Tissue structure forming device and tissue structure forming method

Abstract

A tissue structure forming device and a tissue structure forming method are provided that can reduce the load required to remove a tissue structure. [Solution] A tissue structure forming device that is placed in an environment containing biological tissue to form a tissue structure, comprising a main body portion 10 that defines a hollow portion 11 for forming the tissue structure, the main body portion 10 having an outer surface that contacts the environment, an inner surface 14 that defines the hollow portion, and a plurality of penetration portions 13 that penetrate from the outer surface to the inner surface 14 and allow cells contained in the biological tissue to pass from the environment into the hollow portion 11, at least one of the outer surface and the inner surface 14 being a target surface, and further comprising a peeling portion 18A having a shape that extends in one direction along the target surface, the peeling portion 18A being attached to the main body portion 10 so that it can move across the target surface in the other direction along the target surface and can be placed in the environment together with the main body portion 10.

Description

[Technical Field]

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

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

[0003] One type of regenerative medicine technology, which is a medical technology that revives lost tissues and organs, replaces damaged tissue structures with tissue structures derived from living organisms. One technology for forming tissue structures derived from living organisms 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 form a tissue structure derived from living organisms on the tissue structure forming device (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 define a hollow space having various shapes, such as a flat space, a cylindrical space, or a valve-shaped space. Cells such as fibroblasts and immune cells that invade between the two connective tissue forming surfaces form connective tissue bodies as tissue structures, filling 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. However, the basis for using embryonic stem cells, which require ethical considerations, and induced pluripotent stem cells, which require safety confirmation, in regenerative medicine has yet to be established. Meanwhile, pluripotent stem cells present in vivo, although present in small numbers in living tissues, have progressed through the development stage and are now moving to the clinical stage. One technique for accumulating pluripotent stem cells present in vivo involves placing a tissue structure formation device, a foreign body, into the living tissue, and then accumulating the pluripotent stem cells in the living tissue onto the tissue structure formation device.

[0006] An example of such a tissue structure forming device accumulates pluripotent stem cells in a hollow portion of the device. The tissue structure forming device includes a frame surrounding the hollow portion. The frame defines an opening by two columnar members, which extends in the direction of extension of the columnar members. The hollow portion surrounded by the frame communicates with the environment within the living body through the opening. The width of the opening and the depth of the hollow portion are determined so that fibroblasts fill the hollow portion with fibrous connective tissue, forming a depression in the fibrous connective tissue at a location facing the opening. The width of the opening and the depth of the hollow portion are also determined so that a depression extending from the opening toward the hollow portion is formed in the fibrous connective tissue at a location facing the opening. 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 tissue structure in the hollow portion, in which pluripotent stem cells have accumulated in the depression of the connective tissue (see, for example, Patent Document 8). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Laid-Open No. 2004-261260 [Patent Document 2] Japanese Patent Application Laid-Open No. 2007-312821 [Patent Document 3] Japanese Patent Application Laid-Open No. 2014-030598 [Patent Document 4] Japanese Patent Application Laid-Open No. 2017-169778 [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. During the clinical stage, where large-scale tests are conducted to prove efficacy and safety, there is a strong demand for smooth handling of tissue structure formation devices.

[0009] On the other hand, when a tissue structure forming device is placed in the environment, the entire outer surface of the device is covered with external connective tissue while a tissue structure is being formed in the hollow portion. The external connective tissue covering the entire outer surface of the device is integrated with the tissue structure via a through-hole that connects the hollow portion to the environment. For this reason, removing the tissue structure requires various cumbersome procedures, such as removing the tissue structure forming device, peeling the external connective tissue from the outer surface of the device, and separating the tissue structure from the external connective tissue. [Means for solving the problem]

[0010] A 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 tissue structure. The tissue structure forming device comprises a main body portion that defines a hollow portion for forming the tissue structure, the main body portion having an outer surface that contacts the environment, an inner surface that defines the hollow portion, and a plurality of penetration portions that penetrate from the outer surface to the inner surface and allow cells contained in the biological tissue to pass from the environment to the hollow portion. At least one of the outer surface and the inner surface is a target surface. The tissue structure forming device further comprises a dissection portion having a shape that extends in one direction along the target surface. The dissection portion is attached to the main body portion so as to be movable across the target surface in another direction along the target surface and so as to be placed in the environment together with the main body portion.

[0011] According to the tissue structure forming device, when the tissue structure forming device is placed, the dissection section extending in one direction is placed in the environment together with the main body section. Therefore, the area where the external connective tissue is to be dissected, or the area where the tissue structure is to be dissected, is predetermined before placement as the relative position of the dissection section with respect to the target surface. When the tissue structure forming device or the tissue structure is removed, the dissection section moves in the other direction. The movement of the dissection section achieves dissection over a wide area at the predetermined area. For example, if the target surface is an outer surface, the movement of the dissection section dissects the external connective tissue from the outer surface. If the target surface is an inner surface, the movement of the dissection section dissects the tissue structure from the inner surface.

[0012] In conventional dissection using a dissector, dissection is repeated at various locations, depending on the skill of the operator. In contrast, dissection using the dissector described above achieves wide-area dissection at predetermined locations. As a result, in the case of dissection of external connective tissue, the load required for removal of the tissue structure forming device and even the tissue structure itself is significantly reduced. In the case of dissection of a tissue structure, the load required for removal of the tissue structure itself is significantly reduced. Furthermore, because the movement of the dissector achieves wide-area dissection, the shape precision of the tissue structure is improved compared to repeated dissection using a dissector, which is dependent on the skill of the operator.

[0013] In the tissue structure forming device, the dissection section may include a first wire extending in the one direction over the entire range in which the piercing section is arranged within the target surface. As described above, during the retention period, the dissection portion is positioned so as to follow the target surface. With the tissue structure formation device, compared to when the dissection portion has a strip shape extending in one direction, the dissection portion is less likely to cover the penetration portion because it is a wire. Therefore, even if the dissection portion is positioned so as to follow the target surface, the positioning of the dissection portion is less likely to affect the formation of the tissue structure. Furthermore, the bonds between the tissue structure and the external connective tissue at multiple penetration portions are severed all at once by a single movement of the wire. Therefore, variation in the cut shape of the tissue structure is also reduced compared to when repeated dissection is performed using a dissector.

[0014] In the tissue structure forming device, the target surface may be the outer surface having a cylindrical shape extending in the other direction, and the first wire may have a ring shape extending circumferentially around the target surface and be attached to the main body with a predetermined gap between the outer surface and the first wire.

[0015] According to the tissue structure forming device, the peeling site by the peeling unit is predetermined near the boundary between the outer surface and the external connective tissue, which significantly reduces the load when removing the tissue structure forming device and the tissue structure itself, and also reduces the variation in the cut shape of the tissue structure.

[0016] The tissue structure forming device may further include a guide part connected to the peeling part, the guide part being configured to guide the movement of the peeling part in the other direction. With this configuration, the movement of the peeling part is guided by the guide part, which increases the effectiveness of reducing the removal load and improving shape accuracy.

[0017] In the tissue structure forming device, the peeling portion may be a first wire extending in the one direction over the entire area of ​​the target surface where the penetrating portion is arranged, and the guiding portion may be a second wire connected to the first wire and extending in the other direction to the outside of the target surface.

[0018] With the tissue structure forming device, the guide portion has a linear shape extending in another direction, so the penetration portion is less likely to be covered by the guide portion compared to when the guide portion extends along the opposing surface. Therefore, even if the guide portion is positioned so as to follow the target surface during the retention period, the positioning of the guide portion is less likely to affect the formation of the tissue structure. Furthermore, because the guide portion is likely to have strength against pulling in another direction, it is also suitable for moving the dissection portion by pulling the guide portion in another direction during dissection.

[0019] In the tissue structure forming device, the target surface may have a cylindrical shape extending in the other direction, the one direction being a circumferential direction of the target surface and the other direction being an axial direction of the target surface, the first wire having a ring shape extending in the circumferential direction of the target surface and including a plurality of connecting portions lined up in the circumferential direction, and the second wire extending from the connecting portions in the axial direction of the target surface.

[0020] According to the tissue structure forming device, the looped first wire is guided in the other direction by a plurality of connecting portions, which allows the first wire to move more smoothly in the other direction than when the looped first wire is guided by a single connecting portion.

[0021] The tissue structure forming device may further include a setting section connected to the peeling section, and the setting section may determine the position of the peeling section relative to the target surface by engagement between the main body section and the setting section.

[0022] According to the tissue structure forming device, the relative position of the dissection portion with respect to the target surface is predetermined prior to placement by engagement between the setting portion and the main body portion. The main body portion, which forms the tissue structure therein, is likely to remain stationary in the environment throughout the placement period. Because the main body portion, which is likely to remain stationary, engages with the setting portion, the relative position of the dissection portion with respect to the target surface is also unlikely to change throughout the placement period. As a result, the deviation between the predetermined site and the actual dissection site is further suppressed.

