JP2012161508A - Precursor for tissue reproducing instrument and manufacturing method therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a precursor for a tissue reproducing instrument which can be produced more easily.SOLUTION: This precursor for producing the tissue reproducing instrument which reproduces a tissue comprises: a cylindrical element that is an inner lumen in the longitudinal direction, and made of biodegradable material; and a guide means, made of biodegradable material, the guide means is held on the inner wall of the cylindrical element with a restoring force produced when the guide means is deformed. Preferably, the guide means is kept bent inside the lumen of the inner wall of the cylindrical element and held on the inner wall of the cylindrical element with the force restoring to its original linear shape.

Description

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

  When tissues such as human nerves and tendons are damaged due to accidents, disasters, or diseases and cannot be cured by their own resilience, the patient's perception, sensation, motor ability, etc. are impaired. 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. The main structure of such an instrument is a cylindrical body that prevents the entry of other cells from the outside, and is inserted into the lumen of the cylindrical body to induce nerve cells to grow in the longitudinal direction. Guiding means are provided. In most cases, a fiber bundle is adopted as the guiding means.

  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 without the knowledge and skill cannot handle these instruments.

  In view of the current state of regenerative medicine described above, the present inventors have intensively studied development of a regenerative device that does not handle cells, and have invented a tissue regenerative device made of collagen (Patent Document 1). 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.

  By the way, the tissue regeneration instrument may be improved in ease of handling by swelling with a softening solution such as physiological saline before implantation. At this time, there is a problem that the tissue regeneration instrument is deformed. In order to solve the problem, the present inventors mainly made the outer diameter of the guiding means smaller than the inner diameter of the cylindrical body in the non-swelled state, and the inner diameter of the cylindrical body in the saturated swelling state. An invention is disclosed in which the outer diameter of the guiding means is substantially the same (Patent Document 2). At this time, since the inner diameter of the cylindrical body is larger than the outer diameter of the guiding means at the time of drying, it is necessary to prevent the guiding means from dropping from the cylindrical body at the time of transporting the product. It is necessary to fix to the cylindrical body wall. However, this fixing operation is a complicated operation.

JP 2003-245341 A JP 2008-043597 A

  An object of the present invention is to provide a precursor for a tissue regeneration device that is easier to manufacture.

  The present invention includes a tubular body made of a biodegradable material and a guide means made of a biodegradable material, which is a lumen in the longitudinal direction, and the guide means is formed by the force of the guide means itself. A precursor of a tissue regeneration device is provided which is locked to an inner wall of a body.

  In the present invention, the guiding means is a fiber bundle and is deformed in the lumen of the cylindrical body, and is locked to the inner wall of the cylindrical body by a restoring force of the fiber bundle. The aspect formed is preferable.

  In the present invention, it is preferable that the guiding means is configured such that the lumen of the cylindrical body is dense on a plane orthogonal to the lumen when the saturated swelling state is present.

  The tissue regeneration device of the present invention is easier to manufacture and further reduces the cost of the product.

It is a figure which shows the tissue regeneration instrument produced from the precursor of this invention. It is a figure which shows one embodiment of this invention. It is a real photograph of the embodiment of FIG. FIG. 3 is a diagram showing an embodiment different from the embodiment of FIG. 2 of the present invention. FIG. 5 is a diagram showing an embodiment different from the embodiments of FIGS. 2 and 4 of the present invention. FIG. 6 shows an embodiment different from the FIGS. 2, 4 and 5 aspects of the present invention.

1 Tubular body 2 Guide means, fiber bundle

  The present invention will be described below. FIG. 1 is a view showing a tissue regeneration device produced from the precursor of the present invention. The tissue regeneration device includes a cylindrical body 1 and a guiding means 2 in the lumen of the cylindrical body 1, and the guiding means 2 can slide in the lumen of the cylindrical body 1. A frictional force that does not fall from the lumen of the body 1 is acting. However, in the precursor described later, as described above, since the outer diameter of the guiding means is smaller than the inner diameter of the cylindrical body, the guiding means falls from the cylindrical body. Therefore, in order to prevent this, the present invention becomes important.

