Structure for forming connective tissue body and method for forming connective tissue body

Abstract

To provide a connective tissue body formation structure and the like, the connective tissue formation structure making it possible, when used after implanted in a living body other than a human body, to stably form a sheet-like connective tissue body with a relatively large area because the structure becomes difficult to be deformed and a connective tissue becomes easy to invade into the structure.SOLUTION: A connective tissue body formation structure 1 comprises a plurality of plate members 10 and a plurality of separation members 20. Each plate member 10 has an approximately rectangular planar shape partitioned and formed by opposed two first sides 13a, 13a and opposed two second sides 13b, 13b. The plurality of separation members 20 are provided at side edge parts 11a, 11a on the sides of at least two first sides 13a, 13a of two plate members 10, 10 positioned so as to face each other. Apertures 40 are formed among the plurality of separation members 20. Of the apertures 40, an aperture 40b continuously extending over a center region 11b1 of a side edge part 11b on the side of at least one second side 13b is the longest.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present disclosure relates to a structure for forming a connective tissue structure and a method for forming a connective tissue structure. [Background technology]

[0002] In recent years, there has been active research into regenerative medicine, which aims to restore the functions of cells, tissues, organs, etc. lost due to illness or accidents using artificial materials and cells.

[0003] For example, when a foreign body penetrates deep inside a living body, fibroblasts gradually gather around the foreign body, forming a connective tissue structure mainly composed of fibroblasts and collagen, etc. Using this reaction, technology is being researched to form a connective tissue structure by implanting a foreign body in the living body.

[0004] For example, Patent Document 1 describes a mainly cylindrical substrate for forming a membranous connective tissue structure, which can be placed in an environment where a biological tissue material is present to form a membranous connective tissue structure on the surface of the substrate.

[0005] Patent Document 2 describes a sheet-like or tubular substrate for forming a membranous connective tissue body, which can be placed in an environment where a biological tissue material is present to form a membranous connective tissue body on the substrate surface. In the substrate for forming a sheet-like connective tissue body described in Patent Document 2, multiple sheet-like substrates are provided via spacing members called "connecting parts", and are structured so that they face each other at a distance and are separable from each other.

[0006] Patent Documents 1 and 2 describe that a connective tissue body-forming substrate is implanted as a foreign body in a living body such as a human or placed in a culture device, a connective tissue body is formed inside the connective tissue body-forming substrate, and then the connective tissue body is obtained by removing the connective tissue body-forming substrate from the living body or the culture device. In both connective tissue body-forming substrates, a membrane-like connective tissue body is formed between the opposing surfaces of multiple plates arranged in parallel and facing each other at a distance. In the following, the connective tissue body-forming substrate may be simply referred to as a "substrate" or a "connective tissue body-forming structure".

[0007] When forming connective tissue in the human body, so-called autotransplantation or allotransplantation, it is necessary to make an incision and insert the connective tissue formation substrate into the human body, then suture the incision after insertion, make another incision after the formation of the connective tissue, take out the connective tissue formation substrate from the body, and then suture the incision again, which places a heavy burden on the human body due to the multiple procedures.In addition, since the connective tissue formation substrate is embedded in the human body, there is a natural limit to increasing the size of the connective tissue formation substrate or increasing the amount of connective tissue formation due to the size of the human body, and it is difficult to form a large amount of connective tissue by embedding the connective tissue formation substrate once.

[0008] In addition, as a useful means for forming a large amount of connective tissue bodies, the use of a large connective tissue body forming substrate to prepare a sheet-like connective tissue body with a large area has been considered. In the case of a cylindrical connective tissue body forming substrate as in Patent Document 1, even when a large animal is used, a gap occurs between the cylindrical connective tissue body forming substrate and the living body during implantation, and the substrate cannot easily adhere to the living body, making it difficult to prepare a sheet-like connective tissue body with a large area. In addition, since the connective tissue body formed with the cylindrical connective tissue body forming substrate is cylindrical, there is a difference in area between the inner and outer surfaces of the cylindrical connective tissue body, and the physical properties of the front and back surfaces of the sheet-like connective tissue body obtained by cutting the cylindrical connective tissue body in the longitudinal direction may differ, and the sheet-like connective tissue body may tend to curl in a specific direction. In particular, when the sheet-like connective tissue body has a large area, the difference in physical properties between the front and back surfaces becomes significant, and the quality of the sheet-like connective tissue body is likely to vary. In addition, when the cylindrical connective tissue body forming substrate is large, the living body needs to be incised into a large cylindrical shape, so the incision procedure is not easy and the burden on the living body is large.

