JP5563182B2 - Tissue regeneration device precursor with releasable fixation means - Google Patents

Description

  The present invention relates to a precursor for a tissue regeneration device and a method for producing the tissue regeneration device.

  When an accident, disaster, or disease damages tissues such as human nerves and tendons that cannot be cured by their own resilience, patients suffer from impairments in perception, sensation, and motor skills. For such a patient, after excising the damaged part, a treatment may be performed in which tissue is collected from another part of the patient's human body and transplanted to the excised part. Such an operation is called self-transplantation. Since autotransplantation collects other healthy tissues that are not damaged, there are cases in which disturbances such as perception, sensation, and motor ability occur at the site.

  Therefore, various studies have been made on treatment methods for regenerating tissue and restoring its function by implanting a device with a cell proliferation scaffold at the excision site and growing cells along the scaffold from the tissue edge. ing. This research is part of the world's regenerative medicine, and such a device is called a scaffold.

  In regenerative medicine research using scaffolds, those skilled in the art have relied on special cell functions to easily incorporate drugs or cells into devices. However, a device incorporating such a drug or cell not only simply increases the cost of the device but also requires extra labor in terms of storage and safety management of the device. It also requires doctors to have knowledge and skills in handling drugs or cells. For this reason, a doctor who cannot obtain the knowledge and technique cannot handle these instruments.

  For example, the nerve regeneration tube of Patent Document 1 is very difficult to handle because it uses a gel containing collagen, laminin, and the like. This is because the gel has fluidity and the shape is not stable. Moreover, since the water | moisture content in a gel osmose | permeates a collagen body, even if it crosslinks to a collagen body, a collagen body will decompose | disassemble. With this, long-term storage cannot be performed.

  Moreover, although it is disclosed that the Schwann cells are seeded in the nerve regeneration tube of Patent Document 2, the cells can be handled only by a doctor who has knowledge and skills of handling.

  In view of the current state of regenerative medicine described above, the present inventors have intensively studied the development of a regenerative device that does not handle cells, and have invented a tissue regenerative device made of collagen (Patent Document 3). All of these instruments are composed of collagen, which is a biodegradable and absorbable material, and because they do not use a compound such as a crosslinking agent, they are safely decomposed and absorbed in vivo. Moreover, surprisingly, this instrument allows tissue regeneration without incorporating special cells. That is, since it is not necessary to handle drugs or cells, the manufacturer can manufacture this device at low cost. Furthermore, the manufactured appliance does not decompose or deteriorate over a long period of time. A doctor can easily perform treatment using this instrument by any doctor who has general surgical techniques such as incision and suturing without acquiring skills to handle cells.

  The next challenge in the development of these instruments is to increase the added value by improving the handleability. In addition, as described above, the drug or cell is not incorporated, but the handleability is improved in terms of the structure of the instrument. Here, as a shape that can be most easily handled by a doctor, an instrument provided with a space for inserting tissue ends into the lumens at both ends of a cylindrical body as shown in FIG. 1 can be considered.

  For example, as in Patent Documents 1 and 2, if both ends of the instrument are smooth, suturing by an extremely high technique called end-to-end stitching must be performed. Moreover, even if the instrument and the tissue are sutured, the end face of the instrument and the tissue end face are only in contact with each other, and therefore tissue cells may grow on the outer wall of the instrument.

  On the other hand, even if a device having a space for inserting tissue ends in the lumens at both ends is manufactured in advance, the length of the tissue to be regenerated is not constant, so it can only be used for regenerating limited tissue. . For this reason, such a tool cuts according to the length of the tissue to be regenerated, but the cut surface is of course smooth.

  The present inventors have disclosed a nerve regeneration-inducing tube having a space part into which a tissue end is inserted at least at the end (Patent Document 4). Such instruments are cut to match the length of the nerve to be regenerated. And it can be implanted by inserting the nerve end on the central nerve side into the space. However, the peripheral nerve side still forms a smooth end. Since cells do not grow from the peripheral nerve, the adverse effect of cells growing on the outer wall of the device can be prevented, but end-to-end sutures are still used.

International Publication No. 1998/022155 Pamphlet JP 2005-143799 A JP 2002-320630 A JP 2004-208808 A

  An object of the present invention is to provide a precursor for a tissue regenerating instrument that can be adjusted in length so that it can be applied to all cases in use, and that facilitates the production of a tissue regenerating instrument having spaces for insertion at both ends of the tissue end. Is to provide a body.

  As a result of intensive studies, the inventors of the present invention paid attention to the use of the tissue regeneration device after it has been immersed and swollen with a softening solvent in order to improve the handleability when the device is implanted in a living body. It came to complete.

