WO2012090553A1 - Procédé de fabrication de vaisseau sanguin artificiel - Google Patents

Procédé de fabrication de vaisseau sanguin artificiel Download PDF

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Publication number
WO2012090553A1
WO2012090553A1 PCT/JP2011/069691 JP2011069691W WO2012090553A1 WO 2012090553 A1 WO2012090553 A1 WO 2012090553A1 JP 2011069691 W JP2011069691 W JP 2011069691W WO 2012090553 A1 WO2012090553 A1 WO 2012090553A1
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Prior art keywords
tubular structure
blood vessel
artificial blood
silk
coating
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PCT/JP2011/069691
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English (en)
Japanese (ja)
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朝倉　哲郎
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国立大学法人東京農工大学
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Publication of WO2012090553A1 publication Critical patent/WO2012090553A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A61F2/062—Apparatus for the production of blood vessels made from natural tissue or with layers of living cells

Definitions

  • the present invention relates to a coating composition and a method for producing an artificial blood vessel using the same.
  • the large-diameter artificial blood vessels have already been put into practical use and can withstand clinical use.
  • small-diameter artificial blood vessels with a diameter of 5 mm or less are caused by thickening of the intima due to biocompatibility of typical artificial materials such as polyethylene terephthalate (PET) and polytetrafluoroethylene (PTFE) and occlusion due to thrombus formation.
  • PET polyethylene terephthalate
  • PTFE polytetrafluoroethylene
  • silk thread has high biocompatibility, is thin, strong, has moderate elasticity and flexibility, has good sliding properties, and is easy to tie and hard to fray. It is a natural fiber used as Various regenerated silk materials that utilize the high biocompatibility of silk have been developed so far, and are expected to be used in a wide range of fields such as medicine, biochemistry, food, and cosmetics. In particular, it is attracting attention as a material for regenerative medicine.
  • kite thread structure As an attempt to produce an artificial blood vessel using silk, a kite thread structure is known which is wound by combining braiding operations according to the principle of braid fabrication, and the kite yarns and mixed fibers are glued together with sericin held on the kite surface.
  • Patent Document 1 This string structure has a tensile strength that can withstand practical use by bonding the string with sericin.
  • sericin is highly likely to cause an allergic reaction, it is desirable to remove sericin from the viewpoint of reducing its risk.
  • the silk thread structure is not flexible enough, and the cut end is easily frayed, so that there is a demand for an artificial blood vessel having superior functionality while maintaining the original characteristics of silk such as biocompatibility and required characteristics during surgery. It had been.
  • a tubular structure using silk fibroin fibers obtained by scouring warp and raw silk has a low allergy risk due to sericin and is excellent in biocompatibility, but is not sufficient in terms of functionality. Then, when the present inventors examined, it discovered that it can give elasticity if it coats the tubular structure which consists of silk fibroin with the silk fibroin sponge obtained from the aqueous solution which mixed the polyglycol with the silk aqueous solution, and applied for earlier ( Patent Document 2). However, considering practical use, it has not yet been satisfactory in terms of elasticity and the like, and there has been a demand for an artificial blood vessel that is further excellent in functionality.
  • the present invention has been made in view of the above circumstances, and provides a tubular structure that has excellent properties such as biocompatibility and has excellent strength and elasticity and can be used for small-diameter blood vessels such as peripheral blood vessels. About doing.
  • the present inventor has made various studies on tubular structures utilizing the characteristics of silk.If the tubular structure is coated with a mixture of silk fibroin and polyurethane resin, it has sufficient tensile strength and excellent elasticity. The present inventors have found that a tubular structure suitable for an artificial blood vessel having a smaller diameter, which is flexible and satisfies biocompatibility and characteristics required at the time of operation, can be obtained.
  • the present invention provides a coating composition for a tubular structure containing silk fibroin and a polyurethane resin. Moreover, this invention provides the manufacturing method of a coated tubular structure which coats a tubular structure with the composition for coating of the tubular structure containing a fibroin and a polyurethane-type resin. Moreover, this invention provides the coated tubular structure obtained by the said manufacturing method.
