Sheet for repairing nerve injury, sheet for repairing brain injury, and sheet for repairing spinal cord injury

Abstract

[Problem] To provide: a sheet for biological tissue regeneration treatment which regenerates a biological tissue; a sheet for repairing a nerve injury; a sheet for repairing a brain injury; a sheet for repairing a spinal cord injury; a sheet for repairing a lung injury; a sheet for repairing a peritoneal injury; a sheet for repairing a vascular injury; a culture sheet; and a regeneration treatment method. [Solution] This sheet for biological tissue regeneration treatment comprises: a first surface which includes a roughened surface to be phagocytosed by cells of an in-vivo tissue; and a second surface which is disposed on the reverse side from the first surface. The roughened surface contains polytetrafluoroethylene as a main component.

Description

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

[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 vascular damage repair, a culture sheet, and a regenerative treatment method.

[0002] Various materials are used for dura mater reconstruction in neurosurgery. Expanded polytetrafluoroethylene, one of the materials used 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, the biorepair material described in Patent Document 1 aims to improve biocompatibility by irradiating an expanded polytetrafluoroethylene sheet with an ion beam.

[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, but this application is aimed solely at filling the dura mater defect (in other words, filling the defect with an artificial material), and is not intended to regenerate biological tissue at the defect site.

[0005] Patent No. 4445697

[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.

[0007] The following describes the means for solving the problems using the numbers and symbols used in the description of the invention. These numbers and symbols are added in parentheses for reference purposes to show an example of the correspondence between the claims and the description of the invention. Therefore, the claims should not be interpreted as being limited by the parenthetical descriptions.

[0008] In some embodiments, the biological tissue regeneration treatment sheet comprises a first surface (20) including a roughened surface (20r) to be phagocytosed by cells of biological tissue, 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-mentioned 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, the roughened surface (20r) may have depressions (20d) of approximately the same size as the cells that phagocytose the 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 engage with the irregularities of the roughened surface (20r).

[0013] The biological tissue regeneration treatment sheet may be configured so that when the roughened surface (20r) is placed in contact with the damaged in-vivo tissue (4), the 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 tissue regeneration treatment sheet may be configured so that when the roughened surface (20r) is placed in contact with the damaged tissue in vivo (4), the expression of the mesenchymal stem cells is more pronounced than when the second surface (30) is placed in contact with the damaged tissue in vivo (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 biological tissue (4), new capillaries (B) are generated along the roughened surface (20r).

[0016] The biological tissue regeneration treatment sheet may be configured such 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 region (RG) of the biological tissue (4), a biological membrane (5) and capillaries (B) are generated in the defect region (RG) along the roughened surface (20r).

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

[0018] In some embodiments, the nerve damage repair sheet comprises a first surface (20) including a roughened surface (20r) that is 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 nerve damage repair sheet 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.

[0020] In some embodiments, the sheet for brain injury repair comprises a first surface (20) including a roughened surface (20r) that is 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) that is 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 injured lungs comprises a first surface (20) including a roughened surface (20r) that is 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 injury comprises a first surface (20) including a roughened surface (20r) that is to be phagocytosed by cells of the 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) that is 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 cells (C) to be cultured or biological tissue containing the cells (C) are placed, and a second surface (30) disposed opposite 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 biological tissue regeneration treatment sheet (1A) having 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) disposed on the opposite side of the first surface (20), placing the biological tissue regeneration treatment sheet (1A) on the damaged biological tissue (4) so ​​that the roughened surface (20r) contacts the damaged biological tissue (4), and regenerating tissue at the damaged site of the biological tissue (4) using the roughened surface (20r) as a scaffold. The step of regenerating tissue at the damaged site of the biological tissue (4) includes phagocytosing at least a portion of the roughened surface (20r) by cells of the biological tissue (4).

[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 regenerative treatment method.

[0028] FIG. 1 is a diagram schematically showing a portion of a biological tissue regeneration treatment sheet according to a first embodiment. FIG. 2 is a schematic perspective view schematically showing the biological tissue regeneration treatment sheet according to the first embodiment. FIG. 3 is a schematic cross-sectional view showing an enlarged portion of the biological tissue regeneration treatment sheet according to the first embodiment. FIG. 4 is a photograph showing a rat's head after incision. FIG. 5 is a photograph showing a rat's head after craniotomy. FIG. 6 is a photograph showing a biological tissue regeneration treatment sheet according to the first embodiment placed so as to cover the craniotomy site. FIG. 7 is a photograph showing a biological tissue regeneration treatment sheet covered with autologous bone and bone wax. FIG. 8 is a photograph showing a biological tissue regeneration treatment sheet according to the first embodiment made semitransparent and having a pale yellow, transparent biological membrane formed around the biological tissue regeneration treatment sheet. FIG. 9 is a photograph showing a biological tissue regeneration treatment sheet according to the first embodiment placed so as to block an opening in the peritoneum. FIG. 10 is a photograph (substitute for a drawing) showing a translucent biological membrane formed along the biological tissue regeneration treatment sheet according to the first embodiment, with capillaries newly formed within the biological membrane. FIG. 11 is a photograph (substitute for a drawing) showing a biological membrane newly formed so as to engage with the roughened surface of the biological tissue regeneration treatment sheet. FIG. 12 is a photograph (substitute for a drawing) showing an image of phagocytosis of ePTFE. FIG. 13 is an electron microscope photograph of the roughened surface side of the biological tissue regeneration treatment sheet. FIG. 14 is a photograph (substitute for a drawing) showing the separation of the second surface of the biological tissue regeneration treatment sheet from the biological membrane. FIG. 15 is a photograph (substitute for a drawing) showing a culture subject. FIG. 16 is a micrograph of cells cultured in MSC medium after 0 days. FIG. 17 is a micrograph of cells cultured in MSC medium after 2 days. FIG. 18 is a micrograph of cells cultured in MSC medium after 7 days. FIG. 19 is a micrograph of staining with each marker. Fig. 20 is a photograph substituting a drawing showing the results of scRNA-seq analysis. Fig. 21 is a photograph substituting a drawing showing the results of scRNA-seq analysis. Fig. 22 is a schematic cross-sectional view showing the state in which the biological tissue regeneration treatment sheet according to the first embodiment is placed in tissue in a living body.

[0043] Fig. 23 is a schematic cross-sectional view showing a state in which a biological membrane has been regenerated along the roughened surface of the biological tissue regeneration treatment sheet according to the first embodiment. Fig. 24 is a schematic cross-sectional view showing a state in which the biological tissue regeneration treatment sheet according to the first embodiment has been placed at a brain damaged site. Fig. 25 is a schematic cross-sectional view showing a state in which the biological tissue regeneration treatment sheet according to the first embodiment has been placed at a spinal cord damaged site. Fig. 26 is a schematic cross-sectional view showing a state in which the biological tissue regeneration treatment sheet according to the first embodiment has been placed at a damaged site of a lung structure. Fig. 27 is a schematic cross-sectional view showing a state in which the biological tissue regeneration treatment sheet according to the first embodiment has been placed at a damaged site of a lung structure. Fig. 28 is a schematic cross-sectional view showing a state in which the biological tissue regeneration treatment sheet according to the first embodiment has been placed at a damaged site of a blood vessel. Fig. 29 is a schematic cross-sectional view showing a state in which the biological tissue regeneration treatment sheet according to the first embodiment has been placed at a damaged site of a blood vessel. FIG. 30 is a schematic cross-sectional view showing the state of cells being cultured using a culture sheet. FIG. 31 is a flowchart showing an example of a regenerative treatment method according to the second embodiment. FIG. 32 is a photograph showing the state of placement of a biological tissue regeneration treatment sheet 1A in Example 1. FIG. 33 is a graph showing the results of a rotarod test in Example 1. FIG. 34 is a diagram for explaining a corner test in Example 1. FIG. 35 is a graph showing the results of the corner test in Example 1. FIG. 36(a) is a photograph showing the state of a biological tissue regeneration treatment sheet 1A placed on the outer side of the roughened surface in Example 1, 5.5 months later. FIG. 36(b) is a photograph showing the state of a biological tissue regeneration treatment sheet 1A placed on the inner side of the roughened surface in Example 1, 5.5 months later. FIG. 37 is a photograph showing the state of cells stained with an MSC marker in Example 3. FIG. 38 is a graph showing the results of single-cell RNA sequencing in Example 4. FIG. 39 is a diagram for explaining the involvement of mesenchymal stem cells in anti-inflammatory action.

