JPWO2012029887A1 - Cylindrical structure and manufacturing method thereof - Google Patents

Abstract

An efficient and simple new production method capable of producing a high-quality cylindrical structure will be clarified. In addition, a cylindrical structure with high quality and high uniformity will be clarified. A step of removing the core rod from an intermediate structure obtained by a step including a step of inserting a core rod into a molded body made of a gel-like substance and a step of drying and shrinking the molded body in the direction of the core rod The manufacturing method of the cylindrical structure containing is provided. Or it is a cylindrical structure which includes the protein-containing tubular part in part or all, and the tubular part cuts the tubular part at right angles to the major axis direction at five points of 0.5 cm intervals. In the five cross sections, the tube is a tubular portion having a coefficient of variation of an average value of lengths of four types of inner diameters obtained by measuring the inner diameter from four directions that are different from each other by 45 degrees in angle. A shaped composition is provided.

Description

  The present invention relates to a cylindrical structure and a method for manufacturing the same.

  There are various methods of using the tubular structure, for example, a medical tubular structure for replacing a human blood vessel with an artificial blood vessel substitute. As the raw material, for example, polyester materials and polytetrafluoroethylene materials are often used. Patent Document 1 describes that a cylindrical structure of polytetrafluoroethylene was produced.

  Attempts have also been made to produce artificial blood vessels using biological materials. For example, Patent Document 2 and Patent Document 3 use collagen as a raw material. In Patent Document 2, a Teflon (registered trademark) rod is set up in a glass tube, filled with a collagen aqueous solution around it, further gelled by adding a crosslinking agent, and then the Teflon (registered trademark) rod is taken out to form a cylinder. It is described that the structure was produced. In Patent Document 3, after filling a gap between double tubes with a collagen aqueous solution and dehydrating and gelling, a cylinder placed inside was taken out and dehydrated and dried to produce a cylindrical structure. Have been described.

  Patent Document 4 describes that as a method for producing a cylindrical composition using silk protein derived from silkworm, a cylindrical composition was produced by knitting, assembling or winding silk thread. When silk protein is obtained as a thread, such as silk thread, a cylindrical structure can be produced by such a method. Patent Document 5 describes that a bee-derived silk protein is applied to a pipe-like knitted or tubular structure made of a biomaterial other than a bee-derived protein and dried, and can be used as an artificial blood vessel. Patent Document 6 describes that a cylindrical structure was produced by extrusion molding using a mixture of microfibril cellulose and water as a raw material. Non-Patent Document 1 describes that a cylindrical structure was prepared by applying silkworm-derived silk protein solutions several times around a core rod. Non-Patent Document 2 describes that a cylindrical structure was produced by a method in which a silk protein solution derived from silkworm with high viscosity was applied from a nozzle around a core rod.

  On the other hand, as a method of using a cylindrical structure other than medical use, for example, there is a developing sleeve of a copying machine. In Patent Document 7, a cylindrical structure is formed by extrusion molding from a synthetic resin material, and the cylinder It describes a method for producing a developing sleeve by externally fitting a shaped component onto a shaft rod, heat shrinking, immersing it, and then removing it from the shaft rod.

JP-A-5-076552 International Publication No. 98/54224 JP 2007-204881 JP 2006-45076 JP 2007-125191 A JP 2005-96383 A JP-A-7-108585

'Silk fibroin microtubes for blood vessel engineering' Lovett et al., Biomaterials, 28, 5271 (2007). 'Gel spinning of silk tubes for tissue engineering.' Lovett et al., Biomaterials. 2008 Dec; 29 (35): 4650-7. Epub 2008 Sep 18.

However, the prior art described in the above literature has many problems to be solved in the following points, and has room for improvement.
First, the artificial blood vessel using the polytetrafluoroethylene-based material of Patent Document 1 has low biocompatibility, insufficient tissue healing and invasion of outer membrane tissue, and synthetic resin. When the artificial blood vessel used as a raw material is a thin artificial blood vessel with a tube diameter of less than 8 mm even when a material with low cell affinity, such as polytetrafluoroethylene, is used, a thrombus occurs at the junction with the blood vessel. There were problems to be solved such as easy blood clogging.

  Secondly, the cylindrical structure obtained by cross-linking and gelling collagen of Patent Document 2 with polyanion and carbodiimide is absorbed and decomposed into a living tissue. Because there is a limit, collagen with high hygroscopicity is used as a raw material, collagen that has absorbed moisture has insufficient physical properties and bending elastic modulus, and the collagen gel has been peeled from the glass tube There is no description or description that the collagen gel has been dried and then peeled off, and it was not available when attached to the glass tube, even if the collagen gel was peeled off from the glass tube or the collagen gel was dried Even if it is peeled off, it is highly possible that the shape of the cylindrical structure will be distorted or damaged, so make a cylindrical structure with uniform inner diameter, outer diameter, and wall thickness. In addition, there are many problems to be solved, such as the fact that the aqueous solution containing the cross-linking agent and the collagen aqueous solution need to be mixed in a certain amount for gelation, and the manufacturing process is complicated. there were.

  Thirdly, Patent Document 3 describes that a tubular structure of collagen was prepared. However, this is a complicated manufacturing method in which a collagen aqueous solution is filled in a gap between double tubes, and particularly a thick wall. When making a thin cylindrical structure, the operability was very bad, it was difficult to fill the viscous pre-gelation solution without gaps without bubbles, only gravity in the tube The efficiency of dehydration is low because it is dehydrated and dried depending on the type of tube, and it takes a very long time to dehydrate and dry, especially when producing elongated tubular components, and the dehydrated cylindrical components are peeled off from the inner wall of the tube. There are many problems to be solved, such as it is difficult to produce a cylindrical structure with uniform inner diameter, outer diameter, and wall thickness because there is a high possibility of distortion and damage when taken out of the tube. there were. Furthermore, Patent Document 3 has a technical feature of the invention that a thread-like, tubular, or rod-shaped hydrogel is erected and dehydrated and dried so as not to deform the cross-sectional shape. In such a case, there was a problem to be solved that it was difficult to produce a cylindrical structure without deforming the cross-sectional shape.

  Fourthly, Patent Document 4 describes an example in which silk protein derived from silkworm is used as a raw material for the cylindrical component, but silk protein produced by genetically modified silkworms and arthropods other than rabbits Among silk proteins to be produced, there are silk proteins that are difficult to spin as yarns. From such silk proteins, a cylindrical structure is formed by knitting, assembling, or winding as described in Patent Document 4. It could not be produced. In the method of Patent Document 5, since silk protein is applied and dried on a pipe-shaped knitted fabric or a tubular structure, it is difficult to produce a tubular structure having a uniform thickness. In Patent Document 6, a mixture of microfibril cellulose and water is extruded onto a core tube, and further extruded through a gap with a ring-shaped shaper that corrects the roundness of the outer periphery to be high. Since the cylindrical structure is manufactured by drawing, it is difficult to manufacture the cylindrical structure using a material with high fluidity or low ductility that cannot be extruded. Moreover, since the core tube provided with the inner tube for narrowing the outer diameter of the outer skin tube is used (first embodiment), it is difficult to produce a cylindrical structure having a small inner diameter. In the methods of Non-Patent Document 1 and Non-Patent Document 2, since silk protein is applied around or sprayed around the core rod, it is difficult to produce a cylindrical structure with an equal thickness. Non-Patent Document 2 describes that it is difficult to control the thickness of the cylindrical structure by the method of Non-Patent Document 1.

  Fifth, in the case of the method described in Patent Document 7, the material that can be used as a raw material is heat-shrinkable, and is limited to a specific synthetic resin. It was not applicable to the material. Further, since the gel is subjected to a heat shrinking process, it cannot be applied to a material that is altered by heating, and thus is not suitable for the production of a cylindrical structure using a heat-derived biological material. Also, while the die body and mandrel are rotated relative to each other, the molten synthetic resin material is extruded from the die-like gap to form a cylindrical structure, and the shaft rod and outer mold are further rotated relative to each other to form the thickness of the cylindrical structure. Therefore, since a cylindrical structure using a soft material such as a bio-derived material is distorted or damaged due to relative rotation, the cylindrical structure having the same inner diameter, outer diameter, and thickness using such a soft material. It was difficult to produce.

  The present invention has been made in view of the above circumstances, and the inner diameter, outer diameter, and thickness are uniform and highly uniform, and the efficiency of a high-quality cylindrical structure having high physical strength, flexural modulus, and kink resistance. An object is to provide a simple and convenient production method. Another object of the present invention is to provide a manufacturing method of such a cylindrical structure that can use a heat-unstable material, a highly fluid material, or a gel-like substance as a raw material. And Furthermore, with such an excellent manufacturing method, a high-quality cylindrical structure using bio-derived materials that has uniform inner diameter, outer diameter and wall thickness, high uniformity, high physical property strength, flexural modulus, and kink resistance. The purpose is to provide goods.

  According to the present invention, from an intermediate structure obtained by a process including a step of inserting a core rod into a molded body made of a gel-like substance, and a step of drying and shrinking the molded body in the direction of the core rod, A method for producing a cylindrical structure is provided, which includes a step of removing the core rod.

  It has been demonstrated that this manufacturing method can be used to produce a high-quality cylindrical structure in the examples described later. Therefore, if this manufacturing method is used, a high-quality cylindrical structure can be obtained.

  Further, according to the present invention, a molded body made of a gel-like material by gelling a solution before gelation in a dialysis membrane tube (sometimes referred to as “pre-gelation solution” in this specification). From the intermediate structure obtained in a process comprising the steps of: preparing the molded body on the side surface of the core rod, and drying the adhered molded body and contracting in the direction of the core rod, A method for producing a tubular structure is provided, which includes a step of removing the core rod.

  It has been demonstrated that this manufacturing method can be used to produce a high-quality cylindrical structure in the examples described later. Therefore, if this manufacturing method is used, a high-quality cylindrical structure can be obtained.

  According to the invention, the core rod is obtained from an intermediate structure obtained by a step including a step of inserting a core rod into a molded body made of a gel-like substance and a step of contracting the substance in the direction of the core rod. The manufacturing method of the cylindrical structure for medical treatment including the process of extracting is provided.

  It has been demonstrated that this manufacturing method can be used to produce a high-quality cylindrical structure in the examples described later. Therefore, if this manufacturing method is used, a cylindrical structure suitable for medical use can be obtained.

  Moreover, according to this invention, the cylindrical structure obtained with one of the said manufacturing methods is provided. This cylindrical structure has been proven to be of high quality in the examples described below. Therefore, this cylindrical structure can be used suitably for uses such as medical materials.

  According to the present invention, there is provided a tubular structure including a part or all of a tubular portion containing a protein, wherein the tubular portion is arranged at five points with a 0.5 cm interval with respect to the long axis direction. Tubular parts having an average coefficient of variation of the length of the four types of inner diameters obtained by measuring the inner diameters from four directions with different angles by 45 degrees in five sections when cut at right angles to each other. A tubular structure is provided.

  This cylindrical structure is a cylindrical structure including a highly uniform tubular portion. Therefore, this cylindrical structure can be used suitably for uses such as medical materials.

  According to the present invention, there is provided a tubular structure including a part or all of a tubular portion containing a protein, wherein the tubular portion is arranged at three locations with a 0.5 cm interval with respect to the long axis direction. In three cross-sections cut at right angles to each other, the variation coefficient of the average value of the lengths of the eight types of wall thickness obtained when the wall thickness is measured from 8 directions with different angles by 45 degrees is 0.2 or less. A tubular structure is provided that is a tubular portion.

  This cylindrical structure is a cylindrical structure including a highly uniform tubular portion. Therefore, this cylindrical structure can be used suitably for uses such as medical materials.

  According to the present invention, there is also provided a tubular structure including a part or all of a tubular portion containing a protein, wherein the tubular portion is disposed at eight points with a 0.5 cm interval with respect to the long axis direction. Tubular sections having an average coefficient of variation of the lengths of the four types of inner diameters obtained by measuring the inner diameters from four directions with different angles by 45 degrees in eight sections when cut at right angles A tubular structure is provided.

  This cylindrical structure is a cylindrical structure including a highly uniform tubular portion. Therefore, this cylindrical structure can be used suitably for uses such as medical materials.

  According to the present invention, there is provided a cylindrical structure containing a protein, wherein the cylindrical structure includes a part or all of a tubular part having a length of 2 cm in the major axis direction, , 0.5, 1.0, and 1. From the top surface and bottom surface of the cross section when the tubular part is cut out perpendicularly to the long axis direction from the cylindrical structure, and 0.5, 1.0, and 1. In the five cross-sections obtained by cutting perpendicularly to the major axis direction at a position 5 cm away, each of the four types of inner diameters obtained when the respective inner diameters are measured from four directions with different angles by 45 degrees. A tubular structure is provided which is a tubular portion having a variation coefficient of an average length value of 0.1 or less.

  This cylindrical structure is a cylindrical structure including a highly uniform region. Therefore, this cylindrical structure can be used suitably for uses such as medical materials.

  Moreover, according to this invention, the medical material containing one of the said cylindrical structures is provided. This medical material includes a cylindrical structure that has been proven to be of high quality in Examples to be described later, or a highly uniform cylindrical structure. Therefore, it is thought that this medical material has an excellent therapeutic effect.

  According to the present invention, there is provided an efficient and simple manufacturing method of a high-quality cylindrical structure having a uniform and high uniformity in inner diameter, outer diameter, and thickness, and high physical property strength, flexural modulus, and kink resistance. Is done. In addition, such an excellent manufacturing method is provided in which a heat-unstable material, a highly fluid material, or a gel-like substance can be used as a raw material. Furthermore, with such an excellent manufacturing method, a high-quality cylindrical structure using bio-derived materials that has uniform inner diameter, outer diameter and wall thickness, high uniformity, high physical property strength, flexural modulus, and kink resistance. Things are provided.