The present invention
[1] A precursor for producing a tissue regeneration device for regenerating tissue,
A tubular body that is a lumen in the longitudinal direction and is made of a biodegradable material;
A precursor of a tissue regenerating instrument that is provided in a lumen of the cylindrical body, and includes a guiding means made of a biodegradable material and a fixing means for releasably fixing the guiding means to the cylindrical body;
[2] The length in the longitudinal direction of the guiding means is shorter than the length in the longitudinal direction of the cylindrical body by the tissue insertion portion formation length (D), and one end of the cylindrical body is aligned with one end of the guiding means. A precursor of the tissue regeneration device according to [1],
[3] The tissue regeneration device precursor according to [2], wherein the tissue insertion portion formation length (D) is 2 to 60 mm,
[4] The precursor of the tissue regeneration device according to [1], wherein the fixing means for releasably fixing is any one selected from the group consisting of a filamentous material, a stapler, a binder, and a combination thereof.
[5] The precursor of the tissue regeneration device according to [1], wherein the fixing means for releasably fixing is a hydrophilic polymer binder,
[6] The precursor of the tissue regeneration device according to [5], wherein the hydrophilic polymer is any one selected from the group consisting of collagen, polylysine, polyglutamic acid, polyethylene glycol, and glycosaminoglycan,
[7] A method for producing a tissue regeneration device for regenerating a linear tissue from a precursor of a tissue regeneration device,
The precursor of the tissue regeneration device is:
A tubular body that is a lumen in the longitudinal direction and is made of a biodegradable material;
Provided in the lumen of the cylindrical body, comprising a guiding means made of a biodegradable material and a fixing means for releasably fixing the guiding means to the cylindrical body,
(1) a step of immersing the precursor of the tissue regeneration device in a softening solvent to swell the precursor;
(2) releasing the fixing means and allowing the guiding means to slide in the cylindrical body cavity;
(3) A step of excising a part of the precursor so that the length in the longitudinal direction of the precursor is the length of the tissue to be regenerated plus the tissue insertion portion formation length (D);
(4) A step of excising a part of the guiding means so that the length in the longitudinal direction of the guiding means is shorter than the length in the longitudinal direction of the cylindrical body by the tissue insertion portion formation length (D); And (5) A method for producing a tissue regenerating instrument, including the step of forming a tissue insertion portion in the lumens at both ends of the cylindrical body by disposing the guiding means at the center of the cylindrical body.
[8] The length in the longitudinal direction of the precursor guiding means is shorter than the length in the longitudinal direction of the tubular body of the precursor by the tissue insertion portion formation length (D), and the length of the tubular body of the precursor is One end and one end of the precursor guiding means are aligned,
The method for producing a tissue regeneration-inducing instrument according to [7], wherein the steps (3) and (4) are performed simultaneously,
[9] The fixing means for the precursor is a hydrophilic polymer binder, and the osmotic pressure adjusting solution is physiological saline,
The method for producing a tissue regeneration induction device according to [7], wherein the steps (1) and (2) are performed simultaneously.
[10] A tissue regeneration device for regenerating a tissue produced from a precursor of a tissue regeneration device,
A tubular body that is a lumen in the longitudinal direction and is made of a biodegradable material;
A tissue regeneration device comprising a guiding means comprising a biodegradable material provided in the lumen of the cylindrical body and a tissue insertion portion provided in both end lumens of the cylindrical body;
[11] A tissue regeneration device for regenerating a tissue produced from a precursor of a tissue regeneration device,
The precursor of the tissue regeneration device is:
A tubular body that is a lumen in the longitudinal direction and is made of a biodegradable material;
Provided in the lumen of the cylindrical body, comprising a guiding means made of a biodegradable material and a fixing means for releasably fixing the guiding means to the cylindrical body;
(1) a step of immersing the precursor of the tissue regeneration device in a softening solvent to swell the precursor;
(2) releasing the fixing means and allowing the guiding means to slide in the cylindrical body cavity;
(3) A step of excising a part of the precursor so that the length in the longitudinal direction of the precursor is the length of the tissue to be regenerated plus the tissue insertion portion formation length (D);
(4) A step of excising a part of the guiding means so that the length in the longitudinal direction of the guiding means is shorter than the length in the longitudinal direction of the cylindrical body by the tissue insertion portion formation length (D); And (5) The present invention relates to a tissue regeneration device produced by the step of forming a tissue insertion portion in the lumens at both ends of the tubular body by disposing the guiding means at the center of the tubular body.

  The precursor of the tissue regeneration device of the present invention can be easily produced into a tissue regeneration device having a space for inserting tissue at both ends. For this reason, a doctor can implant such an instrument easily without requiring a special technique.

  The present invention will be described below with reference to the drawings. FIG. 1 is a view showing a tissue regeneration device A having tissue insertion portions at both ends, which is the final object of the present invention.

  “Tissue regeneration device” refers to a device that has a longitudinal direction, is implanted in a living body, and joins the separated tissue ends together, and both ends of the tissue insert for inserting damaged tissue ends. Part 4 is provided. Further, after implantation, damaged tissue is regenerated along the longitudinal direction of the device, while the device itself refers to a device in the field of regenerative medicine that is decomposed and absorbed in vivo.

  The tissue in the present invention is not particularly limited as long as it can be regenerated by the regenerative ability of the human body. Examples thereof include nerves, tendons, ligaments, blood vessels, and esophagus, and it is particularly suitable for use in regeneration of nerves, tendons, and ligaments.

  The “tissue insertion part” refers to a space provided in the tissue regeneration device A in order to connect the tissue regeneration device A and the tissue end. The length in the longitudinal direction of the tissue insertion portion 4 is not particularly limited because it can be appropriately determined by those skilled in the art depending on the type of tissue to be regenerated. For example, in the case of a nerve, it is about 2 to 40 mm, preferably about 2 to 10 mm, from the viewpoint of facilitating nerve insertion. In the case of tendons, from the viewpoint of facilitating insertion of tendons, the length is about 2 to 60 mm, preferably about 5 to 30 mm. Further, in the case of a ligament, from the viewpoint of facilitating insertion of the ligament, it is about 2 to 60 mm, preferably about 5 to 30 mm. By providing the tissue insertion portion 4, the tissue regeneration device A and the tissue end can be easily coupled without requiring a special suturing technique to prevent the tissue cells from growing into the surrounding tissue. Means for

  The present invention provides a precursor B for producing the tissue regeneration device A of FIG. 1 described above. FIG. 2 is a view showing an embodiment of the precursor B of the tissue regeneration device of the present invention. The precursor B of the tissue regeneration device is a lumen in the longitudinal direction, and is a cylindrical body 1 made of a biodegradable material, and a guiding means 2 made of a biodegradable material provided in the lumen of the cylindrical body 1. And the fixing means 3 which fixes the guidance means 2 to the cylinder 1 so that release | release is possible is provided.