[0029] Hereinafter, with reference to the drawings, biological tissue regeneration treatment sheet, nerve damage repair sheet, brain damage repair sheet, spinal cord injury repair sheet, lung injury repair sheet, peritoneal injury repair sheet, blood vessel injury repair sheet, culture sheet, and regeneration treatment method in embodiments will be described. Note that in the following description, the same reference numerals are used for components and parts having the same functions, and repeated description of components and parts with the same reference numerals will be omitted.

[0030] (First embodiment) A biological tissue regeneration treatment sheet 1A in a first embodiment will be described with reference to Figs. 1 to 30. Fig. 1 is a diagram schematically showing a portion of a biological tissue regeneration treatment sheet 1A in the first embodiment. Fig. 2 is a schematic perspective view schematically showing a biological tissue regeneration treatment sheet 1A in the first embodiment. Fig. 3 is a schematic cross-sectional view showing an enlarged portion of a biological tissue regeneration treatment sheet 1A in the first embodiment. Fig. 4 is a photograph substituting for a drawing showing the state in which the head of a rat has been incised. Fig. 5 is a photograph substituting for a drawing showing the state in which the head of a rat has been craniotomy.

[0031] Fig. 6 is a photograph showing the biological tissue regeneration treatment sheet 1A according to the first embodiment placed to cover a craniotomy site. Fig. 7 is a photograph showing the biological tissue regeneration treatment sheet 1A covered with autologous bone and bone wax. Fig. 8 is a photograph showing the biological tissue regeneration treatment sheet 1A according to the first embodiment made semitransparent and a pale yellow, transparent biological membrane formed around the biological tissue regeneration treatment sheet 1A. Fig. 9 is a photograph showing the biological tissue regeneration treatment sheet 1A according to the first embodiment placed to block an opening 40a in the peritoneum 40. Fig. 10 is a photograph showing the semitransparent biological membrane 5 formed along the biological tissue regeneration treatment sheet 1A according to the first embodiment and the formation of capillaries B within the biological membrane 5.

[0032] FIG. 11 is a photograph (substitute for a drawing) showing a newly formed biomembrane 5 that engages with the roughened surface 20r of the biological tissue regeneration treatment sheet 1A. FIG. 12 is a photograph (substitute for a drawing) showing an image of phagocytosis 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 photograph (substitute for a drawing) showing the separation of the second surface 30 of the biological tissue regeneration treatment sheet 1A from the biomembrane 5'. FIG. 15 is a photograph (substitute for a drawing) showing a culture subject. FIG. 16 is a micrograph of cells cultured in MSC medium after 0 days. FIG. 17 is a micrograph of cells cultured in MSC medium after 2 days. FIG. 18 is a micrograph of cells cultured in MSC medium after 7 days. FIG. 19 is a micrograph of staining for each marker. FIGS. 20 and 21 are photographs (substitute for a drawing) showing the results of scRNA-seq analysis.

[0033] Fig. 22 is a schematic cross-sectional view showing a state in which the biological tissue regeneration treatment sheet 1A according to the first embodiment is placed in in vivo tissue 4. Fig. 23 is a schematic cross-sectional view showing a state in which a biological membrane 5 is regenerated along the roughened surface 20r of the biological tissue regeneration treatment sheet 1A according to the first embodiment. Fig. 24 is a schematic cross-sectional view showing a state in which the biological tissue regeneration treatment sheet 1A according to the first embodiment is placed in a brain damaged site. Fig. 25 is a schematic cross-sectional view showing a state in which the biological tissue regeneration treatment sheet 1A according to the first embodiment is placed in a spinal cord damaged site.

[0034] Figures 26 and 27 are schematic cross-sectional views showing a state in which the biological tissue regeneration treatment sheet 1A in the first embodiment is placed at a damaged site of a lung structure 45. Figures 28 and 29 are schematic cross-sectional views showing a state in which the biological tissue regeneration treatment sheet 1A in the first embodiment is placed at a damaged site of a blood vessel 91. Figure 30 is a schematic cross-sectional view showing a state in which cells C are cultured using a culture sheet 1H.

[0035] 1 , the biological tissue regeneration treatment sheet 1A in the first embodiment includes 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.

[0036] As illustrated in FIG. 2 , the first surface 20 includes a roughened surface 20r. In the example illustrated in FIG. 1 , a portion of the first surface 20 is the roughened surface 20r, and another portion 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).

[0037] The roughened surface 20r contains polytetrafluoroethylene as a main component. In other words, the proportion of polytetrafluoroethylene constituting the roughened surface relative to the total material constituting the roughened surface 20r is 50 weight percent or more. The proportion of polytetrafluoroethylene constituting the roughened surface relative to the total 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.

[0038] The entire biological tissue regeneration treatment sheet 1A may contain polytetrafluoroethylene as a main component. In other words, the proportion of polytetrafluoroethylene in the entire material constituting the biological tissue regeneration treatment sheet 1A may be 50 weight percent or more. The proportion of polytetrafluoroethylene constituting the biological tissue regeneration treatment sheet 1A in 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.

[0039] 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 roughness in height Rz than the roughened surface 20r.

[0040] The tissue regeneration treatment sheet 1A in the first embodiment has the property that the roughened polytetrafluoroethylene is phagocytosed by cells of tissue in vivo. Even when polytetrafluoroethylene is brought into contact with tissue in vivo, the polytetrafluoroethylene is not usually phagocytosed by cells of tissue in vivo. In contrast, the first embodiment is configured so that cells of tissue in vivo phagocytose the roughened surface 20r containing polytetrafluoroethylene as a main component. Furthermore, regeneration of tissue in vivo progresses using the roughened surface 20r as a scaffold. Phagocytosis refers to the action of cells of tissue in vivo taking in unnecessary material.

[0041] As described above, the tissue regeneration treatment sheet 1A of the first embodiment realizes tissue regeneration by a novel mechanism that has not been known until now. Furthermore, the tissue regeneration treatment sheet 1A of the first embodiment provides a new application of tissue regeneration for a medical sheet using polytetrafluoroethylene.

[0042] (Optional Additional Configuration) Subsequently, optional additional configurations that can be adopted in the biological tissue regeneration treatment sheet 1A in the first embodiment will be described.

[0043] (Ion-implanted layer 2) As illustrated in FIG. 3 , the roughened surface 20r may be formed by the surface of an 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 the implantation of ionized elements. In the example shown 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 elements implanted by ion implantation are mixed as impurities in polytetrafluoroethylene. Some of the implanted elements may escape from the ion-implanted layer 2.

[0044] 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 as an impurity in the polytetrafluoroethylene, or a layer in which neon is mixed as an impurity in the polytetrafluoroethylene.