[0023] In the tissue structure forming device, the peeling portion may be a first wire extending in the one direction over the entire range of the target surface where the penetrating portion is arranged, and the setting portion may be a second wire connected to the first wire, extending in the other direction, and bending outside the target surface so as to be engageable with the main body portion.

[0024] With the tissue structure forming device, the setting portion is likely to have strength against pulling in the other direction, so that during dissection, the first wire can be moved by pulling the setting portion in the other direction, i.e., it is suitable for guiding the movement of the first wire in the other direction. Furthermore, prior to placement, the relative position of the dissection portion with respect to the target surface is determined by bending the second wire and engaging with the main body portion. This allows the second wire to both set the position of the first wire and guide the movement of the first wire.

[0025] In the tissue structure forming device, the target surface may be the outer surface having a cylindrical shape extending in the other direction, the one direction being a circumferential direction of the target surface and the other direction being an axial direction of the target surface, the first wire having a ring shape extending in the circumferential direction of the target surface, and the second wire extending in the axial direction and being bent by movement in the axial direction so as to abut against the edge of the outer surface.

[0026] According to the tissue structure forming device, the region to be dissected by the first wire is predetermined at the boundary between the outer surface and the external connective tissue. This significantly reduces the load on the tissue structure forming device and the tissue structure itself, and also reduces the variation in the cut shape of the tissue structure. Furthermore, the common second wire both sets the position relative to the first wire and guides the movement relative to the first wire.

[0027] According to the tissue structure forming device, the main body portion may include a partition wall having the outer surface and the inner surface, the partition wall may include an edge portion and the through portion other than the edge portion, and the setting portion may determine the position of the peeling portion on the edge portion.

[0028] According to the tissue structure forming device, even if the dissection unit is positioned so as to follow the target surface during the retention period, the position of the dissection unit is less likely to affect the formation of the tissue structure. A tissue structure formation method for solving the above problem is a tissue structure formation method in which a tissue structure formation device is placed in an environment containing biological tissue to form a tissue structure within the tissue structure formation device, wherein the tissue structure formation device is the tissue structure formation device described above. [Effects of the Invention]

[0029] According to the tissue structure forming device and the tissue structure forming device of the present disclosure, the load required to remove the tissue structure can be reduced. [Brief explanation of the drawings]

[0030] [Figure 1] FIG. 1 is an exploded perspective view of a tissue structure forming device according to one embodiment. [Figure 2] FIG. 2 is a cross-sectional view showing an example of a tissue structure according to an embodiment. [Figure 3] FIG. 3 is a cross-sectional view showing a process for forming a tissue structure in one embodiment. [Figure 4] FIG. 4 is a cross-sectional view showing a process for forming a tissue structure in one embodiment. [Figure 5] FIG. 5 is a cross-sectional view showing a process for forming a tissue structure in one embodiment. [Figure 6] FIG. 6 is a cross-sectional view showing a process for forming a tissue structure in one embodiment. [Figure 7] FIG. 7 is a perspective view of a tissue structure forming device according to a modified example. [Figure 8] FIG. 8 is a perspective 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 according to a modified example. [Figure 10] FIG. 10 is a perspective view of a tissue structure forming device according to a modified example. [Figure 11] FIG. 11 is a perspective view of a tissue structure forming device according to a modified example. [Figure 12] FIG. 12 is a partial cross-sectional view of a tissue structure forming device according to a modified example. DETAILED DESCRIPTION OF THE INVENTION

[0031] The tissue structure forming device and the method for forming the tissue structure forming device will be described below. [Outline of the tissue structure formation device] As shown in FIG. 1 , the tissue structure forming device comprises a main body portion 10 and an auxiliary portion 18. The main body portion 10 defines a hollow portion 11 for forming a tissue structure 20. The auxiliary portion 18 is attached to the main body portion 10. The main body portion 10 comprises a partition wall 12, a first cap 16, and a second cap 17. The auxiliary portion 18 comprises a peeling portion 18A, a guide portion 18B, and a connecting portion 18C. The tissue structure forming device is placed in an environment containing biological tissue for a predetermined period of time. That is, the auxiliary portion 18 is placed in the environment together with the main body portion 10. The period for which the tissue structure forming device is placed is set in advance based on tests for forming the tissue structure 20, etc.

[0032] The environment containing biological tissue may be an in vivo environment containing biological tissue. The in vivo environment containing biological tissue may be the inside of a disease model animal. The environment containing biological tissue may be an in vitro culture system containing biological tissue removed from a living organism. The environment containing biological tissue may be an artificial environment constructed ex vivo to mimic biological tissue in a living organism. The biological tissue may be ectodermal tissue, mesodermal tissue, or endodermal tissue. The biological tissue may be tissue in which pluripotent stem cells 23 exist in a healthy state. The biological tissue may be tissue in which pluripotent stem cells 23 required for tissue repair exist, such as in an injured or defective area. The biological tissue may be subcutaneous tissue containing fibroblasts. The biological tissue may be from a human or any non-human animal that can be a source of pluripotent stem cells 23. The in vivo environment containing 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 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 biological tissue may be subcutaneously located in the limbs, shoulder, back, or abdomen, or may be the abdominal cavity.

[0033] The partition wall 12 defines the hollow portion 11. The partition wall 12 has a plurality of penetrations 13. An inner surface 14 of the partition wall 12 borders the openings of the penetrations 13. An outer surface of the partition wall 12 also borders the openings of the penetrations 13. The first cap 16 and the second cap 17, together with the partition wall 12, define the hollow portion 11.

[0034] When the tissue structure forming device is placed in an environment containing biological tissue, cells, plasma proteins, and the like derived from the biological tissue enter from the environment through the penetrations 13 of the compartment walls 12 into the hollow portion 11 separated by the compartment walls 12. The cells, etc. derived from the biological tissue that have entered the hollow portion 11 use the inner surface 14 bordering the opening of the penetrations 13 as a scaffold to grow loose fibrous tissue 22 and accumulate pluripotent stem cells 23 in the loose fibrous tissue 22. The fibroblasts and pluripotent stem cells 23 grow fibrous connective tissue 21 from the inner surface 14 bordering the opening of the penetrations 13 toward the inside of the hollow portion 11. The fibroblasts and pluripotent stem cells 23 continue to enter and proliferate in the hollow portion 11, growing a membrane-like loose fibrous tissue 22 further inward than the fibrous connective tissue 21 and further accumulating the pluripotent stem cells 23 in the loose fibrous tissue 22. In this way, leaving the tissue structure forming device in place for a predetermined period of time forms a membrane-like fibrous connective tissue 21 along the inner surface 14 in the hollow portion 11 as a tissue structure 20, and also forms a membrane-like loose fibrous tissue 22 supported by the fibrous connective tissue 21.

[0035] The tissue structure 20 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 comes into contact with the appropriate biological tissue or the biological tissue having a decreased function. That is, the cell population containing the pluripotent stem cells 23 in the tissue structure 20, or the pluripotent stem cells 23, may be directly administered to the appropriate biological tissue or the biological tissue having a decreased function.

[0036] The tissue structure 20, the cell population containing pluripotent stem cells 23, and the pluripotent stem cells 23 may be induced to differentiate into target cells outside of living tissue and then administered to living tissue, etc. The tissue structure 20, the cell population containing pluripotent stem cells 23, or the pluripotent stem cells 23 may be cryopreserved and then administered at a desired time. The pluripotent stem cells 23 may also be isolated from the loose fibrous tissue 22. The pluripotent stem cells 23 may be isolated by enzymatic treatment of a tissue structure forming device removed from an environment containing living tissue. The pluripotent stem cells 23 may also be isolated by filtration using a membrane filter, mesh filter, or the like. The pluripotent stem cells 23 isolated from the loose fibrous tissue 22 may or may not be cultured and expanded. The cell population containing pluripotent stem cells 23 partially purified from the loose fibrous tissue 22 may or may not be cultured and expanded.

[0037] The tissue construct 20, a cell population containing pluripotent stem cells 23, or the pluripotent stem cells 23 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 tissue or organ function. The tissue construct 20, a cell population containing pluripotent stem cells 23, or the pluripotent stem cells 23 may be used for tissue construction or cell differentiation in an in vitro culture system. The tissue construct 20, a cell population containing pluripotent stem cells 23, or the pluripotent stem cells 23 may be used for tissue construction or cell differentiation in an ex vivo system.

[0038] The tissue structure 20 may be used as a fluid obtained by grinding the fibrous connective tissue 21 and the loose fibrous tissue 22. The tissue structure 20 may be used as a fluid obtained by grinding only the loose fibrous tissue 22. The fluidized tissue structure 20 may be administered to the diseased site by injection or the like.

