Tissue regeneration substrate

Abstract

To provide a tissue regeneration substrate that has biocompatibility and sufficient strength and can regenerate a tissue.SOLUTION: A tissue regeneration substrate (1) includes: a bioabsorbable substrate (11) formed by knitting a yarn made of a bioabsorbable material; and a coating film (12) constituted of a biocompatible material and covering at least one of the principal surfaces of the bioabsorbable substrate (11).SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a tissue regeneration substrate.

Background Art

[0002] As one of the treatment methods for tracheal injuries caused by diseases or accidents, a method of transplanting an artificial trachea composed of artificial materials is known. Regarding such an artificial trachea, a non-absorbable artificial trachea that achieves both biocompatibility and mechanical strength is known (see, for example, Patent Document 1).

[0003] Regarding the artificial trachea, a tissue regeneration substrate that is transplanted to the site of a tissue or organ to be regenerated using a non-woven fabric of a biocompatible bioabsorbable material is known (see, for example, Patent Document 2).

[0004] Regarding the artificial trachea, a tubular artificial organ including a tubular tissue body composed of fibrous tissue formed in an environment where a living tissue material exists and a tubular reinforcement body composed of a biodegradable material and enclosed in the tubular tissue body is known (see, for example, Patent Document 3).

[0005] Regarding the artificial trachea, a cartilage transplantation kit for trachea regeneration in which a regenerated cartilage body in which chondrocytes are fixed via a hydrogel on the surface of a scaffold member of a biodegradable porous body is fixed to a biodegradable membranous member by a matrix member containing a tissue-inducing substance is known (see, for example, Patent Document 4).

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

[0007] However, there is still no established treatment method for tracheal damage caused by artificial trachea implantation. Conventional techniques, such as those described above, can lead to infections and other problems if non-absorbable artificial tracheas are permanently implanted within the body. Conventional biocompatible artificial tracheas have insufficient physical properties such as airtightness and mechanical strength, and cartilage may not regenerate on their own. Thus, conventional artificial tracheas still require further investigation from the perspective of achieving biocompatibility, sufficient strength, and tissue regeneration.

[0008] One aspect of the present invention aims to realize a tissue regeneration substrate that has biocompatibility and sufficient strength, and is capable of regenerating tissue. [Means for solving the problem]

[0009] To solve the above problems, a tissue regeneration substrate according to one aspect of the present invention comprises a bioabsorbable substrate formed by braiding threads of a bioabsorbable material, and a coating film made of a biocompatible material that covers at least one main surface of the bioabsorbable substrate. [Effects of the Invention]

[0010] According to one aspect of the present invention, a tissue regeneration substrate can be realized that has biocompatibility and sufficient strength, and is capable of regenerating tissue. [Brief explanation of the drawing]

[0011] [Figure 1] This figure schematically shows the structure of a tissue regeneration substrate according to one embodiment of the present invention. [Figure 2] This is a diagram illustrating a bioabsorbable substrate in an embodiment of the present invention. [Figure 3]This figure shows a scanning electron microscope image of the main surface of a specific example of a tissue regeneration substrate according to an embodiment of the present invention. [Figure 4] This figure shows the measurement results of the radial compressive strength of the tubular tissue regeneration substrate in the example. [Figure 5] This figure shows photographs of two examples of the rat tracheal hemiperitoneal defect model used in the examples: (A) the trachea with hemiperitoneal resection and (B) the tracheal regeneration substrate with a sheet-like tissue regeneration material attached to the resected portion of the trachea. [Figure 6] This figure shows an example of photographs taken with a bronchoscope of the tracheal suture site at (A) 2 weeks, (B) 1 month, (C) 2 months, and (D) 6 months in a tracheal hemispheroidal defect model in which a tissue regeneration substrate was sutured in the example. [Figure 7] This figure shows an example of a cross-sectional photograph of the tracheal suture site two weeks after application in a tracheal hemispherical defect model in which a tissue regeneration substrate was sutured in the example. [Figure 8] This figure shows an example of a cross-sectional photograph of the tracheal suture site one month after application in a tracheal hemispherical defect model in which a tissue regeneration substrate was sutured in the example. [Figure 9] This figure shows an example of a cross-sectional photograph of the tracheal suture site two months after the application of a tissue regeneration substrate to a tracheal hemispheric defect model in the example. [Figure 10] This figure shows an example of a cross-sectional photograph of the tracheal suture site 6 months after suture in a tracheal semicircumferential defect model in which a tissue regeneration substrate was sutured in the example. [Figure 11] This figure shows a photograph that enlarges section A in Figure 10. [Figure 12] This figure shows an example of a scanning electron microscope image of the central inner portion of the tracheal suture in a tracheal hemispherical defect model in which a tissue regeneration substrate was sutured in the example. [Figure 13] This figure shows a photograph that enlarges section A in Figure 12. [Modes for carrying out the invention]

[0012] Hereinafter, an embodiment of the present invention will be described in detail. FIG. 1 is a diagram schematically showing the configuration of a tissue regeneration base material according to an embodiment of the present invention. As shown in FIG. 1, the tissue regeneration base material 1 has a bioabsorbable base material 11 and a coating film 12.

