Nerve injury repair sheet, brain injury repair sheet, and spinal cord injury repair sheet

Abstract

The present invention provides a sheet for biological tissue regeneration treatment that regenerates biological tissue, a sheet for repairing nerve damage, a sheet for repairing brain damage, a sheet for repairing spinal cord damage, a sheet for repairing lung damage, a sheet for repairing peritoneal damage, a sheet for repairing blood vessel damage, a culture sheet, and a regeneration treatment method. The sheet for biological tissue regeneration treatment has a first surface including a roughened surface to be phagocytosed by cells of tissue in a living body, and a second surface disposed on the opposite side to the first surface. The roughened surface contains polytetrafluoroethylene as a main component.

Description

[Technical field]

[0001] The present invention relates to a sheet for biological tissue regeneration treatment, a sheet for nerve damage repair, a sheet for brain damage repair, a sheet for spinal cord damage repair, a sheet for lung damage repair, a sheet for peritoneal damage repair, a sheet for blood vessel damage repair, a culture sheet, and a regeneration treatment method. [Background technology]

[0002] Various materials are used for dura mater reconstruction in neurosurgery. Expanded polytetrafluoroethylene, one of the materials for artificial dura mater, is a stable material, but has poor biocompatibility. For example, expanded polytetrafluoroethylene has poor adhesion to the native dura mater. Therefore, in the biorepair material described in Patent Document 1, an expanded polytetrafluoroethylene sheet is irradiated with an ion beam to improve biocompatibility.

[0003] More specifically, the biorepair material described in Patent Document 1 combines fibrin glue with expanded polytetrafluoroethylene, at least a portion of whose surface has been modified by ion bombardment through ion implantation.

[0004] Expanded polytetrafluoroethylene has been applied to dura mater defects. However, this application is aimed at filling the dura mater defects (in other words, filling the defects with an artificial material) and is not intended to regenerate biological tissue at the defects. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 4445697 Summary of the Invention [Problem to be solved by the invention]

[0006] The object of the present invention is to provide a sheet for biological tissue regeneration treatment that regenerates biological tissue, a sheet for nerve damage repair, a sheet for brain damage repair, a sheet for spinal cord damage repair, a sheet for lung damage repair, a sheet for peritoneal damage repair, a sheet for vascular damage repair, a culture sheet, and a regeneration treatment method. [Means for solving the problem]

[0007] The means for solving the problems will be described below using the numbers and symbols used in the description of the embodiment of the invention. These numbers and symbols are added in parentheses for reference purposes to show an example of the correspondence between the description of the claims and the description of the embodiment of the invention. Therefore, the description in parentheses should not be interpreted as limiting the scope of the claims.

[0008] The sheet for biological tissue regeneration treatment in some embodiments comprises a first surface (20) including a roughened surface (20r) to be phagocytosed by cells of tissue in vivo, and a second surface (30) disposed on the opposite side of the first surface (20). The roughened surface (20r) contains polytetrafluoroethylene as a main component.

[0009] In the above sheet for biological tissue regeneration treatment, the roughened surface (20r) may be constituted by the surface of the ion-implanted layer (2).

[0010] The sheet for biological tissue regeneration treatment may be configured so that the cells of the in-vivo tissue infiltrate into the inside of the ion-implanted layer (2).

[0011] In the above-mentioned sheet for biological tissue regeneration treatment, said roughened surface (20r) may have depressions (20d) of approximately the same size as the cells that phagocytose said roughened surface (20r).

[0012] The above-mentioned sheet for biological tissue regeneration treatment may be configured such that, when the roughened surface (20r) is placed in contact with the in vivo tissue (4), new tissue develops from the in vivo tissue (4) along the roughened surface (20r), and the new tissue develops so as to mesh with the irregularities of the roughened surface (20r).

[0013] The above-mentioned sheet for biological tissue regeneration treatment may be configured so that, when the roughened surface (20r) is placed in contact with the damaged in-vivo tissue (4), expression of at least one of mesenchymal stem cells, fibroblasts, myofibroblasts, macrophages, and oligodendrocytes is more pronounced than when the second surface (30) is placed in contact with the damaged in-vivo tissue (4).

[0014] The above-mentioned sheet for biological tissue regeneration treatment may be configured so that when the roughened surface (20r) is placed in contact with the damaged in-vivo tissue (4), expression of the mesenchymal stem cells is more pronounced than when the second surface (30) is placed in contact with the damaged in-vivo tissue (4).

[0015] The sheet for biological tissue regeneration treatment may be configured so that, when the roughened surface (20r) is placed in contact with the damaged in-vivo tissue (4), new capillaries (B) are generated along the roughened surface (20r).

[0016] The above-mentioned sheet for biological tissue regeneration treatment may be configured such that, when the roughened surface (20r) is placed in contact with the edge (4e) of the endogenous tissue (4) so ​​that the roughened surface (20r) faces the defect area (RG) of the endogenous tissue (4), a biological membrane (5) and capillaries (B) are regenerated along the roughened surface (20r) in the defect area (RG).

[0017] The above-mentioned sheet for biological tissue regeneration treatment may be configured so that, when the roughened surface (20r) is left in contact with the in vivo tissue (4) for six months or more, the opaque polytetrafluoroethylene becomes transparent or semi-transparent.

[0018] In some embodiments, the sheet for nerve damage repair comprises a first surface (20) including a roughened surface (20r) to be phagocytosed by cells of an in vivo tissue (4), and a second surface (30) disposed on the opposite side of the first surface (20). The roughened surface (20r) contains polytetrafluoroethylene as a main component.

[0019] The above-mentioned nerve damage repair sheet may be configured so that, when the roughened surface (20r) is placed facing the nerve damage site (RG1) of the biological tissue (4), nerve cells are regenerated using the roughened surface (20r) as a scaffold.

[0020] In some embodiments, the sheet for brain injury repair comprises a first surface (20) including a roughened surface (20r) to be phagocytosed by cells of an in vivo tissue (4), and a second surface (30) disposed on the opposite side of the first surface (20). The roughened surface (20r) contains polytetrafluoroethylene as a main component.

[0021] In some embodiments, the sheet for spinal cord injury repair comprises a first surface (20) including a roughened surface (20r) to be phagocytosed by cells of an in vivo tissue (4), and a second surface (30) disposed on the opposite side of the first surface (20). The roughened surface (20r) contains polytetrafluoroethylene as a main component.

[0022] In some embodiments, the sheet for repairing damaged lungs comprises a first surface (20) including a roughened surface (20r) to be phagocytosed by cells of an in vivo tissue (4), and a second surface (30) disposed on the opposite side of the first surface (20). The roughened surface (20r) contains polytetrafluoroethylene as a main component.

[0023] In some embodiments, the sheet for repairing peritoneal damage comprises a first surface (20) including a roughened surface (20r) to be phagocytosed by cells of an in vivo tissue (4), and a second surface (30) disposed on the opposite side of the first surface (20). The roughened surface (20r) contains polytetrafluoroethylene as a main component.

[0024] In some embodiments, the sheet for repairing vascular injury comprises a first surface (20) including a roughened surface (20r) to be phagocytosed by cells of an in vivo tissue (4), and a second surface (30) disposed on the opposite side of the first surface (20). The roughened surface (20r) contains polytetrafluoroethylene as a main component.

[0025] In some embodiments, the culture sheet comprises a first surface (20) including a roughened surface (20r) on which the cells (C) to be cultured or a biological tissue containing the cells (C) is placed, and a second surface (30) placed on the opposite side of the first surface (20). The roughened surface (20r) contains polytetrafluoroethylene as a main component.