FIG. 1 is a conceptual diagram showing a manufacturing process of a cylindrical structure including a process of inserting a core rod into a molded body after dialysis. FIG. 2 is a conceptual diagram showing a manufacturing process of a cylindrical structure including a process of inserting a core rod into a chisel-shaped molded body that remains after hollowing out the inside of a gel-like substance in the major axis direction. FIG. 3 is a conceptual diagram showing a manufacturing process of a cylindrical structure including a step of inserting a core rod into a rod-shaped molded body obtained by hollowing out the inside of a gel-like substance in the major axis direction. FIG. 4 is a conceptual diagram showing a manufacturing process of a cylindrical structure including a process of fixing a core rod in the major axis direction inside the dialysis membrane tube. FIG. 5 is a conceptual diagram showing a manufacturing process of a cylindrical structure including a process of heating a heat-shrinkable core rod after a process of contracting a molded body made of a gel-like substance. FIG. 6 is a conceptual diagram showing a manufacturing process of a cylindrical structure including a process of heating a core rod coated with a lubricant after a process of shrinking a molded body made of a gel-like substance. FIG. 7 is a conceptual diagram showing the contraction direction of the gel when the core rod is inserted and when the core rod is not inserted. FIG. 8 is a diagram showing a procedure for obtaining the coefficient of variation of the tubular portion. FIG. 9 is a diagram showing a procedure for obtaining a coefficient of variation of a tubular portion having a length of 2 cm. FIG. 10 is a photograph of a cylindrical silk gel before and after cutting both ends of the dialysis membrane tube. FIG. 11 is a photograph when the silk gel into which the core rod having an outer diameter of 0.7 mm is inserted is dried. FIG. 12 is a photograph when the cylindrical structure is bent. FIG. 13 is a photograph obtained by observing a cut surface when a cylindrical structure having an inner diameter of 0.73 mm is cut obliquely with an electron microscope (SEM). FIG. 14 is an SEM photograph of a cut surface when a cylindrical structure having an inner diameter of 0.73 mm is cut at right angles to the major axis direction. FIG. 15 is an SEM photograph showing the denseness of a cylindrical structure having an inner diameter of 0.73 mm. FIG. 16 is a photograph when a cylindrical structure having an inner diameter of 0.73 mm is stretched in the major axis direction. FIG. 17 is a photograph when a holed stick having a diameter of 3.0 mm is inserted into the center of the bottom of a cylindrical silk gel. FIG. 18 is a photograph of a crumpled silk gel after pulling out the punch. FIG. 19 is a photograph when a core rod (a stainless steel rod having a diameter of 3.0 mm) is pierced in the center of a crumpled silk gel. FIG. 20 is a photograph when the silk gel into which a core rod having a diameter of 3.0 mm is inserted is dried. FIG. 21 is a photograph of a silk gel that has been dried and hardened on the side surface of a core rod having a diameter of 3.0 mm. FIG. 22 is a photograph of the dried silk gel soaked in water and extracted from the core bar when it becomes soft. FIG. 23 is a photograph of a cylindrical structure manufactured using a rigid rod enclosed in a heat-shrinkable tube as a core rod. FIG. 24 is a photograph obtained by observing, with an electron microscope (SEM), a cylindrical structure produced using a rigid rod enclosed in a heat-shrinkable tube as a core rod. FIG. 25 is a photograph of a cylindrical structure produced using a stainless steel rod coated with beeswax wax as a core rod. FIG. 26 is a photograph of a cylindrical composition derived from silkworm silk fibroin. FIG. 27 is a photograph of a cylindrical composition derived from silkworm silk sericin. FIG. 28 is a conceptual diagram showing a cone used as a core rod of the Baumkuchen method. FIG. 29 is an SEM photograph of a cross-section of a cylindrical structure produced by the Baumkuchen method when a conical metal rod portion is used as the core rod. FIG. 30 is a conceptual diagram showing a nail used as a core rod of the Baumkuchen method. FIG. 31 is an SEM photograph of a cross-section of a cylindrical structure produced by the Baumkuchen method when a nail is used as the core rod. FIG. 32 is a conceptual diagram showing a procedure for measuring the uniformity of the cylindrical structure. FIG. 33 shows the relationship between the outer diameter (mm) of the gel formed in the dialysis membrane tube described in Example 12 (1) and the concentration of hornet silk protein dissolved in the LiBr aqueous solution (mg / mL). FIG. FIG. 34 shows the results of measuring the compression properties of the cylindrical structure described in Example 12 (1). FIG. 35 shows the “thickness of silk gel with the core rod inserted in the heat-shrinkable tube inserted” described in Example 12 (2), “thickness in the dried state”, and after drying. It is a plot of the length (mm) of the “thickness in a state where the core rod and the heat-shrinkable tube are removed and then rehydrated” against the silk concentration (wt%). FIG. 36 is a plot of wall thickness shrinkage (%) by drying the hornet silk hydrogel described in Example 12 (2) against silk concentration (wt%). FIG. 37 shows the results of measuring the moisture content of the columnar silk gel described in Example 12 (3) by thermogravimetry. FIG. 38 shows the results of measuring the outer diameter and the inner diameter of the cylindrical structure described in Example 12 (4) after allowing the water absorption to sufficiently reach the equilibrium value. FIG. 39 shows the results of measuring the compressive physical properties of the cylindrical structure described in Example 12 (5) and showing the relationship of the compressive stress to the compressive strain. FIG. 40 shows the results of measuring the compression properties of the cylindrical structure described in Example 12 (5) and plotting the value of the compressive stress at 40% compression strain against the silk protein concentration (wt%). . FIG. 41 shows the tensile stress with respect to the tensile strain when stretched in a hygroscopic state for the tubular structure described in Example 12 (6) in Newton (N) and Megapascal (MPa). .

  Hereinafter, embodiments of the present invention will be described in detail. In addition, about the same content, description is abbreviate | omitted suitably in order to avoid the complexity of repetition.

(1) Manufacturing method of cylindrical structure One embodiment of the present invention includes a step of inserting a core rod into a molded body made of a gel-like substance, and a step of drying the molded body and contracting in the direction of the core rod. Is a method for producing a cylindrical structure including a step of removing the core rod from an intermediate structure obtained in a step including According to this manufacturing method, as demonstrated in the examples to be described later, it is possible to manufacture a cylindrical structure having high uniformity in the length direction, less distortion from a perfect circle, and excellent uniformity. . In addition, it is possible to manufacture a cylindrical structure having high physical strength, flexural modulus, and kink resistance. Further, the shape and physical properties of such a cylindrical structure can be controlled with high accuracy and simplicity. This manufacturing method can be performed, for example, according to the procedure shown in FIGS. In addition, the said intermediate structure is a structure of the state in which the side surface of the core rod is covered with the gel or the gel of a dry state (or the state which contact | adhered), for example.

  Moreover, since this manufacturing method can use the solution before gelatinization as a raw material, even if it is difficult to spin as a thread | yarn, a cylindrical structure can be manufactured. Examples of silk proteins that are difficult to spin as yarn include sericin.

  Moreover, since this manufacturing method does not necessarily need to add a crosslinking agent or other additives, even when used for medical materials such as artificial blood vessels, it is possible to avoid the risk of causing adverse events such as calcification in the living body. The obstacle caused by the cross-linking agent is a serious problem particularly in a thin artificial blood vessel having an inner diameter of 6 mm or less. Moreover, a highly fluid raw material can be used as a raw material for producing the cylindrical structure. Moreover, since a heating process is not necessarily required, even a heat-sensitive raw material that changes in quality by heating can be used. Moreover, the dialysis process which sets a precise condition in the manufacturing process of a cylindrical structure is not necessarily required. Since it can be manufactured as a cylindrical structure having a uniform single layer structure without stitches, liquid leakage from the inside to the outside of the pipe does not occur. From the above, this production method is capable of producing a high-quality cylindrical structure, and is a production method excellent in cost, moldability, reproducibility, operability, and simplicity. Moreover, it is excellent in manufacturing efficiency and can be suitably used for mass production of cylindrical components. Such an excellent manufacturing method can be used for manufacturing cylindrical products for various industrial products, but is particularly suitable for manufacturing medical cylindrical components for which high quality products are required. It is. In particular, since it is cylindrical, it is suitable for producing artificial blood vessels or nerve regeneration tubes.

  In the present specification, the “molded body made of a gel-like substance” means, for example, a gel-like substance prepared by gelling a pre-gelation solution containing proteins in a dialysis membrane tube as shown in FIG. It may be a molded body obtained in At this time, a common conventional dialysis method is used. For example, a dialysis membrane tube is immersed in water such as distilled water or ion exchange water or an aqueous solution in which polyethylene glycol or the like for adjusting osmotic pressure is dissolved. It is possible to gel the pregelled solution in the dialysis membrane tube using any conventional dialysis procedure. When such dialysis is performed, low-molecular components other than proteins such as proteins in the dialysis membrane tube flow out to the outside of the dialysis membrane tube, thereby changing the component ratio in the dialysis membrane tube. The pre-gelling solution containing the protein and the like in the dialysis membrane tube becomes a gel. Further, after gelation in the dialysis membrane tube, for example, both ends of the dialysis membrane tube containing a molded body made of a gel-like substance are cut, and a core rod is inserted into one cut surface. Thereafter, the dialysis membrane tube containing the molded body is removed, and after drying and rehydration, the core rod can be pulled out to produce a cylindrical structure. In the present specification, the “dialysis membrane tube” is a bag-like dialysis membrane, and a conventional semipermeable membrane used for dialysis such as cephalon can be used as the dialysis membrane. The shape of the dialysis membrane tube is not particularly limited, such as a cylindrical shape or a polygonal cylindrical shape, or a spherical shape, but preferably a cylindrical shape, and more preferably a cylindrical shape.

  Thus, the method of preparing a gel in a dialysis membrane tube is a simple and efficient method for preparing a gel without requiring a special instrument or a complicated process. Further, since the gel is prepared in the dialysis membrane tube, the core rod can be inserted with the dialysis membrane covering the side surface of the gel after the gel is prepared. For this reason, in the step of inserting the core rod, when the core rod is inserted, the gel is hardly cracked or deformed. Further, in this method, gelation is intentionally generated in the dialysis step, but on the other hand, a conventional method for producing a cylindrical composition using silk protein, for example, non-patent literature (Lovett et al., Biomaterials. 2008). Dec; 29 (35): 4650-7. Epub 2008 Sep 18.), it was common to prevent gelation during the dialysis step. That is, the method of the present invention is greatly different from the conventional method for producing a cylindrical structure using silk protein in terms of technical features and viewpoints.

In addition, the “molded body made of a gel-like substance” is, for example, as shown in FIG. 2, a pinch-like shaped body that remains after the inside of the gel-like substance is cut out in the long axis direction using a perforated bar. It may be. In the case where the above-mentioned shaped body is used as an intermediate structure for producing a cylindrical structure, since this intermediate structure has already formed a hollow, it is suitable for such a molded body when inserting a core rod. Since the load is small, the shape of the molded body is difficult to collapse. In the case of such a preparation method, it is possible to separately prepare a drilling rod for making a hole and a core rod to be inserted into the hole. For example, a cylindrical rod that emphasizes the ability to drill a hole, such as a hole with a sharp tip, and a circle that emphasizes the non-adhesion property of the gel, such as a material that makes it difficult for the gel to adhere to the surface of the core rod A columnar or cylindrical rod can be preferably used. In addition, in the case of such a preparation method, the inner diameter of the narrow shaped molded body can be adjusted with high accuracy or easily by appropriately adjusting the size of the punched rods having different inner diameter sizes. Can be adjusted. In order to reduce the distortion of the inner diameter of the cylindrical structure with respect to the perfect circle, the shape of the punched rod used when hollowing out is preferably a perfect circular cylinder. Further, the shape of the core rod is preferably a perfect circular columnar shape or cylindrical shape in order to reduce distortion of the inner diameter of the cylindrical structure with respect to the perfect circle. In addition, the core rod is a core rod slightly larger than the inner diameter of the punched rod that forms the inner diameter of the narrow-shaped molded body, for example, a hole is formed so that the narrow-shaped molded body does not crack or deform. By using a core rod having an outer diameter that is about 1 to 2 mm larger than the inner diameter of the rod, the elasticity of the gel is the same as when the core rod is passed through a molded body made of a gel-like substance without holes. As a result, the side surface of the core sticks closely to the inner surface of the narrow shaped molded body, so that when the gel is dried, the shrinkage of the gel in the major axis direction is suppressed, and as a result, a high-quality cylinder having a uniform thickness A shaped structure can be obtained. Further, the core rod can be used as it is, but more preferably, a core rod in which the tip of the core rod is formed to be thinner than the inner diameter of the punched rod can be used.

  In addition, the “molded body made of a gel-like substance” is an example of the inside of a gel-like substance using, as shown in FIG. 3, a cylindrical drilling rod that emphasizes the ability to make a hole such as a sharp tip. It may be a cylindrical shaped body obtained by hollowing out in the major axis direction. In the case of such a preparation method, the outer diameter of the cylindrical tubular structure can be adjusted with high accuracy or easily by appropriately adjusting the size of the punched rods having different inner diameters. Can be adjusted. In addition, since the cylindrical molded body obtained by hollowing out has no deposit such as a dialysis membrane tube on the surface, it does not require an operation for removing the deposit, and the surface of the molded body is damaged due to the removal of the deposit. It wo n’t be over. In order to reduce the distortion of the outer diameter of the side surface of the cylindrical structure with respect to the perfect circle, the shape of the punched rod used when hollowing out is preferably a perfect circular cylindrical shape.

  In the present specification, the shape of the “molded body made of a gel-like substance” is not particularly limited, and examples thereof include a columnar shape, a prismatic shape, and a spherical shape. Among these, the columnar shape is suitable for efficiently producing a cylindrical tubular structure. In the present specification, the side surface of the core rod is a surface substantially parallel to the major axis direction of the core rod.

  Another embodiment of the present invention includes a step of preparing a molded body made of a gel-like material by gelling a pre-gelling solution in a dialysis membrane tube, and a step of attaching the molded body to a side surface of a core rod. A method for producing a cylindrical structure including a step of removing the core rod from an intermediate structure obtained by a step including drying the adhered molded body and shrinking the molded body in the direction of the core rod. This manufacturing method has the same effects as the manufacturing method of the cylindrical structure according to the above-described embodiment if used appropriately.