[0039] Furthermore, the tissue structure 20 may omit the loose fibrous tissue 22. Prolonged placement of the tissue structure forming device fills the entire hollow portion 11 with fibrous connective tissue 21 and loose fibrous tissue 22, and then promotes the production of collagen and the like by cells accumulated in the loose fibrous tissue 22. As a result, the entire hollow portion 11 is filled with fibrous connective tissue 21, which is denser than the loose fibrous tissue 22, and the tissue structure 20 is composed of fibrous connective tissue 21.

[0040] The tissue structure 20, which is primarily composed of fibrous connective tissue 21, has high toughness. For this reason, the tissue structure 20, which is primarily 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.

[0041] [Configuration of main body 10] Returning to Figure 1, the partition wall 12 is a cylindrical member having a flattened elliptical cylindrical shape. The inner surface 14 surrounding the hollow portion 11 has a flattened elliptical cylindrical surface shape. The outer surface of the partition wall 12 is the surface opposite to the inner surface 14 and is an example of a symmetric surface.

[0042] The shape of the compartment wall 12 may be cylindrical or a flat hollow rectangular parallelepiped. The inner surface 14 surrounding the hollow portion 11 may have a cylindrical surface or a flat rectangular parallelepiped shape. When the position of the compartment wall 12 needs to be stable in an environment containing biological tissue, a flat elliptical cylindrical shape is preferable to a cylindrical shape for the compartment wall 12. Furthermore, since the spatial size of biological tissue is limited, when the area in which pluripotent stem cells 23 are accumulated needs to be expanded, the shape of the compartment wall 12 is preferably a cylindrical shape or a flat rectangular parallelepiped shape in which the membranous fibrous connective tissue 21 extends three-dimensionally.

[0043] One cylindrical end of the partition wall 12 is closed by a first cap 16. The other cylindrical end of the partition wall 12 is closed by a second cap 17. The first cap 16 and the second cap 17 each have a plurality of air vents. The air vents are used to reduce the pressure in the hollow portion 11 when the tissue structure forming device is placed. When stability of the shape of the partition wall 12 is required in the environment, it is preferable that the first cap 16 and the second cap 17 support the cylindrical ends of the partition wall 12. When uniformity of the thickness H21 of the fibrous connective tissue 21 is required, it is preferable that the air vents of the first cap 16 and the second cap 17 also function as the penetration portion 13.

[0044] The constituent material of the partition wall 12 is compatible with biological tissues. The constituent material of the partition wall 12 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 wall 12 may also be a laminate of a metal material and a synthetic resin.

[0045] The outer surface of the partition wall 12 is configured to allow the peeling portion 18A to move along the outer surface of the partition wall 12. The outer surface of the partition wall 12 may be a smooth surface that allows the peeling portion 18A to slide along the outer surface of the partition wall 12. The outer surface of the partition wall 12 may have a fine surface roughness that reduces contact with the peeling portion 18A so as to facilitate the sliding of the peeling portion 18A.

[0046] The inner surface 14 of the compartment wall 12 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 tissue construct 20. When promotion of the formation of fibrous connective tissue 21 is required, the constituent material of the inner surface 14 is preferably any one selected from the group consisting of polymethylpentene resin, polyfluoroethylene resin, polypropylene resin, polyethylene resin, silicone resin, and mixed resins of these with other resin components.

[0047] The through-holes 13 are circular holes that penetrate from the inner surface 14 to the outer surface of the partition wall 12. The outer surface of the partition wall 12 is in contact with the environment in which the tissue structure forming device is placed. The through-holes 13 are scattered throughout the partition wall 12 except for both axial edges of the partition wall 12, i.e., the cylindrical ends of the partition wall 12. The openings of the through-holes 13 have a circular shape on the inner surface 14 and are scattered throughout the inner surface 14. The through-holes 13 are arranged at equal intervals both in the circumferential direction of the partition wall 12 and in the extension direction of the partition wall 12.

[0048] The through-holes 13 are not limited to circular holes, but may be elliptical, polygonal, linear, or irregularly shaped holes. The openings of the through-holes 13 may have an elliptical, polygonal, or linear shape on the inner surface 14, 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 partition wall 12 may have a combination of a plurality of different shapes or a combination of different sizes as the openings of the through-holes 13. When smooth removal of the fibrous connective tissue 21 is required, the inner surface of the hole of the through-holes 13 is preferably a curved surface, and the through-holes 13 are preferably circular holes.

[0049] The openings of the penetrating parts 13 may be arranged regularly or randomly on the inner surface 14 and outer surface of the partition wall 12. When the thickness H21 of the membranous fibrous connective tissue 21 needs to be uniform within a predetermined range, or when the distribution of the pluripotent stem cells 23 needs to be uniform within a predetermined range, it is preferable that the openings of the penetrating parts 13 be arranged regularly within a predetermined range on the inner surface 14.

[0050] The thickness of the partition wall 12 is the depth of the penetration portion 13. The thickness of the partition wall 12 is large enough to suppress deformation of the partition wall 12 within the biological tissue. The thickness of the partition wall 12 is approximately uniform throughout the range in which the penetration portion 13 is arranged. The thickness of the partition wall 12 is large enough to allow cells and the like in the biological tissue to enter the hollow portion 11. The thickness of the partition wall 12 may be 0.1 mm or more and 2.0 mm or less.

[0051] The opening dimension of the through portion 13 is the dimension of the opening of the through portion 13 on the inner surface 14. The dimension of the opening of the through portion 13 on the inner surface 14 is equal to the dimension of the opening of the through portion 13 on the outer surface of the partition wall 12. The opening dimension of the through portion 13 is large enough to allow cells and the like in biological tissue to pass through the through portion 13. The minimum opening dimension through which cells and the like in biological tissue can pass is approximately 0.01 mm. When the through portion 13 is a circular hole, the opening dimension of the through portion 13 is the diameter of the circular hole. When the through portion 13 is an elliptical hole, the opening dimension of the through portion 13 is the major axis of the elliptical hole. When the opening of the through portion 13 is polygonal or irregularly shaped, the opening dimension is the diameter of a circle circumscribing the opening. The opening dimension of the through portion 13 may be 0.3 mm or more and 3.0 mm or less.

[0052] When the tissue structure forming device is placed in an environment containing biological tissue, the inner surface 14 of the compartment wall 12 has a size that allows it to function as a scaffold for cells derived from the biological tissue. The spacing between the penetrations on the inner surface 14 is the shortest length on the inner surface 14 between adjacent penetrations 13. The spacing between the penetrations on the inner surface 14 is such that the inner surface 14, which is the plane between adjacent penetrations 13, functions as a scaffold for cells and the like in the biological tissue. The spacing between the penetrations on the inner surface 14 may be 0.3 mm or more and 5.0 mm or less.

[0053] The density of the openings on the inner surface 14 of the partition wall 12 is large enough to prevent the entry of cells derived from biological tissues from being inhibited by the fibrous connective tissue 21. The density of the openings on the inner surface 14 of the partition wall 12 is large enough to allow the fibrous connective tissue 21 to form a membrane. The opening occupancy rate of the inner surface 14 is the ratio of the total area occupied by the openings of the penetrating portions 13 to the unit area of ​​the inner surface 14. The opening occupancy rate of the inner surface 14 may be 30% or more and 70% or less.

[0054] The depth of the hollow portion 11 is the hollow depth. When pluripotent stem cells 23 are accumulated in the loose fibrous tissue 22, the hollow depth is sufficiently large so that, during the growth process of the fibrous connective tissue 21, the invasion of the pluripotent stem cells 23 is promoted, making it easier to form loose fibrous tissue 22 than to form fibrous connective tissue 21. The hollow depth is larger than the sum of the desired thickness H21 of the fibrous connective tissue 21 and the thickness H22 of the loose fibrous tissue 22. Note that, when the tissue structure 20 is composed of fibrous connective tissue 21, the hollow depth is equal to the thickness required for the tissue structure 20.

[0055] The hollow depth is the depth of the hollow portion 11 extending from the opening of the through portion 13 on the inner surface 14 in the depth direction of the through portion 13. The depth direction of the through portion 13 is the thickness direction of the partition wall 12 around the through portion 13. When a structure such as a support member 15 is present in the hollow portion 11, the hollow depth is the distance between the inner surface 14 and the structure in the depth direction of the through portion 13. When a structure is not present in the hollow portion 11 and one part of the inner surface 14 faces another part in the depth direction of the through portion 13, such as a cylindrical inner surface 14, the hollow depth is half the distance between one part of the inner surface 14 and another part in the depth direction of the through portion 13. The hollow depth may be 0.5 mm or more and 10 mm or less.