[0026] In some embodiments, the regenerative treatment method is a method for regenerative treatment of humans or non-human animals. The regenerative treatment method includes the steps of: preparing a sheet (1A) for biological tissue regeneration treatment having a first surface (20) at least a part of which is constituted by a roughened surface (20r) mainly containing polytetrafluoroethylene, and a second surface (30) disposed on the opposite side of the first surface (20); placing the sheet (1A) for biological tissue regeneration treatment on the damaged tissue (4) so ​​that the roughened surface (20r) is in contact with the damaged tissue (4); and regenerating tissue at a damaged site of the tissue (4) using the roughened surface (20r) as a scaffold. The step of regenerating tissue at a damaged site of the tissue (4) includes phagocytosis of at least a part of the roughened surface (20r) by cells of the tissue (4). Effect of the Invention

[0027] The present invention can provide a sheet for biological tissue regeneration treatment that regenerates biological tissue, a sheet for nerve damage repair, a sheet for brain damage repair, a sheet for spinal cord damage repair, a sheet for lung damage repair, a sheet for peritoneal damage repair, a sheet for vascular damage repair, a culture sheet, and a regeneration treatment method. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 is a diagram showing a schematic view of a part of the sheet for biological tissue regeneration treatment in the first embodiment. [Diagram 2] FIG. 2 is a schematic perspective view showing the sheet for biological tissue regeneration treatment in the first embodiment. [Diagram 3] FIG. 3 is a schematic cross-sectional view showing an enlarged portion of the sheet for biological tissue regeneration treatment in the first embodiment. [Figure 4] FIG. 4 is a photograph showing the state in which the rat's head has been cut open. [Diagram 5] FIG. 5 is a photograph showing the state in which the rat's head has been opened. [Figure 6] FIG. 6 is a photograph substituting a drawing, showing a state in which the sheet for biological tissue regeneration treatment in the first embodiment is placed so as to cover a craniotomy site. [Figure 7] FIG. 7 is a photograph substituting a drawing, showing the state in which the sheet for biological tissue regeneration treatment is covered with autologous bone and bone wax. [Figure 8] FIG. 8 is a photograph substituting a drawing, showing a state in which the sheet for biological tissue regeneration treatment in the first embodiment has become semitransparent and a pale yellow, transparent biological membrane has been formed around the sheet for biological tissue regeneration treatment. [Figure 9] FIG. 9 is a photograph substituting a drawing, showing a state in which the sheet for biological tissue regeneration treatment in the first embodiment is placed so as to block an opening in the peritoneum. [Figure 10] FIG. 10 is a photograph substituting a drawing, showing a state in which a semi-transparent biological membrane is formed along the sheet for biological tissue regeneration treatment in the first embodiment, and capillaries are newly generated inside the biological membrane. [Figure 11]FIG. 11 is a photograph substituting a drawing, showing a state in which a biological membrane is newly formed so as to engage with the roughened surface of the sheet for biological tissue regeneration treatment. [Figure 12] FIG. 12 is a photograph showing the phagocytosis of ePTFE. [Figure 13] FIG. 13 is an electron microscope photograph of the roughened surface side of the sheet for biological tissue regeneration treatment. [Figure 14] FIG. 14 is a photograph substituting a drawing, showing the state in which the second surface of the sheet for biological tissue regeneration treatment and the biomembrane are separated. [Figure 15] FIG. 15 is a photograph showing the culture subject. [Figure 16] FIG. 16 is a micrograph of the cells cultured in the MSC medium on day 0. [Figure 17] FIG. 17 shows micrographs of cells cultured in MSC medium after two days. [Figure 18] FIG. 18 shows micrographs of cells cultured in MSC medium after 7 days. [Figure 19] FIG. 19 shows micrographs of staining for each marker. [Figure 20] FIG. 20 is a photograph showing the results of the scRNA-seq analysis. [Figure 21] FIG. 21 is a photograph showing the results of scRNA-seq analysis. [Figure 22] FIG. 22 is a schematic cross-sectional view showing a state in which the sheet for biological tissue regeneration treatment in the first embodiment is placed in tissue in a living body. [Diagram 23] FIG. 23 is a schematic cross-sectional view showing a state in which a biological membrane is newly generated along the roughened surface of the sheet for biological tissue regeneration treatment in the first embodiment. [Figure 24] FIG. 24 is a schematic cross-sectional view showing a state in which the sheet for biological tissue regeneration treatment in the first embodiment is placed at a damaged brain site. [Diagram 25] FIG. 25 is a schematic cross-sectional view showing a state in which the sheet for biological tissue regeneration treatment in the first embodiment is placed at a spinal cord damaged site. [Figure 26] FIG. 26 is a schematic cross-sectional view showing a state in which the sheet for biological tissue regeneration treatment in the first embodiment is placed at a damaged site of a lung structure. [Figure 27] FIG. 27 is a schematic cross-sectional view showing a state in which the sheet for biological tissue regeneration treatment in the first embodiment is placed at a damaged site of a lung structure. [Figure 28] FIG. 28 is a schematic cross-sectional view showing a state in which the sheet for biological tissue regeneration treatment in the first embodiment is placed at a damaged site of a blood vessel. [Figure 29] FIG. 29 is a schematic cross-sectional view showing a state in which the sheet for biological tissue regeneration treatment in the first embodiment is placed at a damaged site of a blood vessel. [Diagram 30] FIG. 30 is a schematic cross-sectional view showing a state in which cells are cultured using a culture sheet. [Diagram 31] FIG. 31 is a flowchart showing an example of the regenerative treatment method according to the second embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] Hereinafter, referring to the drawings, the biological tissue regeneration treatment sheet, nerve damage repair sheet, brain damage repair sheet, spinal cord damage repair sheet, lung damage repair sheet, peritoneum damage repair sheet, blood vessel damage repair sheet, culture sheet, and regeneration treatment method in the embodiment will be described. In the following description, the same reference numerals are given to members and parts having the same functions, and repeated description of the members and parts with the same reference numerals is omitted.

[0030] (First embodiment) The sheet for biological tissue regeneration treatment 1A in the first embodiment will be described with reference to Figs. 1 to 30. Fig. 1 is a diagram showing a part of the sheet for biological tissue regeneration treatment 1A in the first embodiment. Fig. 2 is a schematic perspective view showing the sheet for biological tissue regeneration treatment 1A in the first embodiment. Fig. 3 is a schematic cross-sectional view showing an enlarged part of the sheet for biological tissue regeneration treatment 1A in the first embodiment. Fig. 4 is a photograph showing the state in which the head of a rat is incised. Fig. 5 is a photograph showing the state in which the head of a rat is opened. Fig. 6 is a photograph showing the state in which the sheet for biological tissue regeneration treatment 1A in the first embodiment is placed so as to cover the open craniotomy site. Fig. 7 is a photograph showing the sheet for biological tissue regeneration treatment 1A covered with autogenous bone and bone wax. Fig. 8 is a photograph showing the state in which the sheet for biological tissue regeneration treatment 1A in the first embodiment is made semi-transparent and a pale yellow transparent biomembrane is formed around the sheet for biological tissue regeneration treatment 1A. FIG. 9 is a drawing substitute photograph showing a state where the biological tissue regeneration treatment sheet 1A in the first embodiment is placed so as to block the opening 40a of the peritoneum 40. FIG. 10 is a drawing substitute photograph showing a state where a semi-transparent biological membrane 5 is formed along the biological tissue regeneration treatment sheet 1A in the first embodiment and a capillary blood vessel B is generated inside the biological membrane 5. FIG. 11 is a drawing substitute photograph showing a state where the biological membrane 5 is generated so as to engage with the roughened surface 20r of the biological tissue regeneration treatment sheet 1A. FIG. 12 is a drawing substitute photograph showing a phagocytosis image 6 of ePTFE. FIG. 13 is an electron microscope photograph of the roughened surface side of the biological tissue regeneration treatment sheet 1A. FIG. 14 is a drawing substitute photograph showing a state where the second surface 30 of the biological tissue regeneration treatment sheet 1A and the biological membrane 5' are separated. FIG. 15 is a drawing substitute photograph showing a culture object. FIG. 16 is a microscope photograph of the state of cells cultured in a medium for MSCs after 0 days. Figure 17 is a micrograph of the appearance of cells cultured in MSC medium after 2 days. Figure 18 is a micrograph of the appearance of cells cultured in MSC medium after 7 days. Figure 19 is a micrograph of the staining of each marker. Figures 20 and 21 are photographs showing the results of scRNA-seq analysis.FIG. 22 is a schematic cross-sectional view showing a state where the biological tissue regeneration treatment sheet 1A in the first embodiment is placed in a tissue 4 in a living body. FIG. 23 is a schematic cross-sectional view showing a state where a biological membrane 5 is newly generated along the roughened surface 20r of the biological tissue regeneration treatment sheet 1A in the first embodiment. FIG. 24 is a schematic cross-sectional view showing a state where the biological tissue regeneration treatment sheet 1A in the first embodiment is placed in a brain damaged site. FIG. 25 is a schematic cross-sectional view showing a state where the biological tissue regeneration treatment sheet 1A in the first embodiment is placed in a spinal cord damaged site. FIGS. 26 and 27 are schematic cross-sectional views showing a state where the biological tissue regeneration treatment sheet 1A in the first embodiment is placed in a damaged site of a lung structure 45. FIGS. 28 and 29 are schematic cross-sectional views showing a state where the biological tissue regeneration treatment sheet 1A in the first embodiment is placed in a damaged site of a blood vessel 91. FIG. 30 is a schematic cross-sectional view showing a state in which a cell C is cultured using a culture sheet 1H.