  The “precursor of a tissue regeneration device” refers to one that allows a doctor to produce a target tissue regeneration device A according to the damaged state of a patient's tissue. In the present invention, the precursor B of the tissue regeneration device may be simply referred to as “precursor”. For example, it can be produced by steps such as measuring the length of damaged tissue, measuring the length of the instrument, cutting the instrument, swelling the instrument with a solvent, and deforming the instrument. These steps will be described later.

<Cylindrical body>
The “cylindrical body” refers to a structure that prevents cells of a tissue from growing into surrounding tissues. Examples of the shape of the cylindrical body 1 include a cylindrical shape (tube shape) and a rectangular tube shape (triangle, square, pentagon, and hexagon). Among these, from the viewpoint of easy production, a cylindrical shape (tube shape) is preferable, but the present invention is not limited thereto.

  The length in the longitudinal direction of the cylindrical body 1 is not particularly limited because it depends on the biological classification of the patient or animal, the body shape, and the type of tissue, but the excised tissue that can be assumed by those skilled in the art It is preferable that the length is sufficiently longer than the length. The length of excised tissue that can be envisioned by those skilled in the art is, for example, about 1 to 300 mm when the tissue is a human median nerve. When the tissue is a human sciatic nerve, it is about 1 to 500 mm.

  Therefore, for example, when the tissue is a human nerve, the length of the cylindrical body 1 in the longitudinal direction may be about 5 mm or more from the viewpoint of being applicable to regeneration of any human nerve. From the viewpoint of avoiding an increase in production cost due to the amount of raw material used, the thickness is preferably about 10 to 200 mm. For example, when the tissue is a human ligament, the length of the cylindrical body in the longitudinal direction may be about 5 mm or more. It is the same reasoning as the above-mentioned nerve and is preferably about 10 to 100 mm.

  On the other hand, the inner diameter of the cylindrical body 1 can be appropriately set by those skilled in the art depending on the tissue to be regenerated, and is not particularly limited. For example, when the tissue is a nerve, it is about 1 to 20 mm, preferably about 1 to 10 mm from the viewpoint that the handling frequency may be the highest. For example, when the tissue is a human tendon, the thickness is about 1 to 30 mm, preferably about 1 to 20 mm. Furthermore, for example, when the tissue is a human ligament, it is about 1 to 20 mm, preferably about 1 to 10 mm.

  The cylindrical body 1 is made of a biodegradable material because it is used for regenerative medicine. The biodegradable material refers to a material that is decomposed after being implanted in a living body. Examples thereof include polylactic acid, polyglycolic acid, ε-aminocaprolactone, collagen, and glycosaminoglycans such as chitosan, alginic acid and hyaluronic acid. Among these materials, collagen is preferable from the viewpoint that an inflammatory reaction does not occur and decomposition and absorption can be controlled by a crosslinking treatment or the like.

  “Collagen” refers to the main protein component constituting the connective tissue of animals, and the main chain structure of the molecule is (Gly-XY), (Gly-Pro-X) and (Gly-Pro-Hyp). It means what is composed. Here, X and Y are natural and non-natural amino acids other than glycine, proline and hydroxyproline.

  Examples of collagen types include type I, type II, and type III. Among these, from the viewpoint of easy handling, type I and type III are preferable, but are not limited thereto. The collagen in the present invention includes gelatin which is heat-denatured collagen, and is preferably collagen from the viewpoint of cell adhesion.

  Collagen is produced by extraction from living tissue, chemical polypeptide synthesis, recombinant DNA method, and the like. At the time of filing of the present invention, those obtained by extraction from living tissue are preferable from the viewpoint of manufacturing cost. Examples of the origin of biological tissues include cattle, pigs, rabbits, sheep, mice, birds, fish and humans. Examples of the living tissue include skin, tendon, bone, cartilage, and organ. These selections can be appropriately made by those skilled in the art, and the present invention is not limited to these.

  Furthermore, from the viewpoint of facilitating industrial production, it is preferable to select collagen that has been treated so that it can be dissolved in a solvent. Examples thereof include solubilized collagen such as enzyme-solubilized collagen, acid-solubilized collagen, alkali-solubilized collagen, and neutral-solubilized collagen. Among these, acid-solubilized collagen is preferable from the viewpoint of easy handling. Furthermore, it is preferable that it is atelocollagen from which the removal process of the telopeptide which is an antigenic determinant is performed from a viewpoint of the safety | security at the time of in-vivo implantation.

  Here, although manufacture of the cylindrical body 1 is demonstrated, since the conditions in manufacture can be suitably set by those skilled in the art, the invention is not limited to the following description.

  As a method of manufacturing the cylindrical body 1, for example, (i) a method of directly forming the cylindrical body 1 by an industrial manufacturing method such as injection molding, compression molding and extrusion molding, (ii) a film, a woven fabric, a non-woven fabric, etc. And (iii) a method of producing a single yarn by a spinning method and forming it into a tubular shape. These manufacturing methods can be appropriately set by those skilled in the art depending on the raw material of the cylindrical body 1. For example, when the raw material is collagen, from the viewpoint of easy production and low production cost, (iii) a method of producing a single yarn by a spinning method or the like and forming it into a tubular shape is preferable.

  Examples of the single yarn include those produced by a wet spinning method, a dry spinning method, a melt spinning method, and the like. For example, when the raw material is collagen, the wet spinning method is preferable from the viewpoint of easy production and low production costs.