[0013] 〔Bioabsorbable base material〕 The bioabsorbable base material 11 is tubular. The shape of the bioabsorbable base material 11 can be appropriately determined according to the shape of the organ of the living body to be applied and the application form. For example, when replacing the entire tubular organ such as the trachea, the form of the bioabsorbable base material 11 may be tubular. When covering a part of an organ, the form of the bioabsorbable base material 11 may be sheet-like.

[0014] The bioabsorbable base material 11 is formed by knitting a thread of a bioabsorbable material. FIG. 2 is a diagram for explaining the bioabsorbable base material in an embodiment of the present invention. The bioabsorbable base material 11 is formed as a planar region by alternately crossing two or more sets of threads (also referred to as "filamentous bodies"). The set of threads is composed of one thread or a set of two or more threads. The set of threads may be three-dimensionally bundled or arranged in a plane. The fact that the bioabsorbable base material 11 is formed by knitting is preferable from the viewpoint of enhancing the bioabsorbability of the bioabsorbable base material 11.

[0015] The thread constituting the set of threads may be a monofilament thread or a multifilament thread. In the case of a multifilament thread, from the viewpoint of forming a substantially airtight planar region in the tissue regeneration base material 1 and enhancing the strength of the tissue regeneration base material 1, it is preferably one or more, more preferably ten or more, and even more preferably twenty-four or more.

[0016] The tubular bioabsorbable base material 11 is composed of a set string formed by knitting a set of threads. The bioabsorbable base material 11 having a shape other than tubular, such as a sheet shape, can be formed by cutting or opening the set string.

[0017] From the viewpoint of achieving desirable airtightness, strength, and flexibility of the tissue regeneration substrate 1, it is preferable that the braiding angle of the bioabsorbable substrate 11 is 20° or more and less than 90°. The braiding angle is the angle that the axial direction of the braid makes with respect to the longitudinal direction of the bioabsorbable substrate 11, and is represented by θ in Figure 2. The longitudinal direction of the tissue regeneration substrate 1 can be determined as the direction in which specific positions in the shape of the repeating unit of the braided structure formed by the braid are aligned. In Figure 2, for example, the longitudinal direction of the tissue regeneration substrate 1 is represented by the line connecting the rightmost vertices of the shape of the mutually adjacent diagonal, approximately rectangular repeating units formed by the braid.

[0018] A low assembly angle of the bioabsorbable substrate 11 is preferable from the viewpoint of increasing the flexibility of the bioabsorbable substrate 11 and improving the conformability of the tissue regeneration substrate 1 to the shape when applied to an organ. From this viewpoint, an assembly angle of 20° or more is preferable, 30° or more is more preferable, and 40° or more is even preferable.

[0019] On the other hand, the braiding angle should be within the range where braiding is possible, and a higher braiding angle is preferable from the viewpoint of improving the airtightness and strength of the tissue regeneration base material 1. From this viewpoint, the braiding angle should be less than 90°, but from the above viewpoint, it is preferable to be 85° or less, and more preferable to be 80° or less.

[0020] The number of sets of bioabsorbable substrates 11 is preferably 3 or more per inch, and more preferably 25 or more per inch, from the viewpoint of airtightness and strength as described above.

[0021] From the viewpoint of achieving desirable airtightness, strength, and flexibility of the tissue regeneration substrate 1, the basis weight of the bioabsorbable substrate 11 is preferably 0.5 g / m or more and 500 g / m or less. From the viewpoint of sufficiently increasing the flexibility of the tissue regeneration substrate 1, the basis weight of the bioabsorbable substrate 11 is preferably 500 g / m or less, more preferably 400 g / m or less, and even more preferably 300 g / m or less. Furthermore, from the viewpoint of sufficiently increasing the airtightness and strength of the tissue regeneration substrate 1, the basis weight of the bioabsorbable substrate 11 is preferably 0.5 g / m or more, more preferably 1 g / m or more, and even more preferably 2 g / m or more.

[0022] The bioabsorbable substrate 11 should be capable of achieving the desired airtightness, strength, and flexibility of the tissue regeneration substrate 1 based on the physical properties described above. From the viewpoint of achieving these properties when applied to the trachea, it is preferable that the bioabsorbable substrate 11 is woven together without gaps using threads of bioabsorbable material.

[0023] The bioabsorbable substrate 11 is formed from threads of a bioabsorbable material (the threads mentioned above). A bioabsorbable material is a material that is decomposed and absorbed in a living organism, and can be, for example, a polymer compound that disappears by hydrolysis in a living organism, i.e., a bioabsorbable polymer. The bioabsorbable polymer may be a homopolymer or a copolymer. Examples of bioabsorbable polymers include synthetic polymers such as polyglycolic acid, polylactide, poly-ε-caprolactone, lactide-glycolide copolymer, glycolide-ε-caprolactone copolymer, lactide-ε-caprolactone copolymer, polydioxanone, polycitric acid, polymalic acid, poly-α-cyanoacrylate, poly-β-hydroxy acid, polytrimethylene oxalate, polytetramethylene oxalate, polyorthoester, polyorthocarbonate, polyethylene carbonate, poly-γ-benzyl-L-glutamate, poly-γ-methyl-L-glutamate, and poly-L-alanine; polysaccharides such as starch, alginic acid, hyaluronic acid, chitin, pectic acid and their derivatives; and natural polymers such as gelatin, collagen, albumin, and fibrin. Bioabsorbable materials may be used individually or in combination of two or more types. From the viewpoint of achieving desired physical properties as a tissue regeneration substrate 1 and realizing tissue regeneration in organs, the bioabsorbable material is preferably polyglycolic acid or a glycolic acid copolymer.