[0056] Collagen production in the tissue structure forming device can occur competitively between the outer surfaces of the compartment walls 12 and within the hollow portions 11. Even if the opening occupancy rates are equal, if the number of openings is small and the openings are large, the outer surfaces of the compartment walls 12 are likely to be recognized as foreign bodies due to excessively large spacing between the penetrations, and the outer surfaces of the compartment walls 12 are likely to be covered with connective tissue. As a result, the openings of the penetrations 13 are likely to be closed by connective tissue before the tissue structure 20 is formed in the hollow portions 11. Alternatively, pluripotent stem cells 23, such as plasma proteins, fibroblasts, vascular endothelial cells, and mesenchymal cells, have difficulty entering the hollow portions 11, slowing the formation of fibrous connective tissue 21 and loose fibrous tissue 22.

[0057] In contrast, when the above-mentioned range is satisfied, the number of through-holes 13 is appropriately large and the opening dimensions are appropriately small. Therefore, on the outer surface of the partition wall 12, the openings of the through-holes 13 are less likely to be covered with collagen since the spacing between the through-holes is small. Also, on the inner surface 14 of the partition wall 12, there are secured a sufficient number of starting points for the formation of the fibrous connective tissue 21 to form a membrane-like fibrous connective tissue 21.

[0058] The accumulation of pluripotent stem cells 23 is achieved by the pluripotent stem cells 23 in the biological tissue invading the hollow portion 11 and the proliferation of the invaded pluripotent stem cells 23 in the hollow portion 11. The invasion of pluripotent stem cells 23 is promoted by the fact that the penetration portion 13 remains open for most of the predetermined retention period and by the fact that a space for the formation of loose fibrous tissue 22 continues to exist in the hollow portion 11. Within the above-mentioned range, when 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 23 can be promoted to the extent that large depressions or holes opposite the openings of the penetration portion 13 are not formed in the fibrous connective tissue 21. Furthermore, membrane-like fibrous connective tissue 21 is easily formed, and as the growth of the fibrous connective tissue 21 is promoted, the pluripotent stem cells 23 are more likely to accumulate inward of the fibrous connective tissue 21. In particular, when the environment containing the biological tissue is the same as that in the body of a disease model animal, the growth of the fibrous connective tissue 21 tends to be delayed, which increases the probability of accumulating the pluripotent stem cells 23.

[0059] When the thickness of the partition wall 12 is 2.0 mm or less and the opening dimension of the penetration part 13 is 0.3 mm or more, cells and the like in the biological tissue can enter the hollow part 11 even if the penetration part 13 is slightly narrowed by the fibrous connective tissue 21. Because the penetration part 13 is unlikely to be blocked by the fibrous connective tissue 21, the fibrous connective tissue 21 tends to grow to a thickness of 0.05 mm or more and 0.5 mm or less, and pluripotent stem cells 23 tend to accumulate in the loose fibrous tissue 22.

[0060] When the thickness of the partition wall 12 is 2.0 mm or less and the opening dimension of the penetrating portion 13 is 3.0 mm or less, large depressions or holes are unlikely to form in the fibrous connective tissue 21 at the site facing the penetrating portion 13. Suppressing the formation of large depressions in the fibrous connective tissue 21 suppresses the formation of partial weak sites in the fibrous connective tissue 21, making the membranous tissue structure 20 easier to handle.

[0061] When the thickness of the partition wall 12 is 0.1 mm or more, the opening dimension of the through-hole 13 is 3.0 mm or less, and the opening occupancy rate is 70% or less, the mechanical strength of the partition wall 12 is easily obtained. Therefore, deformation of the partition wall 12 is easily suppressed in biological tissue.

[0062] When the interval between penetration parts is 0.5 mm or more, the fibrous connective tissue 21 tends to grow using the inner surface 14 as a scaffold. When the interval between penetration parts is 5.0 mm or less, the fibrous connective tissue 21 growing from around the opening of one penetration part 13 tends to connect with the fibrous connective tissue 21 growing from around the opening of another penetration part 13. Connecting the peripheries of the openings of the penetration parts 13 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 membranous tissue structure 20. Furthermore, when the opening occupancy rate is 30% or more and 70% or less, the fibrous connective tissue 21 tends to spread in a membrane-like manner over the entire inner surface 14.

[0063] The placement period of the tissue structure forming device is preferably a short period of time, about four weeks from the start of placement, during which inflammation caused by the incision required for placement of the tissue structure forming device has subsided. On the other hand, when the environment containing biological 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 thickness of partition wall 12 is 2.0 mm or less and the opening dimension of penetration portion 13 is 3.0 mm or less, even in such an environment, large depressions or holes are unlikely to form in the fibrous connective tissue 21 at the site opposite penetration portion 13 after the placement period has elapsed. Furthermore, when the opening occupancy rate is 30% or more and 70% or less, the fibrous connective tissue 21 tends to spread in a membrane-like manner over the entire inner surface 14. Furthermore, penetration portion 13 is unlikely to be blocked by fibrous connective tissue 21.

[0064] Furthermore, when the hollow depth is 2 mm or more, the hollow portion 11 is significantly prevented from being buried in the fibrous connective tissue 21 during a suitable retention period, making it easier to obtain loose fibrous tissue 22 of sufficient thickness and pluripotent stem cells 23 that accumulate in the loose fibrous tissue 22. In particular, when the environment containing the biological tissue is the same as the in vivo environment of a disease model animal, the growth of the fibrous connective tissue 21 tends to be delayed, increasing the likelihood of accumulating pluripotent stem cells 23.

[0065] Returning to FIG. 1 , the tissue structure forming device includes a support member 15 in the hollow portion 11. The support member 15 may support both ends of the partition wall 12 in the extension direction. For example, the support member 15 may be fitted to the tubular ends of the partition wall 12 so as to close both ends of the hollow portion 11 in the extension direction of the partition wall 12. For example, the support member 15 may be inserted into the tubular interior of the partition wall 12 so as to abut against a portion of the inner surface 14 from inside the hollow portion 11. Support of the partition wall 12 by the support member 15 stabilizes the shape of the hollow portion 11 within the biological tissue.

[0066] The support member 15 may have a flattened elliptical cylindrical shape so that the outer surface of the support member 15 fits along the inner surface 14 of the partition wall 12. When the inner surface 14 of the partition wall 12 has a cylindrical surface, the support member 15 may have a cylindrical shape. When the inner surface 14 of the partition wall 12 has a flattened rectangular parallelepiped shape, the support member 15 may have a rectangular parallelepiped shape. The support member 15 provides a predetermined hollow depth between the inner surface 14 of the partition wall 12 and the outer surface of the support member 15. When the partition wall 12 has a strength that makes it difficult for it to deform in biological tissue, the support member 15 may be omitted from the tissue structure forming device.

[0067] The constituent material of the support member 15 is compatible with biological tissues. The constituent material of the support member 15 may be the same as or different from the constituent material of the partition wall 12. The constituent material of the support member 15 may be a metal material such as stainless steel, titanium, titanium-nickel alloy, or cobalt-chromium alloy, or a synthetic resin such as silicon, PEEK, acrylic, nylon, polycarbonate, polysulfone, polymethylpentene, or polytetrafluoroethylene. The constituent material of the partition wall 12 may be a laminate of a metal material and a constituent resin.

[0068] The through-holes 13 may be formed by etching the partition walls 12 or by laser drilling the partition walls 12 . [Configuration of auxiliary portion 18: peeling portion 18A] The peeling portion 18A is an example of a first wire. The peeling portion 18A extends in one direction along the outer surface of the partition wall 12 and is configured to be movable in another direction along the outer surface of the partition wall 12. The peeling portion 18A may have a linear shape. The direction in which the peeling portion 18A extends may be the circumferential direction of the partition wall 12, or a spiral direction along the outer surface of the partition wall 12. The direction in which the peeling portion 18A moves may be the axial direction of the cylindrical partition wall 12, or a spiral direction along the outer surface of the cylindrical partition wall 12.

[0069] The peeling portion 18A is attached to the partition wall 12. The peeling portion 18A may be attached to the partition wall 12 by having a ring shape that extends around the entire periphery of the partition wall 12. The peeling portion 18A may also be attached to the partition wall 12 by attaching another member connected to the peeling portion 18A to the partition wall 12. The peeling portion 18A is configured to be able to remain in the environment together with the partition wall 12 while attached to the partition wall 12. The peeling portion 18A can move in other directions along the outer surface of the partition wall 12 from the state where it is attached to the partition wall 12.