[0045] (Roughened Surface 20r) From the viewpoint of allowing the roughened surface 20r to be phagocytosed by cells, the roughened surface 20r preferably has depressions 20d of a size comparable to the size of the cells that phagocytose the roughened surface 20r. Note that, in this specification, depressions of a size comparable to the size of the cells that phagocytose the roughened surface 20r refer to depressions with a depth of at least half but not more than twice the diameter of the cells that phagocytose 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 depressions 20d with a depth of 7.5 μm to 30 μm (e.g., depressions 20d with a depth of 7.5 μm to 15 μm and / or depressions 20d with a depth of 15 μm to 30 μm) or depressions 20d with a depth of 10 μm to 40 μm (e.g., depressions 20d with a depth of 10 μm to 20 μm and / or depressions 20d with a depth of 20 μm to 40 μm). In this case, cells that phagocytose the roughened surface 20r (e.g., macrophages) can phagocytose the roughened surface 20r while entering the depressions of the roughened surface 20r.

[0046] (Expanded Polytetrafluoroethylene) In this specification, 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 in a heated state). ePTEF is expanded porous polytetrafluoroethylene made using, for example, the method described in U.S. Pat. No. 3,953,566 or U.S. Pat. No. 4,187,390. Alternatively, polytetrafluoroethylene in this specification may be non-expanded polytetrafluoroethylene.

[0047] (Adhesion between the roughened surface 20r and in vivo tissue) The adhesion between the roughened surface 20r (more specifically, the ion-implanted layer 2) and in vivo tissue may be performed via an adhesive such as fibrin glue, or may be performed without an adhesive. In other words, an adhesive may or may not be applied to the roughened surface 20r. From the viewpoint of filling the gap between the roughened surface 20r and the in vivo tissue with newly generated cells, it is preferable not to apply an adhesive to the roughened surface 20r.

[0048] (Second Surface 30) The second surface 30 may contain polytetrafluoroethylene as a primary component. In other words, the proportion of polytetrafluoroethylene constituting the second surface 30 relative to the total material constituting the second surface 30 may be 50 weight percent or more. The proportion of polytetrafluoroethylene constituting the second surface 30 relative to the total 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. 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.

[0049] (Film Thickness of Sheet for Biological Tissue Regeneration Treatment) The film 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. If the film thickness 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.

[0050] (Body tissue regeneration treatment sheet used in Experiments 1 to 3) The following Experiments 1 to 3 were conducted using a body tissue regeneration treatment sheet 1A having a roughened surface 20r formed by ion implantation of argon ions (Ar+). In Experiments 1 to 3, the proportion of polytetrafluoroethylene constituting the roughened surface to the entire material constituting the roughened surface 20r of the body tissue regeneration treatment sheet 1A was 99 weight percent or more, and the proportion of polytetrafluoroethylene to the entire material constituting the body tissue regeneration treatment sheet 1A was 99 weight percent or more. The film thickness of the body tissue regeneration treatment sheet 1A was 300 μm. The acceleration voltage of the argon ions (Ar+) was 150 keV, and the amount of argon ions (Ar+) implanted into the body tissue regeneration treatment sheet 1A was 1×10 １４ ions / cm ２ It was.

[0051] (Experiment 1) After administering inhalation anesthesia to a rat (Wistar, 8 weeks old, male), an approximately 2 cm midline incision was made ( FIG. 4 ), and an approximately 8 mm circular craniotomy was made to the right of the incision ( FIG. 5 ). A trimmed tissue regeneration treatment sheet 1A was placed to cover the craniotomy site ( FIG. 6 ). The tissue regeneration treatment sheet 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.

[0052] In rats sacrificed 4.5 months after placement, the biological tissue regeneration treatment sheet 1A had become semitransparent, and a pale yellow, transparent biomembrane had formed around the biological tissue regeneration treatment sheet 1A (FIG. 8).

[0053] The formation of a pale yellow, transparent biological membrane along the roughened surface 20r facing the outside of the head was an unexpected result. The semi-transparency of the biological tissue regeneration treatment sheet 1A was also an unexpected result (i.e., it was unexpected that ePTFE, which is an opaque material, would become semi-transparent when placed in the body).

[0054] (Experiment 2) After administering inhalation anesthesia to a mouse (C57BL, 8 weeks old, male), an opening 40a was formed in the peritoneum 40, and a tissue regeneration treatment sheet 1A measuring approximately 1 cm square was placed to close the opening 40a ( FIG. 9 ). The tissue regeneration treatment sheet 1A was placed so that the roughened surface 20r contacted the back surface of the peritoneum 40 and the second surface 30 (more specifically, the non-roughened surface) faced the center of the abdominal cavity. The tissue regeneration treatment sheet 1A and the peritoneum 40 were sutured together at two locations, and then the wound was closed. Six weeks after placement, the mouse was sacrificed and histologically examined. A translucent biomembrane 5 was formed on the surface of the tissue regeneration treatment sheet 1A facing the roughened surface 20r, and clear new capillaries B were observed within the biomembrane 5 ( FIG. 10 ). Hematoxylin-eosin staining and immunohistochemical staining (FIG. 11) revealed numerous multinucleated giant cells in the newly formed biomembrane 5 on the roughened surface 20r side (i.e., the ion-implanted layer 2 side) of the biological tissue regeneration treatment sheet 1A, and some ePTFE phagocytosis 6 was also observed (FIG. 12). As can be seen from FIG. 11, newly formed tissue (more specifically, newly formed biomembrane 5) developed along the roughened surface 20r of the biological tissue regeneration treatment sheet 1A, and the newly formed tissue (more specifically, newly formed biomembrane 5) was formed so as to interlock with the irregularities of the roughened surface 20r. Furthermore, continuous cellular infiltration 7 (more specifically, cellular infiltration into the ion-implanted layer 2) from the roughened surface 20r to the interior of the biological tissue regeneration treatment sheet 1A was observed (FIG. 12). When the roughened surface side (i.e., 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) of the sheet for biological tissue regeneration treatment 1A, no cell infiltration into the interior of the sheet for biological tissue regeneration treatment 1A, no ePTFE phagocytosis image 6, etc. were observed (FIG. 14).

[0055] (Experiment 3: Cultivation of biological membrane) The biological tissue regeneration treatment sheet 1A and the biological membrane generated while bound to the biological tissue regeneration treatment sheet 1A were removed from a rat, fragmented, and the biological membrane side was attached to a 6-well plate (Figure 15). These wells were filled with a medium for iPS cells (Stemflex medium (Thermo Fisher) + penicillin streptomycin + Zell shield (Funakoshi): upper left of FIG. 15), a medium for mesenchymal stem cells (hereinafter referred to as "MSC") (low glucose DMEM + hyclone FBS + kanamycin: upper center of FIG. 15), a medium for glioma cells (high glucose DMEM + Corning FBS + penicillin streptomycin: upper right of FIG. 15), and a medium for fibroblasts (low glucose DMEM + penicillin streptomycin (lower left of Figure 15) was added and primary culture was performed. Regarding the medium for fibroblasts, tissue regeneration treatment sheet 1A treated with trypsin (lower center of Figure 15) and one with only a biomembrane attached (lower right of Figure 15) were also cultured. Among these, cell proliferation was observed in the medium for MSCs only (Figure 16: after 0 days, Figure 17: after 2 days, Figure 18: after 7 days). Cells were immunostained to identify the type of proliferated cells.

[0056] (Cell Immunostaining) Since cell proliferation was observed in the MSC medium, staining was performed primarily 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. Furthermore, the astrocyte marker GFAP and the neuron marker MAP2 were negative. None of the markers were stained in all cells, suggesting the presence of multiple cell types. Therefore, single-cell RNA sequencing (scRNA-seq) analysis was then performed to identify the cell types.

[0057] (scRNA-seq Analysis) ScRNA-seq analysis was performed to identify the type of cells proliferating from the biomembrane formed by binding to the tissue regeneration treatment sheet 1A. More specifically, after placing the tissue regeneration treatment sheet 1A in a rat for eight months, the tissue regeneration treatment sheet 1A and the biomembrane formed by binding to the tissue regeneration treatment sheet 1A were removed from the rat and cultured in a medium for MSCs. The resulting cell suspension was then submitted as a sample to a company contracted for scRNA-seq analysis. Analysis of the genes expressed in each cell allowed the cells to be separated into 12 cell populations (clusters) based on gene expression levels (Figure 20). Based on the characteristic gene expression in each cluster, it was estimated that the proliferated cell types included fibroblasts, MSCs, macrophages, myofibroblasts, and oligodendrocytes (Figure 21).

