues. The constituent material of the partition member 11 may be a metal material such as stainless steel, titanium, a titanium-nickel alloy, or a cobalt-chromium alloy, or a synthetic resin such as a silicone resin, a polymethylpentene resin, a polytetrafluoroethylene resin, a polypropylene resin, a polyethylene resin, PEEK, an acrylic resin, nylon, a polycarbonate resin, or a polysulfone resin. The constituent material of the partition member 11 may be a laminate of a metal material and a synthetic resin.

[0061] The surface of the compartment member 11 may have softness and a water contact angle to promote the formation of the fibrous connective tissue 21. Promoting the formation of the 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 tissue structure 20. When promotion of the formation of the fibrous connective tissue 21 is required, the constituent material of the inner surface 31B of the thin plate portion 31 is preferably any one selected from the group consisting of polymethylpentene resins, polyfluoroethylene resins, polypropylene resins, polyethylene resins, silicone resins, and mixed resins of these resins with other resin components.

[0062] The surface 11A of the partitioning member 11 is configured to enable removal of the linear textured structure 20. The surface 11A of the partitioning member 11 may be a flat surface that allows the linear textured structure 20 to be removed smoothly.

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

[0064] The outer partition wall 12, the inner partition wall 13, the intermediate partition wall 14, and the connecting wall 15 have equal wall heights so as to make the intervals between the two thin plate portions 31 uniform. The wall heights of the outer partition wall 12, the inner partition wall 13, the intermediate partition wall 14, and the connecting wall 15 may be 0.5 mm or more and 5 mm or less. The thickness of the core 16 is thinner than the wall heights of the outer partition wall 12, the inner partition wall 13, the intermediate partition wall 14, and the 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 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 have a straight line shape in a cross section perpendicular to the extension direction of the outer partition wall 12, may be a concave curved surface recessed away from the core 16, or may be a concave folded line recessed away from the core 16.

[0066] The inner partition wall 13 has an elliptical ring shape equivalent 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 may be supported by the connecting wall 15 through engagement with the connecting wall 15. The side surface of the inner partition wall 13 facing the core 16 may have a straight line shape in a cross section perpendicular to the extension direction of the inner partition wall 13, may be a concave curved surface recessed away from the core 16, or may be a concave folded line recessed away from the core 16.

[0067] The intermediate partition wall 14 has an elliptical ring shape equivalent to the intermediate reinforcing region 34 so as to be in contact with the entire intermediate reinforcing 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 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 have a straight line shape in a cross section perpendicular to the extension direction of the intermediate partition wall 14, or may be a concave curved surface recessed away from the core 16, or may be a concave folded line recessed away from the core 16.

[0068] The core 16 has a columnar shape extending in one direction. The extension direction of the core 16 is parallel to the outer partition wall 12, the inner partition wall 13, and the intermediate partition wall 14. One core 16 is disposed between the outer partition wall 12 and the intermediate partition wall 14. One core 16 is equally spaced apart from the outer partition wall 12 and the intermediate partition wall 14. The other core 16 is disposed between the inner partition wall 13 and the intermediate partition wall 14. The other core 16 is equally spaced apart from the inner partition wall 13 and the intermediate partition wall 14. The core 16 is supported by the connecting wall 15 so as to be separable from the connecting wall 15 through engagement with the connecting wall 15 or the like. 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 extension direction of the core 16. In a cross section perpendicular to the extending direction of the core 16, the core 16 may have a polygonal shape with some of the line segments curved.

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

[0070] The two thin plate portions 31, the inner partition wall 13, and the middle partition wall 14 define a hollow portion 30S that houses the other core 16. The distance between the thin plate portion 31 and the core 16 is approximately equal to the distance between the inner partition wall 13 and the core 16. The hollow portion 30S housing the other core 16 is also a tubular space extending in an annular shape. Note that the partition member 11 may omit the other core 16, or one core 16 may have a different cross-sectional shape or cross-sectional area from the other cores 16.