  The “tissue regeneration device” of the present invention 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 are for inserting damaged tissue ends. The tissue insertion part 4 is formed. In addition, after implantation, damaged tissue is regenerated along the longitudinal direction of the device, but 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 include nerves, tendons, ligaments, blood vessels, and canteens. In particular, it can be suitably used for regeneration of nerves, tendons and ligaments where there are relatively many cases.

  The present invention provides a precursor for producing the tissue regeneration device of FIG. 1 described above. FIG. 2 is a view showing an embodiment of the precursor of the tissue regeneration device of the present invention. The precursor of the tissue regeneration device is a lumen in the longitudinal direction, and 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. Is provided. The guiding means 2 is in a deformed state in the lumen of the cylindrical body 1 and is locked in the lumen by a restoring force acting so that the guiding means 2 returns to its original state.

  The “precursor of a tissue regeneration device” refers to a product for a doctor to produce a target tissue regeneration device according to a damaged state of a patient's tissue. In the present invention, the precursor of the tissue regeneration device may be simply abbreviated as “precursor”. The method of producing a tissue regeneration device from a precursor is, for example, produced by steps such as measuring the length of damaged tissue, measuring the length of the device, cutting the device, swelling the device with a solvent, and deforming the device. Can do. These steps will be described later.

  Further, when producing a tissue regeneration device from a precursor, the precursor is immersed and swollen in a softening solvent in order to improve the handleability. The “non-swelled state” refers to the state before the step of immersing / swelling in the solution, and the “saturated swollen state” refers to the state in which the swelling is saturated after being immersed in the solution. The conditions for immersion and swelling in the present invention are based on a softening solvent having a humidity of 60% and a temperature of 25 to 40 ° C. under atmospheric pressure.

  The “softening solvent” refers to a solution that softens the precursor of the tissue regeneration device. Although physiological saline is mainly used, it is not limited to this. “Saline” refers to a 0.9 wt% aqueous sodium chloride solution that is approximately isotonic with human body fluids. The time until sufficient handling is possible depends on the precursor material. The relationship between the saturated swelling state and the precursor material 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). In particular, from the viewpoint of easy production, a cylindrical shape (tube shape) is preferable, but the present invention is not limited to these.

  The length in the longitudinal direction of the cylindrical body 1 is not particularly limited because it depends on the biological classification, body type, and tissue type of the patient or livestock, 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 longitudinal length of the cylindrical body may be about 5 mm or more, and 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. A biodegradable material refers to a material that, when implanted in a living body, is decomposed, preferably absorbed after decomposition. Examples thereof include polylactic acid, polyglycolic acid, ε-aminocaprolactone, collagen, and chitosan. 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), (Gly-Pro-Hyp), etc. It is composed of Here, X and Y are natural or non-natural amino acids other than glycine, proline and hydroxyproline.

  Examples of collagen types include type I, type II, and type III. In particular, from the viewpoint of easy handling, type I and type III are preferable, but 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 animal skin, tendons, bones, cartilage, and organs listed above. 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. In particular, 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 present 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 method such as injection molding, compression molding, and extrusion molding, (ii) a film, a woven fabric, a non-woven fabric, and the like And (iii) a method of producing a single yarn by a spinning method and forming it into a tubular shape, and the like. 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, those produced by a wet spinning method are preferred from the viewpoint of easy production and low production costs.

  The wet spinning method is performed, for example, by discharging an aqueous solution of a biodegradable polymer 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. The diameter of the nozzle to be discharged is about 10 to 200 μm, preferably about 50 to 150 μm, from the viewpoint of increasing the strength of the single yarn. 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 of 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 increasing the strength of the spun yarn, it is preferable to use an ethanol dispersion solution of ethanol and 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 cylindrical body through a drying process. Here, the drying step is performed under conditions such that collagen is not thermally denatured, droplets of the coagulation bath attached around the single yarn are removed, and the single yarn is not broken. 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, so that a part of the single yarn is redissolved and the adjacent single yarns adhere 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 into an ethanol coagulation bath for spinning, the spinning speed (winding speed or pulling speed) is about 10 to 10,000 mm / min, and the humidity is about A method in which air is blown and dried under conditions of 50% or less and a temperature of 43 ° C. or less can be mentioned.