[0009] Furthermore, it is difficult to control the behavior of animals other than humans, especially large animals, during movement. For example, animals such as cows, horses, pigs, and goats generate a large force when walking, so that a part of the substrate for forming a connective tissue body during implantation may break through the skin of the large animal and go out. If the part of the substrate for forming a connective tissue body that has gone out gets caught on a fence in a ranch and the animal walks while doing so, the skin may tear, or the connective tissue body formed in the substrate or the animal may become infected with bacteria through the torn wound. In addition, the embedded substrate itself may be deformed. In the case of a sheet-like substrate as described in Patent Document 2, such deformation may make it impossible to maintain the plate interval, and the desired level of sheet may not be obtained. On the other hand, if the spacing member is carelessly added, although the strength is increased, the opening of the substrate for forming a connective tissue body becomes narrow. If the opening is narrow, it is difficult for the tissue to enter the substrate, and the efficiency of tissue formation decreases. In addition, if the position of the spacing member is inappropriate, the connective tissue body cannot be produced as a continuous large-area sheet. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] JP 2017-113051 A [Patent Document 2] JP 2014-030598 A Summary of the Invention [Problem to be solved by the invention]

[0011] The object of the present disclosure is to provide a structure for connective tissue formation and a method for forming a connective tissue body in which the spacing members that constitute the structure for connective tissue formation are arranged at appropriate positions between a plurality of plate members, thereby ensuring sufficient strength of the structure and allowing at least one opening formed between a plurality of spacing members provided on a plurality of plate members to be formed to extend relatively long, so that when the structure is implanted and used in a living body, the structure is less likely to deform even when an external force is applied to the structure, and furthermore, connective tissue can easily enter the structure through the opening, thereby increasing the efficiency of connective tissue formation, thereby enabling the stable formation of a relatively large sheet-like connective tissue body. [Means for solving the problem]

[0012] [1] A connective tissue formation structure comprising a plurality of plate members and a plurality of spacing members provided on side edges of the plurality of plate members and holding the plurality of plate members in an opposing, spaced-apart state, wherein each plate member has a generally rectangular planar shape defined by two opposing first sides and two opposing second sides, the plurality of spacing members are provided on at least two first side edge portions of two plate members that face each other among the side edges of the plurality of plate members, openings are formed between the plurality of spacing members, and the longest of the openings extends continuously across a central region of at least one of the second side edge portions of the two second side edges. [2] The connective tissue formation structure described in [1] above, wherein the plate member has a substantially rectangular planar shape with the first side being a short side and the second side being a long side. [3] A connective tissue formation structure as described in [1] or [2] above, wherein the spacing member is not present on two diagonally opposite side edges of the plate member. [4] The connective tissue formation structure described in [1], [2] or [3] above, wherein the plate member has a chamfered corner connecting the side edge portion on the first side and the side edge portion on the second side. [5] A connective tissue formation structure according to any one of [1] to [4] above, wherein the spacing member is further provided on at least one of the two second side edge portions of the plate member, and the spacing member provided on the at least one second side edge portion is provided on both side regions located on either side of the central region. [6] A connective tissue formation structure according to any one of [1] to [4] above, wherein the spacing members are further provided on the side edges of the two second sides of the plate member, and the spacing members provided on the side edges of the two second sides are both provided in both side regions located on either side of the central region. [7] The connective tissue formation structure described in any one of [1] to [6] above, wherein the spacing member is integrally formed with at least one of the two plate members that are held in an opposing, spaced-apart state. [8] The connective tissue formation structure according to any one of the above [1] to [6], wherein the spacing member is formed separately from the two plate members which it holds in an opposing, spaced-apart state. [9] A method for forming a connective tissue body, comprising the steps of: (S-1) inserting and embedding a connective tissue body formation structure described in any one of [1] to [8] above into a living body other than a human; (S-2) forming a connective tissue body between the opposing surfaces of the two plate members of the connective tissue body formation structure embedded in the living body; and (S-3) removing the connective tissue body formation structure having the connective tissue body formed therein from the living body.

[10] The method further comprises, prior to the step (S-1), a step (SA) of providing an insertion part into which the connective tissue formation structure can be inserted in the non-human living body, The method for forming a connective tissue body according to the above-mentioned [9], wherein in the step (S-1), the connective tissue body formation structure is inserted through the insertion part and embedded. Effect of the Invention

