JP2007268239A - Artificial blood vessel - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an artificial blood vessel containing collagen excellent in long-term patency even when used in an artery in the vicinity of a heart. <P>SOLUTION: The artificial blood vessel is characterized by having a coating layer mainly composed of a biodegradable synthetic material on an outside of a tubular body containing collagen. The coating layer is preferable to be made of the biodegradable synthetic material such as polyglycolic acid, polylactic acid, poly-ε-caprolactone, trimethylene carbonate, polydioxanone or the like, or a biocompatible material such as Teflon(R), polyurethane, silicone or the like. The polylactic acid is more preferable than any other materials. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an artificial blood vessel mainly using a tubular body containing collagen, which can be used for regenerative medicine.

  At present, artificial blood vessels are used as substitutes for blood vessels such as arteries and veins with disease or damage, and artificial blood vessels using biodegradable materials that can be decomposed and absorbed in vivo are widely developed.

As such an artificial blood vessel, an artificial blood vessel using a synthetic material such as polyphosphoric acid, polyglycolic acid or polycaprolactone as a biodegradable material has been proposed (for example, Patent Document 1). An artificial blood vessel using collagen, which is a constituent material and biodegradable material having better compatibility, has also been proposed (Patent Document 2). The latter artificial blood vessel is a collagen structure in which a plurality of collagen filaments are arranged in parallel in the same layer, and a plurality of layers are bonded so that the arrangement direction of collagen filaments forms an angle between the layer structures. Since it is formed into a tubular shape using a non-woven fabric, it has excellent stitching strength for transplantation, there is no unevenness in fiber density, the inner diameter is constant, and there is no distortion. Therefore, this artificial blood vessel enables transplantation and regeneration even for a defective portion such as a long blood vessel.
JP 2003-246851 A JP 2004-188037 A

  In the patency test in which the artificial blood vessel using the above-mentioned collagen is implanted in the carotid artery of a rabbit, the collagen constituting the artificial blood vessel is almost absorbed after 3 months of implantation, and is opened for more than 3 months thereafter. Good results have been obtained. However, when the artificial blood vessel is used for a large animal such as a pig and used for an artery near the heart, blood pressure is higher in the vicinity of the heart than a small animal such as a rabbit. There is concern about the rupture of the artificial blood vessel for implantation. In addition, it is conceivable that external tissues tend to gather on the artificial blood vessel made of collagen having high biocompatibility and block the lumen of the artificial blood vessel. Furthermore, after implanting an artificial blood vessel, it is preferable as regenerative medicine that no further surgery is required.

  That is, an object of the present invention is to provide an artificial blood vessel containing collagen that has good long-term patency even when used in an artery near the heart.

  Therefore, as a result of intensive studies, the present inventors use an artificial blood vessel characterized by comprising a coating layer mainly containing a biodegradable synthetic material or a biocompatible material on the outside of a tubular body containing collagen. As a result, it was found that the long-term patency was good, and the present invention was achieved.

  The present invention provides an artificial blood vessel comprising a coating layer mainly containing a biodegradable synthetic material or a biocompatible material on the outside of a tubular body containing collagen.

  In one embodiment, the coating layer has a spiral shape in which a tube-like material or a sheet-like material is wound.

  In a further embodiment, the biodegradable synthetic material is one or more selected from the group consisting of polyglycolic acid, polylactic acid, poly-ε-caprolactone, trimethylene carbonate, and polydioxanone.

  In a preferred embodiment, the coating layer is composed of polylactic acid.

  In another embodiment, the biocompatible material is selected from the group consisting of Teflon, polyurethane, and silicone.

  In a certain embodiment, the thickness of the said coating layer is 10 micrometers-1.0 mm.

  In another embodiment, the tubular body is formed by winding a layered structure of collagen.

  In a preferred embodiment, a smooth film layer is provided inside the tubular body.

  The present invention also provides an artificial blood vessel in which an outermost layer of a tubular body containing collagen is coated with a biodegradable synthetic material or a biocompatible material.

  In one embodiment, the biodegradable synthetic material or the biocompatible material is coated by coating, arranging a tube-like material, or winding a sheet-like material.

  In one embodiment, the biodegradable synthetic material is one or more selected from the group consisting of polyglycolic acid, polylactic acid, poly-ε-caprolactone, trimethylene carbonate, and polydioxanone.

  In another embodiment, the biocompatible material is selected from the group consisting of Teflon, polyurethane, and silicone.