  • a tubular structure that has the original properties of silk, that is, high biocompatibility, has sufficient tensile strength, excellent elasticity, is flexible and easily vascularly anastomosed, and has little blood leakage.
  • this tubular structure is excellent in antithrombotic properties, it is particularly suitable for a small-diameter artificial blood vessel having a diameter of 5 mm or less.
  • FIG. 1 is a diagram showing a coating process of a silkworm silk artificial blood vessel.
  • Fig.2 (a) is a figure which shows the scanning electron microscope image of a coating rabbit silk artificial blood vessel.
  • FIG.2 (b) is a figure which shows the scanning electron microscope image of a coating rabbit silk artificial blood vessel.
  • FIG. 3 is a diagram showing the water permeability of the coated rabbit silk artificial blood vessel.
  • FIG. 4 is a view showing the compression elastic modulus of the coated rabbit silk artificial blood vessel.
  • FIG. 5 is a view showing anastomotic thread holding strength of a coated rabbit silk artificial blood vessel.
  • FIG. 6 is a diagram comparing changes in various parameters before and 2 weeks after the operation.
  • PRE pre-operative native carotid artery data
  • POST PROX data obtained on the proximal side of the post-operative artificial blood vessel
  • POST DISTAL data obtained on the distal side of the post-operative artificial blood vessel
  • PSV Maximum systolic flow velocity (cm / s), EDV end diastolic flow velocity (cm / s), PI pulsatility index (no unit), RI resistance coefficient (no unit)
  • CSD vessel diameter (mm)
  • the coating composition of the present invention is a composition used for coating a tubular structure containing silk fibroin and polyurethane resin.
  • the silk fibroin used in the present invention is obtained by scouring silkworms, raw silk, and the like obtained from silkworms or genetically modified silkworms, and wild silkworm layers such as Eli silkworms, silkworms, and tengu. Sericin is removed by the scouring treatment.
  • the scouring method is not particularly limited, and a known method can be used. For example, 12 w / v% Marcel soap heated to 100 ° C., 8 w / v% sodium carbonate mixed aqueous solution, and the above-mentioned cocoon layer, silk thread, raw silk, etc.
  • the silk fibroin is preferably a silk fibroin solution obtained by dissolving silk fibroin fibers in water and / or an organic solvent.
  • a silk fibroin fiber dissolved in water and / or an organic solvent a silk fibroin fiber dissolved in a neutral salt aqueous solution and heated, and then the obtained silk fibroin / salt aqueous solution is desalted; What melt
  • examples of the neutral salt aqueous solution include lithium bromide, lithium chloride, calcium chloride, and lithium thiocyanate.
  • a known method such as a dialysis method or a reverse osmosis method can be employed.
  • water may be removed from the aqueous solution as necessary to obtain a dry product.
  • the aqueous solution is usually spread on a plate, and water is evaporated to produce a silk fibroin film, or spray drying or the like to form a powder.
  • distilled water may be added to prepare an aqueous solution having a silk fibroin concentration of 2 w / v% or less, for example, and freeze-dried to form a sponge (porous).
  • lyophilization is preferred from the viewpoint of handleability and storage stability.
  • the organic solvent examples include hexafluoroisopropanol (HFIP) and hexafluoroacetone (HFA).
  • HFA hexafluoroisopropanol
  • HFA hydrate hexafluoroacetone
  • the concentration of silk fibroin dissolved in water or an organic solvent is usually about 3 to 20 w / v%, preferably 3 to 15 w / v%.
  • the polyurethane-based resin used in the present invention is a resin obtained by reacting polyisocyanate and polyol as main raw materials according to a conventional method.
  • the polyurethane resin is not particularly limited, and examples thereof include polycarbonate urethane resin, polyester urethane resin, polyether urethane resin, silicone modified urethane resin, fluorine modified urethane resin, and polyamino acid urethane resin.