[0031] 1, the biological tissue regeneration treatment sheet 1A in the first embodiment has a first surface 20 and a second surface 30 disposed on the opposite side to the first surface 20. In other words, the biological tissue regeneration treatment sheet 1A has two main surfaces, one of which is the first surface 20 and the other of which is the second surface 30.

[0032] As illustrated in FIG. 2, the first surface 20 includes a roughened surface 20r. In the example illustrated in FIG. 1, a part of the first surface 20 is the roughened surface 20r, and another part of the first surface 20 is the non-roughened surface 20s. Alternatively, the entire first surface 20 may be the roughened surface 20r. In this specification, the term "roughened surface" refers to a surface that has been subjected to a roughening treatment. The maximum height roughness Rz of the roughened surface 20r is, for example, 8 μm or more. The "maximum height roughness Rz" is measured based on JIS B 0601:2013 (corresponding international standard ISO 4287:1997, Amd.1:2009).

[0033] The roughened surface 20r contains polytetrafluoroethylene as a main component. In other words, the ratio of polytetrafluoroethylene constituting the roughened surface to the entire material constituting the roughened surface 20r is 50 weight percent or more. The ratio of polytetrafluoroethylene constituting the roughened surface to the entire material constituting the roughened surface 20r may be 70 weight percent or more, 90 weight percent or more, 95 weight percent or more, or 99 weight percent or more.

[0034] The entire biological tissue regeneration treatment sheet 1A may contain polytetrafluoroethylene as a main component. In other words, the ratio of polytetrafluoroethylene to the entire material constituting the biological tissue regeneration treatment sheet 1A may be 50 weight percent or more. The ratio of polytetrafluoroethylene constituting the biological tissue regeneration treatment sheet 1A to the entire material constituting the biological tissue regeneration treatment sheet 1A may be 70 weight percent or more, 90 weight percent or more, 95 weight percent or more, or 99 weight percent or more. Alternatively, the biological tissue regeneration treatment sheet 1A may be a laminate of a layer composed of polytetrafluoroethylene and a layer composed of another material. In this case, it is sufficient that the main component of the material constituting at least the roughened surface 20r is polytetrafluoroethylene.

[0035] The second surface 30 may be a roughened surface or a smooth surface. In this specification, the term "smooth surface" refers to a surface that has not been subjected to a roughening treatment and has a smaller maximum height roughness Rz than the roughened surface 20r.

[0036] The biological tissue regeneration treatment sheet 1A in the first embodiment has a property that the roughened polytetrafluoroethylene is phagocytosed by cells of the tissue in the living body. Even if polytetrafluoroethylene is brought into contact with the tissue in the living body, the polytetrafluoroethylene is not usually phagocytosed by the cells of the tissue in the living body. In contrast, in the first embodiment, the cells of the tissue in the living body are configured to phagocytosed the roughened surface 20r containing polytetrafluoroethylene as a main component. Furthermore, the regeneration of the tissue in the living body progresses using the roughened surface 20r as a scaffold. Here, phagocytosis means the action of the cells of the tissue in the living body taking in unnecessary things.

[0037] As described above, the biological tissue regeneration treatment sheet 1A in the first embodiment realizes regeneration of biological tissue by a novel mechanism that has not been known so far. Furthermore, the biological tissue regeneration treatment sheet 1A in the first embodiment provides a new application of regeneration of biological tissue in a medical sheet using polytetrafluoroethylene.

[0038] (Optional configuration) Next, optional additional configurations that can be adopted in the body tissue regeneration treatment sheet 1A in the first embodiment will be described.

[0039] (Ion-implanted layer 2) As illustrated in FIG. 3, the roughened surface 20r may be constituted by the surface of the ion-implanted layer 2. In this specification, the term "ion-implanted layer 2" refers to a layer whose physical and / or chemical properties have been modified by implanting an ionized element. In the example illustrated in FIG. 3, the ion-implanted layer 2 has a plurality of minute depressions 20d on its surface due to ion implantation. The ion-implanted layer 2 is a layer in which the element implanted by ion implantation is mixed as an impurity in polytetrafluoroethylene. Some of the ion-implanted element may escape from the ion-implanted layer 2.

[0040] 3, the element ion-implanted into the polytetrafluoroethylene is, for example, argon, neon, etc. In other words, the ion-implanted layer 2 may be a layer in which argon is mixed into the polytetrafluoroethylene as an impurity, or a layer in which neon is mixed into the polytetrafluoroethylene as an impurity.

[0041] (Roughened surface 20r) From the viewpoint of allowing the roughened surface 20r to be phagocytosed by cells, the roughened surface 20r preferably has recesses 20d of a size comparable to the size of the cells that phagocytosed the roughened surface 20r. In this specification, a recess of a size comparable to the size of the cells that phagocytosed the roughened surface 20r means a recess of a depth of 1 / 2 to 2 times the diameter of the cells that phagocytosed the roughened surface 20r. For example, the size of a human macrophage is approximately 15 μm to 20 μm. Therefore, the roughened surface 20r preferably has recesses 20d with a depth of 7.5 μm to 30 μm (for example, recesses 20d with a depth of 7.5 μm to 15 μm and / or recesses 20d with a depth of 15 μm to 30 μm), or recesses 20d with a depth of 10 μm to 40 μm (for example, recesses 20d with a depth of 10 μm to 20 μm and / or recesses 20d with a depth of 20 μm to 40 μm). In this case, cells (for example, macrophages) that phagocytose the roughened surface 20r can phagocytose the roughened surface 20r while entering the recesses of the roughened surface 20r.

[0042] (Expanded polytetrafluoroethylene) In the present specification, the polytetrafluoroethylene may be expanded polytetrafluoroethylene (hereinafter referred to as "ePTEF"). ePTEF is polytetrafluoroethylene that has been subjected to an expansion process (more specifically, polytetrafluoroethylene that has been expanded under heat). ePTEF is expanded porous polytetrafluoroethylene made using the method described in, for example, U.S. Patent No. 3,953,566 or No. 4,187,390. Alternatively, the polytetrafluoroethylene in the present specification may be non-expanded polytetrafluoroethylene.

[0043] (Adhesion between roughened surface 20r and in vivo tissue) The roughened surface 20r (more specifically, the ion-implanted layer 2) may be adhered to the in vivo tissue via an adhesive such as fibrin glue, or may be adhered without an adhesive. In other words, an adhesive may be applied to the roughened surface 20r, or an adhesive may not be applied. From the viewpoint of filling the gap between the roughened surface 20r and the in vivo tissue with newly generated cells, it is preferable that an adhesive is not applied to the roughened surface 20r.

[0044] (2nd page 30) The second surface 30 may contain polytetrafluoroethylene as a main component. In other words, the proportion of the polytetrafluoroethylene constituting the second surface 30 in the entire material constituting the second surface 30 may be 50 weight percent or more. The proportion of the polytetrafluoroethylene constituting the second surface 30 in the entire material constituting the second surface 30 may be 70 weight percent or more, 90 weight percent or more, 95 weight percent or more, or 99 weight percent or more.