  Moreover, in this manufacturing method, the intermediate structure may be an intermediate structure obtained by a process further including a process of fixing the core rod inside the dialysis membrane tube. At this time, the step of preparing the molded body and the step of attaching are performed in parallel in the dialysis membrane tube. For example, it is a process as shown in the upper part of FIGS. In this case, since the external stress is not applied when the molded body is attached to the side surface of the core rod, the shape of the molded body made of a gel-like substance is difficult to collapse. When the dialysis membrane tube is a cylindrical dialysis membrane tube, it is a cylindrical tube with a uniform thickness that the core rod is fixed so that the center line of the major axis direction of the dialysis membrane tube and the core rod is aligned. It is particularly suitable for producing the composition.

  In the present specification, “the step of attaching a molded body made of a gel-like substance to the side surface of the core rod” is performed, for example, on a molded body made of a gel-like substance that has been previously gelled as shown in FIG. A step of creating a state in which the molded body is attached to the side surface of the core rod by piercing the core rod, or as shown in the upper part of FIGS. The step of creating a state in which the molded body is attached to the side surface of the core rod may be used.

  Other embodiments of the present invention include a step of adhering a molded body made of a gel-like substance to a side surface of a core rod, a step of drying the adhered molded body and contracting in the direction of the core rod, and the dried molding And a step of removing the core rod from an intermediate structure obtained in a step including the step of causing the body to absorb moisture. This manufacturing method has the same effects as the manufacturing method of the cylindrical structure according to the above-described embodiment if used appropriately.

Another embodiment of the present invention includes a step of attaching a molded body made of a gel-like substance to a side surface of a heat-shrinkable core rod, a step of drying the adhered molded body and contracting in the direction of the core rod, And a step of removing the core rod from an intermediate structure obtained by a step of heating or cooling the heat-shrinkable core rod to shrink the heat-shrinkable core rod. It is a manufacturing method. This manufacturing method has the same effects as the manufacturing method of the cylindrical structure according to the above-described embodiment if used appropriately.

  Another embodiment of the present invention includes a step of attaching a molded body made of a gel-like substance to the outer surface of a heat-shrinkable tube containing a core rod, and drying the adhered molded body to the core rod direction. A step of pulling out the core rod from an intermediate structure obtained by the step of shrinking the heat-shrinkable tube by heating or cooling the heat-shrinkable tube, and a step of shrinking the heat-shrinkable tube. It is a manufacturing method of a cylindrical structure. This manufacturing method has the same effects as the manufacturing method of the cylindrical structure according to the above-described embodiment if used appropriately.

Another embodiment of the present invention includes a step of applying a lubricant to the side surface of the core rod, a step of attaching a molded body made of a gel-like substance to the side surface of the core rod to which the lubricant is applied, And a step of removing the core rod from an intermediate structure obtained by a step including drying and shrinking the molded body in the direction of the core rod. This manufacturing method has the same effects as the manufacturing method of the cylindrical structure according to the above-described embodiment if used appropriately. This production method is a method capable of efficiently producing a cylindrical structure using protein as a raw material.

  Another embodiment of the present invention includes a step of applying a lubricant to the side surface of the core rod, a step of attaching a molded body made of a gel-like substance to the side surface of the core rod to which the lubricant is applied, A cylindrical structure including a step of removing the core rod from an intermediate structure obtained by drying the molded body and shrinking it in the direction of the core rod, and heating the lubricant. It is a manufacturing method. This manufacturing method has the same effects as the manufacturing method of the cylindrical structure according to the above-described embodiment if used appropriately. This production method is a method capable of efficiently producing a cylindrical structure using protein as a raw material.

  In another embodiment of the present invention, a step of preparing a molded body made of a gel-like material by gelling a solution before gelation in a dialysis membrane tube, and the molded body is heat-shrinkable on the outer surface. A step of attaching to a core rod with a heat-shrinkable tube provided with a tube and a rod-shaped member inside, a step of drying the molded body attached to the core rod with the tube and shrinking in the direction of the core rod with a tube; A cylindrical component comprising: a step of removing a rod-shaped member from the core rod with a tube; a step of contracting the contractible tube; and a step of removing the contracted contractible tube from the contracted molded body. It is a manufacturing method. This manufacturing method has the same effects as the manufacturing method of the cylindrical structure according to the above-described embodiment if used appropriately. The shrinkable tube is, for example, a heat-shrinkable tube, and may be shrunk by heating or cooling. The heat-shrinkable tube is a tube that shrinks depending on temperature.

  In the present specification, the “gel-like substance” is not particularly limited, and examples thereof include a gel-like substance containing a natural polymer such as a protein or a synthetic polymer. When producing a cylindrical structure as a medical material, a gel-like substance containing a naturally derived or synthesized protein is preferably used from the aspect of increasing biocompatibility or tissue healing properties. Can do. Moreover, if the gel-like substance containing the said protein is used, it will become possible to provide the characteristic which each protein has to a cylindrical structure.

  The protein is not particularly limited, and examples thereof include silk protein, collagen, cytokine, and antioxidant enzyme. The natural polymer or synthetic polymer is not particularly limited, and examples thereof include naturally-derived or synthesized dextrin, hyaluronic acid, pectin, and various sugars.

  The gel-like substance may contain, for example, an antithrombotic substance or a cell growth factor. The cell growth factor is not particularly limited, and examples thereof include cell growth factors such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), and nerve growth factor (NGF). be able to. When the gel-like substance contains an antithrombotic substance, formation of a thrombus mass on the surface of the cylindrical structure can be prevented when used for medical purposes such as an artificial blood vessel. The antithrombotic substance is not particularly limited as long as it is a substance that inhibits the formation of a thrombus or dissolves the thrombus, for example, urokinase, streptokinase, tissue plasminogen activator, plasmin, purinolase, heparin, hirudin Thrombomodulin, antiplatelet substance, sulfated silk protein (sulfonated fibroin, sulfonated sericin: JP-A-9-227402).

Examples of the pre-gelation solution include a pre-gelation solution containing any one or both selected from the antithrombotic substance and the cell growth factor in the pre-gelation solution containing the protein.

Examples of the gel substance include a gel substance containing one or both of the antithrombotic substance and the cell growth factor in addition to the gel substance containing the protein.

A tubular structure produced from a gel-like substance containing the protein and a gel-like substance further containing one or both of the antithrombotic substance and the cell growth factor is described in the present specification. It can be manufactured by any one of the manufacturing methods of the embodiment described above, and is particularly suitably used as a medical material such as an artificial blood vessel or a nerve regeneration tube.

  The concentration of the protein contained in the gel substance is not particularly limited, and may be, for example, 0.01, 0.1, 1, 10, 100, 200, 500, or 1000 mg / mL. Alternatively, it may be 1.0, 2.0, 3.0, 5.0, 8.0, 10.0, or 15.0 wt%. This concentration may be greater than or equal to the value shown here or in any value range. Further, the concentration of the antithrombotic substance or the cell growth factor contained in the gel substance is not particularly limited, but if it is contained at a concentration that exhibits an antithrombotic action or a cell proliferation action after the formation of the cylindrical structure. It is enough.

  The type of the protein is not particularly limited, and may be, for example, a fibrous protein or a globular protein. Among them, since fibrous proteins have many repeated arrangements, it is easy to produce a molded body made of a gel-like substance by mixing with a solution before gelation. Therefore, the fibrous protein can be suitably used for efficiently producing a cylindrical structure.

  The fibrous protein is not particularly limited, and examples thereof include silk protein, collagen, keratin, and elastin. Among them, silk protein can be suitably used for producing a cylindrical composition having high physical strength, as demonstrated in the examples described later. In addition, since certain silk proteins have the property that cells do not easily adhere in the presence of serum, using such silk proteins makes it possible to produce an artificial blood vessel that is non-cell-adhesive. For example, non-patent literature (Teramoto, Kameda, Tamada, Biosci. Biotech. Biochem. (2008)) contains silkworm-derived silk protein (in this specification, sometimes referred to as “silk silk”). It is described that a molded body composed of a gel-like substance is difficult to adhere to cells in the presence of serum. In the present specification, “silk protein” is a general term for fibrous proteins constituting the silk thread. For example, it can be purified from silkworms of organisms classified as arthropods such as killer hornets, silkworms, spiders and the like. Silk protein derived from Kirosuzubee or silkworm can dissolve silkworm silk in a neutral salt solution such as an aqueous solution of lithium bromide. Moreover, the silk protein derived from the yellow wasp can be dissolved in a water-soluble halogenated organic solvent. Examples of silkworm-derived silk proteins (in this specification, sometimes referred to as “silk-derived silk proteins”) include fibroin and sericin.

  The origin of the protein is not particularly limited, and examples thereof include the eubacteria kingdom, archaea kingdom, protozoan kingdom, fungus kingdom, plant kingdom, and animal kingdom. Among them, the animal kingdom can procure fibrous protein or silk protein relatively easily. Such a fibrous protein or silk protein is a protein that is relatively easy to control gelation, and is therefore suitable for the above-described method for producing a cylindrical structure. In the present invention, “easily procurable” corresponds to, for example, a case where a raw material can be obtained at low cost, or a case where a desired protein can be easily extracted from the raw material.

  In the animal kingdom, the lower level of the gate is not particularly limited, and examples thereof include an arthropod gate and a chordate gate. Among them, arthropod organisms can procure silk proteins relatively easily. In the arthropod phylum, the lower order eyes are not particularly limited, and examples thereof include bees, butterflies and spiders.

  In the bee order, a family that is a subordinate classification thereof is not particularly limited, and examples thereof include a bee family, a wasp family, and an ant family. Moreover, in the said hornet department, the subfamily which is the subordinate classification is not specifically limited, For example, the hornet subfamily and the wasp subfamily can be mentioned. Furthermore, the genus which is a subordinate class in the vespidae subfamily is not particularly limited, and examples thereof include genus hornet, genus hornet, and genus hornet. Examples of the genus Vespa include Vespa simillima xanthoptera, giant hornet, hornet hornet, hornet, hornet, chiros hornet, and hornet hornet. Among them, the silk protein derived from the yellow wasp can be procured relatively easily.

  In the Lepidoptera, there is no particular limitation on the family that is the lower classification, and examples thereof include the silkworm family, the mosquito family, the lobster family, the Ibotaga family, and the Yamayuga family. Among them, silk protein derived from the silkworm, Bombyxaceae, can be procured relatively easily. Further, in the silkworm family, the subfamily that is a subordinate class thereof is not particularly limited, and examples thereof include the silkworm family. Moreover, in the silkworm subfamily, the genus which is a lower class is not particularly limited, and examples thereof include the silkworm genus. Examples of the silkworm genus include silkworm (Bombyx mori) and mulberry (B. mandarina). Among them, silkworm-derived silk protein can be procured relatively easily. Examples of silkworm larvae include genetically modified silkworms, rabbits, and sericin silkworms (Japanese Patent No. 3374177). Rabbits generally secrete more fibroin, but sericin sputum, a mutant of rabbit, secretes more sericin than fibroin.

  In the present specification, the “gel-like substance” is a substance that can maintain a predetermined shape in a state where an external force is not applied and can be deformed into an arbitrary shape according to the external force, and has an integrated appearance as a whole. Gel-like substances can also be distinguished from lower viscosity and flowable sols. A typical gel-like substance is composed of a three-dimensional network structure in which polymers are crosslinked and a medium such as water. Moreover, since a gel-like substance can maintain a predetermined shape in a state where an external force is not applied, the outer diameter can be measured as in Examples described later.

  In the present specification, the material and shape of the “core rod” are not particularly limited, and examples thereof include a core rod containing a nonpolar material or a material having a low coefficient of friction. In this case, the molded body made of a gel-like substance is difficult to adhere to the core rod, and the core rod can be easily removed from a dried gel (sometimes referred to as “dried gel” in this specification). Note that the nonpolar material includes a material having some polarity as long as the material has low polarity. The nonpolar material or the material having a small friction coefficient is not particularly limited, and examples thereof include glass, a resin made of a nonpolar molecule, and a metal material (for example, stainless steel). Although the said resin is not specifically limited, For example, polyethylene, a polypropylene, a fluororesin (for example, polytetrafluoroethylene (PTFE) etc.) can be mentioned suitably. These materials are preferable because they are less susceptible to rust and corrosion. If these materials are used, it is possible to make a rigid core rod. In order to manufacture a high-quality cylindrical cylindrical structure having a uniform inner diameter and high uniformity, it is preferably a rigid cylindrical core bar having a uniform outer diameter and high uniformity. In order to make it easy to remove the core rod from the dried gel and to produce a cylindrical member having a smooth inner surface, the core rod is preferably a core rod having a smooth surface. Therefore, for example, the side surface of the core rod may be processed in advance so as to be smooth with sandpaper or an abrasive. The coefficient of friction can be measured, for example, according to JIS standard JISK7125. The friction coefficient of the material having the low friction coefficient is, for example, 0.1, 0.05, 0.04, 0.03, 0.02, 0.01, or 0.005. The coefficient of friction may be equal to or less than any one of the values exemplified here, or may be within the range of any two values, but is equal to or greater than zero. This coefficient of friction is preferably low in order to facilitate removal of the core rod from the dried gel. The tip of the core rod preferably has a sharp shape, and can be easily inserted into a molded body made of a gel-like substance. Moreover, the core rod which apply | coated the lubricant may be sufficient. Also in this case, the molded body made of a gel-like substance is difficult to adhere to the core rod, and the core rod can be easily removed from the dried gel. The shape of the core rod may be a cylinder with a hollow inside. In order to manufacture a high-quality cylindrical cylindrical structure having a uniform inner diameter and high uniformity, it is preferable that the cylindrical core rod has a uniform outer diameter, a high uniformity, and a rigidity.

  The diameter of the circle of the cross section cut at right angles to the major axis direction of the cylindrical “core rod” is not particularly limited, but for example, 0.1, 0.3, 0.5, 0.7, 0.9, 1 0.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, or 10.0 mm. This diameter may be less than or equal to any one of the values exemplified herein, or within the range of any two values. In the case of a cylindrical core rod, the diameter is the diameter of a circle outside the cross section (double circle) cut perpendicularly to the long axis direction of the core rod. Depending on the size of the diameter, the inner diameter, outer diameter, or thickness of the cylindrical tubular structure can be adjusted. The smaller this diameter, the more it becomes possible to produce a cylindrical structure with a smaller inner diameter, which was difficult with the conventional method. Such a cylindrical structure having a small inner diameter can be suitably used as a thin artificial blood vessel that has been difficult to manufacture by conventional methods. In addition, by adjusting the wall thickness, it is possible to improve the bending elastic modulus and to manufacture a cylindrical structure that does not cause kinking even when bent.

