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

Abstract

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.SELECTED DRAWING: Figure 10

Description

Technical Field

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

Background Art

[0002] Various materials are used for dura mater reconstruction in neurosurgery. Expanded polytetrafluoroethylene, which is one of the materials for artificial dura mater, is a stable material but has poor biocompatibility. For example, expanded polytetrafluoroethylene has poor adhesiveness to autologous dura mater. Therefore, in the biological repair material described in Patent Document 1, ion beam irradiation is performed on a sheet of expanded polytetrafluoroethylene to improve biocompatibility.

[0003] More specifically, in the biological repair material described in Patent Document 1, a fibrin glue and expanded polytetrafluoroethylene whose at least a part of the surface is modified by ion bombardment by performing ion implantation are combined.

[0004] Applying expanded polytetrafluoroethylene to the defect site of the dura mater has been performed. However, this application is only aimed at filling the defect site of the dura mater (in other words, supplementing the defect site with an artificial object), and it is not assumed to regenerate the biological tissue at the defect site.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to provide a sheet for treating biological tissue regeneration for regenerating biological tissue, a sheet for treating nerve injury, a sheet for treating brain injury, a sheet for treating spinal cord injury, a sheet for treating lung injury, a sheet for treating peritoneal injury, a sheet for treating vascular injury, a culture sheet, and a treatment method for regeneration.

Means for Solving the Problems

[0007] Hereinafter, means for solving the problems will be described using numbers and symbols used in the embodiments for carrying out the invention. These numbers and symbols are added in parentheses for reference to show an example of the correspondence relationship between the description of the claims and the embodiments for carrying out the invention. Therefore, the claims should not be construed in a limiting manner by the description in parentheses.

[0008] The sheet for treating biological tissue regeneration in some embodiments includes a first surface (20) including a roughened surface (20r) that will be phagocytosed by cells of in-vivo 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 sheet for treating biological tissue regeneration, the roughened surface (20r) may be constituted by the surface of the ion implantation layer (2).

[0010] The above sheet for treating biological tissue regeneration may be configured such that the cells of the in-vivo tissue infiltrate into the ion implantation layer (2).

[0011] In the above sheet for treating biological tissue regeneration, the roughened surface (20r) may have a recess (20d) having a size approximately the same as the size of the cells that phagocytose the roughened surface (20r).

[0012] When the roughened surface (20r) of the sheet for treating and regenerating biological tissue is brought into contact with and left in contact with the in-vivo tissue (4), new tissue may progress from the in-vivo tissue (4) along the roughened surface (20r), and the new tissue may progress so as to engage with the irregularities of the roughened surface (20r).

[0013] When the roughened surface (20r) of the sheet for treating and regenerating biological tissue is brought into contact with and left in contact with the damaged in-vivo tissue (4), the expression of at least one of mesenchymal stem cells, fibroblasts, myofibroblasts, macrophages, and oligodendrocytes may be made prominent as compared with the case where the second surface (30) is brought into contact with and left in contact with the damaged in-vivo tissue (4).

[0014] When the roughened surface (20r) of the sheet for treating and regenerating biological tissue is brought into contact with and left in contact with the damaged in-vivo tissue (4), the expression of the mesenchymal stem cells may be made prominent as compared with the case where the second surface (30) is brought into contact with and left in contact with the damaged in-vivo tissue (4).

[0015] When the roughened surface (20r) of the sheet for treating and regenerating biological tissue is brought into contact with and left in contact with the damaged in-vivo tissue (4), capillaries (B) may be formed along the roughened surface (20r).

[0016] When the roughened surface (20r) of the sheet for treating and regenerating biological tissue is brought into contact with and left in contact with the edge (4e) of the in-vivo tissue (4) so as to face the defect region (RG) of the in-vivo tissue (4), a biological membrane (5) and capillaries (B) may be formed along the roughened surface (20r) in the defect region (RG).

[0017] When the roughened surface (20r) of the sheet for treating and regenerating biological tissue is brought into contact with and left in contact with the in-vivo tissue (4) for 6 months or longer, the opaque polytetrafluoroethylene may be made to become transparent or semi-transparent.

[0018] In some embodiments, the sheet for nerve injury repair includes a first surface (20) having a roughened surface (20r) that will 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.

[0019] When the roughened surface (20r) of the above-mentioned sheet for nerve injury repair is placed opposite to the nerve injury site (RG1) of the in-vivo tissue (4), the sheet may be configured such that nerve cells are regenerated using the roughened surface (20r) as a scaffold.

[0020] In some embodiments, the sheet for brain injury repair includes a first surface (20) having a roughened surface (20r) that will 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.

[0021] In some embodiments, the sheet for spinal cord injury repair includes a first surface (20) having a roughened surface (20r) that will 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.

[0022] In some embodiments, the sheet for lung injury repair includes a first surface (20) having a roughened surface (20r) that will 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.

[0023] In some embodiments, the sheet for peritoneal injury repair includes a first surface (20) having a roughened surface (20r) that will 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) mainly contains polytetrafluoroethylene.

[0024] In some embodiments, the sheet for vascular injury repair includes a first surface (20) having a roughened surface (20r) that will 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) mainly contains polytetrafluoroethylene.

[0025] In some embodiments, the culture sheet includes a first surface (20) having a roughened surface (20r) on which cells (C) to be cultured or a biological tissue containing the cells (C) are disposed, and a second surface (30) disposed on the opposite side of the first surface (20). The roughened surface (20r) mainly contains polytetrafluoroethylene.

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

Advantages of the Invention

[0027] According to the present invention, it is possible to provide a sheet for regenerative treatment of biological tissues for regenerating biological tissues, a sheet for nerve injury repair, a sheet for brain injury repair, a sheet for spinal cord injury repair, a sheet for lung injury repair, a sheet for peritoneal injury repair, a sheet for vascular injury repair, a culture sheet, and a regenerative treatment method.