[0013] According to the present disclosure, it is possible to provide a connective tissue formation structure and a method for forming a connective tissue structure, which, when implanted and used in a living body, makes the structure less likely to deform even when an external force is applied to the structure, and moreover, connective tissue can easily penetrate into the structure, thereby increasing the efficiency of connective tissue formation and enabling the stable formation of relatively large sheet-like connective tissue structures. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 is a perspective view showing an example of a connective tissue formation structure according to an embodiment. [Diagram 2] FIG. 2 is a side view taken from the direction of an arrow A in FIG. [Diagram 3] 3(a) is a perspective view seen from the direction of an arrow B in FIG. 1, and FIG. 3(b) is a diagram for explaining the position of the spacing member 20 in the plate member 10 shown in FIG. 3(a). [Figure 4] Figure 4 is a diagram illustrating the relationship between the position of the spacing member 20 and the area of ​​the obtained sheet-like connective tissue body, where Figure 4(a) shows a case where the spacing member 20 is not located on the two diagonal lines 15, 15, and Figure 4(b) shows a case where the spacing member 20 is located on the two diagonal lines 15, 15. [Diagram 5] 5(a) to 5(e) are conceptual diagrams showing various embodiments in which spacing members are provided on each of the side edge portions on the two first sides of a plate member. [Figure 6] 6(a) to 6(e) are conceptual diagrams showing various embodiments in which spacing members are provided on the side edge portions of two first sides and one second side of a plate member. [Figure 7] FIG. 7 is a conceptual diagram showing various embodiments in which spacing members are provided on two first side sides and two second side sides of a plate member. [Figure 8] 8(a) and 8(b) are diagrams showing modified examples of the plate member 10 and the spacing member 20. In FIG. [Figure 9] FIG. 9 is a diagram showing another modified example of the spacing member 20. In FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Hereinafter, the present invention will be described in detail based on an embodiment.

[0016] As a result of extensive research, the inventors have discovered that by optimizing the arrangement and configuration of the spacing members that make up the connective tissue body formation structure, when the connective tissue body formation structure is implanted and used in a living body other than a human, the structure is less likely to deform even when an external force is applied to the structure, and furthermore, connective tissue can more easily penetrate into the structure, thereby increasing the efficiency of connective tissue formation and enabling the stable formation of relatively large sheet-like connective tissue bodies, and have completed the present disclosure based on this finding.

[0017] [Structure for connective tissue formation] A connective tissue formation structure according to an embodiment of the present invention is a connective tissue formation structure comprising a plurality of plate members and a plurality of spacing members provided on the side edges of the plurality of plate members and holding the plurality of plate members in an opposing, spaced apart state, wherein each plate member has a substantially rectangular planar shape defined by two opposing first sides and two opposing second sides, the plurality of spacing members are provided on at least two first side edge portions of two plate members positioned opposite each other among the side edges of the plurality of plate members, openings are formed between the plurality of spacing members, and the opening that extends continuously across the central region of at least one of the second side edge portions of the two second side edge portions is the longest.

[0018] FIG. 1 is a perspective view showing an example of a connective tissue formation structure of an embodiment, and FIG. 2 is a side view seen from the direction of an arrow A in FIG.

[0019] 1 and 2, the connective tissue formation structure 1 includes a plurality of plate members, three plate members 10 in Fig. 1, and a plurality of spacing members, six spacing members 20 in Fig. 1. The spacing members 20 are provided on side edge portions 11 of the plurality of plate members 10, and hold the plurality of plate members 10 in an opposing, spaced apart state.

[0020] When implanted, a connective tissue is formed between the opposing surfaces of two of the plate members 10, 10 that are positioned opposite each other. Hereinafter, the space partitioned by the opposing surfaces of the two plate members 10 that are positioned opposite each other and in which the connective tissue is formed may be referred to as a "partitioned space." The partitioned space 30 is a space that extends along the plate surface direction of the plate member 10.

[0021] Fig. 3(a) is a perspective view from the direction of arrow B in Fig. 1, and Fig. 3(b) is a diagram for explaining the position of the spacing member 20 in the plate member 10 shown in Fig. 3(a). Note that in Figs. 3(a) and 3(b), the spacing member 20 is shown filled in black for ease of explanation. As shown in Fig. 3(a), each plate member 10 has a substantially rectangular planar shape defined by two opposing first sides 13a, 13a and two opposing second sides 13b, 13b. As shown in Figures 1 to 3, the multiple spacing members 20 are provided on at least two first side side edge portions of two opposing plate members 10, 10, among the side edge portions 11 of the multiple plate members 10, i.e., in Figure 1, side edge portions 11a, 11a on the two first sides 13a, 13a sides and side edge portion 11b on the second side 13b side, and an opening 40 is formed between the multiple spacing members 20, 20.

[0022] The openings 40 communicate the partitioned spaces 30 formed between the multiple plate members 10, 10 with the outside of the connective tissue formation structure 1. The openings 40 open perpendicularly to the plate surface direction L of the plate member 10. Here, among the openings 40, the opening 40b that extends continuously across at least one of the side edges 11b, 11b on the second side side of the two second sides 13b, 13b, i.e., across the central region 11b1 of the side edge 11b on the second side side 13b in FIG. 1, is the longest.