  Moreover, as a manufacturing method of the cylindrical body 1, the method of laminating | stacking a single thread | yarn around a cylindrical body in multiple layers is 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 at least one layer of single yarn is preferably less than 10 turns / cm, and the winding density of single yarns of other layers is preferably 10 to 30 turns / cm. For details, refer to the disclosure of Japanese Patent Application Laid-Open No. 2004-072221.

  Moreover, the intensity | strength of the cylindrical body 1 also improves by apply | coating and drying a biodegradable material solution to the side wall of the cylindrical body 1. FIG. The biodegradable material used for this treatment is preferably the same material as the material of the cylindrical body 1 from the viewpoint of improving the adhesiveness with the material of the cylindrical body 1. In addition, for example, when the biodegradable polymer is collagen, the concentration is about 0.1 to 20% (w / w), preferably about 1 to 10% (w / W).

  Moreover, it is preferable that the cylindrical body 1 is further subjected to a crosslinking treatment if necessary. By this crosslinking treatment, it is possible to control the degradation time in vivo of the tissue regeneration device produced from the precursor. 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 even when embedded in a living body. 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>
A guide means 2 is provided in the lumen of the cylindrical body 1. “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 guiding means 2 include a sponge and a fiber bundle, and a fiber bundle is preferable from the viewpoint of providing directionality in the cell growth direction.

  Here, the “fiber bundle” is a scaffold in which cells of damaged tissue induce growth in the longitudinal direction, and a plurality of filaments made of biodegradable materials are arranged in parallel to form a bundle. Say. The “filament” is a general term for single yarn and kite yarn. In particular, from the viewpoint of low production cost, the filamentous material is preferably a single yarn. A single yarn can be manufactured by the same manufacturing method as the single yarn which comprises the cylindrical body 1 mentioned above. Moreover, the external shape of the guidance | induction means 2 is not specifically limited, For example, rod-shaped shapes, such as a quadratic prism, a triangular prism, and a cylinder, are mentioned.

  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.

  Then, a fiber bundle is obtained by adhering adjacent filaments. Examples of the bonding method include a method in which a bundle of filamentous materials is immersed in a biodegradable polymer solution and then dried. Moreover, when the filamentous material is a single yarn made of cross-linked collagen, a method of immersing the bundle of the single yarn in water can be mentioned. When the cross-linked collagen monofilament is immersed in an aqueous solution, its periphery dissolves slightly. Since this dissolved collagen adheres to the adjacent / contacting collagen single yarn, the adhesion is completed by drying. The aqueous solution to be immersed is not particularly limited and includes water itself. In particular, when the filamentous material is obtained from acid- or alkali-soluble collagen and is a crosslinked single yarn, the bundle of single yarn obtained by the above method is not subjected to neutralization treatment. A neutralizing solution can be selected as the aqueous solution. The neutralizing solution can be appropriately selected by those skilled in the art. For example, a bundle of collagen monofilaments obtained from acid-solubilized collagen is neutralized with a basic aqueous solution such as an aqueous calcium hydroxide solution, an aqueous potassium hydroxide solution or an aqueous sodium hydrogen carbonate solution (bicarbonate), thereby producing a fiber bundle. Adjacent thread-like materials partially adhere to each other.

  The guiding means 2 manufactured by the above-described method has a high shape maintaining ability. In the present invention, the guiding means 2 is locked to the inner wall of the cylindrical body 1 by utilizing the shape maintaining ability of the guiding means 2, that is, the restoring force when deformed.

  For example, the embodiment shown in FIG. 2A is an embodiment in which the linear fiber bundle 2 is inserted into the lumen of the cylindrical tubular body 1 in a state of being deformed into a U shape. In this aspect, the linear fiber bundle 2 is assumed to have a normal shape (a state where it is not inserted into the lumen of the cylindrical body 1) (FIG. 2B: first shape). Then, the fiber bundle 2 is inserted into the lumen of the cylindrical body 1 by being deformed from the first shape. This deformation is a deformation that makes the linear fiber bundle 2 U-shaped. Then, the fiber bundle 2 is locked in the lumen of the cylindrical tubular body 1 by a restoring force that tries to return from the second shape to the first shape, which is the original shape.