[0024] In this embodiment, "single yarn" refers to a single thread, specifically a single thread or monofilament that constitutes a multifilament. "Braided yarn" refers to the yarn used when making a braided cord. The braided yarn may be bundled and braided together. From the viewpoint of achieving the desired physical properties of the bioabsorbable material yarn, the single yarn fineness is preferably 1 dtex or more and 200 dtex or less. From the viewpoint of increasing the strength of the bioabsorbable material, the fineness of the single yarn is preferably 1 dtex or more, more preferably 5 dtex or more, even more preferably 7 dtex or more, and even more preferably 8 dtex or more. Furthermore, from the viewpoint of increasing the airtightness and flexibility of the tissue regeneration material 1, the fineness of the single yarn is preferably 80 dtex or less, more preferably 100 dtex or less, and even more preferably 200 dtex or less.

[0025] The fineness of the single filament of the bioabsorbable material yarn varies depending on the number of yarns used in the braid, but it is sufficient that it can achieve sufficient strength as a bioabsorbable base material 11 when used for braiding as a single filament or braided yarn. For example, if the fineness of a braided yarn made by bundling 24 yarns is 200 dtex, then the fineness of each yarn constituting the braided cord is 8.3 dtex. The braided yarn may also be made by further bundling braided yarns together; for example, it is possible to construct a braided cord by bundling three braided yarns, each with a fineness of 200 dtex.

[0026] The strength of the bioabsorbable material yarn can be appropriately determined from the viewpoint of achieving the desired strength of the tissue regeneration base material 1. The strength referred to here is tensile strength, and like fineness, it differs depending on the number of threads used as a braid in the aforementioned braid, but it is sufficient that sufficient strength is exhibited when used as a single thread or braid. From the viewpoint of sufficiently increasing the strength of the tissue regeneration base material 1, the strength of the braided yarn is preferably 0.1 cN / dtex or more, more preferably 1 cN / dtex or more, even more preferably 3 cN / dtex or more, and even more preferably 5 cN / dtex or more. Furthermore, from the viewpoint of sufficiently increasing the flexibility of the tissue regeneration base material 1, the strength of the braided yarn is preferably 30 cN / dtex or less, more preferably 10 cN / dtex or less, and even more preferably 8 cN / dtex or less.

[0027] [Coating film] The coating film 12 covers the outer surface of the bioabsorbable substrate 11. The coating film 12 is a thin film formed by applying a coating material. The coating film 12 forms a covering layer that covers the outer surface of the bioabsorbable substrate 11. As will be described later, since the coating film 12 is formed by coating the outer surface of the woven bioabsorbable substrate 11 with a coating material, it usually includes a portion that soaks into the bioabsorbable substrate 11. From the viewpoint of airtightness, the coating film 12 only needs to cover at least one main surface of the bioabsorbable substrate 11. That is, if the bioabsorbable substrate is in the form of a sheet, the coating film may cover one or both of its front and back surfaces, and if the bioabsorbable substrate is in the form of a tube, it may cover one or both of its inner and outer surfaces. Furthermore, from the viewpoint of improving the airtightness of the tissue regeneration substrate, it is preferable that the coating film covers the entire main surface of the bioabsorbable substrate, i.e., up to the edge of the main surface. Furthermore, it is preferable from the viewpoint of promoting the regeneration of living tissue that the coating film 12 is formed on the outer surface of the bioabsorbable substrate 11, that is, on the outer surface of the organ.

[0028] The coating film 12 is composed of a biocompatible material. A biocompatible material is a material that is non-toxic to living organisms and can maintain its function and durability. The interposition of the coating film 12 between the bioabsorbable substrate 11 and living tissue is preferable from the viewpoint of suppressing irritation to living organisms and enabling tissue regeneration.

[0029] The biocompatible material is preferably a hydrogel. A hydrogel is a substance that contains water internally and is composed of a hydrophilic crosslinked polymer. The hydrophilic crosslinked polymer is miscible with water due to its sufficient affinity for water and retains water in its three-dimensional structure formed by the crosslinked structure. The biocompatible material being a hydrogel is preferable from the viewpoint of increasing the affinity of the tissue regeneration substrate 1 with the body and promoting tissue regeneration.

[0030] Examples of such biocompatible materials include polysaccharides such as starch, hyaluronic acid, alginic acid, chitin, pectic acid and its derivatives; natural polymers such as proteins such as gelatin, collagen, albumin, and fibrin; and polyanionic polysaccharides such as cross-linked hyaluronic acid. The biocompatible material may be one or more types. In particular, from the viewpoint of high biocompatibility and low irritation, it is preferable that the biocompatible material contains cross-linked hyaluronic acid.

[0031] [Method of manufacturing the coating film] The coating film 12 can be prepared by applying a coating material, which is a solution of a biocompatible material, to the surface of a bioabsorbable substrate 11 and drying it. The application and drying of the coating material may be performed multiple times.