Brief Description of the Drawings

[0028]

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MODE FOR CARRYING OUT THE INVENTION

[0029] Hereinafter, with reference to the drawings, the biological tissue regeneration treatment sheet, nerve injury repair sheet, brain injury 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 the embodiment will be described. In the following description, members and parts having the same function are denoted by the same reference numerals, and repeated description of the members and parts denoted by the same reference numerals is omitted.

[0030] (First Embodiment) Referring to FIGS. 1 to 30, the biological tissue regeneration treatment sheet 1A in the first embodiment will be described. FIG. 1 is a diagram schematically showing a part of the biological tissue regeneration treatment sheet 1A in the first embodiment. FIG. 2 is a schematic perspective view schematically showing the biological tissue regeneration treatment sheet 1A in the first embodiment. FIG. 3 is a schematic cross-sectional view showing a part of the biological tissue regeneration treatment sheet 1A in the first embodiment in an enlarged manner. FIG. 4 is a photographic substitute for a drawing showing the state where the head of a rat is incised. FIG. 5 is a photographic substitute for a drawing showing the state where the head of a rat is craniotomized. FIG. 6 is a photographic substitute for a drawing showing the state where the biological tissue regeneration treatment sheet 1A in the first embodiment is placed so as to cover the craniotomy site. FIG. 7 is a photographic substitute for a drawing showing the state where the biological tissue regeneration treatment sheet 1A is covered with autologous bone and bone wax. FIG. 8 is a photographic substitute for a drawing showing the state where the biological tissue regeneration treatment sheet 1A in the first embodiment is semi-translucent and a pale yellow transparent biological membrane is formed around the biological tissue regeneration treatment sheet 1A. FIG. 9 is a photographic substitute for a drawing showing the state where the biological tissue regeneration treatment sheet 1A in the first embodiment is placed so as to close the opening 40a of the peritoneum 40. FIG. 10 is a photographic substitute for a drawing showing the state where a semi-transparent biological membrane 5 is formed along the biological tissue regeneration treatment sheet 1A in the first embodiment and capillaries B are newly formed inside the biological membrane 5. FIG. 11 is a photographic substitute for a drawing showing the state where the biological membrane 5 is newly formed so as to mesh with the roughened surface 20r of the biological tissue regeneration treatment sheet 1A. FIG. 12 is a photographic substitute for a drawing showing the phagocytosis image 6 of ePTFE. FIG. 13 is an electron micrograph of the roughened surface side of the biological tissue regeneration treatment sheet 1A. FIG. 14 is a photographic substitute for a drawing showing the 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 photographic substitute for a drawing showing the object to be cultured. FIG. 16 is a microscopic photograph of the state of the cells cultured in the MSC medium after 0 days. FIG. 17 is a microscopic photograph of the state of the cells cultured in the MSC medium after 2 days. FIG. 18 is a microscopic photograph of the state of the cells cultured in the MSC medium after 7 days. FIG. 19 is a microscopic photograph of the staining of each marker. FIGS. 20 and 21 are photographic substitutes for drawings showing the results of scRNA-seq analysis.FIG. 22 is a schematic cross-sectional view schematically showing a state in which the biological tissue regeneration treatment sheet 1A in the first embodiment is placed in the in-vivo tissue 4. FIG. 23 is a schematic cross-sectional view schematically showing a state in which the biological membrane 5 is newly formed 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 schematically showing a state in which the biological tissue regeneration treatment sheet 1A in the first embodiment is placed at the brain injury site. FIG. 25 is a schematic cross-sectional view schematically showing a state in which the biological tissue regeneration treatment sheet 1A in the first embodiment is placed at the spinal cord injury site. FIGS. 26 and 27 are schematic cross-sectional views schematically showing a state in which the biological tissue regeneration treatment sheet 1A in the first embodiment is placed at the damaged site of the lung structure 45. FIGS. 28 and 29 are schematic cross-sectional views schematically showing a state in which the biological tissue regeneration treatment sheet 1A in the first embodiment is placed at the damaged site of the blood vessel 91. FIG. 30 is a schematic cross-sectional view schematically showing a state in which the cells C are cultured using the culture sheet 1H.

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

[0032] As illustrated in FIG. 2, the first surface 20 includes a roughened surface 20r. In the example described 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 "roughened surface" means a surface 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 (equivalent international standard ISO 4287:1997, Amd.1:2009).

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

[0034] The entire sheet 1A for treating and regenerating biological tissues may contain polytetrafluoroethylene as a main component. In other words, the proportion of polytetrafluoroethylene in the entire material constituting the sheet 1A for treating and regenerating biological tissues may be 50% by weight or more. The proportion of polytetrafluoroethylene constituting the sheet 1A for treating and regenerating biological tissues in the entire material constituting the sheet 1A for treating and regenerating biological tissues may be 70% by weight or more, 90% by weight or more, 95% by weight or more, or 99% by weight or more. Alternatively, the sheet 1A for treating and regenerating biological tissues may be a laminate of a layer made of polytetrafluoroethylene and a layer made of another material. In this case, it is sufficient that the main component of at least the material constituting the roughened surface 20r is polytetrafluoroethylene.

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

[0036] The sheet 1A for treating biological tissue regeneration in the first embodiment has the property that polytetrafluoroethylene subjected to roughening treatment is phagocytosed by cells of in-vivo tissue. Even when polytetrafluoroethylene is brought into contact with in-vivo tissue, usually, the polytetrafluoroethylene is not phagocytosed by cells of the in-vivo tissue. In contrast, in the first embodiment, cells of in-vivo tissue are configured to phagocytose a roughened surface 20r containing polytetrafluoroethylene as a main component. Also, with the roughened surface 20r as a scaffold, the regeneration of biological tissue proceeds. Note that phagocytosis means the action of cells of in-vivo tissue taking in unnecessary substances.