The embodiment shown in FIG. 4A is an embodiment in which the V-shaped fiber bundle 2 is inserted into the lumen of the cylindrical tubular body 1. In this embodiment, a shape in which the linear fiber bundle 2 is kinked into a V shape (a shape in which a fold is attached so that the angle formed by the two sides becomes an acute angle) is normal (inside the cylindrical body 1). The shape is not inserted into the cavity) (FIG. 4B: third shape). That is, the shortest distance between both ends of the fiber bundle 2 is longer than the inner diameter (diameter D) of the cylindrical tubular body 1 and has a certain angle (θ _2-1 ). Then, the fiber bundle 2 is further deformed from the third shape and inserted into the lumen of the cylindrical body 1 (FIG. 4C). This deformation is the shortest distance d ₂ at both ends of the fiber bundle 2 is a cylindrical tubular body 1 having an inner diameter (diameter D) is smaller than the above, also form the two sides of the normal angle formed two sides The deformation is such that the angle is less than the angle. The deformed shape in the lumen of the cylindrical body 1 is defined as a fourth shape. And the restoring force which tries to return the fiber bundle 2 from the 4th shape to the 3rd shape which is the original shape acts in the lumen | bore of the cylindrical cylindrical body 1, and is locked.

In the embodiment shown in FIG. 5A, the linear fiber bundle 2 is kinked into a V-shape (a shape in which bending creases are attached so that the angle formed by the two sides becomes an obtuse angle) (when normal) ( This is a mode in which the shape is not inserted into the lumen of the cylindrical body 1 (FIG. 5B: fifth shape). However, in this embodiment, the fiber bundle 2, the shortest distance d ₃ is cylindrical tubular body 1 of the inner diameter of the vertex from the straight line connecting both ends of the fiber bundle 2 (diameter D) longer than a certain angle It has a shape. Then, the fiber bundle 2 is further deformed from the fifth shape and inserted into the lumen of the cylindrical body 1 (FIG. 5C). This deformation is the shortest distance d ₃ from the straight line to the inflection point connecting both ends of the fiber bundle 2, the cylindrical tubular body 1 having an inner diameter (diameter D) is smaller than the above, also the angle between two sides The deformation is such that the angle is equal to or greater than the angle formed by the two sides at normal times. This deformed shape is defined as a sixth shape. And the restoring force which tries to return the fiber bundle 2 from the 6th shape to the 5th shape which is the original shape acts in the lumen of the cylindrical tube 1 and is locked.
The shape of the fiber bundle may be a shape in which a linear fiber bundle is kinked into a V shape as described above, or a linear fiber bundle is kinked multiple times such as in a W shape. The shape of the fiber bundle may be sufficient, and at one or a plurality of locations of the fiber bundle, a restoring force that tries to return to the original shape from the deformed shape works and is particularly limited as long as it is locked in the cylindrical body. Is not to be done.

Further, as the guiding means 2 as in the embodiment shown in FIG. 6, an embodiment in which a plurality of fiber bundles kinked into a V shape can be used. Specifically, one side of the fiber bundle kinked into a plurality of V shapes is bundled so as to form a cone on the other side. Then, the plurality of fiber bundles, the base of the cone drawn at the end of which is not bundled diameter d ₄ is greater than the cylindrical tubular body 1 having an inner diameter (diameter D), a shape having a certain cone angle ( (Seventh shape). Further deforming from the seventh shape, the fiber bundle is inserted into the lumen of the cylindrical body 1. This deformation, in a plurality of fiber bundles, as the base of the cone drawn at the end of which is not bundled diameter d ₄ is less than the cylindrical tubular body 1 having an inner diameter (diameter D), also conical The deformation is such that the angle is equal to or smaller than the normal cone angle. This deformed shape is the eighth shape. Then, in the lumen of the cylindrical tubular body 1, the fiber bundle is locked by the restoring force that tries to return from the eighth shape to the seventh shape that is the original shape (FIG. 6D: FIG. Sectional drawing of the position of X in 6A). As a method of bundling the plurality of fiber bundles, for example, a method of adhering the filaments in the production of the above-described fiber bundles using an adhesive or an aqueous solution, and another biodegradable filament can be used. The method of turning is mentioned. From the viewpoint of easy production, the former is preferable.