[0032] Furthermore, in the preparation of the coating film 12, heat treatment may be applied after the application and drying of the coating material. Heat treatment can reduce the decomposition rate. The conditions for the heat treatment can be appropriately determined within a range that makes the objective achievable. For example, if the biocompatible material of the coating film 12 is cross-linked hyaluronic acid, the heat treatment temperature may be 80 to 120°C, and the treatment time may be 10 minutes to 1 hour.

[0033] The thickness of the coating film 12 can be increased by applying a thicker layer of the coating material. For example, the thickness of the coating film 12 can be increased by increasing the viscosity of the coating material. Alternatively, the thickness of the coating film 12 can be increased by slowing down the swelling rate of the biocompatible material coating. Alternatively, it can be increased by repeatedly applying and drying the coating multiple times. If the above heat treatment is further applied, the thickness of the coating film 12 can be increased by raising the heat treatment temperature or increasing the treatment time. By applying a thicker layer of the coating material, it is possible to create a coating film 12 that substantially seals gaps in the mesh of the bioabsorbable substrate 11, thereby achieving sufficient airtightness of the tissue regeneration substrate 1.

[0034] Since the coating film 12 is produced by applying the coating material as described above, it exists as a layer of biocompatible material on the side of the bioabsorbable substrate 11 to which the coating material is applied. Figure 3 is a scanning electron microscope image of the main surface of a specific example of a tissue regeneration substrate in an embodiment of the present invention. In Figure 3, row B1 shows a photograph of the outer surface of a tubular tissue regeneration substrate, and row B2 shows a photograph of the inner surface. The photograph in column A1 shows the state without the coating film 12 (i.e., the bioabsorbable substrate). The photograph in column A2 shows the tissue regeneration substrate having a coating film of cross-linked hyaluronic acid that has not undergone heat treatment on its outer surface. The photograph in column A3 shows the tissue regeneration substrate having a coating film of cross-linked hyaluronic acid that has undergone heat treatment on its outer surface.

[0035] As is clear from the photographs in Figure 3, in rows A2 and A3, the gaps between fibers are filled in the outer surface photograph of row B1 compared to the inner surface photograph of row B2, thus confirming the presence of a film derived from biocompatible material on the outer surface of the tissue regeneration substrate. Furthermore, in the inner surface photograph of row B2, more fibrous deposits are observed in rows A2 and A3 compared to row A1. This is thought to indicate that some of the coating material permeated the material during the preparation of the coating film.

[0036] [Support] The tissue regeneration substrate of this embodiment may further include other components besides the bioabsorbable substrate and coating film described above, to the extent that the effects of the present invention are obtained. For example, the tissue regeneration substrate may further include a support.

[0037] The support is positioned in or along the bioabsorbable substrate. The support is a component for supporting the bioabsorbable substrate in the desired shape of the tissue regeneration substrate, and has the function of supporting the desired shape of the biological tissue in the tissue regeneration substrate in the living body, similar to cartilage in biological tissue. For example, if the tissue regeneration substrate is applied to the trachea, the support will act as a substitute for tracheal cartilage.

[0038] The support should be positioned in the tissue regeneration substrate such that it maintains a desired shape for a desired period of time when placed in a living organism. For example, the support may be positioned such that more than half of its length is in contact with a surface (including a virtual surface) parallel to the main surface of the tissue regeneration substrate. If the tissue regeneration substrate is tubular in shape, the support may be positioned in the bioabsorbable substrate, on the inner surface of the bioabsorbable substrate, on the outer surface of the bioabsorbable substrate, in the coating, on the inner surface of the coating, or on the outer surface of the coating. If the tissue regeneration substrate is sheet-shaped, the support may be positioned in the bioabsorbable substrate, on the surface of the bioabsorbable substrate, on the back surface of the bioabsorbable substrate, in the coating, or on the surface of the coating.

[0039] The support can be placed within the bioabsorbable substrate by intertwining it with the weave of the bioabsorbable substrate. Alternatively, the support can be placed within the coating by forming a coating film that covers the main surface of the bioabsorbable substrate after it has been placed on the main surface.

[0040] The support structure is composed of support materials, which are linear components. By constructing the support structure with linear support materials, the support structure ensures the flexibility of the tissue regeneration substrate while performing its desired function.

[0041] The support material is bioabsorbable or biocompatible. Furthermore, the support material is preferably a relatively rigid material from the viewpoint that the support supports a bioabsorbable substrate. Examples of materials for the support material include polyvinylidene fluoride, nylon, polypropylene, polyethylene, polyethylene terephthalate, Teflon®, polycaprolactone, polyglycolic acid, polylactic acid, polyamide 4, cellulose acetate, polyhydroxyalkanoic acid, polyvinyl alcohol, polybutylene succinate, polyparadioxanone, and hydroxyapatite.

[0042] The support is either non-degradable in vivo or has a slower degradation rate than the bioabsorbable material. The degradation rate of the support is evaluated by the weight loss over time when immersed in physiological saline solution (aqueous solution of 0.9 w / v% sodium chloride) at 37°C. This degradation rate can be adjusted by the structure of the support; for example, the degradation rate can be slowed down by using a structure in which the support materials are more densely arranged.