[0058] (Summary of Experimental Results and Analysis Results) From the results of Experiment 1 and Experiment 2, it was confirmed that a biological membrane was formed accompanied by angiogenesis on the surface of the roughened surface 20r side of the biological tissue regeneration treatment sheet 1A (more specifically, on the surface of the ion-implanted layer 2 side). Furthermore, from the results of Experiment 1 and Experiment 2, it was confirmed that the biological tissue regeneration treatment sheet 1A became transparent.

[0059] The results of Experiment 2 showed that when 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 cellular infiltration into the ion-implanted layer 2 and phagocytosis of the polytetrafluoroethylene that constitutes the ion-implanted layer 2.

[0060] The results of Experiment 3 demonstrated cell proliferation in cultures using tissue regeneration treatment sheet 1A and MSC culture medium. Furthermore, immunohistochemistry of the cells confirmed positive stem cell markers (i.e., stem cell expression). Single-cell RNA sequencing analysis confirmed that the cultured cells included fibroblasts, MSCs, macrophages, myofibroblasts, and oligodendrocytes.

[0061] 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).

[0062] (Characteristic 1 of Biological Tissue Regeneration Treatment Sheet 1A) 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 (hereinafter referred to as "Characteristic 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 on the surface of the biological tissue regeneration treatment sheet is more pronounced than when the second surface 30 is placed in contact with damaged in vivo tissue."

[0063] 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 property that "when the roughened surface 20r is placed in contact with damaged biological tissue, the expression of mesenchymal stem cells on the surface of the biological tissue regeneration treatment sheet is more pronounced than when the second surface 30 is placed in contact with damaged biological tissue."

[0064] Since the biological tissue regeneration treatment sheet 1A has property 1, it can be said that the biological tissue regeneration treatment sheet 1A is useful as a medical device for regenerative medicine.

[0065] (Characteristic 2 of sheet 1A for biological tissue regeneration treatment) From the results of Experiment 2 (see Figure 10), it can be said that sheet 1A for biological tissue regeneration treatment has the characteristic 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 "characteristic 2").

[0066] (Characteristic 3 of sheet 1A for biological tissue regeneration treatment) As exemplified in Fig. 22, the sheet 1A for biological tissue regeneration treatment has a characteristic that "when the roughened surface 20r is placed in contact with the edge 4e of the in vivo tissue 4 so that the roughened surface 20r faces the defect region RG of the in vivo tissue 4, a biological membrane 5 and capillaries B are generated in the defect region RG along the roughened surface 20r" (hereinafter referred to as "characteristic 3") (see Fig. 23). Characteristic 3 is a characteristic based on an event that became clear in Experiment 2.

[0067] Since the biological tissue regeneration treatment sheet 1A has property 2 or property 3, it can be said that the biological tissue regeneration treatment sheet 1A is useful as a medical device for regenerative medicine. When the biological tissue regeneration treatment sheet 1A has property 2, nutrients and the like are supplied to the newly formed biological membrane 5 via the capillaries B. Therefore, the biological membrane 5 is quickly formed. Furthermore, when the biological tissue regeneration treatment sheet 1A has property 3, the defective region RG of the in-vivo tissue 4 is quickly sealed by the biological membrane 5.

[0068] 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 in vivo tissue 4, new tissue grows from the in vivo tissue 4 along the roughened surface 20r, and the new tissue grows so as to mesh with the irregularities of the roughened surface 20r."

[0069] 22 and 23 , the sheet 1A for biological tissue regeneration treatment may have a property (hereinafter referred to as "property 4") in which "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." When the sheet 1A for biological tissue regeneration treatment has property 4, the in vivo tissue 4 and the roughened surface 20r are firmly bonded. In addition, body fluids and the like are less likely to leak from the gap between the in vivo tissue 4 and the roughened surface 20r.

[0070] (Characteristic 5 of sheet 1A for biological tissue regeneration treatment) From the results of Experiment 2 (see Figure 12), it can be said that sheet 1A for biological tissue regeneration treatment has the characteristic that "cells of biological tissue infiltrate into the inside of the ion-implanted layer 2" (hereinafter referred to as "characteristic 5").

[0071] As illustrated 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 in the roughened surface 20r. Furthermore, the sheet for biological tissue regeneration treatment 1A may be configured so that cells infiltrate into the interior of a structure formed of polytetrafluoroethylene and an ion-implanted element. (Property 6 of Sheet for Biological Tissue Regeneration Treatment 1A) From the results of Experiment 2 (see, for example, Fig. 8), it can be said that the sheet for biological tissue regeneration treatment 1A has the property that "when the roughened surface 20r is left in contact with in vivo tissue (e.g., membrane tissue in a living body) for six months or more, the opaque polytetrafluoroethylene constituting the roughened surface 20r of the sheet for biological tissue regeneration treatment 1A becomes transparent or translucent" (hereinafter referred to as "Property 6").

[0072] The mechanism by which polytetrafluoroethylene becomes transparent or translucent is unknown, but it is presumed that the in vivo tissue 4, the newly formed biomembrane 5, or the cells that make up these tissues are involved in the process.

[0073] When polytetrafluoroethylene is made transparent or semi-transparent, it may be possible to ascertain the state of the biological tissue on the back side of the biological tissue regeneration treatment sheet 1A.

[0074] (Nerve damage repair sheet 1B) The biological tissue regeneration treatment sheet 1A in the first embodiment described above can be used as nerve damage repair sheet 1 B. In other words, in the description of the biological tissue regeneration treatment sheet 1A in the first embodiment, "biological tissue regeneration treatment sheet 1A" can be read as "nerve damage repair sheet 1B."

[0075] 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 vivo, 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.

[0076] The nerve damage repair sheet 1B having the above-described 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.

[0077] 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."

[0078] (Brain injury repair sheet 1C) Nerve damage repair sheet 1B in the first embodiment described above can be used as brain injury repair sheet 1C by applying it to the brain damaged site. In other words, in the description of biological tissue regeneration treatment sheet 1A (or nerve damage repair sheet 1B) in the first embodiment, "biological tissue regeneration treatment sheet 1A" (or "nerve damage repair sheet 1B") can be read as "brain injury repair sheet 1C."

[0079] The brain injury repair sheet 1C having the above-mentioned properties 1 to 6 functions as a scaffold for tissue regeneration at the brain injury site. For example, as illustrated in Figure 24, when the roughened surface 20r is placed facing the brain injury site RG2 of the in vivo tissue 4, a biological membrane 5 and capillaries B are regenerated along the roughened surface 20r facing the brain injury site RG2. In Figure 24, the brain injury repair sheet 1C is placed in contact with the brain injury site RG2 inside all of the skull 81, dura mater 82, and arachnoid mater 83.

[0080] The brain injury repair sheet 1C may be placed inside the pia mater 84. The brain injury repair sheet 1C may be attached to the pia mater 84 so as to be supported by the pia mater 84.

[0081] (Spinal Cord Injury Repair Sheet 1D) The nerve damage repair sheet 1B in the first embodiment described above can be used as spinal cord injury repair sheet 1D by applying it to the spinal cord injury site. In other words, in the description of biological tissue regeneration treatment sheet 1A (or nerve damage repair sheet 1B) in the first embodiment, "biological tissue regeneration treatment sheet 1A" (or "nerve damage repair sheet 1B") can be read as "spinal cord injury repair sheet 1D."