[0070] The peeling portion 18A may be arranged relative to the outer surface of the partition wall 12 so that a portion of the peeling portion 18A contacts the outer surface of the partition wall 12. The peeling portion 18A may be arranged relative to the outer surface of the partition wall 12 so that the entirety of the peeling portion 18A contacts the outer surface of the partition wall 12. The peeling portion 18A may be arranged relative to the outer surface of the partition wall 12 so that the peeling portion 18A is spaced a predetermined distance from the outer surface of the partition wall 12. The peeling portion 18A may be arranged to face the outer surface of the partition wall 12 with a gap of 0.05 mm or more and 2 mm or less between the outer surface of the partition wall 12 and the peeling portion 18A, for example.

[0071] The constituent material of the peeling portion 18A is compatible with biological tissues. The constituent material of the peeling portion 18A 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, a nylon, a polycarbonate resin, or a polysulfone resin. The constituent material of the peeling portion 18A may also be a laminate of a metal material and a synthetic resin.

[0072] The diameter of the peeling portion 18A may be equal to or smaller than the opening dimension of the through-portion 13, or may be larger than the opening dimension of the through-portion 13. The diameter of the peeling portion 18A may be equal to or smaller than the spacing between the through-portions of the partition wall 12, or may be larger than the spacing between the through-portions of the partition wall 12. The diameter of the peeling portion 18A may be equal to or smaller than the axial width of both axial edges of the partition wall 12, i.e., the cylindrical ends of the partition wall 12, or may be larger than the axial width of the partition wall 12 at the axial ends. The diameter of the peeling portion 18A may be 0.3 mm or more and 5.0 mm or less. When the diameter of the peeling portion 18A is equal to or smaller than the opening dimension of the through-portion 13, even if the peeling portion 18A is positioned so as to overlap the through-portion 13, the opening of the through-portion 13 is prevented from being blocked by the peeling portion 18A. When the diameter of the peeling portion 18A is equal to or smaller than the spacing between the through-portions of the partition wall 12, the peeling portion 18A is prevented from overlapping the opening of the through-portion 13. When the diameter of the peeled-off portion 18A is equal to or smaller than the width of the edge of the partition wall 12 in the axial direction, the peeled-off portion 18A is further prevented from overlapping with the opening of the through-hole 13.

[0073] [Configuration of auxiliary section 18: Guidance section 18B] The guide portion 18B is connected to the peeling portion 18A and guides the movement of the peeling portion 18A in another direction along the outer surface of the partition wall 12. The guiding direction of the guide portion 18B may be the axial direction of the cylindrical partition wall 12, or may be a spiral direction along the outer surface of the cylindrical partition wall 12. The guide portion 18B may have a linear shape constituting the second wire.

[0074] The guide portion 18B guides the movement of the peeling portion 18A by being pulled or pushed in the direction of moving the peeling portion 18A. The guiding direction of the guide portion 18B may be determined by the main body 10. For example, the first cap 16 may have a through-hole extending in the direction of extension of the guide portion 18B, and the guide portion 18B may be inserted into the through-hole. In this way, the direction in which the guide portion 18B is pulled or pushed may be determined by the first cap 16.

[0075] The number of guide portions 18B may be one or two or more. Two or more guide portions 18B may be connected to different portions of the peeling portion 18A. When the guide portions 18B are connected to different portions of the peeling portion 18A, the pulling force or pushing force through the guide portions 18B acts on different portions of the peeling portion 18A. Therefore, the movement of the peeling portion 18A along the outer surface of the partition wall 12 proceeds more smoothly than when the pulling force or pushing force is concentrated at one point in the peeling portion 18A.

[0076] The guide portion 18B may be connected to the peeling portion 18A so as to separate the guide portion 18B by a predetermined distance from the outer surface of the partition wall 12. The guide portion 18B may be connected to the peeling portion 18A so as to bring the guide portion 18B into contact with the outer surface of the partition wall 12.

[0077] The constituent material of the guide portion 18B is compatible with biological tissue. The constituent material of the guide portion 18B may be a metal material such as stainless steel, titanium, titanium-nickel alloy, or cobalt-chromium alloy, or a synthetic resin such as silicone resin, polymethylpentene resin, polytetrafluoroethylene resin, polypropylene resin, polyethylene resin, PEEK, acrylic resin, nylon, polycarbonate resin, or polysulfone resin. The constituent material of the guide portion 18B may be a laminate of a metal material and a synthetic resin. The constituent material of the guide portion 18B may be the same as or different from the constituent material of the release portion 18A.

[0078] The diameter of the guide portion 18B may be equal to or smaller than the opening dimension of the through portion 13, or may be larger than the opening dimension of the through portion 13. The diameter of the guide portion 18B may be equal to or smaller than the spacing between the through portions of the partition wall 12, or may be larger than the spacing between the through portions of the partition wall 12. The diameter of the guide portion 18B may be 0.3 mm or more and 5.0 mm or less. The diameter of the guide portion 18B may be equal to or larger than the diameter of the peeling portion 18A, or may be smaller than the diameter of the peeling portion 18A. When the diameter of the guide portion 18B is equal to or smaller than the opening dimension of the through portion 13, even if the guide portion 18B is arranged to overlap with the through portion 13, the opening of the through portion 13 is prevented from being blocked by the guide portion 18B. When the diameter of the guide portion 18B is equal to or smaller than the spacing between the through portions of the partition wall 12, the guide portion 18B is prevented from overlapping with the opening of the through portion 13.

[0079] Two or more guide portions 18B may be connected at their ends opposite to the end connected to peeling portion 18A by connecting portion 18C. Fig. 1 shows an example in which two guide portions 18B are connected by one connecting portion 18C, and the two guide portions 18B and one connecting portion 18C are formed from one bent second wire.

[0080] In the direction in which peeling portion 18A moves, the length of guide portion 18B may be equal to or longer than the length of partition wall 12. Because the length of guide portion 18B is equal to or longer than the length of partition wall 12, peeling portion 18A moves over the entire outer surface of partition wall 12 by pulling or pushing guide portion 18B.

[0081] When the length of the guide portion 18B is equal to the length of the partition wall 12, the two or more guide portions 18B and the connecting portion 18C may be configured to be engageable with the main body portion 10 and function as setting portions that determine the position of the peeling portion 18A relative to the target surface by engaging with the main body portion 10. For example, in FIG. 1 , when the length of the two guide portions 18B is equal to the length of the partition wall 12, the connecting portion 18C abuts against the first cap 16 or the other end of the partition wall 12 with the peeling portion 18A positioned at one end (edge) of the partition wall 12. As a result, the abutment between the connecting portion 18C and the main body portion 10 determines the position of the peeling portion 18A relative to the outer surface of the partition wall 12. In this way, the second wire composed of the guide portions 18B and the connecting portion 18C may be bent radially from its axially extending portion so as to abut against the main body portion 10 by moving along the outer surface of the partition wall 12 and determine the position of the peeling portion 18A relative to the outer surface of the partition wall 12.

[0082] [Organizational structure 20] As shown in FIG. 2 , the tissue structure 20 may include fibrous connective tissue 21 and loose fibrous tissue 22. The membranous fibrous connective tissue 21 has a first surface 21A that is detached from the inner surface 14 of the compartment wall 12. The membranous loose fibrous tissue 22 is formed over the entire second surface 21B of the fibrous connective tissue 21, which is opposite to the first surface 21A. When the tissue structure forming device is left in place for a predetermined period of time, the membranous fibrous connective tissue 21 is formed in the hollow portion 11, and also the membranous loose fibrous tissue 22 supported by the fibrous connective tissue 21 is formed. A cell population containing pluripotent stem cells 23, or the pluripotent stem cells 23, is accumulated in the loose fibrous tissue 22.

[0083] 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 contain collagen fiber bundles. The collagen fibers of the fibrous connective tissue 21 preferably contain type I collagen. The proportion 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 proportion of type I collagen in the total collagen contained in the fibrous connective tissue 21 is higher than the proportion of type I collagen in the total collagen contained in the loose fibrous tissue 22.

[0084] The thickness H21 of the fibrous connective tissue 21 may be 0.05 mm or more and 0.5 mm or less. When the thickness H21 of the fibrous connective tissue 21 is 0.05 mm or more and 0.5 mm or less, the strength of the membrane-like fibrous connective tissue 21 is ensured, making it easy to handle the tissue structure 20 when administering the pluripotent stem cells 23. When the depth of the hollow portion 11 is 2 mm or more and 5 mm or less and the thickness H21 of the fibrous connective tissue 21 is 0.05 mm or more and 0.5 mm or less, the depth of the hollow portion 11 is sufficiently greater than the thickness of the fibrous connective tissue 21. Therefore, a space for accumulating the pluripotent stem cells 23 is easily ensured within the hollow portion 11.