[0023] As described later, when the connective tissue body formation structure 1 is embedded in a living organism other than a human (hereinafter, simply referred to as "living organism"), the connective tissue enters the compartment space 30 from the outside of the connective tissue body formation structure 1 through the opening 40, and a sheet-like connective tissue body is formed in the compartment space 30. The connective tissue body is composed of an extracellular matrix such as fibroblasts and collagen. In the embodiment shown in Figures 1 to 3, the connective tissue mainly enters the compartment space 30 through the opening 40b, and the formed connective tissue body is harvested as a rectangular sheet shown by a dashed line in Figure 3(a). The harvested connective tissue body sheet is used for transplantation of the pericardium, dura mater, skin, valves, cornea, blood vessels, digestive tract, trachea, etc., to humans, companion animals, livestock animals, rare animals for exhibition, etc.

[0024] In this embodiment, at least one of the longest openings 40b extends continuously in the central region 11b1 of the side edge 11b on the second side 13b side of the connective tissue body formation structure 1 serving as the base material. Therefore, when the connective tissue body formation structure 1 is implanted in a living body, the connective tissue easily enters the compartment space 30 through the wide opening 40b. As a result, a sheet-like connective tissue body is efficiently formed in the compartment space 30.

[0025] In this embodiment, a plurality of spacing members 20 are provided on at least two side edge portions 11a, 11a on the first sides 13a, 13a of the two plate members 10, 10. Therefore, the connective tissue formation structure 1 exhibits high strength and has wide openings 40b. As a result, the connective tissue formation structure 1 of this embodiment has a low risk of deformation during implantation, and it becomes possible to efficiently form connective tissue.

[0026] In the present disclosure, the term "first side" refers to the side closer to the first side than the two diagonals 15, 15 of the plate member 10. More precisely, as shown in FIG. 3(b), the term refers to the side closer to the first side 13a than the two diagonals 15, 15 of the rectangle formed by the two first sides 13a, 13a or their extensions and the two second sides 13b, 13b or their extensions. The term "side edge" refers to a region from the outer periphery of the plate member 10 to a position slightly inside the periphery, the width of which is approximately 10% or less, particularly 5% or less, of the length of the first side 13a. The term "center region of the side edge" refers to a region of the side edge 11b on the second side 13b side that is approximately 70%, preferably approximately 80%, and particularly preferably approximately 90% of the center of the length of the second side 13b. The term "side edge" refers to a region of the side edge 11b on the second side 13b side other than the center region.

[0027] (Preferred embodiment of the structure for forming a connective tissue body) As shown in Fig. 3, in this embodiment, the plate member 10 preferably has a substantially rectangular planar shape with the first side 13a being a short side and the second side 13b being a long side. As a result of this configuration, even if the number of spacing members 20 is the same, the opening 40b can be made wider, and the connective tissue can easily enter the partitioned space 30. Note that, although the embodiment shown in Fig. 3 has six cylindrical spacing members 20 on the side edge portion 11 of the plate member 10, the present invention is not limited to this embodiment, and there is no particular limit to the number or shape of the spacing members.

[0028] However, in the connective tissue body formation structure of the present invention, as shown in FIG. 3(b), it is preferable that the spacing member 20 is not present on the side edge portion 11 of the plate member 10 located on the two diagonal lines 15, 15. With such a configuration, it is possible to obtain a sheet-like connective tissue body having a large area, as shown by the dotted rectangle in FIG. 3. FIGS. 4(a) and 4(b) show the relationship between the position of the spacing member 20 and the area of ​​the obtained sheet-like connective tissue body. FIG. 4(a) shows a connective tissue body formation structure in which the spacing member 20 is not located on the two diagonal lines 15, 15, and FIG. 4(b) shows a connective tissue body formation structure in which the spacing member 20 is located on the two diagonal lines 15, 15. Comparing FIG. 4(a) and FIG. 4(b), the structure shown in FIG. 4(a) is preferable in that a sheet-like connective tissue body having a larger area can be obtained compared to the structure shown in FIG. 4(b). In the embodiment shown in Fig. 4(b), the sum of the area of ​​the plate member 10 and the cross-sectional area of ​​the spacing member 20 is the same as the value in the embodiment shown in Fig. 3. And, although the structure shown in Fig. 4(b) can produce a rectangular sheet having one length substantially equal to the first side 13a, it can be seen that the area of ​​the rectangular sheet that can be produced is smaller than the value in the embodiment shown in Fig. 3.