  Since the artificial blood vessel of the present invention has a coating layer on the outside, the tubular body is ruptured even when high pressure is applied to the lumen due to the progress of decomposition and absorption of the tubular body containing collagen. Can be prevented. Even when external tissues gather around the artificial blood vessel, it is possible to prevent the artificial blood vessel from being blocked by collapsing the lumen. Furthermore, this coating layer can prevent the external tissue from entering the lumen of the artificial blood vessel, and can also prevent adhesion between the collagen tubular body and the external tissue. In addition, the blood vessel can be regenerated from the connection end with the existing blood vessel. Thus, according to the present invention, even when used for an artery near the heart, an artificial blood vessel containing collagen having a good long-term patency is provided. Therefore, after the artificial blood vessel of the present invention is implanted, no further surgery is required.

  The present invention is an artificial blood vessel comprising a coating layer mainly containing a biodegradable synthetic material or a biocompatible material on the outside of a tubular body containing collagen. Hereinafter, the artificial blood vessel of the present invention will be described with reference to the drawings, but the present invention is not limited thereto.

  FIG. 1 is a schematic perspective view showing an embodiment of the artificial blood vessel 1 of the present invention. FIG. 2 is a cross-sectional view taken along line AA of the artificial blood vessel 1 in FIG. The artificial blood vessel 1 of the present invention includes a coating layer 3 containing a biodegradable synthetic material or a biocompatible material on the outside of a tubular body 2 containing collagen, and has a lumen 4.

(Coating layer)
The coating layer 3 provided outside the artificial blood vessel 1 of the present invention contains a biodegradable synthetic material or a biocompatible material. By providing the coating layer 3 on the outer side, the tubular body 2 can be prevented from bursting even if high pressure is applied to the lumen of the tubular body 2 containing the inner collagen as the decomposition and absorption of the tubular body 2 proceeds. . On the contrary, even when external tissues are gathered around the artificial blood vessel 1, it is possible to prevent the artificial blood vessel 1 from being blocked by collapsing the lumen. Further, since the artificial blood vessel 1 has the coating layer 3 containing a biodegradable synthetic material or a biocompatible material, it is possible to prevent the invasion of an external tissue into the lumen of the artificial blood vessel 1, and further, a collagen tube. It is possible to prevent adhesion between the body 2 and the external tissue.

  Since the coating layer 3 has a function of protecting the artificial blood vessel 1 from the tissue gathered in the artificial blood vessel 1 and needs to be in direct contact with an external tissue, a biodegradable synthetic material or a biocompatible material is used. Includes mainly. For example, when the coating layer 3 mainly contains a biodegradable synthetic material, since it is almost decomposed and absorbed in the living body like the collagen constituting the tubular body 2, no further surgery is required.

  The coating layer 3 is not limited as long as it is a coating layer mainly containing a biodegradable synthetic material or a biocompatible material, but is a coating layer made of only a biodegradable synthetic material or a biocompatible material. Alternatively, a layer of biodegradable synthetic material or biocompatible material may be coated with a drug such as heparin. The coating layer is preferably decomposed over time in the living body in order to reduce the burden on the living body.

  The covering layer 3 may be a tube-like layer containing a biodegradable synthetic material or a biocompatible material, and a sheet-like material containing a biodegradable synthetic material or a biocompatible material is wound around. A layer having a spiral configuration may be used. These configurations can adopt forms that can be more easily manufactured according to the purpose, application, characteristics of the material, and the like.

  The tube-shaped product may be manufactured, for example, by knitting a yarn containing a biodegradable synthetic material or a biocompatible material into a tube shape using a loom or a braiding machine. Alternatively, the pellet containing the biodegradable synthetic material or biocompatible material is dissolved in an organic solvent (acetone, hexafluoro-2-propanol, chloroform, dichloromethane, etc.), poured into a mold, freeze-dried, and porous. It is also possible to obtain a tubular product.

  The biodegradable synthetic material contained in the coating layer is not particularly limited as long as it can be decomposed in vivo. However, since it is well absorbed in vivo, polyglycolic acid, Examples include lactic acid, poly ε-caprolactone, and polydioxanone. One material selected from these may be used, or a plurality of materials such as polylactic acid-glycolic acid copolymer, glycolic acid-ε-caprolactone copolymer, lactic acid-ε-caprolactone copolymer are used. May be. In particular, polylactic acid degrades in about 2 months, whereas collagen can be completely decomposed for about 3 years, so it can function as a reinforcing material or protective layer. Is more easily used and is preferably used.