[0071] The depth of the hollow portion 30S is the dimension along the thickness direction of the hollow portion 30S, which is the hollow depth. The hollow depth is the depth of the hollow portion 30S along the depth direction of the through portion 36H. The depth direction of the through portion 36H is the thickness direction of the partition member 11 around the through portion 36H. When a structure such as the core 16 is present in the hollow portion 30S, the hollow depth is the distance between the inner surface 31B and the structure in the depth direction of the through portion 36H. When no structure is present in the hollow portion 30S, the hollow depth is the distance between one thin plate portion 31 and another thin plate portion 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 thickness and wall thickness required for the linear tissue structure 20. Note that the hollow depth is sufficiently large when pluripotent stem cells 20M are accumulated in the loose fibrous tissue 22. In other words, the hollow depth promotes the invasion of the pluripotent stem cells 20M during the growth process of the fibrous connective tissue 21, making it easier for the formation of the loose fibrous tissue 22 to proceed than the formation of the fibrous connective tissue 21.

[0073] In the tissue structure forming device 10, collagen production may occur through competition between the outer surface 31A of the thin plate portion 31 and in the hollow portion 30S. Even if the opening occupancy rates are equal, 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 likely to be recognized as a foreign body due to the excessively large spacing between the penetration portions, and the outer surface 31A of the thin plate portion 31 is likely to be covered with connective tissue. As a result, the openings of the penetration portions 36H are likely to be closed by 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 have difficulty entering the hollow portion 30S, which slows down the formation of the fibrous connective tissue 21 and the formation of the sparse fibrous tissue 22.

[0074] In contrast, when the above-mentioned dimensional range is satisfied, the number of the through-holes 36H is appropriately large and the opening size is appropriately 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 because the intervals between the through-holes are small. Also, on the inner surface 31B of the partitioning member 11, the starting points for the formation of the fibrous connective tissue 21 are secured in sufficient numbers to allow the fibrous connective tissue 21 to be formed in a membrane-like shape.

[0075] The accumulation of the pluripotent stem cells 20M is realized by the invasion of the pluripotent stem cells 20M in the living tissue into the hollow portion 30S, and the proliferation of the invaded pluripotent stem cells 20M in the hollow portion 30S. The invasion of the pluripotent stem cells 20M is promoted by the fact that the penetration portion 36H continues to open during most of the predetermined retention period, and the space in which the sparse fibrous tissue 22 is formed continues to exist in the hollow portion 30S. In the above-mentioned dimensional range, when the hollow depth is 2.0 mm or more, the growth of the sparse fibrous tissue 22 can be promoted more than the growth of the fibrous connective tissue 21. In addition, the invasion of the fibroblasts and the pluripotent stem cells 20M can be promoted to the extent that a large recess or hole opposite the opening of the penetration portion 36H is not formed in the fibrous connective tissue 21. Then, the fibrous connective tissue 21 having a membrane shape is easily formed, and as the growth of the fibrous connective tissue 21 is promoted, the pluripotent stem cells 20M are easily accumulated inward of the fibrous connective tissue 21. In particular, when the environment including the living tissue is the inside of a disease model animal, the growth of the fibrous connective tissue 21 is likely to be delayed, so that the probability of accumulating the pluripotent stem cells 20M increases.

[0076] When the thickness of the thin plate portion 31 is 2.0 mm or less and the opening dimension of the through-hole portion 36H is 0.3 mm or more, cells and the like in the biological tissue can enter the hollow portion 30S even if the through-hole portion 36H is slightly narrowed by the fibrous connective tissue 21. Since the through-hole portion 36H is not easily blocked by the fibrous connective tissue 21, the fibrous connective tissue 21 is likely to grow, and the pluripotent stem cells 20M are likely to accumulate in the loose fibrous tissue 22.

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

[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. Therefore, deformation of the thin plate portion 31 is easily suppressed in the living tissue.