[0029] (Shape of plate member) In FIG. 3, the planar shape of the plate member 10 is shown as a rectangle with four rounded corners, but the planar shape of the plate member 10 in this embodiment may be any shape as long as it is approximately rectangular. For example, the plate member 10 may be a rectangle with all four corners at 90°. However, in this embodiment, the plate member 10 is preferably chamfered at the corners connecting the side edge 11a on the first side 13a side and the side edge 11b on the second side 13b side. If the corners of the plate member 10, especially the four corners, are chamfered, the risk of the connective tissue body formation structure 1 breaking through the living body during implantation and damage to the skin and subcutaneous tissue can be suppressed. In addition, the connective tissue body formation structure 1 can be easily embedded and removed. In addition, the surface of the plate member 10 is preferably smooth from the viewpoint of facilitating the collection of the connective tissue body after formation. However, it is also possible to provide slits or embossing on the surface of the plate member 10 depending on the purpose.

[0030] In the narrow sense, "chamfering" refers to forming a surface by cutting the corners of a member, but in the broad sense, it also means cutting corners to make them rounded. In the present disclosure, "chamfering" is treated as a term that includes both of these meanings. That is, the plate member 10 of the connective tissue formation structure 1 of this embodiment may be chamfered by cutting the corners linearly to make them inclined, or may be chamfered in a rounded shape as shown in FIG. 3(a). The plate member 10 may also be a substantially oval plate member with the entire first side 13a side rounded. The plate member 10 may also be asymmetrical.

[0031] (Spacer) As described above, in the connective tissue body formation structure of the present invention, the number and shape of the spacing members 20 are not particularly limited, and various embodiments can be made. Figures 5 to 7 are conceptual diagrams showing some of such embodiments. In Figures 5 to 7, the plate member 10 is drawn in the same manner as in Figure 3, but the spacing members 20 are shown filled in black for convenience of explanation. Figures 5(a) to 5(e) show spacing members 20 disposed on the side edges 11a, 11a of the two first sides 13a, 13a of the plate member 10, respectively. The structures of the embodiments shown in Figures 5(a) to 5(e) facilitate the infiltration of connective tissue into the partitioned space 30, and are advantageous in efficiently forming a sheet-like connective tissue body.

[0032] In each embodiment shown in FIG. 6(a) to FIG. 6(e), the spacing member 20 is further provided on the side edge 11b on the second side 13b side of one of the two side edges 11b, 11b on the two second sides 13b, 13b sides of the plate member 10. Among these, in each embodiment shown in FIG. 6(b) to FIG. 6(e), the spacing member 20 located on the side edge 11b on the second side 13b side is further provided on both side regions 11b2 located on both sides of the central region 11b1. In the present invention, it is sufficient that the multiple spacing members 20 are provided on at least two side edges 11a on the first side 13a sides, so the configuration shown in FIG. 6(a) to FIG. 6(e) can also be used. With such a configuration, the opening 40b can be made wide, and the risk of the connective tissue formation structure 1 being deformed during implantation can be reduced.

[0033] In the connective tissue formation structure of the present invention, the opening 40b only needs to be the longest and extend continuously over the central region 11b1 of the side edge 11b on at least one of the second sides 13b, so that the embodiment shown in FIG. 7(a) to FIG. 7(e) can be used. In each embodiment shown in FIG. 7, the spacing members 20 are further provided on the side edges 11b, 11b on the two second sides 13b, 13b of the plate member 10, and the spacing members 20 provided on the side edges 11b on the two second sides 13b are both provided on both side regions 11b2 located on either side of the central region 11b1. The embodiment shown in FIG. 7(a) to FIG. 7(e) can greatly reduce the risk of the connective tissue formation structure 1 being deformed during implantation.

[0034] In the connective tissue body formation structure 1 of this embodiment, a plurality of spacing members 20, i.e., two or more, may be provided per partition space 30. However, in this embodiment, it is more preferable to provide three or more spacing members 20, particularly five or more spacing members 20, per partition space 30 in terms of ensuring the strength of the structure. The spacing members 20 are also preferably provided in a dispersed manner on the side edge portion 11 of the connective tissue body formation structure 1, as long as the longest opening 40b is not narrowed. If more spacing members 20 are provided in a dispersed manner, the connective tissue body formation structure 1 becomes even less likely to deform. In addition, since the cross-sectional area of ​​each spacing member 20 can be reduced, it is possible to form a connective tissue body with a larger area. For example, in each embodiment shown in FIG. 6(a) to FIG. 6(e), even though five to six spacing members 20 are provided, it is possible to obtain a sheet of a size close to the maximum of the rectangular shapes that can be taken from the surface of the plate member 10.