  Specific examples of the biodegradable synthetic material include polyglycolic acid [2 to 3 months], L-lactic acid-glycolic acid copolymer (10:90) [10 weeks], D, L lactic acid-glycolic acid copolymer ( 50:50) [1-8 weeks], D, L lactic acid-glycolic acid copolymer (85:15) [3-7 months], glycolic acid-ε-caprolactone copolymer (75:25) [4 months], poly- L-lactic acid [3-5 years], poly-L, D-lactic acid [2-3 months], L-lactic acid-ε-caprolactone copolymer (75:25) [1 year], L-lactic acid-ε-caprolactone copolymer (50:50) [6-8 months], poly-ε-caprolactone [5 years or more], poly-p-dioxanone [6 months], glycolic acid-trimethylene carbonate copolymer (67:23) [6 months], Also Glycolic acid - trimethylene carbonate - dioxanone terpolymer (60:26:14) and the like can be used [2-3 months. These biodegradable synthetic materials can be easily synthesized by known methods, and are also commercially available from manufacturers who produce these synthetic materials or by order / order. Etc. can also be easily obtained. In addition, the description in [] is a reference period for decomposition and absorption in vivo. In consideration of this period, the type of biodegradable synthetic material can be selected according to the purpose and application.

  The biocompatible material is not particularly limited as long as it is not biodegradable but has biocompatibility. Examples thereof include Teflon (registered trademark), polyurethane, and silicone.

  In the present invention, the formation method of the coating layer 3 is not limited as long as a layer mainly composed of a biodegradable synthetic material or a biocompatible material is formed on the outer side of the tubular body 2, and the tubular layer containing collagen is not limited. It can be easily obtained by coating the outermost layer of the body 2 with a biodegradable synthetic material or a biocompatible material. The method for coating the biodegradable synthetic material or the biocompatible material is not particularly limited, and a known method can be used. For example, a method of coating the biodegradable synthetic material or biocompatible material, a method of arranging a tube of the biodegradable synthetic material or biocompatible material, the biodegradable synthetic material or the biocompatible material Coating can be performed by a method of winding a sheet-like material.

  The method for coating the biodegradable synthetic material or biocompatible material is not particularly limited, and a solution of the biodegradable synthetic material or biocompatible material may be added to collagen according to the purpose, material, and application. A method of applying, spraying, and / or impregnating outside of the tubular body 2 containing s. According to this method, the tubular covering layer 3 is formed outside the tubular body 2.

  In addition, as a method of arranging the tube of the biodegradable synthetic material or biocompatible material, a tubular body containing collagen is inserted inside the tube containing the biodegradable synthetic material or biocompatible material. Examples thereof include a method, a method of forming a slit in a longitudinal direction in a tubular material containing a biodegradable synthetic material or a biocompatible material, and expanding the slit to accommodate a tubular body containing collagen. Furthermore, as a method of winding the biodegradable synthetic material or the biocompatible material sheet, the sheet containing the biodegradable synthetic material or biocompatible material is placed outside the tubular body containing collagen. The method of turning is mentioned. A spiral coating layer is formed by a method of winding a sheet. Further, these methods may be combined to perform coating as a multilayer structure. The arrangement of these coating layers can be appropriately selected according to the purpose, material, application and the like.

  In the present invention, the thickness of the coating layer 3 mainly containing a biodegradable synthetic material or a biocompatible material is not particularly limited, but it is easy to form the layer, and a certain reinforcement and protection function can be obtained. Therefore, the thickness of the layer is preferably 10 μm to 1.0 mm.

(Tubular body containing collagen)
The artificial blood vessel 1 of the present invention includes a tubular body 2 containing collagen inside. The tubular body 2 is not particularly limited as long as it contains collagen. However, the use of collagen as a main material is preferable in terms of biocompatibility, tissue regeneration, cell proliferation, and the like. More preferable. The origin of collagen can be extracted from the skin, tendon, bone, cartilage, organ, etc. of animal species such as humans, cows, pigs, rabbits, sheep, mice, birds and fish. The type of collagen is not limited to any type that can be classified, such as type I and type III, but type I is particularly preferred from the viewpoint of handling.

  Examples of the tubular body 2 include a tubular body obtained by forming a collagen nonwoven fabric into a tubular shape. Specifically, such a tubular body is a tubular body formed by winding a collagen nonwoven fabric into a tubular shape, and has a layered structure in which a plurality of collagen filaments are arranged substantially in parallel. A tubular body in which a plurality of layered structures are stacked and bonded so that the arrangement directions form an angle with each other can be used.

  The diameter of the collagen filamentous material constituting the collagen non-woven fabric is not particularly limited, but it is preferable to have a substantially uniform outer diameter of about 5 μm to 1.5 mm, and a substantially uniform outer diameter of about 10 to 200 μm. Those having a diameter are optimal. The collagen filamentous material may be coated with a biodegradable substance. Here, the biodegradable substance includes not only the above-described biodegradable synthetic material but also a natural biodegradable substance, and examples thereof include collagen and hyaluronic acid. The layered structure in which a plurality of collagen filaments are arranged substantially in parallel is a layered structure in which a plurality of filaments are linearly arranged at substantially equal intervals on the same plane. In the same layer, the acute angle formed by the arranged filaments is about 5 ° or less, preferably about 0 °. The interval between collagen filaments in the same layered structure is usually about 0 to 40 mm, preferably about 0 to 10 mm, more preferably about 0 to 1 mm.