[0079] When the through-hole interval is 0.5 mm or more, the fibrous connective tissue 21 is likely to grow using the inner surface 31B as a scaffold. When the through-hole interval is 5.0 mm or less, the fibrous connective tissue 21 growing from the periphery of the opening of one through-hole 36H is likely to be connected to the fibrous connective tissue 21 growing from the periphery of the opening of another through-hole 36H. The connection between the peripheries of the openings of the through-holes 36H in the fibrous connective tissue 21 suppresses the formation of partial weak sites in the fibrous connective tissue 21, making it easier to handle the linear tissue structure 20. Furthermore, when the opening occupancy rate is 30% or more and 70% or less, the fibrous connective tissue 21 is likely to spread in a membrane-like manner over the entire inner surface 31B.

[0080] The retention period of the tissue structure forming device 10 is preferably a short period of time, about 4 weeks from the start of retention, during which inflammation caused by the incision required for retention of the tissue structure forming device 10 subsides. On the other hand, when the environment containing the living tissue is the inside of a disease model animal, the growth of the fibrous connective tissue 21 is likely 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 through portion 36H is 3.0 mm or less, even in such an environment, large recesses or holes are unlikely to be formed in the fibrous connective tissue 21 at the site facing the through portion 36H after the retention period has elapsed. Furthermore, when the opening occupancy rate is 30% or more and 70% or less, the fibrous connective tissue 21 is likely to spread in a membrane-like manner over the entire inner surface 31B. And, the through portion 36H is unlikely to be blocked by the fibrous connective tissue 21.

[0081] When the hollow depth is 2 mm or more, the hollow portion 30S is significantly prevented from being buried in the fibrous connective tissue 21 during the suitable retention period, and it is easy to obtain a loose fibrous tissue 22 with a sufficient layer thickness and pluripotent stem cells 20M accumulated in the loose fibrous tissue 22. In particular, when the environment including the living tissue is the in vivo environment of a disease model animal, the growth of the fibrous connective tissue 21 is likely to be delayed, increasing the probability that the pluripotent stem cells 20M can be accumulated.

[0082] [Line tissue structure 20] As shown in Fig. 3, one example of the linear tissue structure 20 is a linear tissue structure having a curved tubular shape. The linear tissue structure 20 may have a polygonal tubular shape having a polygonal cross section. The cross-sectional shape of the linear tissue structure 20 may be a shape in which some of the line segments of a polygon are curved. The cross-sectional shape of the linear tissue structure 20 may be a rectangle, a hexagon, or an octagon.

[0083] The linear texture structure 20 has an annular hollow portion 20V with the core 16 removed. The annular hollow portion 20V may be a hole having a polygonal cross section. The cross-sectional shape of the annular hollow portion 20V may be a shape in which some of the lines of a polygon are curved. The cross-sectional shape of the annular hollow portion 20V may be a rectangle, a hexagon, or an octagon. The linear texture structure 20 may have a columnar shape in which the annular hollow portion 20V is omitted.

[0084] The outer surface of the linear tissue structure 20 has corners 20C along the extending direction of the linear tissue structure 20. The corners 20C of the linear tissue structure 20 are formed by the contact area between the thin plate portion 31 and the outer partition wall 12, the contact area between the thin plate portion 31 and the middle partition wall 14, and the contact area between the thin plate portion 31 and the inner partition wall 13. The corners 20C extending in one direction in the linear tissue structure 20 make it easy to visually check whether or not the linear tissue structure 20 is twisted or excessively bent when using the linear tissue structure 20.

[0085] The linear texture structure 20 has a cylindrical inner surface 26A. The cylindrical inner surface 26A is a flat surface reflecting the surface shape of the core 16. The linear texture structure 20 has 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 unevenness reflecting 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 sufficiently smaller than the surface roughness Ra of the first outer surface 26B, or 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, the middle partition wall 14, or the inner partition wall 13.

[0086] The corner 20C of the linear textured structure 20 includes a ridge line between the first outer surface 26B and the second outer surface 20S. The corner 20C is formed by 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 check whether the corner 20C exists. This also makes it easier to visually check whether the linear textured structure 20 is twisted or excessively bent.