  In the wet spinning method, for example, an aqueous solution of a biodegradable polymer is discharged into a coagulation bath using a gear pump, a dispenser, various extrusion devices, and the like. In order to perform uniform spinning, a dispenser is preferable from the viewpoint of stable and quantitative discharge of a solution with less pulsation. Moreover, the diameter of the nozzle to discharge is about 10-200 micrometers from a viewpoint of the intensity | strength of a single yarn, Preferably it is about 50-150 micrometers. Further, the concentration of the aqueous solution is about 0.1 to 20% by weight, preferably about 1 to 10% by weight, from the viewpoint of the strength of the single yarn.

  The solvent for the coagulation bath used in wet spinning is not particularly limited as long as it is a solvent, suspension, emulsion, and solution for coagulating the biodegradable polymer. For example, when collagen is used as a raw material for the filamentous material, an inorganic salt aqueous solution, an inorganic salt-containing organic solvent, alcohols, ketones and the like can be mentioned. Examples of the inorganic salt aqueous solution include aqueous solutions of sodium sulfate, sodium chloride, ammonium sulfate, calcium chloride, and magnesium chloride. Moreover, you may use the liquid which melt | dissolved or disperse | distributed these inorganic salts in alcohol or acetone. Examples of alcohols include methanol, ethanol, isopropanol, amyl alcohol, pentanol, hexanol, and ethylene glycol. Examples of ketones include acetone and methyl ethyl ketone. Among these, from the viewpoint of the strength of the spun yarn, it is preferable to use ethanol, an ethanol solution of sodium chloride, and an ethanol dispersion solution of sodium chloride.

  The yarn of the biodegradable material discharged to the coagulation bath is pulled up from the coagulation bath, and then formed into a cylindrical body 1 by winding it around a rod-shaped body through a drying process. Here, in the drying step, the collagen is not thermally denatured, the droplets in the coagulation bath attached to the periphery of the single yarn are removed, and the drying is performed under such conditions that the single yarn does not break. At this time, it is preferable that some solvent remains inside the single yarn. This is because, after being wound into a rod shape, the remaining solvent oozes out to the outside of the single yarn, whereby a part of the single yarn is redissolved and the adjacent single yarns are bonded to each other. By drying in a state where such adjacent single yarns are bonded to each other, the cylindrical body 1 with further improved strength can be formed. As a drying method that satisfies the above requirements, for example, when a collagen aqueous solution is spun by discharging into an ethanol coagulation bath, the spinning speed (= winding speed or pulling speed) is about 10 to 10,000 m / min, humidity A method of blowing and drying air under conditions of about 50% or less and a temperature of 43 ° C. or less can be mentioned.

  Moreover, in the manufacture of the cylindrical body 1, a method of laminating a plurality of layers by wrapping the rod-shaped body several times can be mentioned. At this time, the strength is further improved by making the winding density of the single yarn of at least one layer different from the winding density of the single yarn of the other layers. The winding density in the present invention refers to the number of windings per unit length of the cylindrical body 1 in the longitudinal axis direction. For example, the winding density of the single yarn of at least one layer is preferably less than 10 turns / cm, and the winding density of the single yarn of the other layers is preferably about 10 to 30 turns / cm. For details, refer to the disclosure of Japanese Patent Application Laid-Open No. 2004-072221.

  The strength can also be improved by applying a biodegradable material solution to the side wall of the cylindrical body 1 and drying it. The biodegradable material used for this treatment is preferably the same material as the material of the tubular body 1 from the viewpoint of good adhesion to the material of the tubular body 1. The concentration thereof is, for example, about 0.1 to 20% by weight, preferably about 1 to 10% by weight from the viewpoint of easy handling of the solution when the biodegradable polymer is collagen.

  Moreover, it is preferable that the cylindrical body 1 is further subjected to a crosslinking treatment if necessary. By this crosslinking treatment, the degradation time in the living body of the tissue regeneration device A produced from the precursor can be controlled. Examples of the crosslinking method include chemical crosslinking with a crosslinking agent, γ-ray irradiation, ultraviolet irradiation, electron beam irradiation, plasma irradiation, and thermal dehydration crosslinking. In particular, thermal dehydration crosslinking is preferable from the viewpoint of safety after in vivo implantation. The conditions for thermal dehydration crosslinking are a crosslinking temperature of about 100 to 140 degrees and a crosslinking time of 6 to 72 hours. In particular, from the viewpoint of suppressing crosslinking efficiency and thermal decomposition, the crosslinking temperature is preferably about 110 to 130 degrees and the crosslinking time is 12 to 48 hours.

<Guiding means>
The lumen of the cylindrical body 1 is provided with guiding means 2 made of a biodegradable material. “Induction means” refers to a cell that becomes a scaffold for inducing growth in the longitudinal direction of cells of damaged tissue. Examples of the form include sponges, fiber bundles, and membranes such as woven fabrics, nonwoven fabrics, and sheets that are deformed or shredded. In particular, a sponge is preferable from the viewpoint of allowing cells to grow uniformly in the lumen of the cylindrical body, and a fiber bundle is preferable from the viewpoint of ease of growth in the longitudinal direction of the cylindrical body. The guiding means 2 may be a combination of a sponge and a fiber bundle.

  “Sponge” refers to a porous body in which pores of uniform or non-uniform size are dispersed continuously or discontinuously. The porosity of the sponge is 10 to 99%, preferably about 50 to 99.9%, from the viewpoint of maintaining a scaffold in which cells can grow and a space.