  The “core rod” may be a heat-shrinkable core rod. At this time, for example, after the step of drying the molded body made of the gel-like substance, the “intermediate component” in the present specification heats or cools the heat-shrinkable core rod, and the heat-shrinkable core. The intermediate structure obtained by the process which further includes the process of contracting a stick | rod may be sufficient. In this case, when the diameter of the core rod shrinks due to heating or cooling, a gap is formed between the dried material and the load applied to the dried gel, which is the dried material, when the core rod is pulled out. In this method, the core rod can be pulled out with a low possibility of scratching the dried gel while the molded body is still dried.

  Further, as shown in FIG. 5, for example, the core rod is a core rod enclosed in a heat-shrinkable tube (a core rod with a heat-shrinkable tube having a heat-shrinkable tube on the outer surface and a rod-shaped member inside. ). At this time, the intermediate structure is an intermediate structure obtained in a step further including a step of heating or cooling the heat-shrinkable tube to shrink the heat-shrinkable tube after the drying step. May be. In this case, since a space is formed after the core rod is pulled out, the heat-shrinkable tube tends to shrink. In the present specification, a “heat-shrinkable core rod” or “heat-shrinkable tube” is a core rod or tube that spontaneously shrinks when it reaches a certain temperature. The material of the heat-shrinkable core rod or the heat-shrinkable tube is not particularly limited. For example, FEP resin (a copolymer of tetrafluoroethylene and hexafluoropropylene), polyvinyl chloride, polyester, polyphenylene sulfide, A tetrafluoroethylene-propylene resin can be used. The temperature at which the heat-shrinkable core rod or heat-shrinkable tube shrinks is not particularly limited, and is, for example, 40, 60, 80, 140, or 200 ° C. This temperature may be greater than or equal to any one of the values exemplified herein, or within a range of any two values.

  The core rod may be a core rod having a “lubricant” applied to the side surface of the core rod. At this time, for example, as in the procedure shown in FIG. 6, the “intermediate component” in the present specification further includes a step of heating the lubricant after the step of drying the molded body made of a gel-like substance. The intermediate structure obtained by the process to include may be sufficient. Lubricant reduces the resistance caused by friction between the core rod and the dried gel of the molded product that has shrunk after drying, reducing the load on the dried gel when the core rod is pulled out, and may damage the dried gel. Low. In the present specification, the “lubricant” may be a commonly used conventional lubricant, and is not particularly limited, but is a lubricant that exhibits a lubricating effect without heating, or by heating. Furthermore, a lubricant that increases the lubricating effect can be preferably used. As the lubricant, a low melting point lubricant which is solid at room temperature is particularly preferable. When such a lubricant is used, the lubricant is melted by heating due to the effect of forming a gap between the core rod and the dried gel of the molded article that has shrunk after drying, and the core rod is pulled out. Sometimes the load on the dried gel is further reduced, so the possibility of damaging the dried gel is very low. Examples of such lubricants include waxes, and synthetic waxes include, for example, paraffin wax, and natural waxes include beeswax wax and wood wax. From the viewpoint of being suitable for a medical material, beeswax wax derived from beehives is preferable. The wax is a solid wax and is preferably a low melting point wax that melts when heated, and the melting point is not particularly limited. For example, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 A wax having a melting point of 150, 150 or 160 ° C. is preferred, and a wax having a melting point of 40, 50, 60, 70, 80, 90, or 100 ° C. is more preferred. This temperature may be greater than or equal to any one of the values exemplified herein, or within a range of any two values.

  In the present specification, the method of “drying” is not particularly limited. For example, it may be left in a room to be naturally dried, or may be dried by adjusting temperature, humidity and the like in an incubator. Or you may promote drying by the method of applying a wind using an air blower. Moreover, when drying the molded object which consists of a gel-like substance, when the said molded object is rod-shaped, it is not necessary to stand and dry like patent document 3, and the angle of a major axis direction is not specifically limited. Although the temperature at the time of performing the said drying is not specifically limited, For example, 1, 5, 10, 15, 20, 25, 30, 40, 60, or 90 degreeC is preferable. This temperature may be below any one of the values exemplified herein, or within the range of any two values. Further, the drying time is not particularly limited, and is, for example, 0.5, 1, 3, 5, 10, 12, or 24 hours, and may be within the range of any two values exemplified here. Good. By this drying, the molded body made of a gel-like substance attached to the core rod can be contracted in the direction of the inner core rod by drying. Normally, when the cylindrical hydrogel is dried as it is, the length of the cylindrical structure in the major axis direction contracts. On the other hand, in the manufacturing method of the present embodiment, the gel contraction in the long axis direction is suppressed by sticking a stick in the long axis direction, and the length in the long axis direction of the cylindrical structure is almost the same before and after drying. It is an excellent manufacturing method that is maintained (FIG. 7).

  Further, the shrinkage rate when the molded body made of the gel-like material shrinks in the direction of the inner core rod by drying is not particularly limited, but for example, 5, 25, 50, 60, 70, 80, 90 compared to before shrinkage. 95, 98, or 99% may be contracted. This shrinkage rate may be any one or more of the values exemplified here, or may be within the range of any two values. The shrinkage is preferably 60% or more, more preferably 80% or more, and still more preferably 90% or more from the viewpoint of the denseness or kink resistance of the cylindrical structure. Moreover, this shrinkage rate is less than 100%. In the manufacturing method described above, it is easier to manufacture a cylindrical structure having a desired length when the contraction of the length in the major axis direction is smaller. Although the contraction rate of the length in the major axis direction is not particularly limited, for example, 0, 1, 5, 10, 20, 30, 40, or 50% may be contracted compared to before contraction. This shrinkage rate may be equal to or less than any one of the values exemplified here, or within a range of any two values.

  In this specification, the water or aqueous solution in which the “dialysis membrane tube” is immersed may be a conventional water or aqueous solution generally used for dialysis, and is not particularly limited. For example, water is ion-exchanged water. Or, distilled water can be preferably used. As the aqueous solution, a conventional aqueous solution such as an aqueous solution in which polyethylene glycol for adjusting osmotic pressure is dissolved or an aqueous solution in which ethanol is dissolved (Japanese Patent Laid-Open No. 2006-111667) is used. It can be preferably used. The solvent in the dialysis membrane tube is not particularly limited, but may be water or a water-soluble organic solvent, for example. Further, a pH buffer, an inorganic substance, an organic substance or the like may be dissolved in water in the dialysis membrane tube. In general, bee larvae eject a wax substance from the nasopharyngeal gland and entangle it with wood scraps to form a nest. The discharged filamentous wax contains a lot of fibrous proteins. A neutral salt aqueous solution in which the inorganic substance is dissolved in water, or a water-soluble organic solvent can efficiently elute the fibrous protein from the honeycomb of such fibrous protein. It can be preferably used when producing a cylindrical composition from a bee-derived silk protein.

  Neutral salt aqueous solution includes weak acid salt, neutral salt, or weak acid salt aqueous solution, for example, weak acid salt such as lithium bromide, calcium chloride, copper ethylenediamine, sodium thiocyanate, lithium thiocyanate, magnesium nitrate, etc. And an aqueous solution in which a neutral or weakly basic salt is dissolved in water. In particular, lithium bromide efficiently dissolves bee-derived silk protein (sometimes referred to as “hornet silk” in this specification) and silkworm silk as demonstrated in the examples described later. Can do. Examples of the water-soluble organic solvent include a water-soluble halogenated organic solvent substituted with a halogen group such as dichloroacetic acid, trifluoroacetic acid, hexafluoroisopropanol, or hexafluoroacetone. Water-soluble neutral halogenated organic solvents such as hexafluoroisopropanol and hexafluoroacetone are solvents that can dissolve silk proteins more stably than water-soluble acidic halogenated organic solvents such as trifluoroacetic acid. . The concentration of the salt in the neutral salt aqueous solution is not particularly limited, and is, for example, 0.5, 1, 3, 5, 7, 9, or 12 mol / L, and is within the range of any two values exemplified here. There may be. The pH of the neutral salt aqueous solution is not particularly limited as long as it is in the range of weak acidity to weak alkalinity, but is, for example, pH 5, 6, 7, 8, 9, and preferably pH 5.5, 6.0, 6.5. 7.0, 7.5, 8.0, and 8.5, and more preferably pH 6.5, 7.0, 7.5, 8.0, and 8.5. Or within a range of two values.

  In addition, the dialysis temperature for dialysis of the pre-gelation solution in the dialysis membrane tube is not particularly limited as long as the protein or the like contained in the pre-gelation solution is not decomposed. Among water-soluble halogenated organic solvents, for example, there are those that may decompose proteins contained in the pre-gelation solution at a temperature higher than room temperature in an acidic halogenated organic solvent. In such a case, it is preferable to perform dialysis by cooling, and for example, it is preferable to perform dialysis by cooling to 4 ° C. or lower. The dialysis temperature is preferably a temperature at which the pre-gelation solution in the dialysis membrane tube does not freeze. The dialysis temperature is, for example, −5, 0, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, or 80 ° C., and is within the range of any two values exemplified here. It may be. The time required for gelation is not particularly limited, and is, for example, 0.5, 1, 3, 5, 10, 12, 24, 48, or 96 hours, and any one or more of the values exemplified here, or It may be within the range of any two values. In addition, the amount of the pre-gelation solution to be filled in the dialysis membrane tube is not particularly limited and is appropriately selected depending on the use of the cylindrical structure. For example, 1, 5, 10, 20, 100, 500 , Or 1000 mL, and may be any one or more of the values exemplified here, or within the range of any two values.

  In the present specification, the “intermediate component” is obtained in a step further comprising a step (drying step) of absorbing moisture in the dried molded body after drying the molded body made of a gel-like substance. It may be an intermediate structure. In this case, since the dried molded body absorbs moisture and becomes flexible, the load applied to the gel when the core bar is pulled out from the intermediate structure is small.

  In the present specification, the “step of absorbing moisture in the dried molded body” is not particularly limited. For example, water can be absorbed by putting water in a container and immersing the dried molded body in the water. Further, water may be sprinkled on the dried molded body. Moreover, you may spray on the molded object which water-dried and dried. In this way, by absorbing moisture into the dried molded body, unnecessary stress is not applied to the rehydrated molded body when the core rod is pulled out from the rehydrated molded body, and a high quality cylinder It is possible to produce a shaped structure. The type of water used in the step of absorbing moisture in the dried molded body is not particularly limited. For example, pure water such as ion-exchanged water or distilled water, or an aqueous solution such as physiological saline is preferably used according to the application. Can be used. The amount of water absorbed by the dried molded body is not particularly limited. For example, the moisture amount is 0.1, 0.5, 1, 5, 10, 100, or 1000 times the weight of the dried molded body. It may be less than any one of the values exemplified here, or may be within the range of any two values.

  Since the silk protein hydrogel exhibits a water content of 90% or more (the water content of 90% is a state of water 9 with respect to the silk protein 1), when the silk protein hydrogel is dried, the volume is approximately 1 / Shrink to 10 or less. In this shrinkage process, the density increases and becomes hard, and once the gel made from silk protein (also referred to as “silk gel” in this specification) is dried, the gel is hardened even if it is dipped in water again. Is maintained. Therefore, from the conventional technical common sense, it was difficult to predict the production method of the present invention in which the core rod was pulled out without breaking the shape of the silk gel after the moisture was once absorbed into the silk gel once dried. In particular, in the production method of the present invention, since the moisture is not in direct contact with the portion where the silk gel is in contact with the core rod, from the conventional technical common sense, the portion of the silk gel in contact with the core rod is not damaged. It was difficult to predict that it could be peeled off. In addition, according to the production method of the present invention, it is possible to produce a high-quality cylindrical structure in which the distortion of the cross section is suppressed, as demonstrated in the examples described later. The moisture content of 90% or more may be 90, 92, 94, 96, 98, or 99%, and any one value or more exemplified here, or within the range of any two values. There may be.

  Another embodiment of the present invention is an intermediate structure obtained by a step including a step of inserting a core rod into a molded body made of a gel-like substance and a step of shrinking the molded body in the direction of the core rod. It is a manufacturing method of a medical cylindrical structure including the process of extracting the said core rod. According to the manufacturing method of the present embodiment, it is possible to manufacture a high-quality medical cylindrical structure as demonstrated in the examples described later.

  Other embodiment of this invention may further include the process of extending | stretching the said cylindrical structure which pulled the core rod in the manufacturing method of one of the said cylindrical structures. In this case, the length, the inner diameter, the outer diameter, the thickness, or the mechanical properties of the cylindrical structure can be adjusted. In the conventional method for producing a cylindrical structure, it has been very difficult to produce a flexible protein that can be stretched, in particular, a silk protein tubular structure. As described above, according to the manufacturing method of the present embodiment, this is possible. For example, the tensile strength in the major axis direction is further increased by stretching the tubular structure. In addition, when extending | stretching, you may extend | stretch until the tensile strain becomes 50, 100, 150, or 200%, for example, and it extends within the range of any one value more than illustrated here, or any two values. May be. As the tensile strain increases, the tensile strength improves.

  Other embodiment of this invention is a cylindrical structure obtained with the manufacturing method of one of the said cylindrical structures. As demonstrated in the examples described later, this cylindrical structure is a cylindrical structure having high uniformity in the length direction, less distortion from a perfect circle, and excellent uniformity. Moreover, it is a cylindrical structure excellent in physical strength, bending elastic modulus, denseness, and kink resistance. Since this cylindrical structure is of high quality, it can be suitably used as a medical material, and in particular, can be suitably used for a cylindrical structure such as an artificial blood vessel or a nerve regeneration tube. The kink is a phenomenon that the tube collapses when the tube is bent.

  Other embodiment of this invention is a medical material containing the cylindrical structure obtained with the manufacturing method of one of the said cylindrical structures. The type of medical material is not particularly limited, and may be, for example, an artificial tissue or an artificial organ, or an artificial blood vessel, a nerve regeneration tube, or an artificial heart. Since this medical material contains a high-quality cylindrical structure, it has a high therapeutic effect. Moreover, since this medical material contains the cylindrical structure which can be manufactured efficiently and simply, it can be supplied at low cost.