[0087] 4, the linear tissue structure 20 comprises fibrous connective tissue 21. The fibrous connective tissue 21 comprises a first outer surface 26B peeled off from the inner surface 31B of the thin plate portion 31. The first outer surface 26B has protrusions 21T reflecting the shape of the through-holes 36H, and depressions 21A sandwiched between the protrusions 21T. The width 20W of the protrusions 21T corresponds to the opening dimension of the through-holes 36H.

[0088] The fibrous connective tissue 21 has a higher fiber density than the sparse fibrous tissue 22 and contains fewer cells than the sparse fibrous tissue 22. The fibrous connective tissue 21 contains collagen fibers such as fibrous collagen and fibroblasts. The fibrous connective tissue 21 may contain collagen fiber bundles. The collagen fibers of the fibrous connective tissue 21 preferably contain type I collagen. The ratio of type I collagen in 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 in the total collagen contained in the fibrous connective tissue 21 is higher than the ratio of type I collagen in the total collagen contained in the sparse fibrous tissue 22.

[0089] When the linear tissue structure 20 includes the loose fibrous tissue 22, the loose fibrous tissue 22 is formed over the entire side surface opposite to the first outer surface 26B of the fibrous connective tissue 21. Retention of the tissue structure forming device 10 for a predetermined retention period forms the fibrous connective tissue 21 in the hollow portion 30S, and also forms a membranous loose fibrous tissue 22 supported by the fibrous connective tissue 21. A cell population including the pluripotent stem cells 20M, or the pluripotent stem cells 20M, is accumulated 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, and the linear tissue structure 20 is easy to handle. When the linear tissue structure 20 does not include sparse fibrous tissue 22, the thickness H20 of the fibrous connective tissue 21 is almost equal to the hollow depth, for example, 0.5 mm or more and 10 mm or less. When the linear tissue structure 20 includes sparse 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 the pluripotent stem cells 20M is easily ensured in the hollow portion 30S.

[0091] The thickness HT of the protrusion 21T is equal to or less than the depth of the penetrating portion 36H. The protrusion 21T of the fibrous connective tissue 21 may be omitted. The fibrous connective tissue 21 may have capillaries 24 at the sites corresponding to the penetrating portions 36H. The capillaries 24 are newly generated in the hollow portion 30S through the penetrating portions 36H during the formation of the linear tissue structure 20. When the linear tissue structure 20 includes sparse fibrous tissue 22, the capillaries 24 may reach the sparse fibrous tissue 22.

[0092] The loose fibrous tissue 22 has a lower fiber density than the fibrous connective tissue 21, and has more cells scattered among the 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 content of type III collagen in the loose fibrous tissue 22 is higher than the content of type III collagen in the fibrous connective tissue 21.

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

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

[0095] The pluripotent stem cells 20M contained in the sparse fibrous tissue 22 may express both the mesenchymal stem cell marker CD90 and the mesenchymal stem cell marker CD105. The pluripotent stem cells 20M contained in the sparse fibrous tissue 22 may express the mesenchymal stem cell marker CD90 or the mesenchymal stem cell marker CD105. The pluripotent stem cells 20M contained in the sparse 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 sparse fibrous tissue 22 may contain stem cells having high angiogenic potential. The sparse fibrous tissue 22 may contain, as the stem cells having high angiogenic potential, stem cells expressing the growth factor marker VEGF, or stem cells expressing both the growth factor marker VEGF and the pluripotent stem cell marker SSEA3. The sparse fibrous tissue 22 may contain stem cells expressing the growth factor marker HGF.