[0082] The spinal cord injury repair sheet 1D having the above-described properties 1 to 6 functions as a scaffold for tissue regeneration at the spinal cord injury site. For example, as illustrated in Figure 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 regenerated along the roughened surface 20r facing the spinal cord injury site RG3. In Figure 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.

[0083] The spinal cord injury repair sheet 1D may be placed inside the pia mater 84. The spinal cord injury repair sheet 1D may be attached to the pia mater 84 so as to be supported by the pia mater 84.

[0084] (Lung injury repair sheet 1E) The biological tissue regeneration treatment sheet 1A in the first embodiment described above can be used as lung injury repair sheet 1E. In other words, in the description of the biological tissue regeneration treatment sheet 1A in the first embodiment, "biological tissue regeneration treatment sheet 1A" can be read as "lung injury repair sheet 1E."

[0085] 26 or 27 , the lung injury repair sheet 1E comprises (1) a first surface 20 including a roughened surface 20r that is to be phagocytosed by cells of tissue in vivo, 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.

[0086] 26 or 27 , when the roughened surface 20r is placed in contact with the lung structure 45 (more specifically, the edge 45e defining the defect region RG4 of the lung structure 45) so that the roughened surface 20r faces the defect region RG4 of the lung structure 45 (more specifically, the opening of the lung structure 45), a biological membrane 5 and capillaries B are regenerated along the roughened surface 20r in the defect region RG4.

[0087] In this specification, lung injury includes damage to the visceral pleura 450 and damage to the parietal pleura. In the example shown in Fig. 26, a defect region 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 region RG4. As exemplified 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 exemplified in Fig. 27, it may be configured to be attached to the inside of the visceral pleura 450. In Fig. 26 or 27, the lung injury repair sheet 1E may function as a pneumothorax treatment sheet.

[0088] When the lung injury repair sheet 1E has the above-described property 4, substantially all of the gap between the in vivo tissue 4 (e.g., the visceral pleura 450) and the roughened surface 20r is filled with new tissue. This prevents air from leaking through the gap between the in vivo tissue 4 and the roughened surface 20r. In the example shown in FIG. 26 or 27, the roughened surface 20r is used as a scaffold for the biological membrane 5 and 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 biological membrane 5. This allows the lung injury to be repaired effectively.

[0089] (Peritoneal injury repair sheet 1F) The biological tissue regeneration treatment sheet 1A in the first embodiment described above can be used as the peritoneal injury 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 injury repair sheet 1F."

[0090] The sheet 1F for repairing peritoneal injury comprises (1) a first surface 20 including a roughened surface 20r that is to be phagocytosed by cells of in vivo tissue, 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.

[0091] The sheet 1F for repairing peritoneal injury having the above-described properties 1 to 6 functions as a scaffold for tissue regeneration at the site of peritoneal injury. 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 of ​​the peritoneum 40 (more specifically, the opening 40a), a biological membrane 5 and capillaries B are regenerated along the roughened surface 20r in the defect area.

[0092] When the sheet 1F for repairing peritoneal damage has the above-described property 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 gases from the gap between the peritoneum 40 and the roughened surface 20r. In the example shown in FIG. 10 , the roughened surface 20r is used as a scaffold for the biological membrane 5 and capillaries B to extend across the defect area (see the opening 40a in FIG. 9 ). In this case, the defect area of ​​the peritoneum 40 (more specifically, the opening 40a) is blocked by the biological membrane 5. This allows the peritoneal damage to be repaired effectively.

[0093] (Blood vessel injury repair sheet 1G) The biological tissue regeneration treatment sheet 1A in the first embodiment described above can be used as the blood vessel injury 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 the "blood vessel injury repair sheet 1G." As illustrated in FIG. 28 or 29 , the blood vessel injury repair sheet 1G comprises (1) a first surface 20 including a roughened surface 20r that is to be phagocytosed by cells of tissue in vivo, 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.

[0094] The sheet 1G for repairing blood vessel damage having the above-described properties 1 to 6 functions as a scaffold for tissue regeneration at the site of blood vessel damage. For example, as illustrated in Figure 28 or 29, when the roughened surface 20r is placed in contact with the blood vessel 91 (more specifically, the edge 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, at the opening 91a of the blood vessel 91).

[0095] In the example shown in FIG. 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 shown 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 shown in FIG. 29 , it may be configured to be attached to the inside of the blood vessel 91. When the sheet 1G for repairing blood vessel damage has the above-mentioned property 4, substantially all of the gap between the blood vessel 91 and the roughened surface 20r is filled with new tissue. This prevents blood from leaking from the gap between the blood vessel 91 and the roughened surface 20r. In the example shown in FIG. 28 or 29 , the sheet 1G is configured so that the biological membrane 5 and capillaries B extend across 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 biological membrane 5. Thus, the damaged blood vessels are 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 the culture sheet 1H. In other words, in the description of the biological tissue regeneration treatment sheet 1A in the first embodiment, "biological tissue regeneration treatment sheet 1A" can be read as "culture sheet 1H."

[0097] As illustrated in Figure 30, the culture sheet 1H in the first embodiment comprises (1) a first surface 20 including a roughened surface 20r on which cells C to be cultured or biological tissue containing the cells C are placed, and (2) a second surface 30 placed 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 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 configuration will be omitted.

[0098] The culture sheet 1H may have the property that "when the cells C to be cultured or a biological tissue containing the cells C are 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 is more pronounced than when the cells C to be cultured or a biological tissue containing the cells C are placed in contact with the second surface 30." Note that the cells to be expressed depend on the type of the cells C to be cultured.

[0099] The culture sheet 1H may have the 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. Furthermore, the culture sheet H may 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] (Sheet 1I for treating cerebral infarction) The biological tissue regeneration treatment sheet 1A in the first embodiment described above can be used as a sheet 1I for treating cerebral infarction. In other words, in the description of the biological tissue regeneration treatment sheet 1A in the first embodiment, the "sheet 1A for biological tissue regeneration treatment" can be read as the "sheet 1I for treating cerebral infarction."

[0101] As shown in the examples described below, animal experiments have shown that the use of the cerebral infarction treatment sheet 1I enhances recovery of motor function after cerebral infarction. Therefore, this cerebral infarction treatment sheet 1I is effective. Furthermore, as shown in the examples described below, by the time neovascularization increases and cerebral infarction improves, the color of the cerebral infarction treatment sheet 1I becomes transparent. Therefore, by measuring the transparency of the cerebral infarction treatment sheet 1I, the state of neovascularization can be grasped and the improvement of cerebral infarction can be predicted. Therefore, this specification also provides a cerebral infarction treatment sheet 1I that has the function of analyzing or grasping the state of neovascularization based on its transparency. This specification also provides a cerebral infarction treatment sheet 1I that has the function of analyzing or grasping the improvement of cerebral infarction based on its transparency. For example, by analyzing the cerebral infarction treatment sheet 1I by implanting a sensor in the brain, the transparency of the cerebral infarction treatment sheet 1I can be measured in real time, allowing the improvement of cerebral infarction and the state of neovascularization to be estimated. In this case, since there is no need to sense the entire brain, the state of cerebral infarction can be grasped objectively in a minimally invasive manner. The sheet for treating cerebral infarction 1I is used, for example, by placing the ion irradiation surface facing the surface of the brain.

[0102] (Angiogenesis-promoting sheet 1J) The biological tissue regeneration treatment sheet 1A in the first embodiment described above can be used as the angiogenesis-promoting sheet 1J. 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 "angiogenesis-promoting sheet 1J."

[0103] As described above, it has been shown that the use of the angiogenesis-promoting sheet 1J promotes angiogenesis. For this reason, this specification discloses the angiogenesis-promoting sheet 1J. This specification also provides sheets for various treatments (for example, wound treatment) by promoting neovascularization using the angiogenesis-promoting sheet 1J.