  For example, even if the guiding means 2 is a sponge, by inserting the sponge into the cylindrical body 1 in a compressed state, a restoring force acts on the lumen of the cylindrical body 1, and the sponge is cylindrical. A mode of locking to the lumen of the body 1 can also be mentioned.

  As described above, in the present invention, the restoring force generated when the guiding means 2 is deformed can be locked to the lumen of the cylindrical body 1, and the operation is extremely easy.

  By the way, it is preferable that the precursor of the tissue regenerating instrument described above is not deformed in the treatment with the softening solvent. Specifically, it is smaller than the lumen cross-sectional area of the cylindrical body 1 in the non-swelled state, but an aspect that is substantially the same as the lumen cross-sectional area of the cylindrical body 1 in the saturated swollen state is preferable. “Substantially the same” means that the ratio of the occupied sectional area of the plane orthogonal to the longitudinal direction is 90 to 100 when the lumen sectional area of the cylindrical body 1 is 100. In other words, it refers to a state in which friction with the lumen of the cylindrical body 1 is generated to such an extent that the saturation swelling state guiding means 2 does not fall out of the lumen of the cylindrical body 1. In addition, since the cylindrical body 1 after insertion of the guiding means 2 has a space having a longitudinal direction, the swelling solvent using the softening solvent sufficiently causes the softening solvent to reach the inside of the cylindrical body. The guiding means 2 can swell uniformly. Details of these techniques can be mainly referred to Japanese Patent Application Laid-Open No. 2008-043597. However, if specific numerical values are taken up, for example, in the non-swelled state, the lumen of the cylindrical body 1 When the cross-sectional area is 100, the ratio of the occupied cross-sectional area orthogonal to the longitudinal direction of the guiding means 2 is set to 5-10.

Depending on the material of the guiding means 2, the occupied volume of the guiding means 22 in the saturated swelling state at the temperature when swelling in the softening solvent (about 25 ° C.) and the temperature when implanted in the living body (about 37 ° C.) In some cases, the occupied volume of the induction means 22 in the saturated swelling state differs. In such a case, for example, when the lumen sectional area of the cylindrical body 1 is 100, the ratio of the occupied sectional area of the plane perpendicular to the longitudinal direction is the temperature at which the softening solvent swells (about The swelling property of the guiding means 2 may be appropriately set so that it is 90 to 95 at 25 ° C. and 96 to 100 at the temperature when implanted in a living body (about 37 ° C.).
In addition, the tissue regeneration device may be used as it is after being swollen with a softening solvent, or after being swollen, the kinked portion shown in FIG. 2 or FIG. 4 or the bundled portion shown in FIG. By cutting, the derivative may be used as a state aligned in a single direction.

  In the following, examples of the present invention are described. This example is one embodiment of the present invention, and it goes without saying that the present invention is not limited to the mode described in the example.

Reference Example 1: Production of cylindrical body Enzyme-solubilized collagen was dissolved in water to prepare a 5% (w / w) aqueous solution. By discharging the collagen solution into a 99.5% (v / v) 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, the innermost layer of the cylindrical body 1 was formed by immersing this product in a 5% (w / w) collagen aqueous solution and drying it. 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 collagen cylindrical body was again immersed in a 5% (w / w) collagen aqueous solution and dried, and then subjected to a thermal crosslinking treatment, whereby an inner diameter of 3.0 mm, an outer diameter of 3.3 mm, and a length of 70 mm. A tubular body 1 made of crosslinked collagen was produced.

Reference Example 2: Production of fiber bundle In the above-described wet spinning using an ethanol coagulation bath, a 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 x 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 in length and bundled so that it might become a column shape. A fiber bundle 2 was prepared by impregnating a 7.5% (w / w) sodium hydrogen carbonate aqueous solution with the cylindrical bundle, and then drying. The length and outer diameter of the fiber bundle can be appropriately set according to the examples described later.