  In this specification, the “tubular structure” is a structure having a cylindrical portion. One end or both ends of this cylindrical structure may be connected to another structure. Here, the other component may be, for example, an artificial organ such as an artificial heart, or a material for an artificial blood vessel or a nerve regeneration tube. Moreover, the said cylindrical structure may be integrated with an artificial blood vessel etc. and may become a part of artificial blood vessels. Moreover, this cylindrical structure does not necessarily need to have the same shape from end to end. For example, one end may have a pipe diameter several times that of the other end. Even such a cylindrical structure can be used for applications such as an artificial blood vessel by cutting and using a portion whose tube diameter or wall thickness is uniformly controlled. Moreover, this cylindrical structure does not necessarily have to penetrate through in the major axis direction, and may be closed somewhere. Even if it is such a cylindrical structure, if it cuts and uses the part which the inside has penetrated to the major axis direction, it can be used for uses, such as an artificial blood vessel. Further, in the present specification, the cylindrical structure can also be expressed by a tube, a cylinder, a tube, and the like, for example, a cylindrical structure having a circular cross section cut at a right angle to the long axis, or an elliptical elliptical cylindrical shape In the manufacturing method according to any one of the above-described embodiments, for example, a cylindrical shape, a cylindrical shape, an elliptical columnar shape, an elliptical cylindrical shape, a polygonal columnar shape having different sizes may be mentioned. Or, by selecting a suitable combination of polygonal cylindrical core rods or perforated bars, a high-quality cylindrical structure, elliptical cylindrical structure, or polygonal cylindrical structure having a uniform thickness and different thickness Can be manufactured.

  The cylindrical structure may have a dense single layer structure. In this case, leakage of the liquid flowing inside the cylindrical structure is unlikely to occur. In addition, characteristics such as elastic modulus of the cylindrical structure are likely to be uniform. In the present specification, the “single-layer structure” is a structure formed without stacking two or more layers in the manufacturing process.

  Moreover, the length of this cylindrical structure is not specifically limited, For example, it is 0.5, 1, 2.5, 4, 10, 30, 50, or 100 cm. Moreover, although the internal diameter of this cylindrical structure is not specifically limited, For example, it is 0.5, 0.73, 1, 2, 3, 6, or 10 mm. Moreover, the outer diameter of this cylindrical structure is not particularly limited, but is, for example, 0.8, 1, 1.4, 3, 4.5, 6, 9, or 15 mm. Moreover, the thickness of this cylindrical structure is not specifically limited, For example, it is 0.03, 0.1, 0.3, 0.7, 1, 2, 3, or 6 mm. These lengths may be equal to or less than any one of the values exemplified herein, or within the range of any two values. In addition, the thickness tends to increase the physical property strength in the major axis direction as the thickness increases. In the prior art, it is difficult to control the uniformity as the thickness increases. However, according to any one of the manufacturing methods according to the embodiment, the thickness is controlled with high accuracy even if the thickness is large. It is possible.

  When this cylindrical structure is used as an artificial blood vessel, its method of use is not particularly limited. For example, instead of a diseased blood vessel such as an aneurysm or a vascular stenosis, the blood vessel is cut out and replaced with an artificial blood vessel. Can do. Moreover, this cylindrical structure can be used also as an artificial blood vessel by bypass surgery. Moreover, this cylindrical structure can be used also for shunts when performing artificial dialysis. Moreover, when using this cylindrical structure as a tube for nerve regeneration, the usage method is not specifically limited, For example, the nerve which cut | disconnected can be connected with the tube for nerve regeneration, and nerve regeneration can be promoted.

(2) Cylindrical structure Another embodiment of the present invention is a cylindrical tubular structure that includes part or all of a tubular part containing a protein, and the tubular part includes the tubular part. In five cross-sections when cut at right angles to the major axis direction at five points of 0.5 cm intervals, the four inner diameter lengths obtained when the inner diameter is measured from four directions with different angles by 45 degrees. It is a cylindrical tubular structure which is a tubular portion having a coefficient of variation of an average value of 0.1 or less. This variation coefficient can be obtained, for example, by the procedure shown in FIG. Since this tubular portion has a smooth inner surface with high uniformity of the inner diameter in the major axis direction, the liquid can flow more smoothly inside. In addition, the flow rate is easily kept constant. Therefore, because it is difficult for impurities to adhere to the inner surface of the tubular portion or get caught, when used as an artificial blood vessel, it is easy to adjust the blood flow and it is an excellent cylindrical structure that is difficult to cause thrombus. is there.

  In this specification, the “tubular portion” is a cylindrical structure having a hollow in the long axis direction inside. The length may be appropriately selected depending on the application and is not particularly limited. For example, the length is 0.5, 1, 2, 3, 4, 5, 10, 30, 50, or 100 cm. This length may be greater than any one of the values exemplified herein, or within the range of any two values. The tubular portion may be a part of the tubular structure, or may be the whole. When the tubular part is a part of a cylindrical structure, it may be used as it is, but if the tubular part is cut out, it can be expressed by the coefficient of variation as described above, and the wall thickness is uniform and highly uniform. It can be used as a cylindrical structure. Moreover, when the said tubular part is the whole cylindrical structure, it is possible to use it as a cylindrical structure with uniform thickness and high uniformity as it is.

  Therefore, the tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value “0.1 or less” of the coefficient of variation is not particularly limited, but is, for example, 0.1, 0.08, 0.06, 0.04, 0.02, or 0.01. This numerical value may be below any one of the values exemplified here, or may be within the range of any two numerical values. The coefficient of variation is a numerical value obtained by dividing the standard deviation of a plurality of numerical values obtained by measurement by the average value of the plurality of numerical values obtained by measurement. The coefficient of variation is generally known as an index representing relative variation.

  In another embodiment of the present invention, in the “five cross-sections”, the variation coefficient of the average value of the lengths of the eight types of wall thickness obtained when the wall thickness is measured from eight directions that are different from each other by 45 degrees is It is a cylindrical tubular structure that includes a part or all of a tubular portion of 0.2 or less. Since this tubular portion has a high uniformity of thickness in the major axis direction, the uniformity of physical property strength, bending elastic modulus and the like in the major axis direction is high, and kink and crushing hardly occur. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value “0.2 or less” of the coefficient of variation is not particularly limited, but for example, 0.2, 0.18, 0.16, 0.15, 0.14, 0.12, 0.10,. 08, 0.07, 0.05, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  In another embodiment of the present invention, in the “five cross-sections”, the coefficient of variation of the average value of the lengths of the four types of outer diameters obtained when the outer diameter is measured from four directions with different angles by 45 degrees is It is a cylindrical tube-shaped structure including a part or all of a tubular portion of 0.1 or less. Since the tubular portion has a high uniformity of the outer diameter in the major axis direction, the uniformity of the physical property strength, the bending elastic modulus and the like in the major axis direction is high, and kink and crushing hardly occur. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The value of the coefficient of variation “0.1 or less” is not particularly limited, but for example, 0.1, 0.08, 0.06, 0.05, 0.03, 0.02, 0.01,. 005 or 0.001. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  In another embodiment of the present invention, in the “five cross-sections”, the coefficient of variation of the average value of the lengths of the four types of inner diameters obtained when the inner diameter is measured from four directions with different angles by 45 degrees is 0. It is a cylindrical tubular structure including part or all of a tubular portion of 05 or less. Since this tubular portion is less distorted with respect to the perfect circle of the inner diameter in each cross section, it has high uniformity in physical property strength, bending elastic modulus and the like in the major axis direction, and is unlikely to cause kinking or crushing. Therefore, the tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value of the coefficient of variation “0.05 or less” is not particularly limited, but is, for example, 0.05, 0.04, 0.03, 0.02, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  In another embodiment of the present invention, in the “five cross-sections”, the coefficient of variation of the average value of the lengths of the four types of outer diameters obtained when the outer diameter is measured from four directions with different angles by 45 degrees is It is a cylindrical tube-shaped structure including a part or all of a tubular portion of 0.1 or less. Since this tubular portion is less distorted with respect to a perfect circle of the outer diameter in each cross section, it has high uniformity in physical property strength, bending elastic modulus and the like in the major axis direction, and kinks and crushing hardly occur. Therefore, the tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The value of the coefficient of variation “0.1 or less” is not particularly limited, but for example, 0.1, 0.08, 0.06, 0.05, 0.03, 0.02, 0.01,. 005 or 0.001. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  In another embodiment of the present invention, in the “five cross-sections”, the variation coefficient of the average value of the lengths of the eight types of wall thickness obtained when the wall thickness is measured from eight directions that are different from each other by 45 degrees is It is a cylindrical tube-shaped structure which includes a tubular portion of 0.5 or less in part or in whole. Since this tubular portion has high uniformity in thickness in each cross section, it has high uniformity in physical property strength, bending elastic modulus and the like in the major axis direction, and is unlikely to cause kinking or crushing. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value of the coefficient of variation “0.5 or less” is not particularly limited. For example, 0.5, 0.4, 0.3, 0.2, 0.18, 0.16, 0.15, 0.14 , 0.12, 0.10, 0.08, 0.07, 0.05, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  Another embodiment of the present invention is a cylindrical tubular structure including a tubular portion containing a protein, and the tubular portion is separated from the tubular portion with respect to the major axis direction at two locations at intervals of 0.5 cm. In two cross-sections cut at right angles to each other, the variation coefficient of the average value of the lengths of the eight types of thicknesses obtained when the thicknesses are measured from 8 directions with different angles by 45 degrees is 0.5 or less. It is a cylindrical tubular structure including a tubular part in part or in whole. Since this tubular portion has high uniformity in thickness in each cross section, it has high uniformity in physical property strength, bending elastic modulus and the like in the major axis direction, and is unlikely to cause kinking or crushing. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value “0.5 or less” of the coefficient of variation is not particularly limited, but for example, 0.5, 0.4, 0.3, 0.2, 0.18, 0.16, 0.15, 0. 14, 0.12, 0.10, 0.08, 0.07, 0.05, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  Another embodiment of the present invention is a cylindrical tubular structure including a tubular portion containing a protein, and the tubular portion is separated from the long-axis direction at three locations at intervals of 0.5 cm. In three cross-sections cut at right angles to each other, the variation coefficient of the average value of the lengths of the eight types of wall thickness obtained when the wall thickness is measured from 8 directions with different angles by 45 degrees is 0.2 or less. It is a cylindrical tubular structure including a tubular part in part or in whole. Since the tubular portion has a high thickness uniformity in the major axis direction, the uniformity of the physical property strength, the flexural modulus, and the like in the major axis direction is high, and kink and crushing hardly occur. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value “0.2 or less” of the coefficient of variation is not particularly limited, but for example, 0.2, 0.18, 0.16, 0.15, 0.14, 0.12, 0.10,. 08, 0.07, 0.05, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  In another embodiment of the present invention, in the “three cross sections”, the coefficient of variation of the average value of the lengths of the eight types of wall thickness obtained when the wall thickness is measured from eight directions with different angles by 45 degrees is It is a cylindrical tube-shaped structure which includes a tubular portion of 0.5 or less in part or in whole. Since this tubular portion has high uniformity in thickness in each cross section, it has high uniformity in physical property strength, bending elastic modulus and the like in the major axis direction, and is unlikely to cause kinking or crushing. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value “0.5 or less” of the coefficient of variation is not particularly limited, but for example, 0.5, 0.4, 0.3, 0.2, 0.18, 0.16, 0.15, 0. 14, 0.12, 0.10, 0.08, 0.07, 0.05, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  In another embodiment of the present invention, in the “three cross-sections”, the variation coefficient of the average value of the lengths of the four types of outer diameters obtained when the outer diameter is measured from four directions that are different from each other by 45 degrees. It is a cylindrical tube-shaped structure including a part or all of a tubular portion of 0.1 or less. Since this tubular portion is less distorted with respect to a perfect circle of the outer diameter in each cross section, it has high uniformity in physical property strength, bending elastic modulus and the like in the major axis direction, and kinks and crushing hardly occur. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The value of the coefficient of variation “0.1 or less” is not particularly limited, but for example, 0.1, 0.08, 0.06, 0.05, 0.03, 0.02, 0.01,. 005 or 0.001. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  In another embodiment of the present invention, in the “three cross-sections”, the variation coefficient of the average value of the lengths of the four types of inner diameters obtained when the inner diameter is measured from four directions with different angles by 45 degrees is 0. It is a cylindrical tubular structure including part or all of two or less tubular parts. Since this tubular portion is less distorted with respect to the perfect circle of the inner diameter in each cross section, it has high uniformity in physical property strength, bending elastic modulus and the like in the major axis direction, and is unlikely to cause kinking or crushing. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value of the coefficient of variation “0.2 or less” is not particularly limited, but for example, 0.2, 0.18, 0.15, 0.12, 0.10, 0.08, 0.06, 0.0. 04, 0.02, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  Another embodiment of the present invention is a cylindrical tubular structure including part or all of a tubular portion containing a protein, and the tubular portion includes eight portions at intervals of 0.5 cm. In the eight cross-sections cut at right angles to the major axis direction, the coefficient of variation of the average value of the lengths of the four types of inner diameters obtained when the inner diameters are measured from four directions with different angles by 45 degrees is 0. .1 A cylindrical tubular structure including a part or all of a tubular portion of 1 or less. This tubular portion has high inner diameter uniformity in the major axis direction. The effect of such a tubular portion is as described above. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value “0.1 or less” of the variation coefficient is not particularly limited, and is, for example, 0.1, 0.08, 0.05, 0.02, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  In another embodiment of the present invention, in the “eight cross-sections”, the variation coefficient of the average value of the lengths of the four types of outer diameters obtained when the outer diameter is measured from four different angles by 45 degrees is It is a cylindrical tubular structure including a part or all of a tubular portion of 0.01 or less. Since this tubular portion is less distorted with respect to a perfect circle of the outer diameter in each cross section, it has high uniformity in physical property strength, bending elastic modulus and the like in the major axis direction, and kinks and crushing hardly occur. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value “0.01 or less” of the coefficient of variation is not particularly limited, and is, for example, 0.01, 0.008, 0.006, 0.004, 0.003, 0.002, or 0.001. . This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  In another embodiment of the present invention, in the “eight cross-sections”, the variation coefficient of the average value of the lengths of the eight types of wall thickness obtained when the wall thickness is measured from eight directions with different angles by 45 degrees is It is a cylindrical tubular structure that includes a part or all of a tubular portion of 0.2 or less. Since this tubular portion has high uniformity in thickness in each cross section, it has high uniformity in physical property strength, bending elastic modulus and the like in the major axis direction, and is unlikely to cause kinking or crushing. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value “0.2 or less” of the coefficient of variation is not particularly limited. For example, 0.2, 0.18, 0.16, 0.15, 0.14, 0.12, 0.10, 0.08 , 0.07, 0.05, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  Another embodiment of the present invention is a cylindrical tubular structure containing a protein, in which a tubular part having a length of 2 cm in the long axis direction extends from the tubular structure to the long axis direction. The upper surface and the bottom surface of the cross section of the tubular portion when cut vertically, and perpendicular to the major axis direction at 0.5, 1.0, and 1.5 cm away from the upper surface in the bottom surface direction. The variation coefficient of the average value of the lengths of the four types of inner diameters obtained when the inner diameters of the five cross-sections measured from four directions differing from each other by 45 degrees are 0.1 or less. It is a cylindrical tubular structure including the tubular portion in part or in whole. This variation coefficient can be obtained, for example, by the procedure shown in FIG. This tubular part has a high inner diameter uniformity in the major axis direction, so that the liquid can flow more smoothly through the inside, the flow velocity can be kept constant, and impurities can adhere to or get caught on the inner surface. It is a difficult cylindrical structure. Therefore, when this tubular part is used as an artificial blood vessel, blood flow is easily adjusted to be constant and thrombus is less likely to occur. Further, the cylindrical tubular structure including part or all of this tubular part may be used as it is, but if this tubular part is used as it is, it can be expressed by the coefficient of variation. It can be suitably used as a highly cylindrical structure. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value “0.1 or less” of the coefficient of variation is not particularly limited, but is, for example, 0.1, 0.08, 0.06, 0.04, 0.02, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  Another embodiment of the present invention is a cylindrical tubular structure containing a protein, wherein a tubular portion having a length of 1 cm in the long axis direction is from the tubular structure to the long axis direction. The upper surface of the cross section of the tubular portion when cut vertically, the cross section when cut perpendicularly to the major axis direction at a position 0.5 cm away from the upper surface in the direction of the bottom surface, and the bottom surface. In the two cross-sections, the tubular portion, in which the variation coefficient of the average value of the lengths of the eight kinds of thicknesses obtained when the thicknesses are measured from 8 directions different from each other by 45 degrees is 0.2 or less It is a cylindrical tubular structure included in part or all. Since the tubular portion has a high thickness uniformity in the long axis direction, it has high uniformity in physical property strength, bending elastic modulus, and the like in the long axis direction, and kinks and crushing hardly occur. In addition, the cylindrical tubular structure including part or all of this tubular part may be used as it is, but if this tubular part is used as it is, it can be expressed by the coefficient of variation. It can be suitably used as a high-cylindrical structure. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value “0.2 or less” of the coefficient of variation is not particularly limited. For example, 0.2, 0.18, 0.16, 0.15, 0.14, 0.12, 0.10, 0.08, 0.07, 0.05, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  Another embodiment of the present invention is a cylindrical tubular structure containing a protein, wherein a tubular part having a length of 0.5 cm in the long axis direction is from the tubular structure to the long axis direction. 8 types of wall thickness obtained when the thickness of each of the two cross-sections of the upper surface and the bottom surface of the tubular portion when cut vertically is measured from 8 directions at different angles by 45 degrees The variation coefficient of the average value of the length is 0.5 or less, and the tubular portion includes the tubular portion in part or in whole. Since the tubular portion 0 has high uniformity in thickness in each cross section, it has high uniformity such as physical strength and bending elastic modulus in the major axis direction, and kinks and crushing hardly occur. In addition, the cylindrical tubular structure including part or all of this tubular part may be used as it is, but if this tubular part is used as it is, it can be expressed by the coefficient of variation. It can be suitably used as a high-cylindrical structure. Therefore, the cylindrical tubular structure including part or all of the tubular portion can be suitably used as a medical material for use in an artificial blood vessel or the like. The numerical value “0.5 or less” of the coefficient of variation is not particularly limited. For example, 0.5, 0.4, 0.3, 0.2, 0.18, 0.16, 0.15, 0.14, 0.12, 0.10, 0.08, 0.07, 0.05, or 0.01. This numerical value may be less than or equal to any one of the numerical values exemplified herein, or may be within the range of any two numerical values.