[0104] (Sheet 1K for proliferation of mesenchymal stem cells) The sheet 1A for biological tissue regeneration treatment in the first embodiment described above can be used as the sheet 1K for proliferation of mesenchymal stem cells. In other words, in the description of the sheet 1A for biological tissue regeneration treatment in the first embodiment, "sheet 1A for biological tissue regeneration treatment" can be read as "sheet 1K for proliferation of mesenchymal stem cells."

[0105] As shown in the examples described below, it has been shown that mesenchymal stem cells proliferate when mesenchymal stem cells are grown using the mesenchymal stem cell proliferation sheet 1K. In particular, it has been shown that mesenchymal stem cells proliferate when the artificial dura mater is cultured after placement of the mesenchymal stem cell proliferation sheet 1K. As described above, the sheet of the present invention functions as an angiogenesis-promoting sheet. This is because mesenchymal stem cells can differentiate into blood vessels, and it is possible that the sheet of the present invention proliferates mesenchymal stem cells, which in turn contributes to angiogenesis.

[0106] Therefore, the mesenchymal stem cell proliferation sheet 1K of the present invention is effective in treating diseases associated with mesenchymal stem cells. Furthermore, when the mesenchymal stem cell proliferation sheet 1K of the present invention is cultured in vivo, components contained in the culture supernatant are produced. Therefore, the mesenchymal stem cell proliferation sheet 1K can also be effectively used as a treatment sheet for diseases in which the culture supernatant functions.

[0107] (Anti-inflammatory sheet 1L) The biological tissue regeneration treatment sheet 1A in the first embodiment described above can be used as the anti-inflammatory sheet 1L. 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 "anti-inflammatory sheet 1L." In other words, as explained above, the sheet of the present invention promotes the proliferation of mesenchymal stem cells, which in turn secrete various components. Therefore, the sheet of the present invention effectively functions as the anti-inflammatory sheet 1L.

[0108] The sheet for treating cerebral infarction 1I, the sheet for promoting angiogenesis 1J, the sheet for proliferation of mesenchymal stem cells 1K and the anti-inflammatory sheet 1L can be used and modified in the same manner as the other uses of the sheet for biological tissue regeneration treatment 1A.

[0109] Second Embodiment A regenerative treatment method according to the second embodiment will be described with reference to Figures 1 to 31. Figure 31 is a flowchart showing an example of the regenerative treatment method according to the second embodiment.

[0110] 2, a biological tissue regeneration treatment sheet 1A is prepared in a first step ST1. The first step ST1 is a preparation step.

[0111] The tissue regeneration treatment sheet 1A prepared in the preparation process (first step ST1) has a first surface 20 at least partially 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.

[0112] The preparation process (first step ST1) may include forming an ion-implanted layer 2 on the biological tissue regeneration treatment sheet 1A 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 that is irradiated with ions becomes a roughened surface 20r. Furthermore, the roughened surface 20r is constituted by the surface of the ion-implanted layer 2.

[0113] The preparation step (first step ST1) may include applying a heat treatment to the ion-injected biological tissue regeneration treatment sheet 1A. The ion injection and heat treatment relax the regularity of the polymer structure of polytetrafluoroethylene. This relaxation of the regularity may make the polytetrafluoroethylene more likely to become transparent or translucent in the regeneration step described below. In this heat treatment, the biological tissue regeneration treatment sheet 1A may be placed in a heated atmosphere of 100 degrees Celsius or higher.

[0114] The biological tissue regeneration treatment sheet 1A has already been explained in the first embodiment, so repeated explanation of the biological tissue regeneration treatment sheet 1A will be omitted.

[0115] As exemplified in Fig. 6 or 9, in the second step ST2, the tissue regeneration treatment sheet 1A is placed in tissue within the body. The second step ST2 is a placing step.

[0116] In the placement step (second step ST2), the biological tissue regeneration treatment sheet 1A is placed in the biological tissue so that the roughened surface 20r comes into contact with the damaged biological tissue. The biological tissue 4 in which the biological tissue regeneration treatment sheet 1A is placed is, for example, the brain, spinal cord, lung structure, peritoneum, or blood vessels. The biological tissue 4 in which the biological tissue regeneration treatment sheet 1A is placed may be the pia mater covering the brain, the pia mater covering the spinal cord, or the visceral pleura.

[0117] 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 region RG) so that the roughened surface 20r faces the defect region RG of the endogenous tissue 4 (e.g., an opening in the endogenous tissue 4).

[0118] In the third step ST3, the tissue at the damaged site in the living body is regenerated. The third step ST3 is a regeneration step.

[0119] In the regeneration step (third step ST3), tissue at the 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 the polytetrafluoroethylene that constitutes the roughened surface 20r. The regeneration step (third step ST3) may also include cells of the in vivo tissue 4 phagocytosing the polytetrafluoroethylene that constitutes the ion-implanted layer 2.

[0120] The regeneration step (third step ST3) may include generating 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.

[0121] 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.

[0122] 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 ion-implanted layer 2. The regeneration step (third step ST3) may also include infiltrating cells of the in vivo tissue into depressions in the roughened surface 20r. The regeneration step (third step ST3) may also include infiltrating cells into the structure composed of polytetrafluoroethylene and the ion-implanted element.

[0123] The regeneration process (third step ST3) may include changing the state of the polytetrafluoroethylene that constitutes the roughened surface 20r (more specifically, the polytetrafluoroethylene that constitutes the ion-implanted layer 2) from an opaque state to a transparent or translucent state.

[0124] The regeneration step (third step ST3) may include repairing nerve damage by using the roughened surface 20r as a scaffold to regenerate tissue at the damaged site of the in vivo tissue 4. The regeneration step (third step ST3) may include repairing brain damage or spinal cord damage by using the roughened surface 20r as a scaffold to regenerate tissue at the damaged site of the in vivo tissue. The regeneration step (third step ST3) may include regenerating nerve cells using the roughened surface 20r as a scaffold.

[0125] The regeneration step (third step ST3) may include repairing lung damage, peritoneal damage, or blood vessel damage by regenerating tissue at the damaged site of the in vivo tissue using the roughened surface 20r as a scaffold. The regeneration step (third step ST3) may include generating a new biological membrane 5 at the opening of the lung structure, the opening of the peritoneum, or the opening of the blood vessel by regenerating tissue at the damaged site of the in vivo tissue using the roughened surface 20r as a scaffold.

[0126] The present invention is not limited to the above-described embodiments or modifications, and it is clear that each embodiment or modification can be appropriately modified or changed within the scope of the technical concept of the present invention. Furthermore, various techniques used in each embodiment or modification can be applied to other embodiments or modifications as long as no technical contradiction occurs. Furthermore, optional additional configurations in each embodiment or modification can be omitted as appropriate.

[0127] In the embodiments, the sheet for biological tissue regeneration treatment, sheet for nerve damage repair, sheet for brain damage repair, sheet for spinal cord damage repair, sheet for lung damage repair, sheet for peritoneal damage repair, or sheet for vascular damage repair may be applied to the tissues in the body of a human or the tissues in the body of an animal other than a human.

[0128] The present invention will be specifically described below using examples.

[0129] [Example 1] (Cerebral infarction treatment sheet 1I) Argon ions (Ar ＋A tissue regeneration treatment sheet 1A having a roughened surface 20r formed by ion implantation of argon ions (Ar) was prepared and used as a cerebral infarction treatment sheet 1I. The proportion of polytetrafluoroethylene constituting the roughened surface to the entire material constituting the roughened surface 20r of the cerebral infarction treatment sheet 1I was 99 weight percent or more, and the proportion of polytetrafluoroethylene to the entire material constituting the cerebral infarction treatment sheet 1I was 99 weight percent or more. The thickness of the cerebral infarction treatment sheet 1I was 300 μm ... ＋ The acceleration voltage of the argon ions (Ar) was 150 keV. ＋ ) is injected at a dose of 1 × 10 １４ ions / cm ２ It was.