Example 1 Production of Precursor for Tissue Regeneration Device in the Mode of FIG. 2 A fiber bundle 2 having a length of 110 mm and an outer diameter of 0.5 mm produced according to Reference Example 2 was bent into a U shape near the middle point, By inserting into the lumen of the tubular body 1, a precursor of the tissue regeneration device of the embodiment of FIG. 2 was manufactured. A photograph of the precursor produced in this example is shown in FIG. The ratio of the cross-sectional area orthogonal to the longitudinal direction of the fiber bundle 2 when the lumen cross-sectional area of the cylindrical body 1 is 100 is about 11.1. Moreover, when this precursor was immersed in physiological saline under atmospheric pressure, humidity 60%, and 25 ° C. for 20 minutes to obtain a saturated swelling state, the cylindrical body 1 was not deformed. It was confirmed that a tissue regeneration device as shown in FIG. 1 could be produced.

Example 2 Production of Precursor for Tissue Regeneration Device in the Mode of FIG. 4 A fiber bundle having a length of 100 mm and an outer diameter of 0.5 mm produced according to Reference Example 2 is kinked into a V shape near the midpoint. At this time, the shortest distance between both ends of the fiber bundle 2 is 4.0 mm. The tissue regeneration device of the embodiment shown in FIG. 4 is inserted by deforming the shortest distance between both ends of the kinked fiber bundle 2 to be smaller than the inner diameter of the cylindrical body 1 and then inserting the fiber bundle 2. The precursor of is produced. Note that the ratio of the cross-sectional area perpendicular to the longitudinal direction of the fiber bundle 2 when the lumen cross-sectional area of the cylindrical body 1 is 100 is about 11.1.

Example 3 Manufacture of Precursor for Tissue Regeneration Device in Mode of FIG. 5 A fiber bundle having a length of 50 mm and an outer diameter of 1.0 mm manufactured according to Reference Example 2 is kink-shaped in the vicinity of the midpoint. At this time, the distance from the line connecting both ends to the apex is 4.0 mm.
After changing the distance from the line connecting the both ends of the kinked fiber bundle 2 to the apex so that the inner diameter of the cylindrical body 1 is smaller than 3.0 mm, the fiber bundle 2 is inserted, whereby FIG. The precursor of the tissue regeneration device of the embodiment is manufactured. Note that the ratio of the cross-sectional area perpendicular to the longitudinal direction of the fiber bundle 2 when the lumen cross-sectional area of the cylindrical body 1 is 100 is about 11.1.

Example 4 Production of Precursor for Tissue Regeneration Device in the Mode of FIG. 6 Six fiber bundles having a length of 50 mm and an outer diameter of 0.13 mm produced according to Reference Example 2 were kinked from one end around 10 mm, and 10 mm. A square-shaped fiber bundle consisting of 40 mm is manufactured. Further, the 10 mm side of the ten fiber bundles are bundled so that the side of 40 mm is a cone, and a 5% (w / w) collagen solution is applied to the bundled portions and dried, thereby guiding means 2. Manufacturing. The diameter of a circle drawn at the end on the 40 mm side of 10 fiber bundles is 4.0 mm. The diameter of the circle drawn at the end of the 40 mm side of the six fiber bundles in this guiding means 2 is deformed to be smaller than the inner diameter of 3.0 mm of the cylindrical body 1, and then the fiber bundle 2 is inserted. The precursor of the tissue regeneration device of the embodiment of FIG. 6 is manufactured. Note that the ratio of the cross-sectional area perpendicular to the longitudinal direction of the fiber bundle 2 when the lumen cross-sectional area of the cylindrical body 1 is 100 is about 11.1.

  Since the tissue regeneration device of the present invention has become easier to manufacture, it leads to cost reduction of the product.

Claims (4)

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;
With a guiding means made of biodegradable material,
The precursor of a tissue regenerating instrument, wherein the guiding means is locked to an inner wall of the cylindrical body by a restoring force generated when the guiding means is deformed.   The tissue regeneration device precursor according to claim 1, wherein the guiding means is a fiber bundle. A method for producing a precursor for producing a tissue regeneration device for regenerating tissue,
Prepare a cylindrical body that is a lumen in the longitudinal direction and is made of a biodegradable material,
Inserting a guiding means made of a deformed biodegradable material into the lumen of the cylindrical body,
A method for producing a precursor of a tissue regeneration device, wherein the precursor is locked to an inner wall of the cylindrical body by a restoring force generated when the guiding means is deformed.   The method for producing a precursor for a tissue regeneration device according to claim 3, wherein the guiding means is a fiber bundle.

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