[0043] The support preferably has sufficient rigidity from the viewpoint of maintaining the shape of the tissue regeneration substrate. For example, the support preferably has sufficient rigidity to maintain the original shape of the biological tissue lost by excision, at least during the regeneration of the biological tissue. The sufficient rigidity of the support can be confirmed by visually observing whether the support maintains its original shape in the above-described method for evaluating the rate of degradation. Furthermore, the sufficient rigidity of the support can be increased, for example, by making the support thicker.

[0044] From the viewpoint of providing sufficient flexibility to the tissue regeneration substrate, it is preferable that the support is arranged such that there are gaps between the support members constituting the support in the longitudinal direction of the tissue regeneration substrate. Furthermore, from the viewpoint of more reliably maintaining the shape of the regenerated tissue, it is even more preferable that the support members constituting the support are arranged at approximately equal intervals and approximately parallel to each other. Examples of such supports include supports composed of a plurality of independent annular support members, supports composed of spirally formed support members, and supports formed in a tubular shape from mesh-like support members. From the above viewpoint, it is preferable that the support is a plurality of annular bodies and that each support is arranged apart from one another in the tissue regeneration substrate.

[0045] When the area of ​​biological tissue to which the tissue regeneration substrate should be placed is excised is large, even if the biological tissue and cartilage regenerate, the recovery of the shape of the biological tissue may be insufficient. The support remains in the body for a longer period than the bioabsorbable substrate when the tissue regeneration substrate is placed in the body, and maintains the shape of the biological tissue. In a tissue regeneration substrate with a support, the support remains even after the bioabsorbable substrate and coating film have disappeared, so the biological tissue regenerates by incorporating (adhering to) the support. Therefore, a tissue regeneration substrate with a support is advantageous from the viewpoint of regenerating biological tissue to a desired shape.

[0046] [Characteristics of tissue regeneration substrates] The preferred form of the tissue regeneration substrate in the embodiments of the present invention can also be specified by appropriate physical properties.

[0047] For example, the radial compressive strength of 1 cm of the tissue regeneration substrate may be between 0.1 N and 200 N. Having this compressive strength is preferable from the viewpoint of maintaining the tubular shape during use when the tissue regeneration substrate is applied to organs that form the airways, such as the trachea or bronchi. A higher compressive strength is not problematic, but from the viewpoint of balancing the timing of tissue regeneration and its disappearance in vivo, it is preferable to have a compressive strength of 20 N or less. This compressive strength is determined from the pressing force and strain when the tubular tissue regeneration substrate is compressed radially after being treated under conditions corresponding to its presence in vivo for a desired period of time.

[0048] Furthermore, it is preferable that the tissue regeneration substrate exhibits sufficient airtightness for application to the trachea of ​​the airway if the air pressure at which air leakage occurs in a leak test exceeds 20 cmH2O (1.96 kPa). The leak test is a test that detects whether or not air passes through the tissue regeneration substrate in the thickness direction. The leak test can be performed by airtightly sealing the end of a tubular tissue regeneration substrate, or by sealing the end of a vent tube with a sheet-like tissue regeneration substrate.

[0049] 〔summary〕 The tissue regeneration substrate of the embodiment of the present invention, when applied to organs that form the airways of a living body, such as the trachea, regenerates the tissue of said organs and then decomposes and disappears within the body. During this time, rejection reactions in the body are substantially suppressed. Thus, the tissue regeneration substrate of the embodiment of the present invention can become a tubular braided artificial organ and reinforcing body with lumen retention ability and airtightness, using bioabsorbable materials. Furthermore, as shown in the examples described later, it can regenerate cartilage and functional cilia.

[0050] As is clear from the above description, the tissue regeneration substrate (1) of the first embodiment of the present invention comprises a bioabsorbable substrate (11) formed by braiding threads of a bioabsorbable material, and a coating film (12) made of a biocompatible material that covers at least one main surface of the bioabsorbable substrate. Therefore, according to the embodiment of the present invention, a tissue regeneration substrate that has biocompatibility and sufficient strength and is capable of regenerating tissue can be realized.

[0051] In the second embodiment of the present invention, the tissue regeneration substrate may be constructed in which the bioabsorbable substrate is tightly woven with threads of bioabsorbable material, as in the first embodiment. This configuration is even more effective from the viewpoint of improving the airtightness of the tissue regeneration substrate.

[0052] In a third aspect of the present invention, the tissue regeneration substrate may be in the form of a sheet, as in the first or second aspect. This configuration is advantageous for partially covering organs of a living organism.

[0053] In the fourth aspect of the present invention, the tissue regeneration substrate may be tubular in shape in the first or second aspect. This configuration is advantageous for application to tubular organs such as the trachea.

[0054] In the fifth aspect of the present invention, the tissue regeneration substrate may, in the fourth aspect, have a coating that covers the outer surface of the bioabsorbable substrate. This configuration is advantageous for application to the trachea, reduction of irritation to the body, and promotion of tissue regeneration.

[0055] In the sixth aspect of the present invention, the tissue regeneration substrate may have an assembly angle of 20° or more and less than 90° in any of the first to fifth aspects. This configuration is even more effective in terms of exhibiting good flexibility, airtightness, and strength in the tissue regeneration substrate.

[0056] In the seventh aspect of the present invention, the tissue regeneration substrate may have a basis weight of 0.5 g / m² or more and 500 g / m² or less in any of the first to sixth aspects. This configuration is even more effective in terms of exhibiting good flexibility, airtightness, and strength in the tissue regeneration substrate.