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

[0038] (Optional additional configuration) Subsequently, in the sheet 1A for treating biological tissue regeneration in the first embodiment, an optional additional configuration that can be adopted will be described.

[0039] (Ion implantation layer 2) As illustrated in FIG. 3, the roughened surface 20r may be constituted by the surface of the ion implantation layer 2. In this specification, the "ion implantation layer 2" means a layer whose physical and / or chemical properties are modified by injecting ionized elements. In the example shown in FIG. 3, the ion implantation layer 2 has a plurality of fine recesses 20d on its surface by ion implantation. Also, the ion implantation layer 2 is a layer in which elements injected by ion implantation are mixed as impurities in polytetrafluoroethylene. Note that a part of the ion-injected elements may escape from the ion implantation layer 2.

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

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

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

[0043] (Adhesion between the roughened surface 20r and the in-vivo tissue) The adhesion between the roughened surface 20r (more specifically, the ion implantation layer 2) and the in-vivo tissue may be achieved via an adhesive such as fibrin glue, or may be achieved without an adhesive. In other words, an adhesive may or may not be applied to the roughened surface 20r. From the perspective of filling the gap between the roughened surface 20r and the in-vivo tissue with newly generated cells, it is preferable that no adhesive is applied to the roughened surface 20r.

[0044] (The second surface 30) The second surface 30 may contain polytetrafluoroethylene as a main component. In other words, the proportion of polytetrafluoroethylene that constitutes the second surface 30 in the entire material that constitutes the second surface 30 may be 50 weight percent or more. The proportion of polytetrafluoroethylene that constitutes the second surface 30 in the entire material that constitutes 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 the in-vivo tissue is prevented or suppressed. When the second surface 30 is a non-roughened surface, the second surface 30 is not the ion implantation layer 2.

[0046] (The film thickness of the sheet for in-vivo tissue regeneration therapy) The film thickness of the sheet 1A for in-vivo tissue regeneration therapy is, for example, 50 μm or more and 500 μm or less, 50 μm or more and 300 μm or less, 50 μm or more and 200 μm or less, or 50 μm or more and 150 μm or less. When the film thickness is sufficiently thin, it is easy to place the sheet 1A for in-vivo tissue regeneration therapy along the outer shape of the in-vivo tissue.

[0047] (The sheets for in-vivo tissue regeneration therapy used in Experiments 1 to 3) Experiments 1 to 3 were conducted using a bio - tissue regeneration therapy sheet 1A having a roughened surface 20r formed by ion - implanting 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 bio - tissue regeneration therapy sheet 1A was 99 weight percent or more, and the ratio of polytetrafluoroethylene to the entire material constituting the bio - tissue regeneration therapy sheet 1A was 99 weight percent or more. Also, the film thickness of the bio - tissue regeneration therapy sheet 1A was 300 μm. Further, the acceleration voltage of the argon ions (Ar+) was 150 keV, and the implantation amount of the argon ions (Ar+) into the bio - tissue regeneration therapy sheet 1A was 1×10 14 ions / cm 2 was.

[0048] (Experiment 1) After subjecting a Wistar rat (8 - week - old male) to inhalation anesthesia, a median incision of about 2 cm was made (Figure 4), a circular craniotomy of about 8 mm in diameter was performed in the right region of the incision site (Figure 5), and the trimmed bio - tissue regeneration therapy sheet 1A was placed to cover the craniotomy site (Figure 6). Note that the bio - tissue regeneration therapy sheet 1A was placed such 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. Then, the roughened surface 20r was covered with autologous bone and bone wax (Figure 7), and the wound was closed.

[0049] In the rat sacrificed 4.5 months after placement, the bio - tissue regeneration therapy sheet 1A was semi - transparent, and a pale - yellow transparent bio - membrane was formed around the bio - tissue regeneration therapy sheet 1A (Figure 8).

[0050] The formation of a pale - yellow transparent bio - membrane along the roughened surface 20r facing the outside of the head was an unexpected result. Also, the semi - transparency of the bio - tissue regeneration therapy sheet 1A was an unexpected result (that is, it was unexpected that ePTFE, an opaque material, would become semi - transparent due to in - vivo placement).

[0051] (Experiment 2) After subjecting a mouse (C57BL, 8 weeks old, male) to inhalation anesthesia, an opening 40a was formed in the peritoneum 40, and a bio-tissue regeneration therapy sheet 1A measuring approximately 1 cm square was placed so as to close the opening 40a (FIG. 9). Note that the bio-tissue regeneration therapy sheet 1A was placed such 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 bio-tissue regeneration therapy sheet 1A and the peritoneum 40 were sutured and fixed at two locations, and then the wound was closed. The mouse was sacrificed 6 weeks after the placement, and histological examination was performed. A translucent bio-membrane 5 was formed on the surface of the roughened surface 20r side of the bio-tissue regeneration therapy sheet 1A, and obvious neovascularization of capillaries B was observed inside the bio-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 bio-membrane 5 on the roughened surface 20r side (in other words, the ion implantation layer 2 side) of the bio-tissue regeneration therapy sheet 1A, and a phagocytosis image 6 of ePTFE was also observed in part (FIG. 12). As can be understood from FIG. 11, in the bio-tissue regeneration therapy sheet 1A, new tissue (more specifically, the newly formed bio-membrane 5) advanced along the roughened surface 20r, and the new tissue (more specifically, the newly formed bio-membrane 5) was formed so as to mesh with the unevenness of the roughened surface 20r. In addition, continuous infiltration of cells 7 from the roughened surface 20r to the inside of the bio-tissue regeneration therapy sheet 1A (more specifically, infiltration of cells into the ion implantation layer 2) was observed (FIG. 12). When the roughened surface side (in other words, the ion implantation layer side) of the bio-tissue regeneration therapy sheet 1A was observed using a scanning electron microscope, a large number of fibroblast-like cells and macrophage-like cells were observed on the surface of the bio-tissue regeneration therapy sheet 1A (FIG. 13). On the other hand, regarding the bio-membrane 5' formed on the second surface 30 (more specifically, the non-roughened surface) side of the bio-tissue regeneration therapy sheet 1A, infiltration of cells into the bio-tissue regeneration therapy sheet 1A, a phagocytosis image 6 of ePTFE, etc. were not observed (FIG. 14).