  Examples of the method for producing a sponge include a method in which a solution of a biodegradable material is poured into a mold produced according to a target shape, and formed by a method such as natural drying, vacuum drying, freeze thawing, and vacuum freeze drying. . In particular, the vacuum freeze-drying method is preferable from the viewpoint of forming pores uniformly. Examples of the conditions of the vacuum freeze-drying method include a method of performing a solution of about 0.05 to 30% by weight of a biodegradable material under a condition of about 0.08 Torr or less from the viewpoint of ease of production.

  On the other hand, the “fiber bundle” refers to one composed of at least two filaments, and each filament is about 45 degrees or less, preferably about 30 degrees or less with respect to the longitudinal direction of the cylindrical body 1. An array arranged at an angle of Each filamentous material may be parallel or non-parallel.

  In the present invention, the “filament” constituting the fiber bundle is a general term for single yarn and kite yarn. In particular, from the viewpoint of production cost, a single yarn is preferable. What is necessary is just to manufacture a single yarn with the manufacturing method similar to the single yarn which comprises the cylindrical body 1 mentioned above.

  Further, the filaments of the fiber bundle are filled with about 1 to 99%, preferably about 10 to 30%, of filaments having an outer diameter of about 1 to 10,000 μm from the viewpoint of maintaining a scaffold in which cells can grow and a space. What is necessary is just to fill the lumen | bore of the cylindrical body 1 at a rate. Here, the “filling rate” refers to the ratio of the occupied volume of the fiber bundle to the lumen volume of the cylindrical body 1.

  As a method for forming a fiber bundle, for example, after wet spinning, a single plate is wound around a rectangular plate or frame having at least two opposite sides parallel to each other multiple times so as to be substantially perpendicular to the two sides, and wound. There is a method obtained by cutting the obtained single yarn near two sides. The winding speed of the plate-like body and the frame may be the same as the conditions for manufacturing the tubular body 1 from the single yarn described above.

  A person skilled in the art can appropriately select the shape, material, manufacturing conditions, and the like in the guiding means 2 described above, and the present invention is not limited to these.

  In addition, the length in the longitudinal direction of the guiding means 2 is a viewpoint that can easily produce the tissue regeneration device A including the tissue insertion portion 4 for inserting tissue at both ends, which is the subject of the present invention. As shown in FIG. 3, it is preferable to align one end of the cylindrical body 1 and one end of the guiding means 2 in a state shorter than the length in the longitudinal direction of the cylindrical body 1 by the tissue insertion portion formation length (D). “Tissue insertion part formation length” refers to a length necessary for providing the tissue insertion part 4 at both ends. Hereinafter, in the present invention, the tissue insertion portion formation length may be abbreviated as D. The specific length can be appropriately determined by those skilled in the art depending on the tissue to be regenerated, and is not particularly limited, but may be about 2 to 4 times the length of the tissue insertion portion 4 in the longitudinal direction. That's fine. In particular, about 2 times, that is, about 4 to 60 mm is preferable from the viewpoint of easy tissue insertion. Further, by aligning one end of the cylindrical body 1 and one end of the guiding means 2, the end surface becomes substantially smooth, and therefore the aligned end is also referred to as “smooth end” in the present invention. On the other hand, the other end of the precursor B is not aligned with one end of the cylindrical body 1 and one end of the guiding means 2 and forms a space. In the present invention, this space is also referred to as a “space portion”. Say.

<Fixing means>
The guiding means 2 obtained in this way is inserted into the lumen of the cylindrical body 1. Here, if the guiding means 2 is simply inserted into the lumen of the cylindrical body 1, the guiding means 2 slides down from the lumen of the cylindrical body 1, resulting in a problem that the guiding means 2 is contaminated.

  For example, the collagen body of Patent Document 2 is not fixed to the tube, and the collagen body slides in the tube. The collagen body may fall out of the tube during transportation or use, and the collagen body may be contaminated.

  On the other hand, in order to solve this problem, it can be considered that the collagen body of Patent Document 2 is closely packed in the lumen of the tube. However, there is a possibility that the tube may be deformed by swelling with physiological saline before implantation.

  Similarly, the fiber made of the synthetic bioabsorbable polymer of Patent Document 3 is not fixed to the tubular body, and the fiber bundle slides in the tubular body. For this reason, there is a problem similar to that of Patent Document 2.

  Also in Patent Document 3, it is conceivable to densely fill the lumen of the tubular body with a fiber made of a synthetic bioabsorbable polymer. However, there is a possibility that the tube may be deformed by swelling with physiological saline before implantation.

  In order to prevent this problem, the present invention includes a fixing means 3 for fixing the guiding means 2 to the cylindrical body 1. However, when the fixing means 3 is simply provided, when the organ regeneration device A is manufactured from the precursor B, the tissue regeneration device A provided with the tissue insertion portions 4 for inserting tissues at both ends, which is the subject of the present invention. Can not produce.

  For example, the instrument of Patent Document 4 cuts according to the length of the nerve to be regenerated. And it can be implanted by inserting the nerve end on the central nerve side into the space. However, since the matrix and / or nerve guideway is fixed to the tubular body, there is no problem that the matrix and / or nerve guideway falls off during transportation or use, but the peripheral nerve side forms a smooth end. There is a problem.

  From the above, the precursor B of the present invention includes the fixing means 3 for releasably fixing the guiding means 2 to the cylindrical body 1. The “fixing means for releasably fixing” means that the guiding means 2 is fixed to the cylindrical body 1 at the time of manufacturing and transporting the precursor B, but is released when the organ regeneration device A is produced from the precursor B. The guiding means 2 can be slidable in the lumen of the cylindrical body 1. For example, what is any 1 selected from the group which consists of a filamentous material, a stapler, a binder, and these combinations is mentioned. The thread and the stapler can be fixed so as to penetrate the guiding means 2 from the outer wall of the cylindrical body 1. Then, the fixing means 3 can be released by physically removing the fixing means 3 as it is.