[0057] In the eighth aspect of the present invention, the tissue regeneration substrate may have a yarn fineness of 5 dtex or more in any of the first to seventh aspects. This configuration is even more effective from the viewpoint of achieving the desired strength of the tissue regeneration substrate.

[0058] In the ninth aspect of the present invention, the tissue regeneration substrate may have a single filament fineness of 1 dtex or more and 200 dtex or less in any of the first to eighth aspects. This configuration is even more effective in terms of exhibiting good flexibility, airtightness, and strength in the tissue regeneration substrate.

[0059] In the tissue regeneration substrate according to the tenth aspect of the present invention, in any of the first to ninth aspects, the bioabsorbable material may be a bioabsorbable polymer, and the bioabsorbable polymer may be a homopolymer or copolymer. This configuration is even more effective from the viewpoint of reducing irritation to living organisms and regenerating tissue.

[0060] In the eleventh aspect of the present invention, the tissue regeneration substrate, in any of the first to tenth aspects, may have a bioabsorbable material that is polyglycolic acid or a glycolic acid copolymer. This configuration is even more effective from the viewpoint of reducing irritation to living organisms and regenerating tissue.

[0061] In the tissue regeneration substrate according to the twelfth aspect of the present invention, in any of the first to eleventh aspects, the biocompatible material may be a hydrogel. This configuration is even more effective from the viewpoint of increasing affinity with living organisms and promoting tissue regeneration in living organisms.

[0062] In any of the thirteenth aspect of the present invention, the tissue regeneration substrate may contain one or more biocompatible materials selected from the group consisting of polysaccharides, natural polymers, and crosslinked forms thereof, in any of the first to twelfth aspects. This configuration is even more effective from the viewpoint of increasing affinity with living organisms and promoting tissue regeneration in living organisms.

[0063] In the fourteenth aspect of the present invention, the tissue regeneration substrate may, in any of the first to thirteenth aspects, contain cross-linked hyaluronic acid as the biocompatible material. This configuration is even more effective from the viewpoint of reducing irritation to living organisms and promoting tissue regeneration.

[0064] In any of the first to fourteenth embodiments of the present invention, the tissue regeneration substrate is a support composed of a linear support material that is bioabsorbable or biocompatible, which is non-degradable in vivo or has a slower degradation rate than bioabsorbable materials, and which is disposed in or along a bioabsorbable substrate. This configuration is even more effective from the viewpoint of maintaining the shape of the regenerated biological tissue.

[0065] In the sixteenth aspect of the present invention, the tissue regeneration substrate, in the fifteenth aspect, may have a plurality of annular supports, each support being spaced apart from the others. This configuration is even more effective from the viewpoint of ensuring the flexibility of the tissue regeneration substrate.

[0066] Furthermore, in other embodiments of the present invention, the tissue regeneration substrate may consist only of the bioabsorbable substrate without a coating, if the bioabsorbable substrate also possesses the function of the aforementioned coating. For example, the tissue regeneration substrate in other embodiments of the present invention may have a bioabsorbable substrate formed by braiding threads of a bioabsorbable material, and the bioabsorbable substrate may be tightly woven with threads of the bioabsorbable material.

[0067] Furthermore, as a tissue regeneration substrate composed of a bioabsorbable substrate that also functions as a coating film, the tissue regeneration substrate of another embodiment of the present invention has a bioabsorbable substrate formed by braiding threads of a bioabsorbable material, and the braiding angle in the bioabsorbable substrate may be 20° or more and less than 90°.

[0068] With this configuration in the present invention, it is expected to be applicable to tissue regenerative medicine and contribute to achieving the Sustainable Development Goals (SDGs) for the promotion of health and well-being.

[0069] The present invention is not limited to the embodiments described above, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention. [Examples]

[0070] One embodiment of the present invention is described below.

[0071] [Making braided threads] Using PGA (Kuresurge) manufactured by Kureha Corporation, a braided yarn with a density of 200 dtex and a strength of 7.2 cN / dtex was produced using a melt spinning machine, the "FET spinning machine" (manufactured by FIBER EXTRUSION TECHNOLOGY).

[0072] [Preparation of PGA tubes] Using the above-mentioned braided yarn, PGA tubes 1-4 were fabricated using a braiding machine.

[0073] PGA Tube 1 has an outer diameter of 3.0 mm and is made by braiding three strands of yarn together. On average, the braiding angle of PGA Tube 1 was 49°.

[0074] PGA Tube 2 is made by braiding a single strand of yarn with an outer diameter of 3.0 mm. On average, the braiding angle of PGA Tube 2 was 59°.

[0075] PGA Tube 3 has an outer diameter of 3.5 mm and is made by braiding three strands of yarn together. On average, the braiding angle of PGA Tube 1 was 54°.

[0076] PGA Tube 4 has an outer diameter of 2.5 mm and is made by braiding a single strand of yarn together in sets. On average, the braiding angle of PGA Tube 4 was 45°.