[0045] The second surface 30 is, for example, a non-roughened surface. When the second surface 30 is a non-roughened surface, adhesion between the second surface 30 and in vivo tissue is prevented or suppressed. When the second surface 30 is a non-roughened surface, the second surface 30 is not an ion-implanted layer 2.

[0046] (Thickness of sheet for biological tissue regeneration therapy) The thickness of the sheet for biological tissue regeneration treatment 1A is, for example, 50 μm to 500 μm, 50 μm to 300 μm, 50 μm to 200 μm, or 50 μm to 150 μm. When the sheet is sufficiently thin, it is easy to place the sheet for biological tissue regeneration treatment 1A along the outer shape of the tissue in the body.

[0047] (Body tissue regeneration treatment sheet used in Experiments 1 to 3) The following Experiments 1 to 3 were carried out using a sheet 1A for biological tissue regeneration treatment having a roughened surface 20r formed by ion implantation of argon ions (Ar+). In Experiments 1 to 3, the ratio of polytetrafluoroethylene constituting the roughened surface to the entire material constituting the roughened surface 20r of the sheet 1A for biological tissue regeneration treatment was 99 weight percent or more, and the ratio of polytetrafluoroethylene to the entire material constituting the sheet 1A for biological tissue regeneration treatment was 99 weight percent or more. The film thickness of the sheet 1A for biological tissue regeneration treatment was 300 μm. The acceleration voltage of the argon ions (Ar+) was 150 keV, and the amount of argon ions (Ar+) implanted into the sheet 1A for biological tissue regeneration treatment was 1×10 14 ions / cm 2 It was.

[0048] (Experiment 1) After administering inhalation anesthesia to a rat (Wistar, 8 weeks, male), a midline incision of approximately 2 cm was made (FIG. 4), and a circular craniotomy of approximately 8 mm in size was made on the right side of the incision (FIG. 5), and the trimmed sheet for biological tissue regeneration treatment 1A was placed so as to cover the craniotomy site (FIG. 6). The sheet for biological tissue regeneration treatment 1A was placed so that the second surface 30 (more specifically, the non-roughened surface) faced the inside of the head and the roughened surface 20r faced the outside of the head. The roughened surface 20r was then covered with autologous bone and bone wax (FIG. 7), and the wound was closed.

[0049] In rats sacrificed 4.5 months after placement, the tissue regeneration treatment sheet 1A had become semi-transparent, and a pale yellow, transparent biomembrane had formed around the tissue regeneration treatment sheet 1A (FIG. 8).

[0050] It was an unexpected result that a pale yellow transparent biomembrane was formed along the roughened surface 20r facing the outside of the head. Also, the semi-transparent nature of the sheet for biological tissue regeneration treatment 1A was also an unexpected result (i.e., it was unexpected that the opaque material ePTFE would become semi-transparent when placed in the body).

[0051] (Experiment 2) After inhalation anesthesia was administered to a mouse (C57BL, 8 weeks, male), an opening 40a was formed in the peritoneum 40, and a sheet for biological tissue regeneration treatment 1A of about 1 cm square was placed so as to close the opening 40a (FIG. 9). The sheet for biological tissue regeneration treatment 1A was placed so that the roughened surface 20r was in contact with the back surface of the peritoneum 40, and the second surface 30 (more specifically, the non-roughened surface) was facing the center of the abdominal cavity. The sheet for biological tissue regeneration treatment 1A and the peritoneum 40 were sutured and fixed at two points, and then the wound was closed. Six weeks after placement, the mouse was sacrificed and histologically examined. A semitransparent biological membrane 5 was formed on the surface of the roughened surface 20r side of the sheet for biological tissue regeneration treatment 1A, and clear new capillaries B were observed inside the biological membrane 5 (FIG. 10). By hematoxylin-eosin staining and immunohistochemical staining (FIG. 11), a large number of multinucleated giant cells were observed in the newly formed biomembrane 5 on the roughened surface 20r side (in other words, on the ion-implanted layer 2 side) of the sheet for biological tissue regeneration treatment 1A, and ePTFE phagocytosis 6 was also observed in some areas (FIG. 12). As can be seen from FIG. 11, in the sheet for biological tissue regeneration treatment 1A, newly formed tissue (more specifically, newly formed biomembrane 5) developed along the roughened surface 20r, and the newly formed tissue (more specifically, newly formed biomembrane 5) was formed so as to mesh with the irregularities of the roughened surface 20r. In addition, continuous cell infiltration 7 from the roughened surface 20r to the inside of the sheet for biological tissue regeneration treatment 1A (more specifically, cell infiltration into the inside of the ion-implanted layer 2) was observed (FIG. 12). When the roughened surface side (in other words, the ion-implanted layer side) of the sheet for biological tissue regeneration treatment 1A was observed using a scanning electron microscope, a large number of fibroblast- and macrophage-like cells were observed on the surface of the sheet for biological tissue regeneration treatment 1A (FIG. 13). On the other hand, with regard to the biomembrane 5' formed on the second surface 30 (more specifically, the non-roughened surface) side of the sheet for biological tissue regeneration treatment 1A, no cell infiltration into the inside of the sheet for biological tissue regeneration treatment 1A, no phagocytosis of ePTFE 6, etc. were observed (FIG. 14).

[0052] (Experiment 3: Biomembrane Cultivation) The tissue regeneration treatment sheet 1A and the biomembrane generated in a state of being bound to the tissue regeneration treatment sheet 1A were taken from a rat, fragmented, and the biomembrane side was attached to a 6-well plate (Figure 15). Into these wells, medium for iPS cells (Stemflex medium (Thermo Fisher) + penicillin streptomycin + Zell shield (Funakoshi): upper left of Figure 15), medium for mesenchymal stem cells (hereinafter referred to as "MSC") (low glucose DMEM + hyclone FBS +kanamycin: upper center of Figure 15), medium for glioma cells (high glucose DMEM + Corning FBS +penicillin streptomycin: upper right of Figure 15), and medium for fibroblasts (low glucose DMEM + penicillin streptomycin: lower left of Figure 15) were placed, and primary culture was performed. As for the medium for fibroblasts, trypsin-treated tissue regeneration treatment sheet 1A (bottom center of Figure 15) and one with only a biomembrane attached (bottom right of Figure 15) were also cultured. Among these, cell proliferation was observed only in the medium for MSCs (Figure 16: 0 days after, Figure 17: 2 days after, Figure 18: 7 days after). Immunostaining of the cells was performed to estimate the type of cells that proliferated.

[0053] (Immunostaining of cells) Since cell proliferation was observed in the MSC medium, staining was performed mainly for MSC markers (Figure 19). The MSC markers CD29 and CD105 were positive, but the MSC marker CD90 was negative. The neural stem cell marker SOX2 was positive, while the neural stem cell marker nestin was negative. In addition, the astrocyte marker GFAP and the neuron marker MAP2 were negative. None of the markers were stained in all cells, suggesting that multiple types of cells were mixed. For this reason, single-cell RNA sequencing (scRNA-seq) analysis was then performed to identify the cell type.

[0054] (scRNA-seq analysis) In order to identify the type of cells that proliferated from the biomembrane generated by binding to the tissue regeneration treatment sheet 1A, scRNA-seq analysis was performed. More specifically, after placing the tissue regeneration treatment sheet 1A in a rat for 8 months, the tissue regeneration treatment sheet 1A and the biomembrane generated by binding to the tissue regeneration treatment sheet 1A were taken out of the rat, cultured in a medium for MSC, and the cell suspension was submitted as a sample to a company contracted for scRNA-seq. Analysis of the genes expressed in each cell allowed the cells to be divided into 12 cell populations (clusters) based on the gene expression level (Figure 20). From the characteristic expressed genes in each cluster, it was estimated that the types of cells that proliferated were fibroblasts, MSCs, macrophages, myofibroblasts, and oligodendrocytes (Figure 21).