  The “binder” refers to a polymer composition having a so-called adhesive function, which is interposed between the cylindrical body 1 and the guiding means 2 and has an anchor effect, physical adsorption, covalent bond, ionic bond. , Which can be bonded by a hydrophobic bond, a coordinate bond, a hydrogen bond, or the like. As a fixing method using these binders, for example, after preparing a polymer solution having an adhesive function, the solution is applied to the inner wall of the cylindrical body 1 or the guiding means 2, and the guiding means 2 is the lumen of the cylindrical body 1. And a method of drying the solvent after insertion.

  On the other hand, the release of the binder is achieved by a treatment that is a good solvent for the polymer constituting the binder. Such a good solvent is called a binder solvent in the present invention. However, this binder solvent must be a poor solvent for the biodegradable polymer constituting the precursor B so as not to dissolve the precursor B itself during processing. Therefore, if the binder solvent is determined, the polymer constituting the binder can be easily selected.

  For example, when the biodegradable polymer is collagen and the collagen is cross-linked, such a solvent for binder is not a strong acid or alkali that decomposes the main chain skeleton of collagen. Is applicable. Specific examples include water, methanol, ethanol, acetone, hexane, benzene, xylene, 1,2-dichloromethane, chloroform, tetrahydrofuran and dimethyl sulfoxide. Although water is particularly preferable from the viewpoint of not affecting the living body even if it remains in the device after treatment, the present invention is not limited to these.

  Examples of water include tap water, distilled water, reverse osmosis water, and ion exchange water. Further, it may contain a physiologically acceptable salt such as physiological saline. Here, the tissue regeneration device A is generally immersed in physiological saline to soften the precursor B of the tissue regeneration device. Therefore, the physiological saline is preferable from the viewpoint that the step of swelling the precursor B of the present invention and the step of releasing the binder can be simultaneously performed.

  For example, when the biodegradable polymer is cross-linked collagen and physiological saline is used as the binder solvent, the polymer constituting the binder is not particularly limited as long as it is a hydrophilic polymer. . Examples of such hydrophilic polymers include uncrosslinked collagen, polylysine, polyglutamic acid, polyethylene glycol, and glycosaminoglycans such as alginic acid, chitosan, hyaluronic acid, and chondroitin sulfate. Among these, uncrosslinked collagen is preferred from the viewpoints of adhesiveness with the crosslinked collagen constituting the cylindrical body 1 and the guiding means 2 and that there is no influence on the living body even if it remains in the precursor B after the treatment.

<Production of tissue regeneration equipment>
Hereinafter, a method for producing the tissue regeneration device A from the precursor B of the tissue regeneration device of the present invention will be described with reference to the drawings. Note that the precursor B of the tissue regeneration device is all made of collagen, and the fixing means 3 is a binder of uncrosslinked collagen. However, as described above, the present invention is not limited to these.

The method for producing the tissue regeneration device A of the present invention includes:
(1) A step of swelling the precursor B by immersing the precursor B of the tissue regeneration device in a softening solvent;
(2) releasing the fixing means 3 and allowing the guiding means 2 to slide in the lumen of the cylindrical body 1;
(3) A step of excising a part of the precursor B1 so that the length in the longitudinal direction of the precursor B1 is the length of the tissue to be regenerated plus the tissue insertion portion formation length (D);
(4) A step of excising a part of the guiding means 2 such that the length in the longitudinal direction of the guiding means 2 is shorter than the length in the longitudinal direction of the cylindrical body 1 by the tissue insertion portion formation length (D); And (5) including a step of forming the tissue insertion portion in the lumens at both ends of the cylindrical body by disposing the guiding means at the center of the cylindrical body.

(1) Step of immersing precursor B of tissue regeneration device in softening solvent and swelling precursor B First, in order to improve the handleability of the suture of the precursor B of the tissue regeneration device of the present invention at the time of implantation. Soak in a softening solvent. The softening solvent is not particularly limited as long as it is a solution that softens the precursor B of the tissue regeneration device, but physiological saline is mainly used.

(2) The step of releasing the fixing means 3 and making the guiding means 2 slidable in the lumen of the cylindrical body 1 In the above-mentioned step (1), the uncrosslinked collagen is dissolved in physiological saline, so that the fixing means 3 is released. If the fixing means 3 is a stapler other than uncrosslinked collagen, for example, the stapler may be removed. The fixing means 3 including the stapler may be removed before or after the above-described step (1), but is performed after the step (1) from the viewpoint of facilitating the removal of the fixing means 3 due to the swelling of the precursor B. It is preferable. In this way, in the swollen precursor B1, the frictional resistance increases due to the wetting of the cylindrical body 1 and the guiding means 2, so that the guiding means 2 can slide in the lumen of the cylindrical body 1. However, it does not slide down from the lumen.

(3) Step of excising a part of the precursor B so that the length in the longitudinal direction of the precursor B is the length of the tissue to be regenerated plus the tissue insertion portion formation length (D) Next Furthermore, according to the length of the tissue to be regenerated, a part of the precursor B1 is excised to adjust the length. Specifically, the length in the longitudinal direction of the precursor B is the length obtained by adding the tissue insertion portion formation length (D) to the length of the tissue to be regenerated (hereinafter sometimes abbreviated as L in the present invention). Thus, the precursor B1 is excised (FIG. 4: B1 to B2). For example, when the tissue to be regenerated is a nerve, the length of the nerve to be regenerated (L) is 100 mm, and the tissue insertion portion formation length (D) is 20 mm, the length of the precursor B1 is 120 mm. Cut out so that The resection can be performed using a cutting instrument such as scissors, a microtome, and a scalpel. In this way, in the swollen precursor B2, the frictional resistance increases due to the wetting of the cylindrical body 1 and the guiding means 2 generated in the step (1), so that the guiding means 2 passes through the lumen of the cylindrical body 1. Can slide, but will not slide out of the lumen. In addition, before implementing this process, when the length of the precursor B1 respond | corresponds to the length of the structure | tissue which should be reproduced | regenerated, it considers that this process was implemented without doing anything.