[0077] [Preparation of coating materials] 1.2 g of sodium hyaluronate (HA) was added to 200 mL of ultrapure water at room temperature. The mixture was stirred using a stirring bar, and after visual confirmation that the HA had dissolved, the pH of the solution was adjusted to 4.75 with HCl. Next, 942 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) was dissolved in 3 mL of ultrapure water, and the entire amount was added and dissolved. After that, 570 mg of leucine methyl ester hydrochloride (LME) was added. The prepared solution was dialyzed using a dialysis membrane to remove residual reagents. In this way, coating material 1 containing hyaluronic acid as a biocompatible material was prepared.

[0078] Ultraxanthan V-7 (Ina Food Industry Co., Ltd.) was used as a biocompatible material, and an aqueous solution containing it at a concentration of 0.59% by mass was prepared. This was designated as coating material 2.

[0079] Tragacanth powder (a bell powder chemical) was used as a biocompatible material, and an aqueous solution containing it at a concentration of 1.25% by mass was prepared. This was designated as coating material 3.

[0080] METLOSE 65SH-400 (Shin-Etsu Chemical Co., Ltd.) was used as a biocompatible material, and an aqueous solution containing it at a concentration of 1.04% by mass was prepared. This was designated as coating material 4.

[0081] [Tissue regeneration base material] A support rod, made by splitting and sharpening a bamboo skewer, was inserted into the PGA tube 1 and supported by the support rod. Next, coating material 1 was applied to the outer surface of the PGA tube 1 with a brush and air-dried. This coating and air-drying cycle was repeated 10 times to cover the outer surface of the PGA tube 1 with coating material 1. Then, the PGA tube 1 covered with coating material 1 was dried in a dryer at 90°C for 15 minutes, and then subjected to heat treatment by heating at 120°C for 10 minutes. In this way, a tubular tissue regeneration substrate 1 was produced in which the coating film of coating material 1 covered the outer surface of the PGA tube 1.

[0082] Tissue regeneration substrates 2 to 4 were prepared in the same manner as tissue regeneration substrate 1, except that PGA tubes 2 to 4 were used in place of PGA tube 1.

[0083] Furthermore, tissue regeneration substrates 5 to 7 were prepared in the same manner as the preparation of tissue regeneration substrate 1, except that coating materials 2 to 4 were used in place of coating material 1.

[0084] [Compressive strength] The lateral compressive strength of tissue regeneration substrates 1-4 was measured. Each of the tissue regeneration substrates 1-4 was left standing for 14 days in an environment of 37°C, 5% CO2, and 95% RH, and the strain was determined when a compressive force was applied to each of the tissue regeneration substrates 1-4 along the radial direction. The strain (ε) of the tissue regeneration substrate was determined by finding the difference between the original diameter value (d0) and the diameter value (d) when the compressive force was applied, and dividing by the original diameter value, as shown in the formula below. In addition, the compressive strength of a rat trachea was measured under the same conditions as a control. The results are shown in Figure 4. The higher the compressive force, the stronger the radial compressive strength. (Equation) ε=(d0-d) / d0

[0085] The order of radial compressive strength was as follows: tissue regeneration substrate 3 (solid line), tissue regeneration substrate 1 (dashed line), tissue regeneration substrate 4 (dotted line), and tissue regeneration substrate 2 (dotted line). The lateral compressive strength of tissue regeneration substrate 4 at a strain of 0.4 was equivalent to that of a rat trachea (double-dotted line).

[0086] [Leak test] One end of the tissue regeneration substrate 4 was sealed to prevent air leakage, and a three-way stopper was inserted into the other end. A syringe and pressure gauge were attached to the stopper. The tissue regeneration substrate 4 was placed in water, and air was injected through the syringe. The pressure at which bubbles began to appear from the side of the tissue regeneration substrate 4 was checked. As a result, a pressure resistance of 25 cmH2O was confirmed.

[0087] [Organizational restructuring] Tissue regeneration substrate 4 was applied to the trachea of ​​rats, and the progress of the rat trachea was observed to verify the effects of inhalation of an absorbable artificial trachea and bFGF (basic fibroblast growth factor).

[0088] As shown by the dashed line in the left panel (A) of Figure 5, a half-circumference section of the rat's trachea was cut off over a length of approximately 4 mm to prepare a model of a half-circumference defect in the rat's trachea. This half-circumference defect model was confirmed to be a critical defect.

[0089] On the other hand, the tissue regeneration substrate 4 was cut in the longitudinal direction to prepare a sheet-like tissue regeneration substrate 4.

[0090] Then, as shown by the dashed line in Figure 5 (B), the sheet-like tissue regeneration substrate 4 was placed over the tracheal loss area in the semicircular loss model and sutured to the trachea for fixation. The tissue regeneration substrate 4 was sutured to the defect site in this way, and its biocompatibility and healing process were evaluated (n=5). In addition, the healing-promoting effect was investigated by administering bFGF (basic fibroblast growth factor) via the airway. For the evaluation of the healing-promoting effect, 1) bronchoscopy, 2) pathology, 3) high-speed camera [ciliary vibration frequency (Hz) and transport capacity (μm / s)], and 4) electron microscope [ciliary area (%)] were evaluated. Transport capacity was measured by scattering beads in the trachea and measuring the distance / second. The center and normal area of ​​the PGA were evaluated at 2 weeks, 1 month, 2 months, and 6 months. In addition, bFGF and distilled water were administered intratracheally every other day, and a comparison of the two groups was performed after 2 weeks.