[0130] A mouse model of distal middle cerebral artery occlusion (distal MCA occlusion) (C57BL, 9 weeks, male) was prepared as follows. The mouse was administered inhalation anesthesia, and the left common carotid artery was exposed and temporarily ligated with 6-0 nylon. The temporal region was incised, and the temporal muscle was dissected from the linea temporalis to expose the temporal bone. The distal left middle cerebral artery was visualized through the incision. The bone directly above the middle cerebral artery was removed with a drill, and the middle cerebral artery was cauterized with a bipolar forceps and transected at the tip to create a mouse model of distal middle cerebral artery occlusion (distal MCA occlusion). The mouse was left on a hot plate at 37°C for 1 hour, after which the common carotid artery ligation was released. The mouse was then fixed to a stereo stand and external decompression was performed with a drill. Next, a trimmed cerebral infarction treatment sheet 1I was placed across the normal and infarcted brain, and the wound was closed. 32 shows the placement of the cerebral infarction treatment sheet 1I at the locations indicated by triangles. The placement of the cerebral infarction treatment sheet 1I was divided into two groups: a roughened-surface-inside group (n=3) in which the roughened surface was placed so that it was in contact with the inside of the head, i.e., the brain, and a roughened-surface-outside group (n=3) in which the roughened surface was placed so that it was in contact with the outside of the head, i.e., the non-roughened surface, the brain.

[0131] The roughened surface inside group and the roughened surface outside group were kept for 5.5 months after placement of the cerebral infarction treatment sheet 1I. After that, the recovery of the motor function of the mice was investigated by performing a rotarod test and a corner test.

[0132] Rotarod Test The rotarod is a device that uses a horizontally positioned rotating rod to evaluate an animal's motor coordination and cooperation. After placing a mouse on the rod, the rod begins to rotate, and the time it takes for the mouse to fall off the rod is recorded. The faster the mouse is unable to continue walking and falls off the rod, the more impaired its motor function is thought to be due to cerebral infarction. Conversely, the longer it takes for the mouse to fall off the rod, the more its motor function has recovered and the symptoms of cerebral infarction are thought to be milder.

[0133] In this example, a rotarod for both rats and mice (MK-670, manufactured by Muromachi Kikai Co., Ltd.) was used. The rotarod was set to accelerate at 40 rpm for 60 seconds, then rotate continuously at 40 rpm for 300 seconds. The test was performed using the following procedure: (1) Training was performed several times in the same mode on the day before surgery. (2) Tests were performed on the day before surgery, 4 days after surgery, 7 days after surgery, 14 days after surgery, and 28 days after surgery. (3) The number of seconds until the rats fell off the rod was measured twice, and the average was taken. All values ​​were divided by the preoperative value on the day of surgery.

[0134] The test results are shown in Figure 33. As can be seen from Figure 33, the group with the roughened surface under the inner side showed a faster recovery of motor function than the group with the roughened surface under the outer side. This is thought to be because the use of the cerebral infarction treatment sheet 1I induced mesenchymal stem cell migration and angiogenesis, promoting the recovery of neural function. Therefore, the tissue regeneration treatment sheet of the present invention is useful as a sheet for treating cerebral infarction.

[0135] Corner test: A corner (triangular prism) as shown in Figure 34 was made of cardboard, and a mouse was placed inside. When the mouse reached vertex A, it was observed and recorded whether it made a right or left turn. A similar test was performed 10 times, and the number of right turns and the number of left turns at vertex A were recorded, and the number of right turns / (number of right turns + number of left turns) was calculated. The closer this value was to 0, the stronger the left paralysis, the closer it was to 1, the stronger the right paralysis, and the closer it was to 0.5, the weaker the paralysis. The results are shown in Figure 35.

[0136] As can be seen from Figure 35, the group with the roughened surface under the inner side recovered from paralysis more quickly than the group with the roughened surface under the outer side. This is thought to be because the use of the cerebral infarction treatment sheet 1I induces mesenchymal stem cell migration and angiogenesis, promoting recovery of neural function. Therefore, the tissue regeneration treatment sheet of the present invention is useful as the cerebral infarction treatment sheet 1I.

[0137] (Angiogenesis-Promoting Sheet 1J) After 5.5 months of placement, the mice in which the above-mentioned cerebral infarction treatment sheet 1I was placed underwent craniotomy again to observe the surface of the cerebral infarction treatment sheet 1I. As shown in Figure 36, extracranial blood vessels were observed to have developed on or within the cerebral infarction treatment sheet 1I. In particular, more angiogenesis was observed in the roughened surface inner group (Figure 36(b)) than in the roughened surface outer group (Figure 36(a)). This suggests that the biological tissue regeneration treatment sheet 1A has an angiogenesis-promoting effect. Therefore, it was found that the biological tissue regeneration treatment sheet 1A of the present invention also functions as an angiogenesis-promoting sheet 1J.

[0138] Example 2 (Angiogenesis-Promoting Sheet 1J) A tissue regeneration treatment sheet 1A similar to that of Example 1 was prepared and used as an angiogenesis-promoting sheet 1J.

[0139] After administering inhalation anesthesia to a mouse (C57BL, 8 weeks old, male), an opening 40a was formed in the peritoneum 40, and a tissue regeneration treatment sheet 1A measuring approximately 1 cm square was placed to close the opening 40a ( FIG. 9 ). The tissue regeneration treatment sheet 1A was placed so that the roughened surface 20r contacted the back surface of the peritoneum 40 and the second surface 30 (more specifically, the non-roughened surface) faced the center of the abdominal cavity. The tissue regeneration treatment sheet 1A and the peritoneum 40 were sutured together at two locations, and then the wound was closed. Six weeks after placement, the mouse was sacrificed and histologically examined.

[0140] A translucent biological membrane 5 was formed on the surface of the roughened surface 20r of the biological tissue regeneration treatment sheet 1A, and clear new capillaries B were observed inside the biological membrane 5 ( FIG. 10 ). That is, in Example 2, the blood vessels of the abdominal wall had progressed into the biological tissue regeneration treatment sheet 1A. This suggests that the biological tissue regeneration treatment sheet 1A has an angiogenesis-promoting effect. Therefore, it was found that the biological tissue regeneration treatment sheet 1A of the present invention also functions as an angiogenesis-promoting sheet 1J.

[0141] Example 3 (Sheet 1K for Proliferation of Mesenchymal Stem Cells) A tissue regeneration treatment sheet 1A similar to that of Example 1 was prepared and used as a sheet 1K for proliferation of mesenchymal stem cells.

[0142] After administering inhalation anesthesia to a rat (Wistar, 8 weeks old, male), an approximately 2 cm midline incision was made ( FIG. 4 ), and an approximately 8 mm circular craniotomy was made to the right of the incision ( FIG. 5 ). The trimmed tissue regeneration treatment sheet 1A was placed to cover the craniotomy site ( FIG. 6 ). The tissue regeneration treatment sheet 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.

[0143] In rats sacrificed 4.5 months after placement, the biological tissue regeneration treatment sheet 1A had become semitransparent, and a pale yellow, transparent biomembrane had formed around the biological tissue regeneration treatment sheet 1A (FIG. 8).

[0144] The tissue regeneration treatment sheet 1A and the biomembrane formed in a state bound to the tissue regeneration treatment sheet 1A were removed from a rat, fragmented, and attached with the biomembrane side to a 6-well plate (FIG. 15). Mesenchymal stem cell (MSC) medium (low glucose DMEM + hyclone FBS + kanamycin: top center of FIG. 15) was placed in one of the wells and primary culture was performed. Cell proliferation was observed in this well (FIG. 16: 0 days after 0, FIG. 17: 2 days after 0, FIG. 18: 7 days after 7).