[0052] (Experiment 3: Cultivation of Bio-Membrane) The biological tissue regeneration therapy sheet 1A and the biological membrane generated in a state of being bound to the biological tissue regeneration therapy sheet 1A were taken out from a rat, fragmented, and the biological membrane side was attached to a 6-well plate (Fig. 15). Into these wells, a medium for iPS cells (Stemflex medium (Thermo Fisher) + penicillin streptomycin + Zell shield (Funakoshi): upper left in Fig. 15), a medium for mesenchymal stem cells (Mesenchymal stem cell, hereinafter referred to as "MSC") (low glucose DMEM + hyclone FBS + kanamycin: upper center in Fig. 15), a medium for glioma cells (high glucose DMEM + Corning FBS + penicillin streptomycin: upper right in Fig. 15), and a medium for fibroblasts (low glucose DMEM + penicillin streptomycin: lower left in Fig. 15) were put, and primary culture was performed. Regarding the medium for fibroblasts, those obtained by treating the biological tissue regeneration therapy sheet 1A with Trypsin (lower center in Fig. 15) and those with only the biological membrane attached (lower right in Fig. 15) were also cultured. Among these, cell growth was observed only in the medium for MSC (Fig. 16: after 0 days, Fig. 17: after 2 days, Fig. 18: after 7 days). Immunostaining of the cells was performed to estimate the proliferated cell types.

[0053] (Immunostaining of cells) Since cell growth was observed in the medium for MSC, staining was performed mainly with MSC markers (Fig. 19). CD29 and CD105, which are MSC markers, were positive, but CD90, which is an MSC marker, was negative. SOX2, a neural stem cell marker, was positive, while nestin, a neural stem cell marker, was negative. Also, GFAP, an astrocyte marker, and MAP2, a neuron marker, were negative. None of the markers were stained in all cells, and it was considered that multiple cell types were mixed. Therefore, next, single-cell RNA sequencing (scRNA-seq) analysis was performed to identify cell types.

[0054] (scRNA-seq analysis) To identify the types of cells grown from the biological membrane formed by binding to the biological tissue regeneration therapy sheet 1A, scRNA-seq analysis was performed. More specifically, after leaving the biological tissue regeneration therapy sheet 1A in rats for 8 months, the biological tissue regeneration therapy sheet 1A and the biological membrane formed by binding to the biological tissue regeneration therapy sheet 1A were taken out from the rats, cultured in a medium for MSCs, and the cell suspension was submitted as a sample to a company that undertakes scRNA-seq. As a result of analyzing the genes expressed in each cell, it was possible to divide them 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 fibroblasts, MSCs, macrophages, myofibroblasts, and oligodendrocytes were present as the breakdown of the grown cell types (Figure 21).

[0055] (Summary of experimental results and analysis results) From the results of Experiment 1 and Experiment 2, the formation of a biological membrane accompanied by angiogenesis was confirmed on the surface of the roughened surface 20r side of the biological tissue regeneration therapy sheet 1A (more specifically, the surface on the side of the ion implantation layer 2). In addition, from the results of Experiment 1 and Experiment 2, the transparency of the biological tissue regeneration therapy sheet 1A was confirmed.

[0056] As a result of Experiment 2, when the biological tissue regeneration therapy sheet 1A was left in the peritoneal cavity of mice for a long time, multinucleated cells were observed on the surface of the roughened surface 20r side (more specifically, on the surface of the ion implantation layer 2 side). In addition, as a result of Experiment 2, cell infiltration into the ion implantation layer 2 and an etching image of polytetrafluoroethylene constituting the ion implantation layer 2 were observed.

[0057] From the results of Experiment 3, cell growth was observed in the culture performed using the sheet 1A for living tissue regeneration treatment and the medium for MSCs. In addition, positive staining for stem cell markers (in other words, expression of stem cells) was observed by immunostaining of the cells. From the results of single cell RNA sequence analysis, it was confirmed that the cultured cells contained fibroblasts, MSCs, macrophages, myofibroblasts, and oligodendrocytes.

[0058] From these results, it was confirmed that the sheet 1A for living tissue regeneration treatment has biocompatibility, and it was suggested that tissue repair may be performed using the sheet 1A for living tissue regeneration treatment as a scaffold (in other words, the sheet 1A for living tissue regeneration treatment used in the experiment has the potential as a medical device for regenerative medicine).

[0059] (Characteristic 1 of the sheet 1A for living tissue regeneration treatment) From the results of Experiment 3 and the results of scRNA-seq analysis, it can be said that the sheet 1A for living tissue regeneration treatment has the characteristic (hereinafter referred to as "Characteristic 1") that "when the roughened surface 20r is brought into contact with and left on the damaged in-vivo tissue, the expression of at least one of mesenchymal stem cells, fibroblasts, myofibroblasts, macrophages, and oligodendrocytes on the surface of the sheet for living tissue regeneration treatment becomes prominent as compared with the case where the second surface 30 is brought into contact with and left on the damaged in-vivo tissue".