[0085] The fibrous connective tissue 21 may have protrusions 21T corresponding to the shape of the penetrating portions 13 at locations corresponding to the penetrating portions 13. The thickness HT of the protrusions 21T is equal to or less than the depth of the penetrating portions 13. The width WT of the protrusions 21T is the opening dimension of the penetrating portions 13. The fibrous connective tissue 21 may omit the protrusions 21T. The fibrous connective tissue 21 may have capillaries 24 extending to the sparse fibrous tissue 22 at locations corresponding to the penetrating portions 13. The capillaries 24 are newly generated in the hollow portions 11 through the penetrating portions 13 during the formation of the tissue structure 20.

[0086] The loose fibrous tissue 22 has a lower fiber density than the fibrous connective tissue 21, and more cells are dispersed 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, fibrins, and pluripotent stem cells 23 such as mesenchymal cells. The loose fibrous tissue 22 may contain type III collagen or may contain 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.

[0087] The pluripotent stem cells 23 contained in the sparse fibrous tissue 22 express pluripotent stem cell markers. The pluripotent stem cells 23 may express at least one pluripotent stem cell marker or at least one mesenchymal stem cell marker. The pluripotent stem cells 23 contained in the sparse fibrous tissue 22 may contain mesenchymal stem cells.

[0088] Pluripotent stem cells 23 contained in sparse fibrous tissue 22 may express both the pluripotent stem cell marker SSEA3 and the pluripotent stem cell marker SSEA4. Pluripotent stem cells 23 contained in sparse fibrous tissue 22 may express the pluripotent stem cell marker SSEA3 or the pluripotent stem cell marker SSEA4.

[0089] The pluripotent stem cells 23 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 23 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 23 contained in the sparse fibrous tissue 22 may express both the mesenchymal stem cell marker CD90 and the pluripotent stem cell marker SSEA3.

[0090] 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.

[0091] The sparse fibrous tissue 22 may contain stem cells with high angiogenic potential. The sparse fibrous tissue 22 may contain, as stem cells with 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.

[0092] The ratio of the total number of pluripotent stem cells 23 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 by treating the sparse fibrous tissue 22 in a 0.25% collagenase type I solution at 37°C for 1.5 hours and then calculating the number of cells recovered from the decomposed tissue as the total cell number. The stem cell ratio can be calculated by calculating the number of cells expressing at least one marker selected from the group consisting of the mesenchymal stem cell marker CD90, the mesenchymal stem cell marker CD105, the pluripotent stem cell marker SSEA3, and the 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.

[0093] 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. 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. 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.

[0094] [Tissue structure formation method] As shown in Figure 3, when the tissue structure forming device is placed in an environment containing biological tissue, the auxiliary part 18 and the main part 10 are placed together with the auxiliary part 18 attached to the main part 10. The auxiliary part 18 is placed outside the hollow part 11 together with the environment containing biological tissue. Therefore, the area to be detached from the outer surface of the external connective tissue formed on the outer surface of the partition wall 12 is determined in advance before placement as the relative position of the detachment part 18A with respect to the outer surface of the partition wall 12. Then, liquid components 25 such as extracellular matrix derived from biological tissue enter the hollow part 11 through the penetration part 13. The hollow part 11 of the tissue structure forming device is filled with the liquid components 25 derived from biological tissue.

[0095] When hollow portion 11 of the tissue structure forming device is filled with liquid component 25, cells such as pluripotent stem cells 23 derived from biological tissue and fibroblasts invade hollow portion 11 through penetration portion 13. The fibroblasts that have invaded hollow portion 11 begin to form loose fibrous tissue 22 from the outer surface of partition wall 12 toward the inside of hollow portion 11, using inner surface 14 that borders the opening of penetration portion 13 as a scaffold.

[0096] 4, the loose fibrous tissue 22 formed using the inner surface 14 as a scaffold promotes the production of collagen and other substances by cells accumulated in the loose fibrous tissue 22 on the inner surface 14, which is easily recognized as a foreign body. As a result, the loose fibrous tissue 22 formed using the inner surface 14 as a scaffold grows fibrous connective tissue 21, which is denser than the loose fibrous tissue 22, from the opening edge of the penetration portion 13 toward the inside of the hollow portion 11, from the inner surface 14.

[0097] The inside of the hollow portion 11, which is more likely to be recognized as a foreign body than the outside of the hollow portion 11, further promotes the invasion of fibroblasts and pluripotent stem cells 23. Fibroblasts and pluripotent stem cells 23 that continue to invade the hollow portion 11 form loose fibrous tissue 22 inward of the fibrous connective tissue 21 during the growth of the fibrous connective tissue 21. The pluripotent stem cells 23 that invade the hollow portion 11 continue to accumulate in the loose fibrous tissue 22.

[0098] 5, the fibroblasts and pluripotent stem cells 23 that continue to enter the hollow portion 11 form a membranous fibrous connective tissue 21 that spreads over the entire inner surface 14, connecting the opening edges of the penetration portion 13 with the fibrous connective tissue 21. The fibroblasts and pluripotent stem cells 23 that continue to enter the hollow portion 11 form a membranous loose fibrous tissue 22 and capillaries 24 that follow the spread of the fibrous connective tissue 21. During this time, external connective tissue, primarily composed of fibrous connective tissue 21, is also formed on the outer surface of the partition wall 12, which is recognized as a foreign body, so as to cover part of the detached portion 18A.

[0099] The inside of the hollow portion 11, which is more likely to be recognized as a foreign body than the outside of the hollow portion 11, continues to accumulate pluripotent stem cells 23 in the loose fibrous tissue 22, even while the fibrous connective tissue 21 is being formed in a membrane-like shape. The pluripotent stem cells 23 accumulated in the loose fibrous tissue 22 proliferate within the loose fibrous tissue 22. As a result, cells derived from biological tissues that have entered the hollow portion 11 grow the membranous loose fibrous tissue 22 further inward than the membranous fibrous connective tissue 21, and accumulate many pluripotent stem cells 23 in the loose fibrous tissue 22.

[0100] When the tissue structure 20 comprises fibrous connective tissue 21 and loose fibrous tissue 22, the tissue structure forming device is removed from the environment containing biological tissue before the fibrous connective tissue 21 fills the hollow portion 11. When the tissue structure 20 is composed of fibrous connective tissue 21, the tissue structure forming device is removed from the environment containing biological tissue after a period during which the fibrous connective tissue 21 fills the hollow portion 11.

[0101] As shown in FIG. 6 , when the tissue structure forming device is removed from the environment, the dissecting portion 18A moves in the axial direction of the compartment wall 12. The movement of the dissecting portion 18A is achieved, for example, by pulling the connecting portion 18C in the axial direction of the compartment wall 12. At this time, the relative position of the dissecting portion 18A with respect to the outer surface of the compartment wall 12 is predetermined before the tissue structure forming device is placed. Therefore, the movement of the dissecting portion 18A, for example, by pulling the connecting portion 18C once, maintains a predetermined distance between the outer surface of the compartment wall 12 and the dissecting portion 18A. The predetermined distance is, for example, a distance that brings the dissecting portion 18A into contact with the outer surface of the compartment wall 12. The movement of the dissecting portion 18A then expands the dissection in the axial direction at a predetermined site in the external connective tissue.

[0102] In conventional dissection using a dissector, dissection, which depends on the skill of the operator, is repeated at various locations on the outer surface of the compartment wall 12. In contrast, dissection using the above-described auxiliary unit 18 achieves wide-area dissection at a predetermined location. Furthermore, such dissection of the external connective tissue separates the tissue structure 20 from the external connective tissue, enabling the tissue structure 20 to be removed from the tissue structure forming device.

[0103] As described above, according to the above embodiment, the following effects can be obtained. (1) The load required to remove the tissue structure forming device and the load required to remove the tissue structure 20 are significantly reduced.

[0104] (2) Since the movement of the peeling portion 18A realizes peeling over a wide range, the variation in the cut shape of the tissue structure 20 is suppressed, and the shape accuracy of the tissue structure 20 is improved, compared to repeated peeling using a peeler, which depends on the skill of the operator.

[0105] (3) When the peeling portion 18A is a wire, the penetrating portion 13 is unlikely to be covered by the peeling portion 18A. Therefore, even if the peeling portion 18A is arranged along the outer surface of the partition wall 12, the arrangement of the peeling portion 18A is unlikely to affect the formation of the tissue structure 20.

[0106] (4) When the peeling portion 18A is disposed so as to contact the outer surface of the partition wall 12, the peeling site in the external connective tissue is predetermined at the boundary between the outer surface of the partition wall 12 and the external connective tissue. When a predetermined gap is formed between the peeling portion 18A and the outer surface of the partition wall 12, the peeling site in the external connective tissue is predetermined near the boundary between the outer surface of the partition wall 12 and the external connective tissue. In either case, variation in the cut shape of the tissue structure 20 is further suppressed.