  The above-mentioned collagen nonwoven fabric is a cloth-like structure formed by adhering collagen filaments of layered structures in contact with each other at their contact portions. In the collagen non-woven fabric, an acute angle formed by the arrangement direction of the filaments arranged in the first layered structure and the filaments arranged in the second layered structure, that is, the filaments between adjacent layered structures. The angle at which the longitudinal axes intersect each other forms a specific angle. The angle is not particularly limited, but is preferably substantially a right angle because the strength as a nonwoven fabric and manufacturing are easy.

  It does not specifically limit as a manufacturing method of the said tubular body 2, A well-known method can be used. This will be specifically described by taking as an example a tubular body obtained by forming a collagen nonwoven fabric into a tubular shape. First, a collagen nonwoven fabric can be produced by laminating and adhering a plurality of layered structures in which a plurality of collagen filaments are arranged substantially in parallel so that the arrangement direction of the collagen filaments forms an arbitrary angle. In addition, between the layered structures, collagen filaments of adjacent layered structures are bonded to each other at the contact portion. Further, as the collagen filamentous material, a fiber that is spun using a solubilized collagen solution as a spinning stock solution can be used. As the solubilized collagen, collagen that has been treated so that it can be dissolved in a solvent can be used.

  The solvent of the solubilized collagen solution is not particularly limited as long as it can solubilize collagen. Typical examples include a dilute acid solution such as hydrochloric acid, acetic acid, and nitric acid; a liquid mixture of a hydrophilic organic solvent such as ethanol, methanol, and acetone; and water; You may use these individually or in mixture of 2 or more types by arbitrary ratios. Of these, water is most preferred. The collagen concentration of the collagen solution is not particularly limited as long as it can be spun, but is preferably about 4 to 10% (w / v), more preferably about 5 to 7% (w / v). ). A known spinning method may be used.

  The collagen non-woven fabric may be further subjected to various known physical or chemical cross-linking treatments as necessary. The stage which performs a crosslinking process is not ask | required. That is, the non-woven fabric may be formed from a filamentous material that has been subjected to various cross-linking treatments, or various cross-linking treatments may be performed after the non-woven fabric is formed. Two or more types of cross-linking treatments may be used in combination, and the order of the treatments is not limited. Examples of physical crosslinking methods include γ-ray irradiation, ultraviolet irradiation, electron beam irradiation, plasma irradiation, and crosslinking treatment by thermal dehydration reaction. Examples of the chemical crosslinking method include reaction with aldehydes such as dialdehyde and polyaldehyde, epoxies, carbodiimides, isocyanates, tannin treatment, chromium treatment, and the like. By this crosslinking treatment, it is possible to dramatically delay the time taken for decomposition and absorption when transplanted into a living body as compared with the case of non-crosslinking, and the physical strength is also improved. Therefore, when a collagen non-woven fabric is filled or prosthetic with a defect in a living body, it is possible to maintain the necessary membrane strength in the body until the tissue regeneration is completed.

  Moreover, the collagen nonwoven fabric obtained by the above method may be coated with the above-described biodegradable substance. An example of a method for coating a collagen nonwoven fabric with a biodegradable substance is binder treatment. The binder treatment is a treatment in which a nonwoven fabric is impregnated with a solution-like material and then dried by an appropriate drying method to reinforce the bonding between the filaments in the nonwoven fabric. The solution material is preferably an aqueous solution of a biodegradable substance. By this binder treatment, the collagen non-woven fabric is formed into a film shape, and the physical strength is improved much more than that of the untreated non-woven fabric, and therefore the stitching strength is remarkably improved.

  As the method for producing the tubular body, a known method can be used. For example, a method of laminating a collagen nonwoven fabric by repeatedly winding a collagen nonwoven fabric around a cylinder or a side surface of a tube can be used. The material of the cylinder or tube is not particularly limited, but a material with high water repellency such as polyfluorinated ethylene fiber and polypropylene is preferable. The suture strength can be controlled by increasing the number of times the collagen nonwoven fabric is wound, or by increasing the number of laminations of the layered structure when producing the collagen nonwoven fabric, that is, the total number of laminations of the collagen thread. Therefore, what is necessary is just to determine the frequency | count of lamination | stacking suitably according to the objective.

  The tubular body containing collagen produced in this way is suitable as a vascular regeneration material by including the coating layer 3 mainly containing the above-described biodegradable synthetic material or biocompatible material on the outside thereof. Can be used.