[0060] In addition, from the results of Experiment 3 and the results of scRNA-seq analysis, it can be said that the sheet 1A for living tissue regeneration treatment has the characteristic that "when the roughened surface 20r is brought into contact with and left on the damaged in-vivo tissue, the expression of mesenchymal stem cells on the surface of the sheet for living tissue regeneration treatment becomes prominent as compared with the case where the second surface 30 is brought into contact with and left on the damaged in-vivo tissue".

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

[0062] (Characteristics 2 of the Sheet 1A for Regenerative Therapy of Living Tissue) From the results of Experiment 2 (see Fig. 10), it can be said that the sheet 1A for regenerative therapy of living tissue has the characteristic that "when the roughened surface 20r comes into contact with and is placed on the damaged in-vivo tissue, capillaries B are newly formed along the roughened surface 20r" (hereinafter referred to as "Characteristic 2").

[0063] (Characteristics 3 of the Sheet 1A for Regenerative Therapy of Living Tissue) As illustrated in Fig. 22, when the roughened surface 20r of the sheet 1A for regenerative therapy of living tissue comes into contact with and is placed on 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, the sheet 1A has the characteristic that "in the defect region RG, a biological membrane 5 and capillaries B are newly formed along the roughened surface 20r" (hereinafter referred to as "Characteristic 3") (see Fig. 23). The Characteristic 3 is a characteristic based on the event found by Experiment 2.

[0064] Since the sheet 1A for regenerative therapy of living tissue has Characteristic 2 or Characteristic 3, it can be said that the sheet 1A for regenerative therapy of living tissue is useful as a medical device for regenerative medicine. When the sheet 1A for regenerative therapy of living tissue has Characteristic 2, nutrients and the like are supplied to the biological membrane 5 newly formed via the capillaries B. Therefore, the biological membrane 5 is newly formed rapidly. Also, when the sheet 1A for regenerative therapy of living tissue has Characteristic 3, the defect region RG of the in-vivo tissue 4 is rapidly blocked by the biological membrane 5.

[0065] As illustrated in Fig. 22 and Fig. 23, the sheet 1A for regenerative therapy of living tissue may have the characteristic that "when the roughened surface 20r comes into contact with the in-vivo tissue 4, new tissue progresses from the in-vivo tissue 4 along the roughened surface 20r, and the new tissue progresses so as to mesh with the unevenness of the roughened surface 20r".

[0066] (Characteristics 4 of the Sheet 1A for Regenerative Therapy of Living Tissue) As illustrated in FIGS. 22 and 23, the sheet 1A for treating and regenerating living tissue may have the property that "when the roughened surface 20r is brought into contact with and left in the living tissue 4 in vivo, substantially all of the gaps between the living tissue 4 and the roughened surface 20r are filled with the newly formed tissue" (hereinafter referred to as "Property 4"). When the sheet 1A for treating and regenerating living tissue has Property 4, the living tissue 4 and the roughened surface 20r are firmly bonded. Also, it is difficult for body fluids and the like to leak from the gap between the living tissue 4 and the roughened surface 20r.

[0067] (Property 5 of the sheet 1A for treating and regenerating living tissue) From the results of Experiment 2 (see FIG. 12), it can be said that the sheet 1A for treating and regenerating living tissue has the property that "cells of the living tissue in vivo infiltrate into the ion implantation layer 2" (hereinafter referred to as "Property 5").

[0068] As illustrated in FIG. 12, the sheet 1A for treating and regenerating living tissue may be configured such that cells of the living tissue in vivo infiltrate into the recesses of the roughened surface 20r. Also, the sheet 1A for treating and regenerating living tissue may be configured such that cells infiltrate into the structure composed of polytetrafluoroethylene and the ion-implanted element.

[0069] (Property 6 of the sheet 1A for treating and regenerating living tissue) From the results of Experiment 2 (see FIG. 8 for example), it can be said that the sheet 1A for treating and regenerating living tissue has the property that "when the roughened surface 20r is brought into contact with and left in the living tissue (for example, a membrane tissue in vivo) for 6 months or more, the opaque polytetrafluoroethylene constituting the roughened surface 20r of the sheet 1A for treating and regenerating living tissue becomes transparent or semi-transparent" (hereinafter referred to as "Property 6").

[0070] The mechanism of the transparency or semi-transparency of polytetrafluoroethylene is unknown. However, it is presumed that any of the living tissue 4, the newly formed biological membrane 5, and the cells constituting them are involved in the transparency or semi-transparency of polytetrafluoroethylene.

[0071] When polytetrafluoroethylene is made transparent or translucent, 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] (Sheet 1B for nerve injury repair) The biological tissue regeneration treatment sheet 1A in the above-described first embodiment can be used as a sheet 1B for nerve injury repair. 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 "sheet 1B for nerve injury repair".

[0073] As illustrated in FIG. 24 or FIG. 25, the nerve injury repair sheet 1B includes: (1) a first surface 20 including a roughened surface 20r that will be phagocytosed by cells of the 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. Since the roughened surface 20r, the first surface 20, and the second surface 30 have been described, repetitive descriptions of these configurations are omitted.

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

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

[0076] (Sheet 1C for brain injury repair) The nerve injury repair sheet 1B in the above-described first embodiment can be used as a brain injury repair sheet 1C by applying it to the brain injury site. In other words, in the description of the biological tissue regeneration treatment sheet 1A (or the nerve injury repair sheet 1B) in the first embodiment, it is possible to replace "biological tissue regeneration treatment sheet 1A" (or "nerve injury repair sheet 1B") with "brain injury repair sheet 1C".