[0035] The shape of the spacing member 20 is not particularly limited. In the connective tissue body formation structure 1 of this embodiment, the shape of the spacing member 20 is not limited to a cylindrical shape, and may be, for example, a cylindrical shape having an oval cross section or an elliptical cross section as shown in FIG. 6(b) and FIG. 6(c), etc. In particular, a curved oval spacing member 20 as shown in FIG. 6(e) is preferable because it can form a connective tissue body with a large area even if the number of spacing members is increased, and the strength of holding the plate member 10 is high relative to the cross-sectional area. With such a configuration, the risk of deformation of the connective tissue body formation structure 1 during implantation can be reduced. In addition, spacing members 20 of a plurality of cross-sectional shapes, for example, a cylindrical spacing member 20 and a spacing member 20 of an oval cross-sectional shape, may be mixed in one connective tissue body formation structure 1.

[0036] (Construction of a connective tissue formation structure) In the connective tissue formation structure of the present invention, a plurality of plate members 10, i.e., two or more, may be provided, and there is no particular limit to the number of plate members 10. In Figs. 1 and 2, a connective tissue formation structure 1 having three plate members 10 is shown, but the present invention is not limited to such an embodiment. However, while increasing the number of plates 10 increases the number of connective tissue sheets that can be harvested, it also increases the burden on the living body that is the implantation target, so that the number of plate members 10 is preferably about 2 to 5, and particularly about 3 to 4.

[0037] In addition, although the three plate members 10 have the same shape and size in Figs. 1 and 2, the shape and / or size of each plate member 10 may be different in this embodiment. The shape, size, and position of the spacing member 20 may also be different for each partition space 30. However, in the connective tissue formation structure 1 of this embodiment, it is preferable that each plate member 10 has the same shape and size, and the position of the spacing member 20 is also the same for each partition space 30. In particular, if the spacing member 20 penetrates the central plate member 10 as shown in Fig. 1, there is an advantage that the cut-out position of the connective tissue sheet can be aligned in each partition space 30. However, only one of the plate members 10 may be different from the others. For example, if a mark such as a mark is attached to the long side 13b of the outer surface of the terminal plate member 10 to clearly indicate the side into which the connective tissue is likely to penetrate, the operator can refer to it when deciding the direction of implantation in the living body. For the same purpose, the plate member 10 may be asymmetrical. 8(a) and 8(b) are conceptual diagrams showing an embodiment of such an asymmetric plate member 10 and a spacing member 20 provided thereon. According to the embodiment shown in Fig. 8(b), it is possible to make the opening 40b wide while making it difficult to deform. As a similar configuration, it is also possible to make the spacing member 20 have the shape and arrangement shown in Fig. 9.

[0038] In the connective tissue formation structure 1 of this embodiment, the spacing member 20 may be integrally formed with at least one of the two plate members 10 that are held in an opposing, spaced-apart state. An integrally formed connective tissue formation structure generally has excellent strength, and therefore has the advantage of reducing the risk of breakage or deformation during implantation, for example.

[0039] In the connective tissue body formation structure 1 of this embodiment, the spacing member 20 may be formed separately from the two plate members 10 that are held in an opposing, spaced apart state. For example, the plate members 10 and the spacing member 20 that are formed separately may be joined by screwing, bonding, welding, or the like. A connective tissue body formation structure 1 having such a configuration, particularly a connective tissue body formation structure 1 in which the plate members 10 and the spacing member 20 are screwed together, has the advantage that the formed connective tissue body can be easily harvested after removal from the living body.

[0040] The connective tissue formation structure 1 of this embodiment may also have a configuration in which a spacing member 20 formed integrally with one plate member 10 is joined to another plate member 10 formed separately. For example, in the connective tissue formation structure 1 shown in Fig. 1, spacing members 20 may be formed integrally on both sides of the central plate member 10, and two terminal plate members 10 may be joined to both sides thereof.

[0041] The material constituting the plate member 10 and the spacing member 20 is not particularly limited, but it is preferable that the material has a strength (hardness) sufficient to suppress large deformation when implanted in a living body, chemical stability, and resistance to sterilization treatment by autoclave or the like, and does not release substances that adversely affect the connective tissue to be formed or the living body, or does not release such substances in large amounts. From this viewpoint, the material constituting the plurality of plate members 10 and the spacing member 20 is preferably a resin material such as an acrylic resin or a silicone resin, or a metal material with high rust resistance such as stainless steel, titanium, cobalt, chromium, or a nickel-titanium alloy. The surfaces of the plurality of plate members 10 and the spacing member 20 may be covered with the above-mentioned resin material or metal material. The above-mentioned resin material forms the connective tissue in the living body faster than the above-mentioned metal material.

[0042] Moreover, in the plurality of plate members 10, it is preferable that a connective tissue formation promoting substance that promotes the formation of connective tissue is provided on one of the two opposing inner surfaces. Examples of the connective tissue formation promoting substance include blood, fat, collagen, gelatin, and substances containing growth factors and the like. When the connective tissue formation promoting substance is provided on only one of the two opposing inner surfaces, it becomes easy to distinguish the front and back sides of the sheet-like connective tissue removed from the connective tissue formation structure 1, improving product management such as packaging of the connective tissue.