[0098] The ratio of the total number of pluripotent stem cells 20M contained in the sparse fibrous tissue 22 to the total number of cells contained in the sparse fibrous tissue 22 is the stem cell ratio. The stem cell ratio can be calculated as the total cell number, which is the number of cells recovered from the decomposed tissue when the sparse fibrous tissue 22 is treated in a 0.25% collagenase type I solution at 37°C for 1.5 hours. The stem cell ratio can be calculated as 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. The stem cell ratio of the sparse 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 sparse 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 stem cells contained in the sparse fibrous tissue 22 to the number of pluripotent stem cells contained in the sparse fibrous tissue 22 is the mesenchymal stem cell ratio. The mesenchymal stem cell ratio can be calculated as the number of cells expressing the mesenchymal stem cell marker CD90 or the mesenchymal stem cell marker CD105 as the number of mesenchymal stem cells. The mesenchymal stem cell ratio can be calculated as 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 as the number of pluripotent stem cells. 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] [Tissue structure formation method] As shown in FIG. 5, when the tissue structure forming device 10 is placed in an environment containing biological tissue, liquid components 20L such as extracellular matrix derived from biological tissue invade the hollow portion 30S through the through-hole portion 36H of the linear region 36. The hollow portion 30S of the tissue structure forming device 10 is filled with the liquid components 20L derived from biological tissue. When the hollow portion 30S of the tissue structure forming device 10 is filled with the liquid components 20L, cells such as pluripotent stem cells 20M and fibroblasts derived from biological tissue invade the hollow portion 30S through the through-hole portion 36H. The fibroblasts that have invaded the hollow portion 30S begin to form sparse fibrous tissue 22 from the inner surface 31B toward the inside of the hollow portion 30S in the linear region 36, using the inner surface 31B bordering the opening of the through-hole portion 36H as a scaffold.

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

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

[0103] 7, the fibroblasts and pluripotent stem cells 20M that continue to enter the hollow portion 30S form a membranous fibrous connective tissue 21 that spreads throughout the linear region 36 so as to connect the opening edges of the penetrating portion 36H with the fibrous connective tissue 21. The fibroblasts and pluripotent stem cells 20M that continue to enter the hollow portion 30S form a membranous loose fibrous tissue 22 and capillaries 24 that follow the spread of the fibrous connective tissue 21.

[0104] The inside of the hollow portion 30S, which is more likely to be recognized as a foreign body than the outside of the hollow portion 30S, continues to accumulate pluripotent stem cells 20M in the sparse fibrous tissue 22 even while the fibrous connective tissue 21 is being formed in a membrane-like shape. The pluripotent stem cells 20M accumulated in the sparse fibrous tissue 22 proliferate within the sparse fibrous tissue 22. As a result, the cells derived from biological tissues that have entered the hollow portion 30S grow the membranous sparse fibrous tissue 22 further inward than the membranous fibrous connective tissue 21, and accumulate many pluripotent stem cells 20M in the sparse fibrous tissue 22.

[0105] When 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 hollow portion 30S is filled with the fibrous connective tissue 21. When 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 during which the fibrous connective tissue 21 fills the hollow portion 30S.

[0106] When the tissue structure forming apparatus 10 is taken out of the environment, first, the connective tissue formed on the outer surface 31A of the thin plate portion 31 is dissected from the outer surface 31A. In dissection using a dissector, dissection that depends on the skill of the operator is repeated at various locations on the surface of the tissue structure forming apparatus 10. At this time, the dissection of the external connective tissue proceeds more smoothly to the extent that the thin plate portion 31 has a flat plate shape.

[0107] Next, from the tissue structure forming device 10 from which the connective tissue has been peeled off, the thin plate portion 31 is separated from the partitioning member 11. The thin plate portion 31 may be slid relative to the partitioning member 11 along the surface direction of the thin plate portion 31, or the thin plate portion 31 may be peeled off from the partitioning member 11. Then, from the partitioning member 11 separated from the thin plate portion 31, the linear tissue structure 20 covering the core 16 and the core 16 are removed from the connecting wall 15. The linear tissue structure 20 taken out from the hollow portion 30S has the core 16 removed.