[0107] (5) Since the movement of the peeling portion 18A is guided by the guide portion 18B, the effectiveness of obtaining the effects equivalent to the above (1) to (3) is increased. (6) When the guide portion 18B is a wire that does not easily cover the penetration portion 13, even if the guide portion 18B is positioned along the outer surface of the partition wall 12, the positioning of the guide portion 18B is unlikely to affect the formation of the tissue structure 20.

[0108] (7) When the guide portion 18B is a wire extending in the axial direction, it is easy for the guide portion 18B to have strength against pulling in the axial direction. Therefore, when dissecting the external connective tissue, it is also suitable to move the dissection portion 18A by pulling the guide portion 18B in the axial direction.

[0109] (8) When the annular peeling portion 18A is guided in the axial direction by two or more connecting portions, the movement of the peeling portion 18A along the axial direction proceeds more smoothly than when the peeling portion 18A is guided by one connecting portion.

[0110] (9) The main body portion 10, which forms the tissue construct 20 therein, is likely to remain stationary in the environment throughout the entire placement period. When the relative position of the dissection portion 18A with respect to the outer surface of the partition wall 12 is predetermined before placement by the abutment of the connecting portion 18C with the main body portion 10, the abutment between the main body portion 10, which is likely to remain stationary, and the connecting portion 18C is also likely to be maintained. Therefore, the relative position of the dissection portion 18A with respect to the outer surface of the partition wall 12 is unlikely to change throughout the entire placement period. As a result, the deviation between the predetermined dissection site with respect to the external connective tissue and the actual dissection site is further suppressed.

[0111] The above embodiment may be modified as follows. Target Face The target surface is not limited to the outer surface of the partition wall 12, but may be the inner surface 14 of the partition wall 12, or both the outer surface and the inner surface 14 of the partition wall 12.

[0112] [Main body 10] The cylinder end of the partition wall 12 may be open and not closed by the first cap 16. The cylinder end of the partition wall 12 may be open and not closed by the second cap 17. The first cap 16 or the second cap 17 may have a large vent hole that opens most of the cylinder end.

[0113] In this modified example, when a foreign body such as a support member 15 is present in the hollow portion 11, the outer surface of the support member 15 functions as a scaffold for cells derived from biological tissue that enter the hollow portion 11 from the end of the tube. Fibrous connective tissue 21 is formed from the inner surface 14 toward the hollow portion 11, and also from the outer surface of the support member 15 toward the hollow portion 11. In this case, the tissue structure 20 formed in the hollow portion 11 may have a three-layer structure in which loose fibrous tissue 22 is sandwiched between the fibrous connective tissue 21 in contact with the inner surface 14 and the fibrous connective tissue 21 in contact with the outer surface of the support member 15. That is, the membranous loose fibrous tissue 22 in which pluripotent stem cells 23 have accumulated may be sandwiched between the membranous fibrous connective tissue 21. When most of the end of the tube is open and the foreign body such as the support member 15 functions as a scaffold for forming the fibrous connective tissue 21, the hollow depth is half the distance between the inner surface 14 and the foreign body in the depth direction of the penetration portion 13.

[0114] The tissue structure 20 may be processed into a two-layer structure of fibrous connective tissue 21 in contact with the outer surface of the support member 15 and loose fibrous tissue 22 in contact with the fibrous connective tissue 21, via intra-layer peeling of the loose fibrous tissue 22 in the three-layer structure. The tissue structure 20 may also be processed into a two-layer structure of fibrous connective tissue 21 in contact with the inner surface 14 and loose fibrous tissue 22 in contact with the fibrous connective tissue 21, via intra-layer peeling of the loose fibrous tissue 22 in the three-layer structure.

[0115] The outer surface of the partition wall 12 may have ridges extending in the direction of movement of the peeling portion 18A. For example, the outer surface of the partition wall 12 may have ridges extending in the axial direction of the cylindrical partition wall 12, or may have ridges that spiral around the outer surface of the cylindrical partition wall 12. The ridges on the outer surface of the partition wall 12 increase the mechanical strength of the partition wall 12 in the direction of movement of the peeling portion 18A. In this case, the peeling portion 18A has grooves that allow the ridges of the partition wall 12 to pass through when moving in one direction.

[0116] [Supplementary part 18] The shape of the peeling portion 18A is not limited to a ring shape that covers the entire circumference of the partition wall 12. If the outer surface of the partition wall 12 has one or more ridges, the shape of the peeling portion 18A may be a shape that conforms to each ridge of the partition wall 12 and engages with each ridge. The attachment of the peeling portion 18A to the partition wall 12 may be by engaging each ridge of the partition wall 12 with the peeling portion 18A.

[0117] The attachment of the peeling portion 18A to the partition wall 12 is not limited to the shape of the peeling portion 18A, and may be achieved by attaching the guide portion 18B to the main body portion 10. For example, the partition wall 12 may have a cylindrical shape, and the first cap 16 may have an insertion hole along the axial direction of the partition wall 12 for passing the guide portion 18B. In this case, the peeling portion 18A may be attached to the main body portion 10 by passing the guide portion 18B through the insertion hole.

[0118] As shown in FIG. 7, the tissue structure forming device may include two or more dissection units 18A. The two or more dissection units 18A may be aligned in the direction of movement of the dissection units 18A. The extension direction of each dissection unit 18A may be the same as the extension direction of the other dissection units 18A, or may be different from the extension direction of the other dissection units 18A. When the extension directions of the dissection units 18A are different from each other, the external connective tissue and the tissue structure 20 are dissected from different directions. This makes the dissection of the external connective tissue and the tissue structure 20 more reliable.

[0119] As shown in FIG. 8 , one direction in which the peeling unit 18A extends may be the axial direction of the cylindrical partition wall 12, and the other direction in which the peeling unit 18A moves may be the circumferential direction of the cylindrical partition wall 12. For example, the peeling unit 18A may have a linear shape extending in the axial direction of the partition wall 12. The peeling unit 18A may be disposed so as to face the outer surface of the partition wall 12, or so as to face the inner surface 14 of the partition wall 12. In this case, the guide unit 18B may have a linear shape bent at both ends of the axial direction of the peeling unit 18A so as to sandwich the axial edge of the partition wall 12. In this modified example, the movement of the peeling unit 18A advances peeling along one direction of the partition wall 12 in the circumferential direction, which is the other direction of the cylindrical partition wall 12. In this modified example, the tissue structure forming device may also include two or more peeling units 18A. Furthermore, the first cap 16 and the second cap 17 may be provided with insertion grooves along the circumferential direction of the partition wall 12 for passing the peeling portion 18A and the guiding portion 18B therethrough, respectively.

[0120] 9, the tissue structure forming device may include two peeling units 18A. When the partition wall 12 has a cylindrical shape, the two peeling units 18A may be arranged in the axial direction of movement of the peeling units 18A, with a gap therebetween that is the same as the length of the partition wall 12. Alternatively, the guide unit 18B may extend along the axial direction of the partition wall 12, and the length of the guide unit 18B in the axial direction may be equal to the length of the partition wall 12 in the axial direction.

[0121] In this case, the two dissection portions 18A may be arranged so as to overlap with the axial ends of the partition wall 12 when viewed from a viewpoint facing the outer surface of the partition wall 12 when the tissue structure forming device is placed in an environment. Furthermore, the connecting portion 18C may be arranged so that the connecting portion 18C abuts against the outer surface of the first cap 16 when the two dissection portions 18A face the axial ends of the partition wall 12. The two guide portions 18B and the connecting portion 18C are configured to be engageable with the main body portion 10 by abutment of the connecting portion 18C with the first cap 16, and may thereby function as a setting portion that determines the position of the dissection portion 18A relative to the target surface by engagement with the main body portion 10.

[0122] According to this modified example, the tissue structure forming device is provided with auxiliary part 18 that is movable along the outer surface of partition wall 12, but movement of auxiliary part 18 relative to partition wall 12 in the environment is suppressed to the extent that connecting part 18C abuts against the outer surface of first cap 16. Furthermore, because the tissue structure forming device remains in the environment with connecting part 18C abutting against the outer surface of first cap 16, the position of connecting part 18C can be easily grasped when removing the tissue structure forming device. This also facilitates movement of peeling part 18A relative to the outer surface of partition wall 12.

[0123] In this modified example, when the peeling unit 18A is disposed so as to face the inner surface 14 of the partition wall 12, the target surface is set to the inner surface 14 of the partition wall 12. This reduces the load when removing the tissue structure 20 by moving the peeling unit 18A, and also improves the shape accuracy of the tissue structure 20. When the peeling unit 18A is disposed so as to face both the inner surface 14 and the outer surface of the partition wall 12, the facing surfaces are set to both the outer surface and the inner surface 14 of the partition wall 12.