[0043] (Formation of connective tissue) Thus, unlike conventional connective tissue body formation substrates, the connective tissue body formation structure 1 of the embodiment focuses on the arrangement, shape, and size of the spacing members. From the viewpoint of improving the productivity of connective tissue bodies, the connective tissue body formation structure 1 is used in a living body other than a human and is embedded in subcutaneous tissue. The connective tissue body formation structure of the embodiment has a wide opening 40b, so that connective tissue in the living body can easily enter after each meal. In addition, since the position of the spacing member 20 is appropriate, a large-area sheet-like connective tissue body can be efficiently produced. Moreover, since there is a low risk of deformation during embedding, the connective tissue body can be stably formed in the living body. In particular, if the connective tissue body formation structure 1 has a chamfered corner of the plate member 10, there is a low risk of damaging the biology of the subject to be embedded.

[0044] The connective tissue formation structure 1 is used by being implanted in a living body other than human. Examples of living bodies other than human include mammals such as dogs, cows, pigs, horses, goats, sheep, and rabbits, as well as birds, fish, and other animals. Among these, preferred are cows, horses, pigs, and goats, which have a larger implantation area than humans, can produce a large amount of connective tissue with one implantation, and are widely raised as livestock.

[0045] The connective tissue body formation structure 1 is embedded in the living body in the subcutaneous tissue of the limbs, shoulders, back, abdomen, etc. After a part of the epidermis and dermis (hereinafter also referred to as skin) on the outside of the subcutaneous tissue is peeled off from the living body, the connective tissue body formation structure 1 is inserted into the subcutaneous tissue by inserting it, and then the partially peeled skin is sutured to the living body, thereby embedding the connective tissue body formation structure 1 in the subcutaneous tissue. The sheet-like connective tissue body formation structure 1 can be inserted while cutting open the subcutaneous tissue when being inserted. For example, the connective tissue body formation structure 1 is inserted into the living body from an insertion part formed by incising the living body. Since the insertion part into which the sheet-like connective tissue body formation structure 1 is inserted is linear, the insertion part can be formed by a simple incision procedure.

[0046] [Method of forming connective tissue] Next, a method for forming a connective tissue body according to an embodiment will be described. The method for forming a connective tissue body according to an embodiment includes a step (S-1) of inserting and embedding the connective tissue body formation structure 1 into a living body other than a human, a step (S-2) of forming a connective tissue body between the opposing surfaces of the two plate members of the connective tissue body formation structure embedded in the living body, and a step (S-3) of removing the connective tissue body formation structure having the connective tissue body formed therein from the living body.

[0047] In step (S-1), the connective tissue body formation structure 1 is inserted into a predetermined site in a living body other than a human, and the connective tissue body formation structure 1 is embedded in the living body. The connective tissue body formation structure 1 is embedded in subcutaneous tissue of the limbs, shoulders, back, abdomen, etc. As an example, a part of the skin such as the epidermis and dermis that cover the subcutaneous tissue from the outside is peeled off from the living body, the connective tissue body formation structure 1 is inserted into the subcutaneous tissue in a plugging manner, and the partially peeled skin is sutured to the living body, thereby embedding the connective tissue body formation structure 1 in the subcutaneous tissue. When inserting the connective tissue body formation structure 1, the connective tissue body formation structure 1 can be inserted while cutting open the subcutaneous tissue.

[0048] In step (S-2) carried out after step (S-1), the connective tissue body formation structure 1 is embedded in a living body for a predetermined time, and a sheet-like connective tissue body is formed between the opposing surfaces of the two plate members 10 of the connective tissue body formation structure 1. During the embedding of the connective tissue body formation structure 1, connective tissue within the living body enters the compartment space 30 through the openings 40 of the connective tissue body formation structure 1, and the connective tissue in the compartment space 30 grows, thereby forming a connective tissue body in the compartment space 30. The connective tissue body is composed of fibroblasts and an extracellular matrix such as collagen.

[0049] In step (S-3) carried out after step (S-2), the connective tissue body formation structure 1 containing the connective tissue body formed in the compartment space 30 is removed from the living body. When the connective tissue body formed in the compartment space 30 is bonded to biological tissue present around the connective tissue body formation structure 1, the surrounding biological tissue and the connective tissue body formation structure 1 are cut, and the connective tissue body formation structure 1 is removed from the living body.