[0055] (Summary of experimental and analytical results) From the results of Experiments 1 and 2, it was confirmed that a biomembrane accompanied by angiogenesis was formed on the roughened surface 20r side of the sheet for biological tissue regeneration treatment 1A (more specifically, the surface on the side of the ion-implanted layer 2). In addition, from the results of Experiments 1 and 2, it was confirmed that the sheet for biological tissue regeneration treatment 1A became transparent.

[0056] The results of experiment 2 showed that when the tissue regeneration treatment sheet 1A was left in the peritoneum of a mouse for a long period of time, multinucleated cells appeared on the surface on the roughened surface 20r side (more specifically, on the surface on the ion-implanted layer 2 side). In addition, the results of experiment 2 showed the infiltration of cells into the ion-implanted layer 2 and the phagocytosis of the polytetrafluoroethylene that constitutes the ion-implanted layer 2.

[0057] From the results of Experiment 3, cell proliferation was observed in the culture performed using the tissue regeneration treatment sheet 1A and the medium for MSCs. In addition, immunohistochemistry of the cells confirmed that the cells were positive for stem cell markers (in other words, the expression of stem cells). From the results of single-cell RNA sequencing analysis, it was confirmed that the cultured cells included fibroblasts, MSCs, macrophages, myofibroblasts, and oligodendrocytes.

[0058] These results confirmed that the biological tissue regeneration treatment sheet 1A has biocompatibility, and suggested that tissue repair may be carried out using the biological tissue regeneration treatment sheet 1A as a scaffold (in other words, the biological tissue regeneration treatment sheet 1A used in the experiment has potential as a medical device for regenerative medicine).

[0059] (Characteristics of tissue regeneration sheet 1A 1) From the results of Experiment 3 and the results of the scRNA-seq analysis, it can be said that the biological tissue regeneration treatment sheet 1A has the property (hereinafter referred to as "Property 1") that "when the roughened surface 20r is placed in contact with damaged in vivo tissue, the expression of at least one of mesenchymal stem cells, fibroblasts, myofibroblasts, macrophages, and oligodendrocytes is more pronounced on the surface of the biological tissue regeneration treatment sheet compared to when the second surface 30 is placed in contact with damaged in vivo tissue."

[0060] Furthermore, from the results of Experiment 3 and the results of the scRNA-seq analysis, it can be said that the biological tissue regeneration treatment sheet 1A has the characteristic that "when the roughened surface 20r is placed in contact with damaged in vivo tissue, the expression of mesenchymal stem cells on the surface of the sheet for biological tissue regeneration treatment is more pronounced when compared to when the second surface 30 is placed in contact with damaged in vivo tissue."

[0061] Since the sheet 1A for biological tissue regeneration treatment has property 1, it can be said that the sheet 1A for biological tissue regeneration treatment is useful as a medical device for regenerative medicine.

[0062] (Characteristics of tissue regeneration sheet 1A 2) From the results of Experiment 2 (see Figure 10), it can be said that the sheet 1A for biological tissue regeneration treatment has the property that "when the roughened surface 20r is placed in contact with damaged biological tissue, capillaries B are generated along the roughened surface 20r" (hereinafter referred to as "Property 2").

[0063] (Characteristics of tissue regeneration sheet 1A 3) As illustrated in Fig. 22, the sheet 1A for biological tissue regeneration treatment has a property that "when the roughened surface 20r is placed in contact with the edge 4e of the biological tissue 4 so that the roughened surface 20r faces the defect area RG of the biological tissue 4, a biological membrane 5 and capillaries B are generated along the roughened surface 20r in the defect area RG" (hereinafter referred to as "property 3") (see Fig. 23). Property 3 is a property based on an event discovered by experiment 2.

[0064] Since the sheet 1A for biological tissue regeneration treatment has the characteristic 2 or the characteristic 3, it can be said that the sheet 1A for biological tissue regeneration treatment is useful as a medical device for regenerative medicine. When the sheet 1A for biological tissue regeneration treatment has the characteristic 2, nutrients and the like are supplied to the newly formed biomembrane 5 via the capillaries B. Thus, the biomembrane 5 is rapidly formed. When the sheet 1A for biological tissue regeneration treatment has the characteristic 3, the defective region RG of the in-vivo tissue 4 is rapidly sealed by the biomembrane 5.

[0065] As illustrated in Figures 22 and 23, the sheet 1A for biological tissue regeneration treatment may have the property that "when the roughened surface 20r is placed in contact with the endogenous tissue 4, new tissue grows from the endogenous tissue 4 along the roughened surface 20r, and the new tissue grows so as to mesh with the irregularities of the roughened surface 20r."

[0066] (Characteristics of tissue regeneration sheet 1A 4) 22 and 23, the biological tissue regeneration treatment sheet 1A may have a property that "when the roughened surface 20r is placed in contact with the in vivo tissue 4, substantially all of the gap between the in vivo tissue 4 and the roughened surface 20r is filled with newly formed tissue" (hereinafter referred to as "property 4"). When the biological tissue regeneration treatment sheet 1A has property 4, the in vivo tissue 4 and the roughened surface 20r are firmly bonded. In addition, body fluids and the like are unlikely to leak from the gap between the in vivo tissue 4 and the roughened surface 20r.

[0067] (Characteristics of tissue regeneration sheet 1A 5) From the results of experiment 2 (see FIG. 12), it can be said that the sheet 1A for biological tissue regeneration treatment has the property that "cells of in vivo tissue infiltrate into the ion-implanted layer 2" (hereinafter referred to as "property 5").

[0068] As shown in Fig. 12, the sheet for biological tissue regeneration treatment 1A may be configured so that cells of in vivo tissue infiltrate into the depressions of the roughened surface 20r. The sheet for biological tissue regeneration treatment 1A may also be configured so that cells infiltrate into the inside of the structure formed of polytetrafluoroethylene and ion-implanted elements.

[0069] (Characteristics of tissue regeneration sheet 1A 6) From the results of Experiment 2 (see, for example, Figure 8), it can be said that the sheet 1A for biological tissue regeneration treatment has the property that "when the roughened surface 20r is left in contact with in vivo tissue (for example, membrane tissue in the body) for six months or more, the opaque polytetrafluoroethylene constituting the roughened surface 20r of the sheet 1A for biological tissue regeneration treatment becomes transparent or translucent" (hereinafter referred to as "Property 6").

[0070] The mechanism by which polytetrafluoroethylene becomes transparent or semi-transparent is unknown. However, it is presumed that either in vivo tissue 4, newly formed biomembrane 5, or the cells that compose these are involved in the transparent or semi-transparent state of polytetrafluoroethylene.

[0071] When polytetrafluoroethylene is made transparent or semi-transparent, it may be possible to grasp the state of the biological tissue on the back side of the biological tissue regeneration treatment sheet 1A.

[0072] (Nerve Damage Repair Sheet 1B) The biological tissue regeneration treatment sheet 1A in the above-mentioned first embodiment can be used as the nerve damage repair sheet 1B. In other words, in the description of the biological tissue regeneration treatment sheet 1A in the first embodiment, the "biological tissue regeneration treatment sheet 1A" can be read as the "nerve damage repair sheet 1B".

[0073] As illustrated in Fig. 24 or 25, the nerve damage repair sheet 1B comprises (1) a first surface 20 including a roughened surface 20r that is to be phagocytosed by cells of tissue in a living body, and (2) a second surface 30 disposed on the opposite side of the first surface 20. The roughened surface 20r contains polytetrafluoroethylene as a main component. The roughened surface 20r, the first surface 20, and the second surface 30 have already been described, and therefore repeated description of their configurations will be omitted.

[0074] The nerve damage repair sheet 1B having the above-mentioned properties 1 to 6 functions as a scaffold for tissue regeneration at the nerve damage site. For example, as illustrated in Fig. 24, when the roughened surface 20r is placed facing the nerve damage site RG1 of the in vivo tissue 4, a biological membrane 5 and capillaries B are generated along the roughened surface 20r facing the nerve damage site RG1.

[0075] The nerve damage repair sheet 1B may be configured so that "when the roughened surface 20r is placed facing the nerve damage site RG1 of the in-vivo tissue 4, nerve cells are regenerated using the roughened surface 20r as a scaffold."