[0091] Figure 6 shows the internal structure of the trachea in the hemispherical defect model. Figures 7 to 10 show cross-sectional views of the hemispherical defect model at 2 weeks, 1 month, 2 months, and 6 months, respectively. In Figures 7 to 10, the dashed lines indicate the tracheal portion of the hemispherical defect model, and the arrows indicate the portion covered with the tissue regeneration substrate 4 in that model. Figure 11 shows a magnified view of section A in Figure 10. The area enclosed by the dashed line in Figure 11 represents chondrocytes. Furthermore, Figure 12 shows the cilia regenerated at 1 month in the hemispherical defect model. Figure 13 shows a magnified view of section A in Figure 12.

[0092] 1. Bronchoscopy revealed no stenosis or granulation tissue formation throughout the entire period, as shown in Figure 6, and neovascularization was observed starting one month later.

[0093] 2. Pathological observation revealed only minimal foreign body reaction due to the material. After two weeks, the presence of tissue regeneration substrate 4 was confirmed, and affinity with the tissue was observed (Figure 7). After one month, newly formed blood vessels were observed in the area of ​​tissue regeneration substrate 4 (Figure 8). After two months, regenerated tissue covering the inside of tissue regeneration substrate 4 was observed (Figure 9). After six months, chondrocyte regeneration was observed in the center of the PGA (Figures 10 and 11).

[0094] 3. Observation of cilia with a high-speed camera showed that the vibration frequency of normal areas was around 12, while the PGA center improved to near normal levels after 6 months, with frequencies of 7.00, 6.90, 8.15, and 10.29 at each period. The normal transport capacity was around 30, and the PGA center showed an improving trend during the same period, with frequencies of 5.65, 12.39, 15.06, and 19.57.

[0095] 4. Observation with an electron microscope revealed that the ciliary area in the center of the PGA expanded to 13.0, 28.8, 30.4, and 30.2 over a period of one month (Figures 12 and 13). Furthermore, the bFGF-administered group showed improvements in vibration frequency, transport capacity, and ciliary area. The vibration frequency was 6.91 in the distilled water group and 9.63 in the bFGF group, with bFGF administration showing a significant improvement (p=0.0010).

[0096] As described above, the novel PGA artificial trachea demonstrated excellent biocompatibility, and morphological and functional tracheal regeneration was observed after six months. Furthermore, a healing-promoting effect was confirmed with transairal bFGF administration.

[0097] PGA sheets currently used clinically have poor pressure resistance, making it difficult to seal air leaks from the central airways. According to this embodiment, it may be possible to develop a material with excellent airtightness and biocompatibility by bundling PGA braids in layers. Furthermore, by inventing a new PGA material shape that has biocompatibility and strength (high airtightness), it may be possible to seal air leaks from the central airways (trachea or bronchi). [Industrial applicability]

[0098] This invention is expected to be used in tissue regeneration medicine in treatments requiring partial tissue resection. [Explanation of Symbols]

[0099] 1 Tissue regeneration base material 11 Bioabsorbable Substrates 12. Coating film

Claims

1. A tissue regeneration substrate comprising a bioabsorbable substrate formed by braiding threads of a bioabsorbable material and a coating film covering at least one main surface of the bioabsorbable substrate, the bioabsorbable material is polyglycolic acid or glycolic acid copolymer; A tissue regeneration substrate, wherein the coating film is composed of a hydrogel.

2. The tissue regeneration substrate according to claim 1 , wherein the bioabsorbable substrate is tightly woven with threads of the bioabsorbable material.

3. The tissue regeneration substrate according to claim 1 or 2, wherein the bioabsorbable substrate is in the form of a sheet.

4. The tissue regeneration substrate according to claim 1 or 2, wherein the bioabsorbable substrate is tubular.

5. The tissue regeneration substrate according to claim 4 , wherein the coating film covers the outer peripheral surface of the bioabsorbable substrate.

6. The tissue regeneration substrate according to claim 1 , wherein the braid angle in the bioabsorbable substrate is equal to or greater than 20° and less than 90°.

7. The tissue regeneration substrate according to claim 1, wherein the bioabsorbable substrate has a basis weight of 0.5 g / m 2 or more and 500 g / m 2 or less.

8. The tissue regeneration substrate according to claim 1, wherein the braiding fineness of the yarn is 5 dtex or more.

9. The tissue regeneration substrate according to claim 1, wherein the single yarn fineness of the yarn is 1 dtex or more and 200 dtex or less.

10. The tissue regeneration substrate according to claim 1 , wherein the bioabsorbable material is a bioabsorbable polymer, and the bioabsorbable polymer is a homopolymer or a copolymer.

11. The tissue regeneration substrate according to claim 1 , wherein the hydrogel comprises at least one selected from the group consisting of polysaccharides, natural polymers, and crosslinked products thereof.

12. The tissue regeneration substrate according to claim 1 , wherein the hydrogel comprises cross-linked hyaluronic acid.

13. The tissue regeneration substrate according to claim 1, further comprising a support member made of a linear support material that is bioabsorbable or biocompatible, which is non-degradable in vivo or has a degradation rate slower than that of the bioabsorbable material, and which is disposed within or along the bioabsorbable substrate.

14. The tissue regeneration substrate according to claim 13, comprising a plurality of annular supports, each of which is spaced apart from one another.

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