[0050] Furthermore, the method for forming a connective tissue body of the embodiment further includes a step (SA) of providing an insertion part into which the above-mentioned connective tissue body formation structure 1 can be inserted in a living body other than a human prior to the step (S-1), and in the step (S-1), it is preferable to insert and implant the connective tissue body formation structure 1 through the insertion part. The insertion part provided in the step (SA) can be easily formed by making a small incision in the living body, compared to conventional cylindrical connective tissue body formation substrates. Furthermore, the sheet-like connective tissue body formation structure 1 can be inserted by slightly cutting the insertion part, without repeatedly cutting the living body. This reduces the burden on the animal and makes the work easier.

[0051] Furthermore, the method for forming a connective tissue body of the embodiment may further include a step (SB) of separating the connective tissue body from the compartment space 30 of the connective tissue body formation structure 1 taken out from the living body after the step (S-3). In the step (SB) performed after the step (S-3), the connective tissue body is separated from the compartment space 30 of the connective tissue body formation structure 1 taken out from the living body to obtain a sheet-like connective tissue body. When the connective tissue is formed on the outer surface of the connective tissue body formation structure 1, the connective tissue body is removed from the outer surface of the connective tissue body formation structure 1 and then separated from the compartment space 30. A connective tissue body having a desired shape can be obtained by appropriately adjusting the interval between the multiple plate members 10 and the shape of the inner surface 10a of the plate member 10.

[0052] Furthermore, when the obtained connective tissue is used for xenotransplantation to humans, etc., it is preferable to subject the connective tissue to immunogen removal treatments such as decellularization, dehydration, and fixation in order to prevent rejection after transplantation. Examples of decellularization include methods of eluting and washing the extracellular matrix by ultrasonic treatment, surfactant treatment, and enzyme treatment such as collagenase. Examples of dehydration include washing with a water-soluble organic solvent such as methanol, ethanol, and isopropyl alcohol. Examples of fixation include treatment with an aldehyde compound such as glutaraldehyde and formaldehyde.

[0053] Although the embodiments have been described above, the present invention is not limited to the above embodiments, but includes all aspects included in the concept and scope of the claims of the present disclosure, and can be modified in various ways within the scope of the present disclosure. [Explanation of symbols]

[0054] 1 Structure for connective tissue formation 10 Plate members 11 Side edge 11a: Side edge portion on the first side 11b Side edge portion on the second side 11b1: Central region of the side edge on the second side 11b2 Side area of ​​the side edge on the second side 13a Side 1 13b Side 2 15 Diagonal 20 Spacer 30 Compartment Space 40 Opening 40b Longest opening L: Plate surface direction of plate member

Claims

1. A plurality of plate members; a plurality of spacing members provided on side edges of the plurality of plate members and holding the plurality of plate members in a facing, spaced apart state; A structure for forming a connective tissue body comprising: Each plate member has a rectangular shape defined by first sides which are two opposing short sides and second sides which are two opposing long sides, or a rectangular shape with chamfered corners, in plan view; the plurality of spacing members are provided on at least two first side edge portions of two plate members that face each other among the side edge portions of the plurality of plate members, and are not located on two diagonal lines of the rectangle, and are not located in a region surrounded by at least one of the two second sides and the two diagonal lines; An opening is formed between the plurality of spacing members, A structure for connective tissue formation, characterized in that among the openings, the opening that extends continuously across the central region of at least one of the side edges on the second side of the two second sides is the longest.

2. The connective tissue formation structure according to claim 1 , wherein the plate member has a chamfered corner connecting a side edge portion of the first side and a side edge portion of the second side.

3. 3. The connective tissue formation structure according to claim 1 or 2, wherein the spacing member is further provided on at least one of the side edge portions on the second side of the plate member, and the spacing member provided on the side edge portion on at least one of the second sides is provided on both side regions located on either side of the central region.

4. 3. The connective tissue formation structure according to claim 1 or 2, wherein the spacing members are further provided on the side edges of the two second sides of the plate member, and the spacing members provided on the side edges of the two second sides are both provided in both side regions located on either side of the central region.

5. The connective tissue formation structure according to any one of claims 1 to 4, wherein the spacing member is integrally formed with at least one of the two plate members that are held in an opposing, spaced-apart state.

6. The connective tissue formation structure according to any one of claims 1 to 4, wherein the spacing member is formed separately from the two plate members which it holds in an opposed, spaced-apart state.

7. A step (S-1) of inserting and implanting the connective tissue formation structure according to any one of claims 1 to 6 into a living body other than a human; A step (S-2) of forming a connective tissue between the opposing surfaces of the two plate members of the connective tissue formation structure implanted in the living body; A step (S-3) of removing the connective tissue formation structure from the living body. A method for forming a connective tissue structure, comprising the steps of:

8. The method further includes a step (SA) of providing an insertion part into which the connective tissue formation structure can be inserted, in the non-human living body, prior to the step (S-1), The method for forming a connective tissue body according to claim 7, wherein in the step (S-1), the connective tissue body formation structure is inserted through the insertion portion and embedded.

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