[0076] (Brain Damage Repair Sheet 1C) The nerve damage repair sheet 1B in the above-mentioned first embodiment can be used as brain damage repair sheet 1C by applying it to a brain damaged site. In other words, in the explanation of the biological tissue regeneration treatment sheet 1A (or the nerve damage repair sheet 1B) in the first embodiment, the "biological tissue regeneration treatment sheet 1A" (or the "nerve damage repair sheet 1B") can be read as the "brain damage repair sheet 1C".

[0077] The sheet for repairing brain injury 1C having the above-mentioned characteristics 1 to 6 functions as a scaffold for tissue regeneration at the brain damaged site. For example, as illustrated in Fig. 24, when the roughened surface 20r is placed facing the brain damaged site RG2 of the tissue in vivo 4, a biological membrane 5 and capillaries B are newly generated along the roughened surface 20r facing the brain damaged site RG2. In Fig. 24, the sheet for repairing brain injury 1C is placed in contact with the brain damaged site RG2 inside all of the skull 81, dura mater 82, and arachnoid mater 83.

[0078] The sheet for brain injury repair 1C may be placed inside the pia mater 84. The sheet for brain injury repair 1C may be attached to the pia mater 84 so as to be supported by the pia mater 84.

[0079] (Spinal Cord Injury Repair Sheet 1D) The nerve damage repair sheet 1B in the above-mentioned first embodiment can be used as a spinal cord injury repair sheet 1D by applying it to a spinal cord injury site. In other words, in the explanation of the biological tissue regeneration treatment sheet 1A (or the nerve damage repair sheet 1B) in the first embodiment, the "biological tissue regeneration treatment sheet 1A" (or the "nerve damage repair sheet 1B") can be read as the "spinal cord injury repair sheet 1D".

[0080] The spinal cord injury repair sheet 1D having the above-mentioned properties 1 to 6 functions as a scaffold for tissue regeneration at the spinal cord injury site. For example, as illustrated in Fig. 25, when the roughened surface 20r is placed facing the spinal cord injury site RG3 of the in vivo tissue 4, a biological membrane 5 and capillaries B are generated along the roughened surface 20r facing the spinal cord injury site RG3. In Fig. 25, the spinal cord injury repair sheet 1D is placed in contact with the spinal cord injury site RG3 inside the dura mater 82 and arachnoid mater 83.

[0081] The sheet for repairing spinal cord injury 1D may be placed inside the pia mater 84. The sheet for repairing spinal cord injury 1D may be attached to the pia mater 84 so as to be supported by the pia mater 84.

[0082] (Lung Injury Repair Sheet 1E) The biological tissue regeneration treatment sheet 1A in the above-mentioned first embodiment can be used as the lung injury repair sheet 1E. In other words, in the description of the biological tissue regeneration treatment sheet 1A in the first embodiment, the "biological tissue regeneration treatment sheet 1A" can be read as the "lung injury repair sheet 1E".

[0083] As illustrated in Fig. 26 or 27, the sheet 1E for repairing lung injury comprises (1) a first surface 20 including a roughened surface 20r that is to be phagocytosed by cells of tissues in the body, and (2) a second surface 30 disposed on the opposite side of the first surface 20. The roughened surface 20r contains polytetrafluoroethylene as a main component. The roughened surface 20r, the first surface 20, and the second surface 30 have already been described, and therefore repeated description of their configurations will be omitted.

[0084] The sheet 1E for repairing damaged lungs having the above-mentioned properties 1 to 6 functions as a scaffold for tissue regeneration at the site of damaged lungs. For example, as illustrated in Fig. 26 or 27, when the roughened surface 20r is placed in contact with the lung structure 45 (more specifically, the edge 45e defining the defective region RG4 of the lung structure 45) so that the roughened surface 20r faces the defective region RG4 of the lung structure 45 (more specifically, the opening of the lung structure 45), a biological membrane 5 and capillaries B are newly generated along the roughened surface 20r in the defective region RG4.

[0085] In this specification, the lung injury includes injury to the visceral pleura 450 and injury to the parietal pleura. In the example shown in FIG. 26, a defect area RG4 (more specifically, an opening) exists in the visceral pleura 450. The lung injury repair sheet 1E is attached to the visceral pleura 450 so as to cover the defect area RG4. As illustrated in FIG. 26, the lung injury repair sheet 1E may be configured to be attached to the outside of the visceral pleura 450, or as illustrated in FIG. 27, the lung injury repair sheet 1E may be configured to be attached to the inside of the visceral pleura 450. In FIG. 26 or FIG. 27, the lung injury repair sheet 1E may function as a pneumothorax treatment sheet.

[0086] When the sheet 1E for repairing lung injury has the above-mentioned characteristic 4, substantially all of the gap between the in vivo tissue 4 (for example, the visceral pleura 450) and the roughened surface 20r is filled with new tissue. This prevents air from leaking from the gap between the in vivo tissue 4 and the roughened surface 20r. In the example shown in FIG. 26 or FIG. 27, the roughened surface 20r is used as a scaffold for the biomembrane 5 and the capillaries B to extend across the defect region RG4. In this case, the defect region RG4 of the lung structure 45 is blocked by the biomembrane 5. This allows the lung injury to be repaired appropriately.

[0087] (Peritoneal Damage Repair Sheet 1F) The biological tissue regeneration treatment sheet 1A in the above-mentioned first embodiment can be used as the peritoneal damage repair sheet 1F. In other words, in the description of the biological tissue regeneration treatment sheet 1A in the first embodiment, the "biological tissue regeneration treatment sheet 1A" can be read as the "peritoneal damage repair sheet 1F".

[0088] The sheet 1F for repairing peritoneal damage comprises (1) a first surface 20 including a roughened surface 20r that is to be phagocytosed by cells of tissues in the body, and (2) a second surface 30 disposed on the opposite side of the first surface 20. The roughened surface 20r contains polytetrafluoroethylene as a main component. The roughened surface 20r, the first surface 20, and the second surface 30 have already been described, and therefore a repeated description of their configurations will be omitted.

[0089] The sheet 1F for repairing peritoneal damage having the above-mentioned properties 1 to 6 functions as a scaffold for tissue regeneration at the site of peritoneal damage. For example, as illustrated in Fig. 9, when the roughened surface 20r is placed in contact with the peritoneum 40 (more specifically, the edge portion defining the opening 40a of the peritoneum 40) so that the roughened surface 20r faces the defect area (more specifically, the opening 40a) of the peritoneum 40, a biological membrane 5 and capillaries B are regenerated along the roughened surface 20r in the defect area.

[0090] When the sheet 1F for repairing peritoneal damage has the above-mentioned characteristic 4, substantially all of the gap between the peritoneum 40 and the roughened surface 20r is filled with new tissue. This prevents leakage of body fluids or gas from the gap between the peritoneum 40 and the roughened surface 20r. In the example shown in FIG. 10, the biomembrane 5 and capillaries B are configured to extend across the defect area (see the opening 40a in FIG. 9) using the roughened surface 20r as a scaffold. In this case, the defect area of ​​the peritoneum 40 (more specifically, the opening 40a) is blocked by the biomembrane 5. This allows the peritoneal damage to be repaired appropriately.

[0091] (Blood vessel injury repair sheet 1G) The biological tissue regeneration treatment sheet 1A in the above-mentioned first embodiment can be used as a blood vessel damage repair sheet 1G. In other words, in the description of the biological tissue regeneration treatment sheet 1A in the first embodiment, the "biological tissue regeneration treatment sheet 1A" can be read as a "blood vessel damage repair sheet 1G".

[0092] As illustrated in Fig. 28 or 29, the sheet 1G for repairing vascular damage comprises (1) a first surface 20 including a roughened surface 20r that is to be phagocytosed by cells of tissues in the body, and (2) a second surface 30 disposed on the opposite side of the first surface 20. The roughened surface 20r contains polytetrafluoroethylene as a main component. The roughened surface 20r, the first surface 20, and the second surface 30 have already been described, and therefore repeated description of their configurations will be omitted.