[0124] The peeling portion 18A is not limited to a wire, and may be a blade having a strip shape extending in one direction along the outer surface of the partition wall 12. For example, as shown in FIG. 10 , when the partition wall 12 is cylindrical, the peeling portion 18A may have a strip shape extending in the circumferential direction of the partition wall 12. In this case, the guide portion 18B may have a strip shape extending in one direction along the outer surface of the partition wall 12, and the peeling portion 18A and the guide portion 18B may be cut out from a single cylinder having an elliptical cylindrical shape. Furthermore, the connecting portion 18C may have a strip shape extending along the outer surface of the first cap 16, and the peeling portion 18A, the guide portion 18B, and the connecting portion 18C may be cut out from a single cylinder having an elliptical cylindrical shape.

[0125] The guide portion 18B is not limited to a wire, and may be a rail along the outer surface of the partition wall 12. The rail along the outer surface of the partition wall 12 may be a ridge provided on the outer surface of the partition wall 12. In this case, the peeling portion 18A has a shape similar to the ridge of the partition wall 12, and is guided in its movement along the ridge of the partition wall 12. The rail along the outer surface of the partition wall 12 may extend along the axial direction of the cylindrical partition wall 12, or may extend in a spiral direction along the outer surface of the cylindrical partition wall 12.

[0126] The guide portion 18B may be configured to be connected to the peeling portion 18A at one end in the direction of movement of the peeling portion 18A, and to engage with the main body portion 10 at the other end. For example, the outer surface of the partition wall 12 or the outer surface of the first cap 16 may have a protrusion that protrudes in the radial direction of the partition wall 12. The other end of the guide portion 18B may have a hook shape that can be hooked onto the protrusion. As a result, the position of the peeling portion 18A is set at a predetermined position, such as the edge of the partition wall 12, by hooking the other end of the guide portion 18B onto the protrusion.

[0127] As shown in Fig. 11, the partition wall 12 may have a weld 19 extending in one direction. When the partition wall 12 has a cylindrical shape, the weld 19 may extend in the axial direction or in a spiral direction having an axial component and a circumferential component. The partition wall 12 having the weld 19 makes it easy to form the cylindrical partition wall 12 from a single thin plate by rolling the single thin plate so that the weld 19 is joined.

[0128] In this case, the peeling portion 18A may be configured to be movable in the extension direction of the welded portion 19 of the partition wall 12. For example, if the welded portion 19 is a protrusion that protrudes from the outer surface of the partition wall 12 and extends in the axial direction, the peeling portion 18A may be configured to have an open annular shape over the entire circumferential direction of the partition wall 12 except for the welded portion 19 and to be in contact with the outer surface of the partition wall 12. Alternatively, the peeling portion 18A may be configured to have an open annular shape over the entire circumferential direction of the partition wall 12 except for the welded portion 19 and to leave a gap between the peeling portion 18A and the outer surface of the partition wall 12 that is smaller than the amount of protrusion of the welded portion 19. In this case, the guide portion may be a convex portion 18A1 having a protruding shape that protrudes similarly to the welded portion 19, connect both ends of the peeling portion 18A having an open annular shape, and engage with the welded portion 19 so as to guide the peeling portion along the extension direction of the welded portion 19.

[0129] As shown in FIG. 12 , the first cap 16 may include a housing 16A that houses the peeling portion 18A. The housing 16A houses the peeling portion 18A so as to cover a portion of the peeling portion 18A. The housing 16A is disposed, for example, so as to cover an end portion of the outer surface of the partition wall 12, and a gap for housing the peeling portion 18A is formed between the outer surface of the partition wall 12 and the inner surface of the housing 16A. In this case, the first cap 16 may be fitted into the cylindrical end of the partition wall 12 so as to close the through-hole 13 at the cylindrical end of the partition wall 12. An fitting depth W, which is the distance between the axial edge of the partition wall 12 and the tip of the first cap 16, may be longer than the axial length of the housing 16A.

[0130] According to this modification, the exfoliation portion 18A is less likely to be covered with external connective tissue, and therefore the external connective tissue can be easily exfoliated by the exfoliation portion 18A. Furthermore, when the axial length of the accommodation portion 16A is shorter than the fitting depth W, the penetration portion 13, which contributes to the formation of the tissue structure 20, is less likely to be blocked by the accommodation portion 16A, and therefore the formation of the tissue structure 20 proceeds smoothly.

[0131] Corners that come into contact with the environment in the tissue structure forming device, such as the edge of the first cap 16 and the edge of the partition wall 12, may have a smooth, chamfered curved surface. The tissue structure forming device may have a double-tube structure. The double-tube structure is composed of an inner tube and an outer tube that is in contact with the outer surface of the inner tube and is inserted onto the inner tube. The inner tube has an inner through-portion that penetrates from the outside to the inside of the inner tube. The outer tube has an outer through-portion that penetrates from the outside to the inside of the outer tube. The shape and size of the opening of the inner through-portion are approximately the same as the shape and size of the opening of the outer through-portion. The tissue structure forming device arranges the inner through-portion and the outer through-portion so that the inner through-portion and the outer through-portion face each other. The tissue structure forming device then passes cells from the environment outside the outer tube into the interior of the inner tube.

[0132] In this case, in the tissue structure forming device, the inner tube constitutes the main body portion and the outer tube constitutes the peeling portion. When the outer tube moves relative to the inner tube, for example, when the outer tube moves in its axial or circumferential direction, the external connective tissue is cut at the boundary between the inner and outer penetrating portions. [Explanation of symbols]

[0133] 10...Main body 11...Hollow part 12...Partition wall 13...Penetration section 14...Inner 18…Auxiliary part 18A...Peeling section 18B…Guiding part 18C...Connection part 20…Organizational structure 21...fibrous connective tissue 21A…Side 1 21B…Second side 22...Lose fibrous tissue 23…Pluripotent stem cells 24...Capillaries

Claims

1. A tissue structure forming device that is placed in an environment containing biological tissue to form a tissue structure, a body defining a hollow portion for forming the tissue structure; The main body portion is an outer surface in contact with the environment; an interior surface bounding the hollow portion; a plurality of penetration portions that penetrate from the outer surface to the inner surface and allow cells contained in the biological tissue to pass from the environment into the hollow portion; At least one of the outer surface and the inner surface is a target surface, Further, a peeling portion having a shape extending in one direction along the target surface is provided, The peeling portion is The device is attached to the main body so as to be movable along the target surface in another direction along the target surface and to be retained in the environment together with the main body. A tissue structure forming device characterized by:

2. The peeling portion includes a first wire extending in the one direction over the entire range of the target surface where the penetrating portion is arranged. The tissue structure forming device according to claim 1 .

3. the target surface is the outer surface having a cylindrical shape extending in the other direction, The first wire has a ring shape extending in the circumferential direction of the outer surface, and is attached to the main body with a predetermined gap between the outer surface and the first wire. The tissue structure forming device according to claim 2 .

4. Further comprising a guide portion connected to the peeling portion, The guide portion is configured to guide the movement of the peeling portion in the other direction. The tissue structure forming device according to claim 1 .

5. the peeling portion is a first wire extending in the one direction over an entire range in which the penetrating portion is arranged on the target surface, The guide portion is a second wire connected to the first wire and extending in the other direction to the outside of the target surface. The tissue structure forming device according to claim 4 .

6. the target surface has a cylindrical surface shape extending in the other direction, the one direction is a circumferential direction of the target surface, the other direction is an axial direction of the target surface, the first wire has a loop extending in the circumferential direction of the target surface and includes a plurality of connecting portions arranged in the circumferential direction; The second wire extends from the connecting portion in the axial direction of the target surface. The tissue structure forming device according to claim 5 .

7. Further comprising a setting section connected to the peeling section, The setting portion determines the position of the peeling portion relative to the target surface by engagement between the main body portion and the setting portion. The tissue structure forming device according to claim 1 .

8. the peeling portion is a first wire extending in the one direction over an entire range in which the penetrating portion is arranged on the target surface, The setting portion is a second wire connected to the first wire, extending in the other direction, and bent outside the target surface so as to be engageable with the main body portion. The tissue structure forming device according to claim 7 .

9. the target surface is the outer surface having a cylindrical shape extending in the other direction, the one direction is a circumferential direction of the target surface, the other direction is an axial direction of the target surface, the first wire has a loop extending in the circumferential direction of the target surface, The second wire extends in the axial direction and is bent by the axial movement so as to abut against the edge of the outer surface. The tissue structure forming device according to claim 8 .

10. the main body portion includes a partition wall having the outer surface and the inner surface, The partition wall has an edge portion and has the through-portion other than the edge portion, The setting portion determines the position of the peeling portion on the edge portion. The tissue structure forming device according to claim 7 .

11. A tissue structure formation method for forming a tissue structure in an environment containing biological tissue by placing a tissue structure formation device, the method comprising: The tissue structure forming apparatus is the tissue structure forming apparatus according to any one of claims 1 to 10. A method for forming a tissue structure comprising:

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