(4) A step of excising a part of the guiding means 2 so that the length in the longitudinal direction of the guiding means 2 is shorter than the length in the longitudinal direction of the cylindrical body 1 by the tissue insertion portion formation length (D); Then, the guiding means 2 is slid in the lumen of the cylindrical body 1 and protruded from the one end of the cylindrical body 1 by the tissue insertion portion formation length (D) (FIG. 5: B2 to B3). The length of the guiding means 2 in the longitudinal direction is adjusted by cutting off the protruding portion (FIG. 5: B3 to B4). This length is substantially the same as the length of the excised tissue of the affected area. For example, when the tissue to be regenerated is a nerve, the tissue insertion portion formation length (D) is 20 mm, and the length of the precursor B is 120 mm, the length in the longitudinal direction of the guiding means 2 obtained by the above operation The length (L: length of nerve to be regenerated) is 100 mm.

  Here, as shown in FIG. 3, the length of the longitudinal method of the guiding means 2 is shorter than the length in the longitudinal direction of the cylindrical body 1 by the tissue insertion portion formation length (D). In the case of a structure in which one end of means 2 is aligned (structure having a smooth end), if part of the precursor B′1 on the smooth end 5 side is removed in the above-described step (2), this step is also performed simultaneously. Therefore, it is preferable (FIG. 6: B′1 to B′2).

(5) Step of forming the tissue insertion portion 4 in the lumens at both ends of the cylindrical body 1 by disposing the guiding means 2 in the center of the cylindrical body 1 Thereafter, the longitudinal center point of the guiding means 2 and the cylindrical shape If the body 1 is slid so that the midpoints in the longitudinal direction overlap each other, the length in the longitudinal direction is half the tissue insertion part formation length (D) (D / 2). Can be provided at both ends (FIG. 7: B4 to A or B′2 to A).

  As described above, the tissue regeneration device A produced from the precursor B of the tissue regeneration device of the present invention has the tissue insertion portions 4 at both ends, so that it is implanted only by inserting the tissue end. Therefore, the implantation operation can be easily performed without performing suturing or the like. Further, it is possible to prevent the adverse effect that cells grow along the outer wall of the cylindrical body 1.

  Examples of the present invention are shown below, but the present invention is not limited thereto.

Example 1: Manufacture of precursor B of tissue regeneration device (1) Manufacture of cylindrical body 1 Enzyme-solubilized collagen was dissolved in water to prepare a 5% aqueous solution. By discharging the collagen solution into a 99.5% ethanol coagulation bath, a collagen single yarn having a diameter of about 200 μm was spun. The collagen single yarn pulled up from the ethanol coagulation bath was wound around a cylindrical mold made of polyfluorinated ethylene fiber having an outer diameter of 3.0 mm at a speed of about 4,000 mm / min, and then dried. Next, this product was immersed in a 5% collagen aqueous solution and dried to form the innermost layer of the cylindrical body 1. Further, the collagen single yarn is wound again around the innermost layer of the cylindrical body 1 at a speed of about 4,000 mm / min, and the pressure is reduced (1 torr) in a vacuum dry oven (EYELA: VOS-300VD type). The following was subjected to thermal dehydration crosslinking reaction at 120 ° C. for 24 hours. The obtained cylindrical body was again immersed in a 5% collagen aqueous solution, dried, and then subjected to a thermal crosslinking treatment, whereby a cylindrical body made of crosslinked collagen having an inner diameter of 3.0 mm, an outer diameter of 3.3 mm, and a length of 70 mm. Body 1 was produced.

(2) Manufacture of the guiding means 2 In the above-described wet spinning using the ethanol coagulation bath, the single yarn pulled up from the coagulation bath is blown and dried under conditions of a temperature of about 25 degrees and a humidity of 50% or less, about 150 mm × 150 mm. Wrapped around a frame with a rectangular shape. The spinning speed at this time was about 4,000 mm / min. Next, a thermal dehydration cross-linking reaction was performed at 120 ° C. for 24 hours in a vacuum dry oven (manufactured by EYELA: VOS-300VD type) under reduced pressure (1 torr or less) while being wound around the frame. And the wound thread | yarn was cut | disconnected so that length might be set to about 50 mm, and it bundled so that it might become a column shape with an outer diameter of about 3.0 mm. This cylindrically bundled product is impregnated with 5% by weight collagen aqueous solution, and thermally crosslinked again under reduced pressure (1 torr or less) at 120 ° C. for 24 hours in a vacuum dry oven (manufactured by EYELA: VOS-300VD type). In this way, the guiding means 2 made of a fiber bundle made of crosslinked collagen having an outer diameter of about 3.0 mm and a length of 50 mm was produced. The length of the guiding means 2 in the longitudinal direction is 20 mm shorter than the length of the cylindrical body 1 in the longitudinal direction. That is, the tissue insertion portion formation length (D) is 20 mm.