[0093] The sheet 1G for repairing blood vessel damage having the above-mentioned properties 1 to 6 functions as a scaffold for tissue regeneration at the site of blood vessel damage. For example, as illustrated in Fig. 28 or 29, when the roughened surface 20r is placed in contact with the blood vessel 91 (more specifically, the edge portion 95e defining the opening 91a of the blood vessel 91) so that the roughened surface 20r faces the damaged region RG5 of the blood vessel 91 (more specifically, the opening 91a of the blood vessel 91), a biological membrane 5 and capillaries B are regenerated along the roughened surface 20r in the damaged region RG5 (more specifically, in the opening 91a of the blood vessel 91).

[0094] 28 or 29, the sheet 1G for repairing blood vessel damage is attached to the blood vessel 91 so as to cover the damaged region RG5 (more specifically, the opening 91a) of the blood vessel 91. As illustrated in Fig. 28, the sheet 1G for repairing blood vessel damage may be configured to be attached to the outside of the blood vessel 91, or as illustrated in Fig. 29, the sheet 1G for repairing blood vessel damage may be configured to be attached to the inside of the blood vessel 91.

[0095] When the sheet 1G for repairing blood vessel damage has the above-mentioned characteristic 4, substantially all of the gap between the blood vessel 91 and the roughened surface 20r is filled with new tissue. Therefore, blood is prevented from leaking from the gap between the blood vessel 91 and the roughened surface 20r. In the example shown in FIG. 28 or FIG. 29, the biomembrane 5 and the capillaries B are configured to extend over the damaged region RG5 (more specifically, the opening 91a) of the blood vessel 91, using the roughened surface 20r as a scaffold. In this case, the damaged region RG5 (more specifically, the opening 91a) of the blood vessel 91 is blocked by the biomembrane 5. Therefore, the blood vessel damage is repaired appropriately.

[0096] (Culture sheet 1H) In the biological tissue regeneration treatment sheet 1A in the first embodiment, the roughened surface 20r functions well as a scaffold for biological tissue regeneration. Therefore, the biological tissue regeneration treatment sheet 1A in the first embodiment may be used as a culture sheet 1H. In other words, in the description of the biological tissue regeneration treatment sheet 1A in the first embodiment, the "biological tissue regeneration treatment sheet 1A" can be read as the "culture sheet 1H".

[0097] As illustrated in FIG. 30, the culture sheet 1H in the first embodiment includes (1) a first surface 20 including a roughened surface 20r on which the cells C to be cultured or a biological tissue containing the cells C are disposed, and (2) a second surface 30 disposed on the opposite side of the first surface 20. The roughened surface 20r contains polytetrafluoroethylene as a main component. The roughened surface 20r is phagocytosed by the above-mentioned cells C. The roughened surface 20r, the first surface 20, and the second surface 30 have already been described, and therefore a repeated description of their configurations will be omitted.

[0098] The culture sheet 1H may have a property that "when the cells C to be cultured or a biological tissue containing the cells C is placed in contact with the roughened surface 20r, the expression of at least one of mesenchymal stem cells, fibroblasts, myofibroblasts, macrophages, and oligodendrocytes on the surface of the culture sheet 1H becomes more pronounced compared to when the cells C to be cultured or a biological tissue containing the cells C is placed in contact with the second surface 30." The cells to be expressed depend on the type of the cells C to be cultured.

[0099] The culture sheet 1H may have a property that the above-mentioned cells C infiltrate into the inside of the ion-implanted layer 2. The culture sheet 1H may be configured so that the above-mentioned cells C infiltrate into the depressions of the roughened surface 20r. The culture sheet H may also be configured so that the above-mentioned cells C infiltrate into the inside of a structure formed of polytetrafluoroethylene and an ion-implanted element.

[0100] Second embodiment The regenerative treatment method according to the second embodiment will be described with reference to Figures 1 to 31. Figure 31 is a flow chart showing an example of the regenerative treatment method according to the second embodiment.

[0101] 2, a body tissue regeneration treatment sheet 1A is prepared in a first step ST1. The first step ST1 is a preparation step.

[0102] The biological tissue regeneration treatment sheet 1A prepared in the preparation process (first step ST1) has a first surface 20 at least a portion of which is constituted by a roughened surface 20r containing polytetrafluoroethylene as a main component, and a second surface 30 arranged on the opposite side of the first surface 20.

[0103] The preparation process (first step ST1) may include forming an ion-implanted layer 2 on the sheet 1A for biological tissue regeneration treatment by irradiating the first surface 20 with ions (e.g., argon ions, neon ions, etc.). By irradiating the first surface 20 with ions, the portion of the first surface 20 irradiated with ions becomes a roughened surface 20r. The roughened surface 20r is constituted by the surface of the ion-implanted layer 2.

[0104] The preparation step (first step ST1) may include applying a heat treatment to the sheet 1A for biological tissue regeneration treatment into which ions have been injected. The regularity of the polymer structure of polytetrafluoroethylene is relaxed by the ion injection and heat treatment. This relaxation of the regularity may facilitate the polytetrafluoroethylene becoming transparent or semi-transparent in the regeneration step described below. In this heat treatment, the sheet 1A for biological tissue regeneration treatment may be placed in a heated atmosphere of 100 degrees Celsius or higher.

[0105] The sheet for biological tissue regeneration treatment 1A has already been explained in the first embodiment, so repeated explanation of the sheet for biological tissue regeneration treatment 1A will be omitted.

[0106] As exemplified in Fig. 6 or Fig. 9, in the second step ST2, the sheet for biological tissue regeneration treatment 1A is placed in the tissue inside the body. The second step ST2 is a placing step.

[0107] In the placement step (second step ST2), the sheet 1A for biological tissue regeneration treatment is placed in the tissue inside the body so that the roughened surface 20r comes into contact with the damaged tissue inside the body. The tissue inside the body 4 on which the sheet 1A for biological tissue regeneration treatment is placed is, for example, the brain, spinal cord, lung structure, peritoneum, or blood vessels. The tissue inside the body 4 on which the sheet 1A for biological tissue regeneration treatment is placed may be the pia mater covering the brain, the pia mater covering the spinal cord, or the visceral pleura.

[0108] As illustrated in Figure 22, the placement process (second step ST2) may include placing the roughened surface 20r in contact with the endogenous tissue 4 (more specifically, the edge 4e that defines the defect area RG) so that the roughened surface 20r faces the defect area RG of the endogenous tissue 4 (e.g., an opening of the endogenous tissue 4).

[0109] In the third step ST3, tissue at the damaged site of the in vivo tissue is regenerated. The third step ST3 is a regeneration step.

[0110] In the regeneration step (third step ST3), tissue at a damaged site of the in vivo tissue 4 is regenerated using the roughened surface 20r as a scaffold. The regeneration step (third step ST3) includes cells of the in vivo tissue 4 phagocytosing at least a portion of the roughened surface 20r. More specifically, the regeneration step (third step ST3) includes cells of the in vivo tissue 4 phagocytosing polytetrafluoroethylene constituting the roughened surface 20r. The regeneration step (third step ST3) may include cells of the in vivo tissue 4 phagocytosing polytetrafluoroethylene constituting the ion-implanted layer 2.

[0111] The regeneration step (third step ST3) may include regenerating a biological membrane 5 along the biological tissue regeneration treatment sheet 1A. The biological membrane 5 may include at least one of mesenchymal stem cells, fibroblasts, myofibroblasts, macrophages, and oligodendrocytes. Alternatively, or additionally, the biological membrane 5 may include capillaries B.

[0112] When the placement step (second step ST2) includes placing the roughened surface 20r facing the defect region RG of the in vivo tissue 4, the regeneration step (third step ST3) may include generating a biological membrane 5 and capillaries B along the roughened surface 20r in the defect region RG. The regeneration step (third step ST3) may include generating a biological membrane 5 so that the defect region RG is blocked by the biological membrane 5.