[0145] Since cell proliferation was observed in the MSC medium, staining for MSC markers was performed (Figure 37). The MSC markers CD29 and CD105 were positive. The MSC marker CD90 was negative. The neural stem cell marker SOX2 was positive, while the neural stem cell marker nestin was negative. These results suggest that the biological tissue regeneration treatment sheet 1A has the effect of proliferating mesenchymal stem cells. Therefore, the biological tissue regeneration treatment sheet 1A of the present invention can be used as the mesenchymal stem cell proliferation sheet 1K.

[0146] Example 4 (Anti-inflammatory Sheet 1L) In Example 4, single cell RNA sequencing (scRNA-seq) analysis of cells grown on the tissue regeneration treatment sheet 1A was carried out.

[0147] A tissue regeneration treatment sheet 1A similar to that in Example 1 was prepared. The tissue regeneration treatment sheet 1A was placed in a male rat (Wistar, 8 weeks old) in the same manner as in Example 3. Eight months after placement, the tissue regeneration treatment sheet 1A and the biomembrane formed by binding to the tissue regeneration treatment sheet 1A were extracted from the rat. The cells were cultured in a medium for MSCs in the same manner as in Example 3, and the resulting cell suspension was submitted as a sample to a company contracted for scRNA-seq. Analysis of the genes expressed in each cell resulted in the separation into 12 cell populations (clusters) based on gene expression levels (Figure 20). Two mesenchymal stem cell populations were identified (Figure 38). This indicates that mesenchymal stem cells proliferate on the tissue regeneration treatment sheet 1A.

[0148] Here, Tanaka et al. have reported that mesenchymal stem cells suppress the immune system through TGF-β (Tanaka, Yoshiya, et al., Treatment and regeneration of inflammatory arthritis using mesenchymal cells. Journal of the Japanese Society of Immunology. 2015) (Figure 39).

[0149] Taking these results together, it is believed that the tissue regeneration treatment sheet 1A suppresses immunity by promoting the proliferation of mesenchymal stem cells, i.e., has an anti-inflammatory effect. Therefore, the tissue regeneration treatment sheet 1A of the present invention is useful as an anti-inflammatory sheet 1L.

[0150] 1A: Sheet for biological tissue regeneration treatment 1B: Sheet for nerve damage repair 1C: Sheet for brain damage repair 1D: Sheet for spinal cord damage repair 1E: Sheet for lung damage repair 1F: Sheet for peritoneal damage repair 1G: Sheet for blood vessel damage repair 1H: Cultured sheet 2: Ion-implanted layer 4: In vivo tissue 4e: Edge 5: Biological membrane 5': Biological membrane 6: Phagocytosis image 7: Cell infiltration 20: First surface 20d: Depression 20r: Roughened surface 20s: Non-roughened surface 30: Second surface 40: Peritoneum 40a: Opening 45: Lung structure 45e: Edge 81: Skull 82: Dura mater 83: Arachnoid mater 84: Pia mater 91: Blood vessel 91a: Opening 95e: Edge 450: Visceral pleura B: Capillaries C: Cells H: Culture sheet RG: Defective area RG1: Nerve damaged area RG2: Brain damaged area RG3: Spinal cord damaged area RG4: Defective area RG5: Damaged area

Claims

1. A nerve injury repair sheet that contacts a roughened surface containing polytetrafluoroethylene as a main component with a nerve injury site, causes the roughened surface to be phagocytosed by cells of the in-vivo tissue, expresses mesenchymal stem cells on the roughened surface, induces angiogenesis along the roughened surface, and regenerates nerve cells at the nerve injury site using the roughened surface as a scaffold, the nerve injury repair sheet comprising: a first surface that will come into contact with the nerve injury site and will be phagocytosed by cells of the in-vivo tissue, the first surface including the roughened surface; and a second surface disposed on the opposite side of the first surface, wherein the roughened surface contains polytetrafluoroethylene as a main component.

2. A nerve injury repair sheet for the brain that contacts a roughened surface containing polytetrafluoroethylene as a main component with a nerve injury site in the brain, causes the roughened surface to be phagocytosed by cells of the in-vivo tissue, expresses mesenchymal stem cells on the roughened surface, induces angiogenesis along the roughened surface, and regenerates nerve cells at the nerve injury site in the brain using the roughened surface as a scaffold, the nerve injury repair sheet for the brain comprising: a first surface that will come into contact with the nerve injury site in the brain and will be phagocytosed by cells of the in-vivo tissue, the first surface including the roughened surface; and a second surface disposed on the opposite side of the first surface, wherein the roughened surface contains polytetrafluoroethylene as a main component.

3. A nerve injury repair sheet for the spinal cord that contacts a roughened surface containing polytetrafluoroethylene as a main component with a nerve injury site in the spinal cord, causes the roughened surface to be phagocytosed by cells of the in-vivo tissue, expresses mesenchymal stem cells on the roughened surface, induces angiogenesis along the roughened surface, and regenerates nerve cells at the nerve injury site in the spinal cord using the roughened surface as a scaffold, the nerve injury repair sheet for the spinal cord comprising: a first surface that will come into contact with the nerve injury site in the spinal cord and will be phagocytosed by cells of the in-vivo tissue, the first surface including the roughened surface; and a second surface disposed on the opposite side of the first surface, wherein the roughened surface contains polytetrafluoroethylene as a main component.

4. By bringing a roughened surface containing polytetrafluoroethylene as a main component into contact with a brain injury site inside the arachnoid membrane, the roughened surface is phagocytosed by cells of the in-vivo tissue, mesenchymal stem cells are expressed on the roughened surface, capillaries are newly formed along the roughened surface, and a sheet for repairing brain injury that repairs the tissue of the brain injury site using the roughened surface as a scaffold (excluding a sheet applied to the dura mater of the brain, a sheet that wraps cerebral blood vessels, and a sheet that wraps cerebral aneurysms). The sheet comes into contact with the brain injury site and includes a first surface that includes the roughened surface to be phagocytosed by cells of the in-vivo tissue, and a second surface disposed on the opposite side of the first surface. The roughened surface is a sheet for repairing brain injury containing polytetrafluoroethylene as a main component.

5. By bringing a roughened surface containing polytetrafluoroethylene as a main component into contact with a spinal cord injury site inside the arachnoid membrane, the roughened surface is phagocytosed by cells of the in-vivo tissue, mesenchymal stem cells are expressed on the roughened surface, capillaries are newly formed along the roughened surface, and a sheet for repairing spinal cord injury that repairs the tissue of the spinal cord injury site using the roughened surface as a scaffold (excluding a sheet applied to the dura mater of the spinal cord). The sheet comes into contact with the spinal cord injury site and includes a first surface that includes the roughened surface to be phagocytosed by cells of the in-vivo tissue, and a second surface disposed on the opposite side of the first surface. The roughened surface is a sheet for repairing spinal cord injury containing polytetrafluoroethylene as a main component.

6. The sheet for repairing nerve injury according to any one of claims 1 to 3, wherein the roughened surface is constituted by the surface of an ion implantation layer.

7. The sheet for repairing nerve injury according to claim 6, wherein the cells of the in-vivo tissue are configured to infiltrate inside the ion implantation layer.

8. The sheet for repairing nerve injury according to any one of claims 1 to 3, wherein the roughened surface has recesses having a size comparable to the size of the cells that phagocytose the roughened surface.

9. The nerve injury repair sheet according to any one of claims 1 to 3, wherein when the roughened surface is brought into contact with and left in the living tissue, new tissue progresses from the living tissue along the roughened surface, and the new tissue progresses so as to mesh with the irregularities of the roughened surface.

10. The nerve injury repair sheet according to any one of claims 1 to 3, wherein when the roughened surface is brought into contact with and left in the living tissue for 6 months or longer, the opaque polytetrafluoroethylene is configured to become transparent or translucent.

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