[0077] The brain injury repair sheet 1C having the above-described characteristics 1 to 6 functions as a scaffold for tissue regeneration at the brain injury site. For example, as illustrated in FIG. 24, when the roughened surface 20r is placed opposite to the brain injury site RG2 of the in-vivo tissue 4, a biological membrane 5 and capillaries B are newly formed along the roughened surface 20r facing the brain injury site RG2. In FIG. 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.

[0078] 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.

[0079] (Spinal cord injury repair sheet 1D) The nerve injury repair sheet 1B in the above-described first embodiment can be used as a spinal cord injury repair sheet 1D by applying it to the spinal cord injury site. In other words, in the description of the biological tissue regeneration treatment sheet 1A (or the nerve injury repair sheet 1B) in the first embodiment, it is possible to replace "biological tissue regeneration treatment sheet 1A" (or "nerve injury repair sheet 1B") with "spinal cord injury repair sheet 1D".

[0080] The spinal cord injury repair sheet 1D having the above characteristics 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 opposite to 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 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 the arachnoid mater 83.

[0081] 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.

[0082] (Sheet 1E for lung injury repair) The biological tissue regeneration treatment sheet 1A in the above-described first embodiment can be used as a sheet 1E for lung injury repair. 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 "sheet 1E for lung injury repair".

[0083] As illustrated in FIG. 26 or FIG. 27, the lung injury repair sheet 1E includes (1) a first surface 20 including a roughened surface 20r that will be phagocytosed by cells of the in-vivo tissue, and (2) a second surface 30 disposed on the opposite side of the first surface 20. The roughened surface 20r mainly contains polytetrafluoroethylene. Since the roughened surface 20r, the first surface 20, and the second surface 30 have been described, repeated descriptions of these configurations are omitted.

[0084] The lung injury repair sheet 1E having the above characteristics 1 to 6 functions as a scaffold for tissue regeneration at the lung injury site. For example, as illustrated in FIG. 26 or FIG. 27, when the roughened surface 20r is brought into contact with and placed on 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 (more specifically, the opening) of the lung structure 45, in the defective region RG4, a biological membrane 5 and capillaries B are regenerated along the roughened surface 20r.

[0085] In addition, 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, there is a defective region RG4 (more specifically, an opening) in the visceral pleura 450. Further, the lung injury repair sheet 1E is attached to the visceral pleura 450 so as to cover the defective region 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, 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 lung injury repair sheet 1E 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 the newly formed tissue. Therefore, air leakage from the gap between the in-vivo tissue 4 and the roughened surface 20r is prevented. Further, in the example shown in FIG. 26 or FIG. 27, the biological membrane 5 and the capillaries B are configured to develop so as to span the defective region RG4 with the roughened surface 20r as a scaffold. In this case, the defective region RG4 of the lung structure 45 is blocked by the biological membrane 5. Therefore, the lung injury is preferably repaired.

[0087] (Peritoneal injury repair sheet 1F) The biological tissue regeneration therapy sheet 1A in the above-described first embodiment can be used as a peritoneal injury repair sheet 1F. In other words, in the description of the biological tissue regeneration therapy sheet 1A in the first embodiment, "biological tissue regeneration therapy sheet 1A" can be read as "peritoneal injury repair sheet 1F".

[0088] The peritoneal injury repair sheet 1F includes: (1) a first surface 20 including a roughened surface 20r that will be phagocytosed by cells of in-vivo tissues; and (2) a second surface 30 disposed on the opposite side of the first surface 20. The roughened surface 20r mainly contains polytetrafluoroethylene. Since the roughened surface 20r, the first surface 20, and the second surface 30 have been described, repeated descriptions of these configurations are omitted.

[0089] The peritoneal injury repair sheet 1F having the above-described characteristics 1 to 6 functions as a scaffold for tissue regeneration at the peritoneal injury site. For example, as illustrated in FIG. 9, when the roughened surface 20r is brought into contact with and left on the peritoneum 40 (more specifically, the edge defining the opening 40a of the peritoneum 40) so that the roughened surface 20r faces the defect region (more specifically, the opening 40a) of the peritoneum 40, in the defect region, a biological membrane 5 and capillaries B are newly formed along the roughened surface 20r.

[0090] When the peritoneal injury repair sheet 1F has the above-described characteristic 4, substantially all of the gap between the peritoneum 40 and the roughened surface 20r is filled with newly formed tissue. Therefore, leakage of body fluid or gas from the gap between the peritoneum 40 and the roughened surface 20r is prevented. Also, in the example shown in FIG. 10, the biological membrane 5 and capillaries B are configured to develop so as to span the defect region (see the opening 40a in FIG. 9) with the roughened surface 20r as a scaffold. In this case, the defect region (more specifically, the opening 40a) of the peritoneum 40 is blocked by the biological membrane 5. Therefore, the peritoneal injury is preferably repaired.

[0091] (Vascular injury repair sheet 1G) The biological tissue regeneration treatment sheet 1A in the above-described first embodiment can be used as a blood vessel injury repair sheet 1G. 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 "blood vessel injury repair sheet 1G".

[0092] As illustrated in FIG. 28 or FIG. 29, the blood vessel injury repair sheet 1G includes: (1) a first surface 20 including a roughened surface 20r that will be phagocytosed by cells of the 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. Since the roughened surface 20r, the first surface 20, and the second surface 30 have been described, repetitive descriptions of these configurations are omitted.

[0093] The blood vessel injury repair sheet 1G having the above-described characteristics 1 to 6 functions as a scaffold for tissue regeneration at the blood vessel injury site. For example, as illustrated in FIG. 28 or FIG. 29, when the roughened surface 20r is brought into contact with and left on 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 newly formed along the roughened surface 20r in the damaged region RG5 (more specifically, at the opening 91a of the blood vessel 91).