  Another embodiment of the present invention is a medical material including any one of the above cylindrical structures. The type of the medical material is not particularly limited, and may be, for example, an artificial tissue or an artificial organ, or an artificial blood vessel, a nerve regeneration tube, or an artificial heart. Since this medical material contains a high-quality cylindrical structure, it has a high therapeutic effect.

  Another embodiment of the present invention includes a step of gelling an aqueous solution containing a protein to prepare a molded body made of a gel-like substance, a step of attaching the molded body to a side surface of a core rod, and the attached molding And a step of removing the core rod from the intermediate structure obtained in the step including the step of drying the body and contracting in the direction of the core rod. Or it is a cylindrical structure obtained by this manufacturing method. Or in the cylindrical structure which concerns on embodiment of this invention, it is the method of controlling the mechanical physical property or thickness of a cylindrical structure by adjusting the density | concentration of the protein in aqueous solution, or a draw ratio. According to this method, the mechanical properties or thickness of the cylindrical structure can be controlled to a high degree. The mechanical physical properties include, for example, tensile physical properties or compressed physical properties. Moreover, according to this method, the cylindrical structure of high tensile strength or a compression physical property can be manufactured.

  As mentioned above, although embodiment of this invention was described, these are illustrations of this invention and various structures other than the above are also employable. Moreover, it is also possible to adopt a combination of the configurations described in the above embodiments.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further, this invention is not limited to these.

<Example 1> Cylindrical structure of wasp-derived silk protein (1) Gelation of wasp-derived silk protein A gel derived from a wasp cocoon was prepared by the following procedure. First, lithium bromide (LiBr) was dissolved in ion-exchanged water to prepare a 9 mol / L LiBr aqueous solution as a neutral salt aqueous solution. In this aqueous solution, the moth wasp nest was stirred at 37 ° C. for about 15 minutes until there was no undissolved protein component. Here, 1 g of soot was dissolved in 20 mL of a 9 mol / L LiBr aqueous solution (pH 8.2). The obtained aqueous solution was suction filtered with a Kiriyama funnel (Kiriyama Seisakusho, using a filter paper with 7 micron retention particles) to separate and remove insoluble components. The hornet's nest, which is the starting material, is mainly composed of wood scraps, but these nest components are insoluble in the 9 mol / L LiBr aqueous solution, so they are removed as insoluble components, and silk protein is selected. A solution prior to gelation was obtained.

  5 mL of this pre-gelling solution was placed in a cylindrical dialysis membrane tube made of cellulose (cellulose tube size 8/32, Sanko Junyaku Co., Ltd.) and dialyzed in ion-exchanged water for 4 days (FIG. 1). This dialysis process is performed while exchanging ion-exchanged water until the increase in the electric conductivity of ion-exchanged water due to LiBr being released outside the tube does not exceed 5 μS / cm even after 24 hours. went. LiBr was removed from the pre-gelation solution in the dialysis membrane tube by this dialysis. At the same time, the pre-gelation solution in the dialysis membrane tube solidified, and a gel containing silk protein was produced. The dialysis membrane tube containing this gel was cut at two points near both ends to obtain a cylindrical silk gel (FIG. 10). The cylindrical silk gel had a diameter of 7 mm. At this time, the cellulose membrane of the dialysis membrane tube on the surface of the silk gel keeps the silk gel covered.

(2) Insertion of core rod A core rod (a stainless steel rod having a diameter of 0.7 mm) with a sharp tip was stabbed in the long axis direction from the center of the bottom of the cylindrical silk gel. The surface of the stainless steel rod used as the core rod was previously polished with a metal abrasive (the same applies hereinafter). When the core rod completely penetrated the gel, the dialysis membrane tube covering the gel was peeled off.

(3) Production of cylindrical structure The silk gel in which the core rod was inserted was blown at room temperature and dried for half a day (FIG. 11). By drying, the silk gel became hard around the core bar. Further, the dried silk gel was immersed in water and extracted from the core bar when it became soft. By the above, the cylindrical cylindrical structure of the wasp-derived silk protein with a total length of 50 mm was produced. This tubular structure did not cause kinking even when bent to some extent (FIG. 12).

(4) Observation with an electron microscope The produced cylindrical structure was observed with an electron microscope (SEM) (FIG. 13). From the photograph by SEM, it was found that the produced cylindrical structure had a uniform thickness and a smooth inner surface. The inner diameter was 0.73 mm, the outer diameter was 1.39 mm, and the wall thickness was 0.33 mm (FIG. 14). Regarding the inner diameter and thickness of the cylindrical structure, various shapes of the cylindrical structure can be prepared by appropriately adjusting the diameter of the columnar silk gel and the diameter of the core rod.

  Moreover, it was found from the SEM photographs of the cross-sections (500, 2000, 4000, and 6000 times) of the cylindrical structure that the silk protein was densely set (FIG. 15). Such a cylindrical structure prevents leakage of fluid passing through the inside of the pipe and can exhibit excellent mechanical properties.

(5) Stretching The cylindrical structure was stretched in the major axis direction using a hand-drawing stretcher (Imoto Seisakusho) in a water-absorbing state (FIG. 16). As a result, it was possible to stretch up to 2 times. This means that the mechanical properties can be improved and the tube diameter and tube length can be adjusted. Moreover, it was able to be modified into tubes having different tube diameters and mechanical properties by fixing and drying in the stretched state.

<Example 2> Cylindrical composition of wasp-derived silk protein Cylindrical cylindrical shape of wasp-derived silk protein having the shape shown in Table 1 by changing the core rod diameter to 0.9 cm in the same manner as in Example 1. A construct was made. The obtained cylindrical structure had the same compactness and kink resistance as Example 1.

<Example 3> Cylindrical composition of wasp-derived silk protein (1) Gelation of wasp-derived silk protein A columnar silk gel of wasp-derived silk protein having a diameter of 7 mm was obtained in the same manner as in Example 1.

(2) Insertion of core rod A cylindrical hole rod (glass tube) having an outer diameter of 3.0 mm and an inner diameter of 2.0 mm is inserted in the long axis direction from the center of the bottom of the cylindrical silk gel (FIG. 17) and pulled out. A hole was made with and the silk gel was crumpled (FIG. 18). Next, a core rod (a stainless steel rod having a diameter of 3.0 mm) was pierced into the hole of the silkworm-shaped silk gel (FIG. 19). When the core rod completely penetrated the hole in the crumpled silk gel, the dialysis membrane tube covering the gel was peeled off.

(3) Production of cylindrical structure The silk gel in which the core rod was inserted was blown at room temperature and dried for half a day (FIG. 20). By drying, the silk gel became hard around the core rod (FIG. 21). Further, the dried silk gel was soaked in water and extracted from the core when it became soft (FIG. 22). By the above, the cylindrical cylindrical structure of the hornet origin silk protein of the shape shown in Table 1 was produced. The obtained cylindrical structure had the same compactness and kink resistance as Example 1.

<Example 4> Cylindrical component of wasp-derived silk protein Cylindrical protein of wasp-derived silk protein having the shape shown in Table 1 in the same manner as in Example 3, except that the diameter of the core rod and the punched rod was changed to 7.0 mm. A cylindrical structure was produced. The obtained cylindrical structure had the same compactness and kink resistance as Example 1.

The results are shown in Table 1.

<Example 5> Cylindrical structure of wasp-derived silk protein As shown in Fig. 3, a cylindrical structure of wasp-derived silk protein can be produced by a method obtained by partially modifying the method of Example 1. it can. Specifically, from the columnar silk gel obtained in the step (1) of Example 1, a cylindrical hole is used to form a cylindrical column having an outer diameter smaller than the outer diameter of the original columnar silk gel. Cut out the silk gel. A core rod is inserted into a cylindrical silk gel obtained by hollowing out the silk gel by the same method as in Example 1. In this case, the cellulose membrane of the dialysis membrane tube is removed when the cylindrical silk gel is cut out. Others are the same as in the first embodiment. In this method, it is easy to adjust the outer diameter and thickness of a cylindrical tubular structure. As a result, a dense, kink-resistant tubular structure similar to the tubular structure of the wasp-derived silk protein obtained in Example 1 is obtained.

<Example 6> Cylindrical structure of wasp-derived silk protein As shown in FIG. 4, a cylindrical cylindrical structure of wasp-derived silk protein was produced by a method in which the method of Example 1 was partially modified. Specifically, in the step (1) of Example 1, the dialysis membrane is such that the center line of the cylindrical dialysis membrane tube in which the core rod is pre-filled with the solution before gelation coincides with the longitudinal axis of the core rod. Gelation was carried out with the tube fixed. Others were the same as in Example 1. As a result, a dense, kink-resistant tubular structure similar to the tubular structure of the wasp-derived silk protein obtained in Example 1 was obtained.

<Example 7> Cylindrical structure of wasp-derived silk protein As shown in FIG. 5, a cylindrical structure of wasp-derived silk protein was produced by a method obtained by partially modifying the method of Example 1. Specifically, first, a cylindrical heat-shrinkable tube was put on the side surface of a stainless steel rigid core rod. The heat-shrinkable tube is a heat-shrinkable tube made of a conventional FEP resin (a copolymer of tetrafluoroethylene and hexafluoropropylene) that shrinks spontaneously when it reaches a certain temperature (JEOL Ltd. FEP heat shrinkage) Tube 025) was used. Gelation is carried out while fixing the core rod enclosed in the heat-shrinkable tube to the cylindrical dialysis membrane tube containing the pre-gelation solution and the dialysis membrane tube so that the center line in the longitudinal direction of the core rod matches. It was. Thereafter, the same procedure as in Example 1 was performed until the silk gel was dried to obtain a dry gel.

  Thereafter, the core rod was pulled out while leaving a heat-shrinkable tube inside the dried gel. Since the surface of the core rod was covered with a heat-shrinkable tube, the core rod could be easily pulled out. Next, the heat-shrinkable tube was shrunk by heating to 140 ° C. for 1 minute, and after cooling to room temperature, the heat-shrinkable tube was extracted from the dried gel. A cylindrical tubular structure produced by this method is shown in FIG. Although the thickness of this cylindrical structure was as thin as 0.05 mm, it was found that there was no disorder in shape. Furthermore, FIG. 24 shows the result of observation with another electron microscope (SEM) of another cylindrical structure manufactured by the same method.