(Smooth film layer)
As shown in FIG. 3, the artificial blood vessel 1 of the present invention may further include a smooth film layer 5 as an innermost layer. The luminal surface of the artificial blood vessel 1 is smoothed by the smooth film layer 5. Therefore, it is possible to prevent blood coagulation caused by adhesion of blood cell components such as leukocytes and platelets, and further adhesion of blood components such as proteins. Therefore, the smooth film layer 5 can function as a layer (antithrombotic layer).

  Such a smooth film layer 5 is comprised with a biodegradable substance. Examples of biodegradable substances include collagen and hyaluronic acid as described above. In order to construct a cell group (endothelial cells, smooth muscle cells, fibroblasts) belonging to the endothelium, mesothelium, and integument as a tissue. The collagen present is preferred. Furthermore, in order to further improve the antithrombogenicity, it is also possible to apply an antithrombogenic material to the surface of the smooth film layer 5 that is the innermost layer in contact with blood. Examples of the antithrombotic material include heparin, low molecular weight heparin, warfarin, nafamostat mesylate, and heparin is preferable. Further, for the purpose of suppressing platelet adhesion and aggregation, an antiplatelet drug such as aspirin which has an effect of preventing thrombus formation may be applied.

  Various known methods can be used as a method for producing the smooth film layer 5 made of a biodegradable substance. An example is as follows: collagen in a state in which the concentration of the hydrophilic organic solvent used for spinning the collagen solution is lowered, the collagen filament is spun at a high water content, and semi-dissolved in the adsorbed water. The thread is wound around a cylinder or tube; the threads are then fused together to form a film, which can be dried to produce a film layer. The appropriate moisture content of the collagen thread that can be wound in this semi-dissolved state is 10 to 50% by weight, preferably 15 to 30% by weight. Another example is as follows: Collagen filaments (dried state) obtained by spinning a solubilized collagen solution are wound around the side of a cylinder or tube, and the resulting wound product is prepared as a collagen solution. Then, it is immersed in the hydrophilic organic solvent used for a certain period of time and then pulled up; then, the collagen filaments are dissolved in the adsorbed hydrophilic organic solvent so that they are fused together to form a film. Can be produced. Alternatively, a low-concentration collagen solution is poured into a tubular mold and freeze-dried to produce a sponge-like tube, which is then immersed in the solvent used for preparing the collagen solution for a certain period of time and then pulled up, and then the sponge-like tube Is dissolved in the adsorbing solution to form a film, which may be dried to produce a smooth film layer.

  The artificial blood vessel 1 of the present invention must be sterilized by a known method such as γ-ray sterilization or ultraviolet sterilization before being used for medical purposes. The same medical treatment can be achieved by using a filamentous material including one or several kinds of biodegradable synthetic materials other than collagen, such as polyglycolic acid, polylactic acid, polylactic acid polyglycolic acid copolymer, and polyphosphoric acid. It is possible to produce a non-woven fabric.

(Kit form)
The artificial blood vessel 1 of the present invention described above is an integral type provided with the coating layer 3 on the outer side of the tubular body 2 containing collagen, but this can also be carried out indirectly. For example, (i) the tubular body 2 containing the collagen and the covering layer 3 are prepared, and (ii) the tubular body 2 containing collagen is placed at a predetermined position during the operation, The artificial blood vessel 1 of the present invention can be disposed by disposing the covering layer 3 on the surface.

  Therefore, the artificial blood vessel 1 of the present invention can be provided in the form of a kit including the tubular body 2 containing the collagen and the coating layer 3, for example.

  Examples of the artificial blood vessel of the present invention are shown below, but the present invention is not limited to these. Hereinafter,% indicates% (w / w) (mass%) unless otherwise specified.