[0094] In the example described in FIG. 28 or FIG. 29, the blood vessel injury repair sheet 1G 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 blood vessel injury repair sheet 1G may be configured to be attached to the outside of the blood vessel 91, or as illustrated in FIG. 29, it may be configured to be attached to the inside of the blood vessel 91.

[0095] When the sheet 1G for vascular injury repair has the above-described characteristic 4, substantially all of the gap between the blood vessel 91 and the roughened surface 20r is filled with new tissue. Thus, blood leakage from the gap between the blood vessel 91 and the roughened surface 20r is prevented. Also, in the example shown in FIG. 28 or FIG. 29, the living tissue membrane 5 and the capillary B are configured to develop so as to span the damaged region RG5 (more specifically, the opening 91a) of the blood vessel 91 with 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 living tissue membrane 5. Thus, the vascular injury is preferably repaired.

[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 FIG. 30, the culture sheet 1H in the first embodiment includes (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 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-described cells C. Since the roughened surface 20r, the first surface 20, and the second surface 30 have been described, repeated descriptions of these configurations are omitted.

[0098] When the culture sheet 1H is arranged in contact with the roughened surface 20r with the cell C to be cultured or the biological tissue containing the cell C, compared with the case where the cell C to be cultured or the biological tissue containing the cell C is arranged in contact with the second surface 30, at least one of mesenchymal stem cells, fibroblasts, myofibroblasts, macrophages, and oligodendrocytes on the surface of the culture sheet 1H may have a prominent expression. Note that the cells and the like to be expressed depend on the type of the cell C to be cultured.

[0099] The culture sheet 1H may have a property that the above-described cell C infiltrates into the ion implantation layer 2. The culture sheet 1H may be configured such that the above-described cell C infiltrates into the recesses of the roughened surface 20r. Further, the culture sheet H may be configured such that the above-described cell C infiltrates into the structure composed of polytetrafluoroethylene and the ion-implanted element.

[0100] (Second Embodiment) With reference to FIGS. 1 to 31, a regenerative therapy method in the second embodiment will be described. FIG. 31 is a flowchart showing an example of the regenerative therapy method in the second embodiment.

[0101] As illustrated in FIG. 2, in the first step ST1, a biological tissue regeneration therapy sheet 1A is prepared. The first step ST1 is a preparation step.

[0102] The biological tissue regeneration therapy sheet 1A prepared in the preparation step (the first step ST1) has a first surface 20 that is at least partially 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.

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

[0104] The preparation process (the first step ST1) may include applying a heat treatment to the biological tissue regeneration treatment sheet 1A into which ions have been implanted. By ion implantation and heat treatment, the regularity of the polymerization structure of polytetrafluoroethylene is relaxed. Due to the relaxation of the regularity, in the regeneration process described later, polytetrafluoroethylene may be more likely to be made transparent or translucent. In this heat treatment, the biological tissue regeneration treatment sheet 1A may be placed in a heating atmosphere of 100 degrees Celsius or higher.

[0105] Since the biological tissue regeneration treatment sheet 1A has been described in the first embodiment, repeated description of the biological tissue regeneration treatment sheet 1A is omitted.

[0106] As illustrated in FIG. 6 or FIG. 9, in the second step ST2, the biological tissue regeneration treatment sheet 1A is placed in the in-vivo tissue. The second step ST2 is a placement process.

[0107] In the placement process (the second step ST2), the biological tissue regeneration treatment sheet 1A is placed in the in-vivo tissue such that the roughened surface 20r contacts the damaged in-vivo tissue. The in-vivo tissue 4 in which the biological tissue regeneration treatment sheet 1A is placed is, for example, the brain, spinal cord, lung structure, peritoneum, blood vessel. The in-vivo 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.

[0108] As illustrated in FIG. 22, the placement step (second step ST2) may include placing and contacting the roughened surface 20r against the living tissue 4 (more specifically, the edge 4e defining the defect region RG), such that the roughened surface 20r faces the defect region RG (e.g., the opening) of the living tissue 4.

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

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

[0111] 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 contain at least one of mesenchymal stem cells, fibroblasts, myofibroblasts, macrophages, and oligodendrocytes. Alternatively, or additionally, the biological membrane 5 may contain capillaries B.

[0112] When the above-described placement step (second step ST2) includes placing the roughened surface 20r opposite to the defect region RG of the living tissue 4, the regeneration step (third step ST3) may include generating the 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 the biological membrane 5 such that the defect region RG is blocked by the biological membrane 5.

[0113] The regeneration process (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 process (third step ST3) may also include infiltrating cells of the in-vivo tissue into the interior of the ion implantation layer 2. The regeneration process (third step ST3) may include infiltrating cells of the in-vivo tissue into the recesses of the roughened surface 20r. The regeneration process (third step ST3) may also include infiltrating cells into the interior of a structure composed of polytetrafluoroethylene and the ion-implanted element.

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

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

[0116] The regeneration process (third step ST3) may include repairing lung damage, peritoneal damage, or vascular damage by regenerating the tissue at the damaged site of the in-vivo tissue using the roughened surface 20r as a scaffold. The regeneration process (third step ST3) may include regenerating the biological membrane 5 at the opening of the lung structure, the opening of the peritoneum, or the opening of the blood vessel by regenerating the tissue at the 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-described embodiments or each modification example, and it is obvious that each embodiment or each modification example can be appropriately modified or changed within the scope of the technical idea of the present invention. Also, various techniques used in each embodiment or each modification example are applicable to other embodiments or other modification examples as long as no technical contradiction occurs. Furthermore, any additional configuration in each embodiment or each modification example can be appropriately omitted.