  Before heating, the heat-shrinkable tube is attached to the dry gel, so it cannot be easily pulled out as it is, but the FEP resin shrinks at the same temperature (60 ° C-120 ° C) or more. By heating at a high temperature, the heat-shrinkable tube shrinks, and the heat-shrinkable tube can be easily extracted from the dried gel in a state cooled to room temperature. In this method, when the core rod and the heat-shrinkable tube are extracted, the dry gel is not burdened at all, so that the shape is not easily collapsed even with a thin cylindrical structure. The method using such a heat-shrinkable tube is used when the cylindrical cylindrical structure has a small inner diameter (inner diameter of about 3 mm or less), or in the case of a long cylindrical cylindrical structure (about 50 mm in length). In the above), the core rod and the heat-shrinkable tube can be easily removed regardless of the inner diameter and length of the cylindrical structure, and the burden on the cylindrical structure is small. It was the manufacturing method of the cylindrical structure.

<Example 8> Cylindrical structure of wasp-derived silk protein As shown in FIG. 6, a cylindrical cylindrical structure of wasp-derived silk protein was prepared by partially modifying the method of Example 7. Specifically, first, as a core rod, a stainless steel core rod in which a lubricant of beeswax wax (manufactured by GAIA, White Bees Wax) collected from a honeybee nest was applied to the side surface of the core rod was used. Beeswax wax is a lubricant that melts at about 60 ° C. The same procedure as in Example 7 was followed until the silk gel was adhered around the core rod coated with beeswax wax and the silk gel was dried to obtain a dry gel.

  Thereafter, the dried gel with the core rod coated with beeswax wax was immersed in 70 ° C. hot water. This heating causes the beeswax wax to melt, so that the beeswax wax serves as a lubricant between the core rod and the dried gel, and the spillage of the solid beeswax wax causes the melt between the core rod and the dried gel. Due to the gap, the core rod could be easily extracted from the dried gel. Since the beeswax wax adhered to the inside of the dried gel tube from which the core rod was removed, the beeswax wax was removed by immersing the dried gel in xylene, which is a good solvent for the beeswax wax. It was confirmed using a calorimetric analyzer (DSC) that the beeswax wax was removed from the dried gel tube. This method, as in Example 7, does not impose any burden on the dried gel when the core rod is pulled out, so the inner diameter and length of the cylindrical structure can be reduced even with a thin cylindrical structure. Regardless of shape, it is hard to collapse. FIG. 25 shows a cylindrical tubular structure of wasp-derived silk protein produced by this method. It can be seen that this cylindrical structure also has no shape disturbance.

<Example 9> Cylindrical composition of silkworm-derived silk fibroin In the same manner as in Example 1, the hornet of hornet was changed to a silkworm of silkworm silk, and a cylindrical structure of silkworm-derived silk fibroin was produced. (FIG. 26). As a result, a dense, kink-resistant tubular structure similar to the tubular structure of the wasp-derived silk protein obtained in Example 1 was obtained. That is, a high-quality cylindrical structure was obtained regardless of the origin of the silk protein.

<Example 10> Cylindrical composition of silkworm-derived silk sericin In the same manner as in Example 1, the hornet of hornet was changed to the cocoon of silkworm sericin to produce a cylindrical structure of silkworm-derived silk sericin. (FIG. 27). In the step of obtaining silk sericin gel, LiBr was removed from the pre-gelation solution in the dialysis membrane tube by dialysis, and then the dialysis membrane tube was immersed in a 10% aqueous ethanol solution and left at 4 ° C. for 12 hours. As a result, a transparent gel of silk sericin could be obtained. A method for preparing such a silk sericin gel is described in, for example, Japanese Patent Application Laid-Open No. 2006-111667. As a result, a cylindrical composition having the same compactness and kink resistance as the cylindrical structure of the wasp-derived silk protein obtained in Example 1 was obtained.

<Comparative Example 1> A silk-shaped silk fibroin-derived cylindrical structure produced by the Baumkuchen method Silkworm-like silk fibroin is coated by multiple coatings of protein-containing solutions around the core rod (Baumkuchen method) to produce a silkworm. A cylindrical tubular composition of the derived silk fibroin was produced. This Baumkuchen method is described, for example, in non-patent literature (Lovett et al., Biomaterials, 28, 5271 (2007)). In addition, in the silk protein derived from a wasp, a cylindrical structure could not be produced by this Baumkuchen method. Therefore, in the comparative example 1, the cylindrical structure was produced using the silk fibroin derived from a silkworm. Specifically, the step of coating 94 mg / mL silk fibroin aqueous solution on the metal rod portion of the cone (FIG. 28) and drying at 37 degrees was repeated for 2 days until the wall thickness was constant. Next, the dried silk fibroin gel was immersed in ethanol and solidified, and the metal rod portion of the cone was extracted, thereby producing a cylindrical tubular structure of silkworm-derived silk fibroin. FIG. 29 shows a photograph of the cross-section obtained by cutting the produced cylindrical structure at intervals of 0.5 cm with an SEM. From this cross-sectional photograph, the shape of the obtained cylindrical structure is greatly disturbed. It was revealed.

<Comparative example 2> Cylindrical structure of silkworm-derived silk fibroin produced by the Baumkuchen method In the same manner as in comparative example 1, the cone is replaced with a nail (FIG. 30), and the cylindrical structure of silkworm-derived silk fibroin A product was made. The photograph which observed the cross section when the produced cylindrical structure was cut | disconnected by 0.5 cm space | interval with SEM is shown in FIG. 31, but it is from these cross-sectional photographs that the shape of the produced cylindrical composition is greatly disturbed. It was revealed.

Example 11 Evaluation of Uniformity of Cylindrical Structure The cylindrical composition of wasp-derived silk protein produced in Example 1 and Example 3 was examined for uniformity in the major axis direction and cross-sectional uniformity. Each cylindrical structure was cut at intervals of 0.5 cm, and the outer diameter, inner diameter, and thickness of the cylindrical structure at each cut surface were measured using an electron microscope (FIG. 32). The outer diameter and inner diameter were measured from four directions at 45 degrees. The thickness was measured from 8 directions by 45 degrees. The cylindrical structure produced in Example 1 was cut at 5 locations (Sample 1), and the cylindrical structure produced in Example 3 was cut at 8 locations (Sample 2) to examine each cut surface (Table 2, 3).

(1) Evaluation of lengthwise uniformity of cylindrical structure As shown in Tables 2 and 3, the cylindrical structures (Samples 1 and 2) prepared in Example 1 and Example 3 have an outer diameter. The inner diameter and the wall thickness are evenly aligned in the major axis direction. When the uniformity is expressed by the coefficient of variation of the average length, the outer diameter is 0.05 or less, the inner diameter is 0.08 or less, and the wall The thickness was found to be 0.15 or less.

(2) Evaluation of strain from a perfect circle In the measured value of the inner diameter or the outer diameter, the average value of the coefficient of variation obtained from each cut surface is an index representing the strain from the perfect circle of each cut surface. In addition, in the measurement value of the wall thickness, the average value of the coefficient of variation obtained for each cut surface is an index representing the wall thickness distortion. As shown in Tables 2 and 3 above, the cylindrical structures (Samples 1 and 2) produced in Example 1 and Example 3 have zero distortion in the outer diameter and inner diameter of the perfect circle in terms of the average value of the coefficient of variation. It was very low, less than .05, and it was almost close to a perfect circle. Further, the distortion of the wall thickness was as low as 0.3 or less as the average value of the coefficient of variation, and the wall thickness was uniform.

<Example 12> Evaluation of cylindrical composition at different silk protein concentrations In the method described in Example 7 above, the concentration of silk protein (derived from wasps) in the solution before gelation was changed to produce a cylindrical structure. did. The specific procedure is as follows. In addition, the description of the procedure similar to Example 7 was abbreviate | omitted here.

(1) Evaluation of gel outer diameter and compression properties Silk protein concentration ranges from 25 to 125 mg / mL (25, 38, 50, 62, 68, 75, 76, 88, 90, 100, 113, 125 mg / mL The gel was prepared in a dialysis membrane tube into which a core rod included in a heat shrinkable tube was inserted in advance. Furthermore, after the dialysis membrane tube containing the gel was cut at two points near both ends, the outer diameter of the gel was measured. The result is shown in FIG. The horizontal axis represents the silk protein concentration, and the vertical axis represents the outer diameter of the gel. From this result, it is understood that a columnar gel having a diameter corresponding to the inner diameter (about 7 mmφ) of the cellulose tube was formed in the silk protein concentration within the above range. In addition, since the aqueous solution of the wasp-derived silk is easily gelled, it is difficult to accurately measure the concentration of the aqueous solution. Therefore, the silk protein concentration of the pre-gelation solution shown here was the mass (mg) of silk protein dissolved in 1 mL of 9 mol / L LiBr aqueous solution.

  After preparing a pre-gelation solution with a silk protein concentration in the range of 1.7-8.0 wt% (1.7, 2.6, 3.4, 4.2, 5.0, 5.8, 7.3, 8.0 wt%), it was enclosed in a heat-shrinkable tube. A gel was prepared in a dialysis membrane tube into which a core rod had been inserted in advance. Furthermore, after the dialysis membrane tube containing the gel was cut at two points near both ends, the compression property of the gel was measured. The result is shown in FIG. As described above, the gel formed in the same cellulose tube had almost the same diameter regardless of the difference in silk protein concentration, but the compression property of the gel depends on the silk protein concentration as shown in FIG. It can be seen that the concentration increases as the concentration increases. This figure also shows that the silk protein gel used this time has a relatively high compressive stress.

(2) Evaluation of wall thickness and shrinkage rate Silk protein concentration ranges from 1.6 to 7.7 wt% (1.6, 2.4, 3.2, 4.0, 4.7, 4.9, 5.5, 5.6, 6.2, 7.0, 7.7 wt%) After preparing the gel solution before gelation, a gel was prepared in a dialysis membrane tube into which a core rod encapsulated in a heat-shrinkable tube was previously inserted. Furthermore, after peeling the dialysis membrane tube, "the thickness of the silk gel with the core rod contained in the heat shrinkable tube inserted", "the thickness in the dried state", and after drying " After removing the core rod and the heat shrinkable tube, the length of the “wall thickness in a rehydrated state” was measured. A core rod having a diameter of 3.2 mm was used. FIG. 35 shows the result of plotting the length of each thickness against the concentration of silk protein in the pre-gelation solution. Furthermore, FIG. 36 shows the result of calculating the shrinkage rate in the process from the gel before drying (hydrogel) to the dry state and plotting it against the silk protein concentration in the solution before gelation. From these results, it can be seen that the shrinkage rate of the gel varies depending on the silk concentration, but all shrink in the range of 90 to 97%. Since an aqueous solution of wasp-derived silk is easily gelled, it was difficult to accurately measure the concentration of the aqueous solution. Therefore, the silk protein concentration of the pre-gelation solution shown here is represented by the ratio (%) of the mass of silk protein to the total mass of the 9 mol / L LiBr aqueous solution in which the silk protein is dissolved.

(3) Evaluation of moisture content Gelation of silk protein concentration in the range of 1.6 to 7.7 wt% (1.6, 2.4, 3.2, 4.0, 4.7, 4.9, 5.5, 5.6, 6.2, 7.0, 7.7 wt%) After preparing the pre-solution, a gel was prepared in a dialysis membrane tube into which a core rod contained in a heat-shrinkable tube was previously inserted. After removing the dialysis membrane tube, “silk gel with the core rod inserted in the heat-shrinkable tube” and “dried state”, and after drying, remove the core rod and heat-shrinkable tube. After that, the water content of the three types of cylindrical components in the “rehydrated state” was measured. The moisture content was determined by measuring the weight of water in the total weight of the sample using a thermogravimetric apparatus. The result is shown in FIG. From this result, it was found that the gel (hydrogel) before drying had a moisture content of 90% or more. Moreover, it turned out that a moisture content falls to 10% or less by drying. Furthermore, the water content rose to about 50% by rehydration, but the amount was found to be about half compared to the water content of the gel before drying. This suggests that the rehydrated state has a different structure from that of the gel before drying, and in the description of (5) of Example 1 above, Yes (the gel before drying could not be stretched).

(4) Evaluation of the shape of the rehydrated cylindrical structure The silk protein concentration is in the range of 1.6 to 7.7 wt% (1.6, 2.4, 3.2, 4.0, 4.7, 4.9, 5.5, 5.6, 6.2, 7.0, 7.7 wt%) before gelation solution was prepared, and then a gel was prepared in a dialysis membrane tube into which a core rod included in a heat shrink tube was inserted in advance. After drying, the core rod is pulled out and heated to remove the heat-shrinkable tube, and then the tubular structure is immersed in water and left to stand until the water absorption of the tubular structure reaches an equilibrium value. The outer diameter and inner diameter of the object were measured. The results are shown in FIG. It can be seen that the outer diameter and wall thickness (outer diameter-inner diameter) in the rehydrated state increase depending on the silk protein concentration, but the inner diameter is almost constant. Therefore, it can be seen that by adjusting the silk protein concentration, the outer diameter and thickness of the cylindrical structure in a state where the water absorption has reached the equilibrium value can be highly controlled while the inner diameter is constant.

(5) Evaluation of compression properties Gelation of silk protein concentration in the range of 1.6 to 7.7 wt% (1.6, 2.4, 3.2, 4.0, 4.7, 4.9, 5.5, 5.6, 6.2, 7.0, 7.7 wt%) After preparing the pre-solution, a gel was prepared in a dialysis membrane tube into which a core rod contained in a heat-shrinkable tube was previously inserted. After drying, the core rod is pulled out and heated to remove the heat-shrinkable tube, and then the tubular structure is immersed in water and left to stand until the water absorption of the tubular structure reaches an equilibrium value. The compressive stress of the object was measured. The results are shown in FIGS. 39 and 40. FIG. 39 shows the results showing the relationship of compressive stress to compressive strain. Moreover, the result of having plotted the value of the compressive stress in 40% of distortion with respect to silk protein concentration (wt%) was shown in FIG. It was found that as the silk protein concentration increased, the compressive stress of the tubular structure in the rehydrated state increased. Therefore, it can be seen that by adjusting the silk protein concentration, the compression property of the cylindrical structure in a state where the water absorption has reached the equilibrium value can be highly controlled.