[0108] As described above, according to the above embodiment, the following effects can be obtained. (1) The corner 20C of the linear textured 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 20C composed of surfaces having different surface structures assists in visual confirmation of the posture of the linear textured structure 20. As a result, twists and excessive bends in the linear textured structure 20 can be easily identified and repaired, which facilitates the handling of the linear textured structure 20.

[0109] (2) When the hollow portion 30S is divided in a curved shape, such as multiple rings or a spiral shape, the environment required for placement is smaller than 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 having a ring and an outer cylindrical surface having a ring, 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 in the device surface requires troublesome procedures such as peeling off the external connective tissue and separating the external connective tissue from the tissue structure.

[0110] In this regard, since the thin plate portion 31 has a flat plate shape, the device surface is configured to be substantially flat in accordance with the surface shape of the thin plate portion 31. Therefore, even if the linear hollow portions 30S are adjacent to each other, a narrow recess is not formed in the device surface.

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

[0112] (4) In the two thin plate portions 31, the outer edge reinforcement region 32, the inner edge reinforcement region 33, and the intermediate reinforcement region 34 border the linear region 36, so that the reduction in mechanical strength of the thin plate portion 31 itself due to the presence of a mesh is also suppressed. Furthermore, when the partition member 11 includes the central core 16, the effects equivalent to those of (1) to (3) above are obtained when the tubular linear tissue structure 20 is formed.

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

[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 is provided that is more suitable for forming the linear texture structure 20. Even when such a very thin thin plate portion 31 has a linear region 36, the reduction in mechanical strength 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 suppressing the reduction in strength by the reinforcing region becomes more remarkable.

[0115] (7) Since 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 the outer peripheral surface of the core 16 is flat surfaces, the linear tissue structure 20 can be smoothly removed from the hollow portion 30S.

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

[0117] The above embodiment may be modified as follows. [Thin plate part 31] As shown in FIG. 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 thicker than the linear region 36 borders the linear region 36, the mechanical strength of the thin plate portion 31 itself is further suppressed from decreasing. 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 in plate thickness between the linear region 36 and the reinforcement region. The step 36D may be disposed on the outer surface 31A of the thin plate portion 31 or on the inner surface 31B of the thin plate portion 31. When the step 36D is larger than 0.5 mm, it is preferable that the step 36D is disposed 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 where the mesh is connected in a curved line may be a region where the mesh is connected in a straight line. That is, the thin plate portion 31 may be straight or may be a combination of a curved line and a straight line. At least one of a curved line, a straight line, and a combination of these is a linear shape. The thin plate portion 31 may have a linear region 36 where the mesh is connected in this linear shape.

[0119] 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 omit the connecting reinforcement region 35 and the outer edge reinforcement region 32. The thin plate portion 31 may have a through portion 36H throughout the entire thin plate portion 31.

[0120] [Housing material] Furthermore, the two thin plate portions 31 may form one housing member. For example, as shown in FIG. 9, two thin plate parts 31 having an elliptical flat plate shape are connected to face each other with a gap corresponding to the wall height of the partition member 11. In this case, both ends in the short diameter direction and one end in the long diameter direction of one thin plate part 31 may be connected to both ends in the short diameter direction and one end in the long diameter direction of the other thin plate part 31 by a connecting member 51. The connecting member 51 may include a strip-shaped part extending in a cross shape in the short diameter direction and the long diameter direction of the thin plate part 31, and a hook disposed at the tip of the strip-shaped part. The connecting member 51 may be arranged so that the strip-shaped part faces one thin plate part 31 (the thin plate part 31 on the back side of the paper in FIG. 9) and the hook is hooked on the other thin plate part 31 (the thin plate part 31 on the front side of the paper in FIG. 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 one storage member. Then, the partition member 11 is inserted between the two thin plate portions 31 from the other end in the long diameter direction of the thin plate portion 31. Also, the partition member 11 is pulled out from between the two thin plate portions 31 from the other end in the long diameter direction of the thin plate portion 31. In other words, the storage member including the two thin plate portions 31 is configured so that the partition member 11 can be inserted and removed.