[0118] The sheet for treating biological tissue regeneration, the sheet for repairing nerve injury, the sheet for repairing brain injury, the sheet for repairing spinal cord injury, the sheet for repairing lung injury, the sheet for repairing peritoneal injury, or the sheet for repairing vascular injury in the embodiment may be applied to human in-vivo tissues or in-vivo tissues of animals other than humans.

Description of Reference Numerals

[0119] 1A: Sheet for treating biological tissue regeneration 1B: Sheet for repairing nerve injury 1C: Sheet for repairing brain injury 1D: Sheet for repairing spinal cord injury 1E: Sheet for repairing lung injury 1F: Sheet for repairing peritoneal injury 1G: Sheet for repairing vascular injury 1H: Culture sheet 2: Ion implantation layer 4: In-vivo tissue 4e: Edge 5: Biological membrane 5': Biological membrane 6: Phagocytosis image 7: Infiltration of cells 20: First surface 20d: Dimple 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: Spider web membrane 84: Soft membrane 91: Blood vessel 91a: Opening 95e: Edge 450: Visceral pleura B: Capillary C: Cell H: Culture sheet RG: Defective area RG1: Nerve injury site RG2: Brain injury site RG3: Spinal cord injury site RG4: Defective area RG5: Damaged area

Claims

1. A first surface including a roughened surface to be phagocytosed by cells of a living tissue, a second surface disposed on the opposite side of the first surface, and comprising, wherein the roughened surface contains polytetrafluoroethylene as a main component, a sheet for treating and regenerating living tissue.

2. The roughened surface is constituted by the surface of an ion implantation layer, The sheet for treating and regenerating living tissue according to Claim 1.

3. The interior of the ion implantation layer is configured such that the cells of the living tissue infiltrate therein, The sheet for treating and regenerating living tissue according to Claim 2.

4. The roughened surface has recesses of a size similar to the size of the cells that phagocytose the roughened surface, The sheet for treating and regenerating living tissue according to Claim 1.

5. When the roughened surface is brought into contact with and left on 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, The sheet for treating and regenerating living tissue according to Claim 1.

6. When the roughened surface is brought into contact with and left on the damaged living tissue, the expression of at least one of mesenchymal stem cells, fibroblasts, myofibroblasts, macrophages, and oligodendrocytes becomes prominent as compared with the case where the second surface is brought into contact with and left on the damaged living tissue, The sheet for treating and regenerating living tissue according to Claim 1.

7. When the roughened surface is brought into contact with and left on the damaged living tissue, the expression of the mesenchymal stem cells becomes prominent as compared with the case where the second surface is brought into contact with and left on the damaged living tissue, The sheet for treating and regenerating living tissue according to Claim 6.

8. When the roughened surface is brought into contact with and left on the damaged living tissue, capillaries are formed to be new along the roughened surface, The sheet for treating and regenerating living tissue according to Claim 1.

9. When the roughened surface is brought into contact with and left on the edge of the living tissue so that the roughened surface faces the defect region of the living tissue, a biological membrane and capillaries are formed to be new along the roughened surface in the defect region, The sheet for treating and regenerating living tissue according to Claim 1.

10. When the roughened surface is brought into contact with and left on the living tissue for 6 months or more, the opaque polytetrafluoroethylene is configured to become transparent or semi-transparent. The sheet for treating biological tissue regeneration according to any one of claims 1 to 9.

11. A first surface including a roughened surface that will be phagocytosed by cells of the in-vivo tissue, A second surface disposed on the opposite side of the first surface Comprising, The roughened surface contains polytetrafluoroethylene as a main component Sheet for nerve injury repair.

12. When the roughened surface is placed opposite to the nerve injury site of the in-vivo tissue, it is configured such that nerve cells are regenerated using the roughened surface as a scaffold The sheet for nerve injury repair according to claim 11.

13. A first surface including a roughened surface that will be phagocytosed by cells of the in-vivo tissue, A second surface disposed on the opposite side of the first surface Comprising, The roughened surface contains polytetrafluoroethylene as a main component Sheet for brain injury repair.

14. A first surface including a roughened surface that will be phagocytosed by cells of the in-vivo tissue, A second surface disposed on the opposite side of the first surface Comprising, The roughened surface contains polytetrafluoroethylene as a main component Sheet for spinal cord injury repair.

15. A first surface including a roughened surface that will be phagocytosed by cells of the in-vivo tissue, A second surface disposed on the opposite side of the first surface Comprising, The roughened surface contains polytetrafluoroethylene as a main component Sheet for lung injury repair.

16. A first surface including a roughened surface that will be phagocytosed by cells of the in-vivo tissue, A second surface disposed on the opposite side of the first surface Comprising, The roughened surface contains polytetrafluoroethylene as a main component Sheet for peritoneal injury repair.

17. A first surface including a roughened surface that will be phagocytosed by cells of the in-vivo tissue, A second surface disposed on the opposite side of the first surface Comprising, The roughened surface contains polytetrafluoroethylene as a main component Sheet for blood vessel injury repair.

18. A first surface including a roughened surface on which cells to be cultured or biological tissue containing the cells are placed, A second surface disposed on the opposite side of the first surface Comprising, The roughened surface contains polytetrafluoroethylene as a main component Culture sheet.

19. A method for treating regeneration of non-human animals, Preparing a sheet for treating biological tissue regeneration having a first surface at least partially constituted by a roughened surface containing polytetrafluoroethylene as a main component and a second surface disposed on the opposite side of the first surface; A step of placing the sheet for treating biological tissue regeneration on the biological tissue such that the roughened surface contacts the damaged biological tissue in vivo; A step of regenerating the tissue at the damaged site of the biological tissue in vivo using the roughened surface as a scaffold; Comprising: The step of regenerating the tissue at the damaged site of the biological tissue in vivo includes the cells of the biological tissue in vivo phagocytosing at least a part of the roughened surface. Regenerative therapy method.

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