(6) Evaluation of Stretching FIG. 41 shows the tensile stress with respect to the tensile strain when the cylindrical structure produced from the hornet silk protein is stretched in a hygroscopic state (when stretched twice, the strain is equivalent to 100%). It is expressed in Newton (N) and Mega Pascal (MPa). The concentration of the silk protein in the pre-gelation solution was in the range of 1.5 to 5.8 wt% (1.5, 3.0, 4.4, 5.8 wt%). From this result, it can be seen that the cylindrical structure can be stretched to a strain of about 150% (2.5 times). In addition, the stress increases due to stretching, suggesting that the tensile strength in the major axis direction is improved. Furthermore, it can be seen that as the silk concentration (wt%) increases, the tensile stress (N) increases when a certain amount of tensile strain is applied. Therefore, it can be seen that the tensile physical properties of the cylindrical structure can be controlled to a high degree by adjusting the silk protein concentration and the draw ratio.

  As described above, as a result of the above examples, it has been clarified that the cylindrical structure and the manufacturing method thereof of the present invention have many excellent technical features that are difficult to predict from the prior art. That is, the cylindrical structure produced by the manufacturing method of the above example has excellent technical characteristics with high uniformity in the length direction and little distortion from a perfect circle, and the material is a living body. Because it is derived from the protein of origin, it is highly biocompatible and does not cause fluid leakage from the side of the cylindrical structure, which is often a problem in a cylindrical structure manufactured in a tubular shape by knitting or weaving fibers. It became clear that it was a high-quality cylindrical structure. Furthermore, it has been clarified that the manufacturing method of the above embodiment is an efficient and simple manufacturing method of an excellent cylindrical structure that does not require complicated procedures and high manufacturing costs.

  Moreover, the internal diameter of the cylindrical structure was arbitrarily controllable with high precision by changing the outer diameter of the core rod inserted into the gel. Moreover, it was possible to easily produce even a cylindrical structure having a small diameter of 1 mm or less. The outer diameter of the cylindrical structure could be arbitrarily controlled with high accuracy by changing the inner diameter of the cylindrical dialysis membrane tube or the perforated bar. In addition, the cylindrical structure produced by the production method of the above-mentioned example is not disturbed in shape and has an inner diameter, an outer diameter, and a wall thickness as compared with those produced by the conventional production method of a silk protein tubular structure. It was uniform and the inner and outer surfaces of the tube of the cylindrical structure were extremely smooth, and the degree of completion was extremely high.

  The wall thickness of the cylindrical component could be arbitrarily controlled with high accuracy by changing the inner diameter of the cylindrical dialysis membrane tube or the perforated bar. Moreover, as a result of accurately adjusting the inner diameter and outer diameter of the cylindrical structure, the wall thickness was uniform. Furthermore, by controlling the wall thickness, it becomes possible to control the strength of the tubular structure, the control of the flexural modulus, and the tube shape stability to the extent that no kinking occurs even when bent. In this way, it has been almost impossible to produce a silk protein cylindrical structure whose thickness is controlled with high accuracy while maintaining flexibility.

  The length of the cylindrical structure could be easily prepared by changing the length of the columnar or cylindrical gel before drying. Normally, a columnar or cylindrical protein hydrogel contracts in the major axis direction when dried as it is. For this reason, there has been a concern that the length of the cylindrical structure may be shortened by drying. Surprisingly, in the manufacturing method of the above embodiment, the rod in the long axis direction of the cylindrical or cylindrical gel before drying is used. The contraction in the major axis direction was suppressed by sticking, and the length in the major axis direction was almost maintained before and after drying. And since the shrinkage | contraction of a major axis direction is suppressed in that way, the thickness adjustment with high precision was attained as mentioned above.

  The gelation step does not require complicated operations, and can be performed efficiently and simply in the dialysis membrane tube. Since the gel is produced in the dialysis membrane tube in this way, it is possible to prevent the gel from being deformed, such as a crack in the gel due to the gel swelling in the step of inserting the core rod. It was. Moreover, the dialysis membrane tube which is easy to tear is easy to remove, and the outer surface of the gel is hardly damaged when it is removed from the gel. Since the scratches on the outer surface of the gel are related to the smoothness of the outer surface of the tube after drying, it is possible to produce a cylindrical structure with a smooth outer surface by creating the gel in the dialysis membrane tube Met. On the other hand, in the conventional method for producing a silk protein tubular structure, a production method for gelation in a dialysis membrane tube has not been known. Moreover, in the drying process of the gel in the said Example, it was possible to complete drying within one day, without performing complicated operation at normal temperature and a normal pressure.

  Moreover, the cylindrical structure of the silk protein obtained in the above examples could be further stretched to adjust the length, tube diameter, and mechanical properties. The prior art which proposed or suggested such a method until now was not known. In the first place, there has been no method that can produce a cylindrical structure of silk protein that is flexible enough to be stretched.

  That is, the manufacturing method of the cylindrical structure of the present invention is an extremely excellent method capable of manufacturing a high-quality cylindrical structure efficiently and simply. In addition, the method for producing a cylindrical structure according to the present invention can use a gel-like substance as a raw material for producing the cylindrical structure, and is excellent in easily adjusting the shape of the cylindrical structure. Manufacturing method. And the cylindrical structure manufactured with the manufacturing method of this invention is especially suitable for uses, such as a medical material.

  The technical features of the present invention have been described based on the embodiments. The above embodiments are merely examples, and it is understood by those skilled in the art that various modified examples having the same effects as those of the present invention are possible, and that such modified examples are also within the scope of the present invention.

Claims (42)

  A step of removing the core rod from an intermediate structure obtained by a step including inserting a core rod into a molded body made of a gel-like substance and drying the molded body and contracting in the core rod direction. The manufacturing method of a cylindrical structure containing this.   The manufacturing method of the cylindrical structure of Claim 1 which is an intermediate structure obtained by the process in which the said intermediate structure further includes the process which makes the said dry molded object absorb a water | moisture content.   The manufacturing method of the cylindrical structure of Claim 1 whose said molded object is a rod-shaped molded object obtained by hollowing out the inside of a gel-like substance to a major axis direction.   The method for producing a cylindrical structure according to claim 1, wherein the molded body is a narrow-shaped molded body that remains after hollowing out the inside of a gel-like substance in the major axis direction.   The intermediate structure obtained by the process further comprising the step of preparing the molded body by gelling the solution before gelation in the dialysis membrane tube before the step of drying the molded body The manufacturing method of the cylindrical structure of Claim 1 which is a body.   The step of preparing a molded body made of a gel-like substance by gelling the solution before gelation in the dialysis membrane tube, the step of attaching the molded body to the side surface of the core rod, and the attached molded body A method for producing a cylindrical structure, comprising a step of removing the core rod from an intermediate structure obtained by a step including drying and contracting in the direction of the core rod.   The intermediate structure is an intermediate structure obtained in a process further including the step of fixing a core rod in the longitudinal direction inside the dialysis membrane tube, the step of preparing the molded body, and the step of attaching The manufacturing method of the cylindrical structure of Claim 6 which is an intermediate structure obtained by being performed in parallel in the said dialysis membrane tube.   The manufacturing method of the cylindrical structure of Claim 6 which is an intermediate structure obtained by the process in which the said intermediate structure further includes the process which makes the said dry molded object absorb a water | moisture content.   The core rod is a heat-shrinkable core rod, and the intermediate structure is obtained by a step further comprising a step of contracting the core rod by heating or cooling the core rod after the step of shrinking. The manufacturing method of the cylindrical structure of Claim 6 which is a structure.   The core rod is a core rod contained in a heat-shrinkable tube, and the intermediate structure heats or cools the heat-shrinkable tube after the shrinking step to thereby heat-shrink the tube. The manufacturing method of the cylindrical structure of Claim 6 which is an intermediate structure obtained by the process which further includes the process of shrinking.   The manufacturing method of the cylindrical structure of Claim 6 whose said core rod is a core rod by which the lubricant was apply | coated to the side surface.   The core rod is a core rod having a side surface coated with a lubricant, and the intermediate structure is an intermediate structure obtained in a step further including a step of heating the lubricant after the shrinking step. The manufacturing method of the cylindrical structure of Claim 6.   A step of preparing a molded body made of a gel-like substance by gelling a solution before gelation in a dialysis membrane tube, the molded body having a heat-shrinkable tube on the outer surface, and a rod-shaped member inside A step of attaching to the core rod with heat-shrinkable tube, a step of drying the molded body attached to the core rod with tube and shrinking in the direction of the core rod with tube, and a rod-like member from the core rod with tube The manufacturing method of a cylindrical structure including the process of extracting, the process of heating and shrinking the said heat-shrinkable tube, and the process of removing the said heat-shrinkable tube from the shrink | contracted molded object.   The manufacturing method of the cylindrical structure of Claim 1 with which the said gel-like substance contains a protein.   The method for producing a cylindrical composition according to claim 14, wherein the gel-like substance containing a protein further contains one or both of an antithrombotic substance and a cell growth factor.   The manufacturing method of the cylindrical structure of Claim 6 whose solution before the said gelatinization is the aqueous solution containing protein.   The method for producing a cylindrical structure according to claim 16, wherein the solution containing the protein before gelation further contains one or both of an antithrombotic substance and the cell growth factor.   The manufacturing method of the cylindrical structure of Claim 14 whose said protein is a fibrous protein.   The manufacturing method of the cylindrical structure of Claim 14 whose said protein is a silk protein.   The manufacturing method of the cylindrical structure of Claim 1 which further includes the process of extending | stretching the said intermediate structure which pulled out the said core rod.   The manufacturing method of the cylindrical structure of Claim 1 whose said cylindrical structure is a single layer structure.   The manufacturing method of the cylindrical structure of Claim 1 whose said cylindrical structure is a cylindrical structure for medical use.   The method for producing a cylindrical structure according to claim 22, wherein the medical use is for an artificial blood vessel or a nerve regeneration tube.   A cylindrical structure obtained by the production method according to claim 1.   The tubular structure according to claim 22, wherein the tubular structure is for medical use.   The cylindrical structure according to claim 23, wherein the medical use is for an artificial blood vessel or a nerve regeneration tube.   A tubular structure including a protein-containing tubular part in part or in whole, wherein the tubular part is obtained by cutting the tubular part at right angles to the major axis direction at five points of 0.5 cm intervals. Cylindrical structure which is a tubular part having a coefficient of variation of an average value of lengths of four types of inner diameters obtained by measuring the inner diameters from four directions having different angles by 45 degrees in five cross sections. .   In the five cross sections, the variation coefficient of the average value of the lengths of the eight types of wall thickness obtained when the wall thickness is measured from eight directions having different angles by 45 degrees is 0.2 or less. The cylindrical structure as described.   In the five cross sections, the variation coefficient of the average value of the lengths of the four types of outer diameters obtained when the outer diameter is measured from four directions with different angles by 45 degrees is 0.1 or less. The cylindrical structure as described.   The average value of the coefficient of variation of the lengths of the eight types of thicknesses obtained when the thicknesses are measured from eight directions having different angles by 45 degrees at the five cut surfaces is 0.5 or less. The cylindrical structure as described in.   A tubular structure including a part or all of a tubular part containing protein, wherein the tubular part is obtained by cutting the tubular part at right angles with respect to the major axis direction at three points of 0.5 cm intervals. In the three cross-sections, a tubular shape having a variation coefficient of an average value of lengths of eight types of thicknesses obtained when the thicknesses are measured from eight directions having different angles by 45 degrees by 0.2 degrees or less. Composition.   A tubular structure containing a part or all of a tubular portion containing a protein, wherein the tubular portion is obtained by cutting the tubular portion at right angles to the major axis direction at 8 points of 0.5 cm intervals. Cylindrical component which is a tubular part having a coefficient of variation of an average value of lengths of four types of inner diameters obtained by measuring the inner diameters from four directions having different angles by 45 degrees in eight sections. .   A tubular structure containing a protein, wherein the tubular structure includes a part or all of a tubular part having a length in a major axis direction of 2.0 cm, and the tubular part comprises the tubular structure. The top surface and bottom surface of the cross section when the tubular part is cut out perpendicularly to the long axis direction from the object, and at positions 0.5, 1.0, and 1.5 cm away from the top surface in the bottom surface direction perpendicular to the top surface The average value of the lengths of the four types of inner diameters obtained when the inner diameters of the five cross sections cut perpendicularly to the major axis direction are measured from four directions at different angles by 45 degrees. A tubular structure, which is a tubular part having a coefficient of variation of 0.1 or less.   The cylindrical structure according to claim 27, wherein the protein is a fibrous protein.   The cylindrical structure according to claim 27, wherein the protein is a silk protein.   The cylindrical structure according to claim 27, wherein the cylindrical structure has a single layer structure.   The cylindrical structure according to claim 27, wherein the cylindrical structure is for medical use.   The cylindrical structure according to claim 37, wherein the medical use is for an artificial blood vessel or a nerve regeneration tube.   The medical material containing the cylindrical structure of Claim 27.   40. The medical material according to claim 39, wherein the medical material is an artificial blood vessel, a nerve regeneration tube, or an artificial heart. A step of gelling an aqueous solution containing a protein to prepare a molded body made of a gel-like substance; a step of attaching the molded body to a side surface of the core bar; and drying the adhered molded body in the direction of the core bar In the cylindrical structure obtained by the method of manufacturing the cylindrical structure, including the step of removing the core rod from the intermediate structure obtained in the process including the step of shrinking,
A method for controlling the mechanical properties of the cylindrical structure by adjusting the concentration of the protein in the aqueous solution. A step of gelling an aqueous solution containing a protein to prepare a molded body made of a gel-like substance; a step of attaching the molded body to a side surface of the core bar; and drying the adhered molded body in the direction of the core bar In the cylindrical structure obtained by the method of manufacturing the cylindrical structure, including the step of removing the core rod from the intermediate structure obtained in the process including the step of shrinking,
A method of controlling the thickness of the cylindrical structure by adjusting the concentration of the protein in the aqueous solution.