<Example 1>
(1) Manufacture of a tubular body containing collagen (1-1) Preparation of a wound collagen product Porcine-derived type I and type III mixed collagen powder (manufactured by Nippon Ham Co., Ltd., SOFD type, Lot No. 0102226) is distilled for injection A 5% aqueous collagen solution was prepared by dissolving in water (Otsuka Pharmaceutical Co., Ltd.). This 5% collagen aqueous solution is filled in a syringe (Disposable Barrels / Pistons, 55 cc, manufactured by EFD), and the collagen aqueous solution is air-pumped from the needle attached to the syringe with an air pump by 99.5% (v / v). It discharged to the 1st ethanol tank filled with ethanol (the Wako Pure Chemical Industries Ltd. make, special grade). At this time, Ultra Dispensing Tips (manufactured by EFD, 30G, ID: φ0.16 mm) was used as a needle attached to the syringe. After the discharged 5% collagen aqueous solution was dehydrated and turned into a filamentous material, the filamentous material was pulled up from the first ethanol tank. The collagen filaments pulled up from the first ethanol tank are completely separated from the first ethanol tank, and the second ethanol tank (99.5% (v / v) ethanol (manufactured by Wako Pure Chemical Industries, Ltd., It was soaked at room temperature for about 30 seconds and further solidified. Subsequently, the collagen filamentous material was pulled up from the second ethanol tank, and wound up on a plate-shaped member (a square with a side of 15 cm and a thickness of 5 mm) rotating at 15 rpm. In order to wind up the collagen filaments evenly around the plate member, a mechanism for periodically moving the horizontal position of the collagen filaments is provided between the plate member and the second ethanol tank. The speed was 1.5 mm / second (the filamentous material was wound at an interval of about 6 mm) and the reciprocating width was about 12 cm. The winding is set so that the rotation axis of the plate-like member is changed by 90 degrees every 360 windings, and the 360 windings are repeated 8 times (total number of windings is 2880). A collagen wound product having a layered structure of eight layers of collagen filaments on both sides was obtained.

(1-2) Production of Collagen Nonwoven Fabric The collagen wound product produced in (1-1) above was prepared by vacuum drying oven (produced by EYELA; VOS-300VD) and oil rotary vacuum pump (produced by ULVAC; GCD135). -XA type) was subjected to thermal dehydration crosslinking reaction at 120 ° C. under reduced pressure (1 Torr (133 Pa) or less) for 24 hours. Separately, porcine-derived type I and type III mixed collagen powder (manufactured by Nippon Ham Co., Ltd., SOFD type, Lot No. 010226) is dissolved in distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.), and 1% aqueous collagen solution Was prepared. The 1% collagen aqueous solution was impregnated into the collagen nonwoven fabric after the thermal dehydration crosslinking reaction, dried, and then cut along each piece (periphery) of the plate member to obtain two collagen nonwoven fabrics.

(1-3) Production of a polyfluorinated ethylene tube having a smooth film layer coated with heparin Similar to (1-1) above, porcine-derived type I and type III mixed collagen powder (manufactured by Nippon Ham Co., Ltd., SOFD type) , Lot N.0102226) was dissolved in distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) to prepare a 5% collagen aqueous solution. This 5% collagen aqueous solution was filled into a syringe (Disposable Barrels / Pistons, 55 cc, manufactured by EFD), and the collagen aqueous solution was supplied from the needle attached to the syringe by air pressure of 99.5% (v / v) ethanol (air pump). It was discharged into a first ethanol tank filled with Wako Pure Chemical Industries, Ltd. (special grade). At this time, Ultra Dispensing Tips (manufactured by EFD, 32G, ID: φ0.11 mm) was used as a needle attached to the syringe. After the discharged 5% collagen aqueous solution was dehydrated and turned into a filamentous material, it was pulled up from the first ethanol tank. The collagen filaments pulled up from the first ethanol tank were filled with an aqueous ethanol solution having a water content of 15% (v / v) to 20% (v / v) completely separated and independent from the first ethanol tank. A filamentous material containing moisture was prepared by immersing in a second ethanol bath at room temperature for about 30 seconds. Subsequently, the collagen filament was pulled up from the second ethanol tank and wound around a polyfluorinated ethylene tube having an outer diameter of 6.0 mm rotated at 150 rpm. A device for periodically reciprocating the filamentous material in the axial direction of the polyfluorinated ethylene tube between the polyfluorinated ethylene tube and the second ethanol tank so that the filamentous material is evenly wound around the polyfluorinated ethylene tube. The reciprocating speed was 1.5 mm / second (the filamentous material was wound at intervals of 0.25 mm). The filamentous material having a high water content was fused with each other after the completion of winding, and a tubular film layer adhered to the polyfluorinated ethylene tube was formed. The film layer was dried by air drying while attached to the polyfluorinated ethylene tube to produce a polyfluorinated ethylene tube having a smooth film layer. Subsequently, heparin (Aventis Pharma Co., Ltd., Novo Heparin Injection 1000), which is an antithrombotic material, was applied to the entire smooth film layer while being stretched using a spatula. The amount of heparin applied was about 180 units per cm ^{2 of} film layer. Thus, a polyfluorinated ethylene tube having a smooth film layer coated with heparin was obtained.