[0122] According to this modified example, the partitioning member 11 can be inserted into and removed from the accommodation member, which facilitates handling of the tissue structure forming device 10 required to form the linear tissue structure 20. Note that insertion and removal of the partitioning member 11 into and from the gap between the two thin plate portions 31 is not limited to translation of the partitioning member 11 on the spreading surface of the thin plate portions 31, and may also be rotation of the partitioning member 11.

[0123] [Line tissue structure] 10, the annular hollow portion 20V of the linear texture structure 20 may be a circular hole. That is, the linear texture structure 20 may be a tubular body having a rectangular outer cross section and having holes with circular cross sections. [Explanation of symbols]

[0124] 10…Tissue structure forming device 11...Partition member 12...Outer compartment wall 13…Inner partition wall 14...Intermediate partition wall 15…Connecting wall 16…Central core 20... Linear tissue structure 20C…Corner 20V…Annular hollow section 26A…Cylinder inner surface 26B…1st outer surface 26S…Second outer surface 21...Fibrous connective tissue 21A…Recess 21B…Second side 22...Lose fibrous tissue 23…Pluripotent stem cells 24...Capillaries 31...Thin plate part 30S…Hollow part 32…Outer edge reinforcement area 33…Inner edge reinforcement area 34…Middle reinforcement area 35…Connection reinforcement area 36…linear area 36H...Penetration part

Claims

1. A linear textured structure, comprising: a first outer surface which is an uneven surface extending in the extension direction of the linear texture structure; A flat second outer surface extending in the extension direction and connected to the first outer surface via a ridge line; Equipped with The recesses between adjacent protrusions on the first outer surface have a mesh shape. A linear textured structure comprising:

2. The linear tissue structure is a tubular connective tissue having a polygonal outer cross section. The linear texture structure according to claim 1 .

3. The linear tissue structure is a tubular connective tissue having circular or polygonal pores in cross section. The linear texture structure according to claim 2 .

4. A tissue structure forming device that is placed in an environment containing biological tissue to form a linear tissue structure, Two thin plate portions each having a flat plate shape; A partition member that is sandwiched between the thin plate portions and configured to be separable from the thin plate portions, the thin plate portion includes a linear region having a mesh formed of a plurality of through-holes, and when viewed from a viewpoint facing the thin plate portion, one of the linear regions overlaps with another of the linear regions; the partition member has a flat surface and a shape that borders the linear region when viewed from a viewpoint facing the thin plate portion, The linear regions in the two thin plate portions and the partition member define a linear hollow portion for forming the linear texture structure. A tissue structure forming device comprising:

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

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

7. the linear region has a multi-ring configuration consisting of a plurality of annular regions; The reinforcement region bordering one of the annular regions is arranged so as to border a part of the other annular region adjacent to the reinforcement region. The tissue structure forming apparatus according to claim 5 or 6.

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

9. The thickness of the reinforcing region is greater than that of the linear region. The tissue structure forming apparatus according to claim 5 or 6.

10. The partition member is The hollow portion further includes a center core extending linearly in accordance with the shape of the linear region. The tissue structure forming device according to claim 4 .

11. 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-hole is 0.01 mm or more and 3.0 mm or less, The opening occupancy rate of the through-hole portion in the linear region is 30% or more and 70% or less. The tissue structure forming device according to claim 4 .

12. The distance between the two thin plate portions is 0.5 mm or more and 5 mm or less. The tissue structure forming device according to claim 4 .

13. The two thin plate portions extend in a plane including one direction, The two thin plate portions constitute an accommodation member that accommodates the partition member between the thin plate portions in a removable manner along the one direction. The tissue structure forming device according to claim 4 .

14. A method for forming a tissue structure, comprising placing a tissue structure forming device in an environment including biological tissue other than that of a human, and forming the linear tissue structure in the tissue structure forming device, The tissue structure forming apparatus is the tissue structure forming apparatus according to any one of claims 4 to 6. A method for forming a tissue structure comprising the steps of:

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