[0113] The regeneration step (third step ST3) may include filling substantially all of the gap between the in vivo tissue 4 and the roughened surface 20r with new tissue. The regeneration step (third step ST3) may also include infiltrating cells of the in vivo tissue into the inside of the ion-implanted layer 2. The regeneration step (third step ST3) may also include infiltrating cells of the in vivo tissue into the recesses of the roughened surface 20r. The regeneration step (third step ST3) may also include infiltrating cells into the inside of the structure composed of polytetrafluoroethylene and the ion-implanted element.

[0114] The regeneration process (third step ST3) may include changing the state of the polytetrafluoroethylene constituting the roughened surface 20r (more specifically, the polytetrafluoroethylene constituting the ion-implanted layer 2) from an opaque state to a transparent or translucent state.

[0115] The regeneration step (third step ST3) may include repairing nerve damage by regenerating tissue at a damaged site of the in vivo tissue 4 using the roughened surface 20r as a scaffold. The regeneration step (third step ST3) may include repairing brain damage or spinal cord damage by regenerating tissue at a damaged site of the in vivo tissue using the roughened surface 20r as a scaffold. The regeneration step (third step ST3) may include regenerating nerve cells using the roughened surface 20r as a scaffold.

[0116] The regeneration step (third step ST3) may include repairing lung damage, peritoneal damage, or blood vessel damage by regenerating tissue at a damaged site of the in vivo tissue using the roughened surface 20r as a scaffold. The regeneration step (third step ST3) may include regenerating a biological membrane 5 at an opening of the lung structure, an opening of the peritoneum, or an opening of a blood vessel by regenerating tissue at a damaged site of the in vivo tissue using the roughened surface 20r as a scaffold.

[0117] The present invention is not limited to the above-mentioned embodiments or modifications, and it is clear that each embodiment or modification can be appropriately modified or changed within the scope of the technical idea of ​​the present invention. In addition, various techniques used in each embodiment or modification can be applied to other embodiments or other modifications as long as no technical contradiction occurs. Furthermore, any additional configuration in each embodiment or modification can be omitted as appropriate.

[0118] In the embodiments, the sheet for biological tissue regeneration treatment, the sheet for nerve damage repair, the sheet for brain damage repair, the sheet for spinal cord damage repair, the sheet for lung damage repair, the sheet for peritoneum damage repair, or the sheet for vascular damage repair may be applied to the in vivo tissues of humans or the in vivo tissues of animals other than humans. [Explanation of symbols]

[0119] 1A: Sheet for biological tissue regeneration therapy 1B: Sheet for nerve damage repair 1C: Brain injury repair sheet 1D: Sheet for spinal cord injury repair 1E: Lung injury repair sheet 1F: Peritoneal injury repair sheet 1G: Vascular injury repair sheet 1H: Culture sheet 2: Ion implantation layer 4: In vivo tissue 4e: Edge 5: Biomembranes 5': Biomembrane 6: Devouring statue 7: Cell invasion 20: 1st page 20d: dent 20r: Roughened surface 20s: Non-roughened surface 30: 2nd side 40: Peritoneum 40a: opening 45: Lung structure 45e: Edge 81: Skull 82 :Dura mater 83: Arachnoid membrane 84: Pia mater 91: Blood vessels 91a: Opening 95e: Edge 450: Visceral pleura B: Capillary C: Cell H: Culture sheet RG: Defective region RG1: nerve injury site RG2: Brain injury site RG3: Spinal cord injury site RG4: Defective area RG5: Damage area

Claims

1. A sheet for repairing nerve damage, which comprises a roughened surface containing polytetrafluoroethylene as a main component, and which, when brought into contact with a nerve damage site, causes the roughened surface to be phagocytosed by cells of tissue in a living body, causes mesenchymal stem cells to be expressed on the roughened surface, causes capillary blood vessels to be generated along the roughened surface, and causes nerve cells at the nerve damage site to be regenerated using the roughened surface as a scaffold, A first surface including the roughened surface that is to be contacted with the nerve damage site and phagocytosed by cells of the in vivo tissue; a second surface disposed opposite the first surface; Equipped with The roughened surface contains the polytetrafluoroethylene as a main component. Sheet for repairing nerve damage.

2. A sheet for repairing nerve damage in the brain, which comprises a roughened surface containing polytetrafluoroethylene as a main component, and which, when brought into contact with a nerve damage site in the brain, causes the roughened surface to be phagocytosed by cells of tissue in the living body, causes mesenchymal stem cells to be expressed on the roughened surface, causes capillary blood vessels to be generated along the roughened surface, and causes regeneration of nerve cells at the nerve damage site in the brain using the roughened surface as a scaffold, a first surface including the roughened surface that is to be contacted with the nerve damage site in the brain and phagocytosed by cells of the in vivo tissue; a second surface disposed opposite the first surface; Equipped with The roughened surface contains the polytetrafluoroethylene as a main component. Sheet for repairing nerve damage.

3. A sheet for repairing nerve damage in the spinal cord, which, when a roughened surface containing polytetrafluoroethylene as a main component is brought into contact with a nerve damage site in the spinal cord, causes the roughened surface to be phagocytosed by cells of tissue in the living body, causes mesenchymal stem cells to be expressed on the roughened surface, causes capillary blood vessels to be generated along the roughened surface, and causes regeneration of nerve cells at the nerve damage site in the spinal cord using the roughened surface as a scaffold, a first surface including the roughened surface that is to be brought into contact with the nerve damage site in the spinal cord and phagocytosed by cells of the in vivo tissue; a second surface disposed opposite the first surface; Equipped with The roughened surface contains the polytetrafluoroethylene as a main component. Sheet for repairing nerve damage.

4. A sheet for repairing brain injury (excluding a sheet to be applied to the cerebral dura mater, a sheet for wrapping cerebral blood vessels, and a sheet for wrapping cerebral aneurysms) which, by contacting a roughened surface containing polytetrafluoroethylene as a main component with a brain injury site inside the arachnoid membrane, causes the roughened surface to be phagocytosed by cells of tissue in the living body, causes mesenchymal stem cells to be expressed on the roughened surface, causes capillaries to be generated along the roughened surface, and repairs tissue at the brain injury site using the roughened surface as a scaffold, A first surface including the roughened surface that is to be contacted with the damaged brain site and phagocytosed by cells of the in vivo tissue; a second surface disposed opposite the first surface; Equipped with The roughened surface contains the polytetrafluoroethylene as a main component. Brain injury repair sheet.

5. A sheet for repairing spinal cord injuries (excluding a sheet to be applied to the spinal dura mater) which, by contacting a roughened surface containing polytetrafluoroethylene as a main component inside the arachnoid membrane with a site of spinal cord injury, causes the roughened surface to be phagocytosed by cells of tissue in the living body, causes mesenchymal stem cells to be expressed on the roughened surface, causes capillary blood vessels to be generated along the roughened surface, and repairs tissue at the site of spinal cord injury using the roughened surface as a scaffold, a first surface including the roughened surface that is to be brought into contact with the injured site of the spinal cord and phagocytosed by cells of the in vivo tissue; a second surface disposed opposite the first surface; Equipped with The roughened surface contains the polytetrafluoroethylene as a main component. Sheet for repairing spinal cord injuries.

6. The roughened surface is formed by the surface of an ion-implanted layer. The sheet for repairing nerve damage according to any one of claims 1 to 3.

7. The ion-implanted layer is configured so that the cells of the in vivo tissue are infiltrated into the inside of the ion-implanted layer. The sheet for repairing nerve damage according to claim 6.

8. The roughened surface has depressions of a size comparable to the size of the cells that phagocytose the roughened surface. The sheet for repairing nerve damage according to any one of claims 1 to 3.

9. When the roughened surface is placed in contact with the in vivo tissue, new tissue develops from the in vivo tissue along the roughened surface, and the new tissue develops so as to mesh with the irregularities of the roughened surface. The sheet for repairing nerve damage according to any one of claims 1 to 3.

10. The opaque polytetrafluoroethylene is configured to become transparent or semi-transparent when the roughened surface is indwelled in contact with the in vivo tissue for six months or more. The sheet for repairing nerve damage according to any one of claims 1 to 3.

Images