(1-4) Production of a tubular body containing collagen Porcine-derived type I and type III mixed collagen powder (manufactured by Nippon Ham Co., Ltd., SOFD type, Lot No. 0102226) and distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) Was prepared as an adhesive for adhering the smooth film layer. The adhesive was thinly stretched with a spatula and applied to a width of 5 mm along one side of one surface of the collagen nonwoven fabric prepared in (1-2). This coated part was affixed in the longitudinal direction of the polyfluorinated ethylene tube having the smooth film layer produced in (1-3) above and dried to adhere the smooth film layer and the collagen nonwoven fabric. Next, this adhesive was applied to the entire surface of the collagen nonwoven fabric to be bonded, and the collagen nonwoven fabric was wound around the tube. After winding 4 times, excess collagen non-woven fabric was cut off by a breaker. A tubular body having a smooth film layer was obtained by natural drying at room temperature for 4 hours. The obtained tubular body was subjected to thermal dehydration crosslinking under the same conditions as in (1-2) above for 24 hours. After thermal dehydration crosslinking, neutralization was performed by immersing in a 3.75% aqueous sodium bicarbonate solution for about 1 hour, and then immersed in an 1.875% aqueous sodium bicarbonate solution for about 8 hours. Next, it was immersed in distilled water for injection for about 12 hours to wash sodium bicarbonate. After washing with distilled water, thermal dehydration crosslinking was performed again for 24 hours under the same conditions as in (1-2) above, thereby terminating the thermal dehydration crosslinking. The polyfluorinated ethylene tube was pulled out from the crosslinked tubular body to obtain a tubular body containing collagen having an inner diameter of 6.0 mm, an outer diameter of 7.0 mm, and a total length of about 12 cm (FIG. 4).

(2) Preparation of coating layer containing biocompatible material A 45 mm square Teflon (registered trademark) sheet (Nichias) was selected as the coating layer.

(3) Manufacture of artificial blood vessel In a pig which is an animal larger than a rabbit, an experiment was conducted in which the artificial blood vessel of the present invention was implanted in an artery near the heart by the following method. A crown-type minipig (male, body weight of about 5 kg; Japan Farm Co., Ltd.) was initially anesthetized. For initial anesthesia, a mixture of 3 mL ketamine hydrochloride (animal ketal: Sankyo Yale Pharmaceutical Co., Ltd.), azaperone 5 mL (animal stress nil: Sankyo Co., Ltd.), and 1 mL atropine sulfate (Fuso Pharmaceutical Co., Ltd.) Was administered. Next, general anesthesia was performed by inhaling an isoflurane inhalant (Escaine: Merck Whey) into a miniature pig. A thoracotomy was performed under general anesthesia to expose the descending aorta. The exposed descending aorta is excised approximately 3.0 cm, and the stumps containing the collagen with the inner diameter of 6.0 mm prepared in (1) above are excised by continuous anastomosis using 5-0 sutures. Sutured. Under the present circumstances, it cut and used so that the length of the longitudinal direction of the tubular body containing collagen might be set to 3.0 cm. Next, the Teflon (registered trademark) sheet-like material prepared in the above (2) was wound so as to cover the tubular body containing the collagen and the anastomosis portion. That is, the coating layer has a spiral shape in which two layers of Teflon (registered trademark) sheets are wound. The wound coating layer was fixed by wrapping the periphery with 1-0 suture and then binding. As a result, the artificial blood vessel of the present invention was indirectly produced. Thereafter, blood flow was resumed.

  The implanted artificial blood vessel was excised on each period of 2 months and 3 months after implantation, and cell proliferation was confirmed by patency and HE staining. The results are shown in FIGS. As can be seen from FIG. 5 and FIG. 6, the artificial blood vessel produced by the above method was confirmed to be patency without rupture even after 3 months and with collagen remaining, and the lumen was thickened. Was also not recognized. Further, as a result of HE staining, proliferation of endothelial cells and smooth muscle cells was confirmed from the central and peripheral stumps to the artificial blood vessel side (FIGS. 7 and 8).

<Comparative Example 1>
In the above (3) in Example 1, the same procedure as in Example 1 was performed except that a sheet-like material made of Teflon (registered trademark) was not wound outside the tubular body containing collagen. That is, the tubular body containing collagen produced in Example 1 was replaced and transplanted to the descending aorta of the pig as it was. The implanted artificial blood vessel was removed on each period of 2 months and 3 months after implantation, and the patency state was confirmed. As a result, stenosis due to thickening of the vascular intima was confirmed at the implantation site 2 months after implantation (FIG. 9). Furthermore, the implantation site 3 months after implantation was blocked (FIG. 10).

<Example 2>
(1) Production of tubular body containing collagen The steps (1-1) to (1-4) were performed in the same manner as in Example 1. That is, the same tubular body as in Example 1 was used. However, the tubular body containing collagen was prepared to have an inner diameter of 8.0 mm, an outer diameter of 9.0 mm, and a total length of about 12 cm.