(3) Production of Precursor B ′ of Tissue Regeneration Device in FIG. 3 Fixing means 3 made of 5% collagen aqueous solution (binder) was applied around the guiding means 2 made of crosslinked collagen. Next, one end of the guiding means 2 was inserted into the lumen of the cylindrical body 1 so as to align with one end of the cylindrical body 1. By drying in this state, the guiding means 2 was fixed to the cylindrical body 1 with a binder of uncrosslinked collagen, and the precursor B of the tissue regeneration device shown in FIG. 3 was obtained. That is, the guiding means 2 is present in the lumen on one end side of the cylindrical body 1 to form the smooth end 5, but the guiding means 2 is not present in the lumen on the other end side of the cylindrical body 1. The precursor B thus obtained was subjected to 25 kGy γ-ray sterilization treatment.

Example 2: Production of tissue regeneration device A The precursor B 'of the tissue regeneration device obtained in Example 1 was immersed in physiological saline for 20 minutes to swell the device precursor B'. Next, the precursor B′1 was excised using a microtome at a position 20 mm from the smooth end 5 (FIG. 6: B′1 to B′2). That is, the length of the cylindrical body 1 in the longitudinal direction is 50 mm, and the length of the guiding means 2 in the longitudinal direction (L: the length of the tissue to be regenerated) is 30 mm. Thereafter, the tissue regenerating instrument A provided with the tissue insertion portions 4 at both ends was produced by sliding the guiding means 2 10 mm in the lumen of the cylindrical body 1 and disposing it at a substantially central position (FIG. 7: B). '2-A).

  The precursor of the tissue regeneration device of the present invention can be easily produced into a tissue regeneration device having a space for inserting tissue at both ends. For this reason, a doctor can easily implant such an instrument without requiring a special technique, and regenerative medicine using a scaffold will spread to the medical industry.

It is a figure which shows the tissue regeneration instrument A which is the final objective of this invention. It is a figure which shows one embodiment (B) of the precursor of the structure | tissue regeneration instrument of this invention. It is a figure which shows the modification (B ') of the precursor of the tissue regeneration instrument of this invention. It is a figure which shows the process of excising the precursor B1 of the tissue reproduction | regeneration instrument of FIG. 2 swollen. FIG. 5 is a diagram showing a step of cutting off the protruding portion after sliding and protruding the guiding means 2 from the tissue regeneration device precursor B2 after the step of FIG. FIG. 4 is a diagram showing a step of excising a swollen precursor B′1 of the tissue regeneration device of FIG. 3. It is a figure which shows the process of sliding the guidance means 2 and providing the structure | tissue insertion part 4 at both ends after the process of FIG. 5 or FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Cylindrical body 2 Guidance means 3 Releasable fixing means 4 Tissue insertion part 5 Smooth end A Tissue regeneration instrument B, B1-B4, B ', B'1, B'2 Tissue regeneration instrument precursor

Claims (6)

A precursor for producing a tissue regeneration device for regenerating tissue,
A tubular body that is a lumen in the longitudinal direction and is made of a biodegradable material;
Provided in the lumen of the cylindrical body, comprising a guiding means made of a biodegradable material and a fixing means for releasably fixing the guiding means to the cylindrical body ,
The fixing means for releasably fixing is a hydrophilic polymer binder,
The fixing means is released by immersing in a softening solvent,
The guide means is slidable inside the cylindrical body by releasing the fixing means,
A precursor of a tissue regeneration device, wherein the softening solvent is water .   The length in the longitudinal direction of the guiding means is shorter than the length in the longitudinal direction of the cylindrical body by a tissue insertion portion formation length (D), and one end of the cylindrical body and one end of the guiding means are aligned. The precursor of the tissue regeneration device according to 1.   The tissue regeneration device precursor according to claim 2, wherein the tissue insertion portion formation length (D) is 2 to 60 mm. The precursor of a tissue regeneration device according to claim 3 , wherein the hydrophilic polymer is any one selected from the group consisting of collagen, polylysine, polyglutamic acid, polyethylene glycol, and glycosaminoglycan. A method of producing a tissue regeneration device for regenerating linear tissue from a precursor of a tissue regeneration device,
The precursor of the tissue regeneration device is:
A tubular body that is a lumen in the longitudinal direction and is made of a biodegradable material;
Provided in the lumen of the cylindrical body, comprising a guiding means made of a biodegradable material and a fixing means for releasably fixing the guiding means to the cylindrical body ,
The fixing means for releasably fixing is a hydrophilic polymer binder,
The fixing means is released by immersing in a softening solvent,
The guide means is slidable inside the cylindrical body by releasing the fixing means,
The softening solvent is a precursor of a tissue regeneration device, which is water,
(1) a step of immersing the precursor of the tissue regeneration device in a softening solvent to swell the precursor;
(2) releasing the fixing means and allowing the guiding means to slide in the cylindrical body cavity;
(3) A step of excising a part of the precursor so that the length in the longitudinal direction of the precursor is the length of the tissue to be regenerated plus the tissue insertion portion formation length (D);
(4) A step of excising a part of the guiding means so that the length in the longitudinal direction of the guiding means is shorter than the length in the longitudinal direction of the cylindrical body by the tissue insertion portion formation length (D); And (5) including a step of forming a tissue insertion portion in both end lumens of the cylindrical body by disposing the guiding means in the center of the cylindrical body ,
A method for producing a tissue regeneration device, wherein the steps (1) and (2) are performed simultaneously . The length in the longitudinal direction of the precursor guiding means is shorter than the length in the longitudinal direction of the tubular body of the precursor by a tissue insertion portion formation length (D), and the one end of the tubular body of the precursor and the end One end of the precursor guiding means,
6. The method for producing a tissue regeneration guidance device according to claim 5 , wherein the steps (3) and (4) are performed simultaneously.

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