(2) Manufacture of a coating layer containing a biodegradable synthetic material Ten polylactic acid yarns (Toray Industries, Ecodia, 33T-LA10) having a weight average molecular weight of 180 to 200,000 are placed on a table-type twisting machine (Marusan, AMT-2). ). The combined yarn was knitted using a Lilian string knitting machine (Marusan, CK-N) to obtain a tube-shaped article (coating layer) having an inner diameter of about 9 mm.

(3) Manufacture of artificial blood vessel The tubular body containing the collagen of outer diameter 9.0m obtained by said (1) is used as the tube-shaped thing of biodegradable synthetic material of inner diameter 9.0mm obtained by said (2). An artificial blood vessel was manufactured by inserting it into the inside.

  Since the artificial blood vessel of the present invention has a coating layer on the outside, the tubular body is ruptured even when high pressure is applied to the lumen due to the progress of decomposition and absorption of the tubular body containing collagen. Can be prevented. Even when external tissues gather around the artificial blood vessel, the lumen can be prevented from being crushed and the artificial blood vessel can be blocked. Furthermore, this coating layer can prevent the external tissue from entering the lumen of the artificial blood vessel, and can also prevent adhesion between the collagen tubular body and the external tissue. In addition, the blood vessel can be regenerated from the connection end with the existing blood vessel. As described above, according to the present invention, an artificial blood vessel having a good long-term patency is provided even when used for an artery near the heart. Therefore, after the artificial blood vessel of the present invention is implanted, no further surgery is required. Therefore, in the field of regenerative medicine, it is possible to reduce the burden on the patient and provide a good prognosis.

1 is a schematic perspective view showing an embodiment of an artificial blood vessel of the present invention. It is AA sectional drawing of the artificial blood vessel in FIG. It is sectional drawing at the time of providing the smooth film layer inside in the artificial blood vessel of this invention. It is a photograph of the tubular body containing the collagen of the present invention. It is a photograph which shows the state of the implantation location 2 months after the implantation of the artificial blood vessel of the present invention in Example 1. It is a photograph which shows the state of the implantation location 3 months after the implantation of the artificial blood vessel of this invention in Example 1. FIG. 2 is an optical micrograph of HE staining two months after implantation of the artificial blood vessel of the present invention in Example 1. FIG. 2 is an optical micrograph of HE staining 3 months after implantation of the artificial blood vessel of the present invention in Example 1. FIG. It is a photograph which shows the state of the implantation location 2 months after the implantation of the artificial blood vessel without the coating layer in the comparative example 1. It is a photograph which shows the state of the implantation location 3 months after the implantation of the artificial blood vessel without the coating layer in the comparative example 1.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Artificial blood vessel 2 Tubular body containing collagen 3 Coating layer containing biodegradable synthetic material 4 Lumen 5 Smooth film layer

Claims (12)

  An artificial blood vessel comprising a coating layer mainly containing a biodegradable synthetic material or a biocompatible material on the outside of a tubular body containing collagen.   The artificial blood vessel according to claim 1, wherein the coating layer has a spiral shape in which a tube-like material or a sheet-like material is wound.   The artificial biodegradable material according to claim 1 or 2, wherein the biodegradable synthetic material is one or more selected from the group consisting of polyglycolic acid, polylactic acid, poly-ε-caprolactone, trimethylene carbonate, and polydioxanone. Blood vessels.   The artificial blood vessel according to any one of claims 1 to 3, wherein the coating layer is made of polylactic acid.   The artificial blood vessel according to claim 1 or 2, wherein the biocompatible material is selected from the group consisting of Teflon (registered trademark), polyurethane, and silicone.   The artificial blood vessel according to any one of claims 1 to 5, wherein the coating layer has a thickness of 10 µm to 1.0 mm.   The artificial blood vessel according to any one of claims 1 to 6, wherein the tubular body is formed by winding a layered structure of collagen.   The artificial blood vessel according to any one of claims 1 to 7, further comprising a smooth film layer inside the tubular body.   An artificial blood vessel in which an outermost layer of a tubular body containing collagen is coated with a biodegradable synthetic material or a biocompatible material.   The artificial blood vessel according to claim 9, wherein the coating of the biodegradable synthetic material or the biocompatible material is performed by coating, arranging a tube-like material, or winding a sheet-like material.   The artificial biodegradable synthetic material according to claim 9 or 10, wherein the biodegradable synthetic material is one or more selected from the group consisting of polyglycolic acid, polylactic acid, poly-ε-caprolactone, trimethylene carbonate, and polydioxanone. Blood vessels.   The artificial blood vessel according to claim 9 or 10, wherein the biocompatible material is selected from the group consisting of Teflon (registered trademark), polyurethane, and silicone.

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