  • the polyisocyanate is not particularly limited as long as it is a compound having two or more isocyanate groups in the molecule.
  • aliphatic diisocyanates such as hexamethylene diisocyanate and 2,2,4-trimethylhexamethylene diisocyanate; isophorone diisocyanate, Examples thereof include alicyclic diisocyanates such as hydrogenated xylylene diisocyanate, dicyclohexylmethane diisocyanate and norbornane diisocyanate; aromatic diisocyanates such as tolylene diisocyanate, diphenylmethane diisocyanate, naphthalene diisocyanate, tolidine diisocyanate and xylylene diisocyanate. These can be used alone or in combination of two or more.
  • the polyol is not particularly limited.
  • Polyester polyols such as polyhexamethylene isophthalate adipate diol, polyethylene succinate diol, polybutylene succinate diol, polyethylene sebacate diol, polybutylene sebacate diol, poly- ⁇ -caprolactone diol; polyoxytetramethylene glycol, polyoxy Propylene glycol, polyoxyethylene
  • Polycarbonate polyols such as polyhexamethylene carbonate diol
  • polyether polyols such emissions propylene glycol
  • Patent acrylic polyols such as those described in 2000-119362 J
  • the polyurethane resin used in the present invention is preferably an aqueous (water-soluble or water-dispersible) polyurethane resin.
  • the aqueous polyurethane resin can be produced by a conventional method.
  • a method for imparting water to the polyurethane resin for example, an anionic group or an ionic group of a cationic group is introduced into the urethane skeleton, or a nonion is used.
  • transducing a sex group is mentioned.
  • An aqueous polyurethane resin having an ionic group can be obtained by, for example, the above-mentioned polyisocyanate, polyol, a compound imparting an ionic hydrophilic group, a known chain extender, if necessary, and the like by a one-shot method or a prepolymer method. Can be manufactured.
  • the compound imparting the ionic hydrophilic group is not particularly limited, but examples of the compound imparting the anionic hydrophilic group include 2,2-dimethylolpropionic acid, 2,2-dimethylolbutanoic acid and the like. Can be mentioned. These are used after neutralizing with amines such as trimethylamine, triethylamine, tri-n-propylamine, tributylamine, triethanolamine, potassium hydroxide, sodium hydroxide, ammonia and the like. Further, alkanolamines are preferred as those imparting a cationic group, and examples thereof include N-methyldiethanolamine and triethanolamine.
  • a commercially available product may be used as the aqueous polyurethane resin.
  • water-dispersible polyurethane resins such as Neo Sticker 100C (Nika Kagaku) and Evaphanol (Nikka Kagaku) can be used.
  • the content of silk fibroin is preferably 0.1 to 10% by mass, and preferably 0.2 to 5% by mass from the viewpoint of biocompatibility.
  • the content of the polyurethane resin varies depending on the type of the resin.
  • the content of the polyurethane resin varies depending on the type of the resin.
  • 5 to 50% by mass is preferable, and 15 to 30% by mass. Is preferred.
  • the blending ratio (mass ratio) of silk fibroin and polyurethane resin is preferably in the range of 50: 1 to 1: 100 from the viewpoint of improving tensile strength and elasticity, and more preferably 10: 1 to 1: 100, especially 1. 1: 1 to 1: 100 are preferred.
  • the coating composition of the present invention is preferably prepared by dissolving or dispersing silk fibroin and polyurethane resin in water, an organic solvent, or a mixture thereof.
  • an aqueous polyurethane resin is used as the polyurethane resin, it is preferably dissolved or dispersed in water.
  • a non-aqueous polyurethane resin is used, it is preferably dissolved in an organic solvent.
  • a composition in which silk fibroin and an aqueous polyurethane resin are dissolved or dispersed in water is preferable from the viewpoint of improvement in tensile strength and elasticity.
  • either silk fibroin or polyurethane resin may be dissolved or dispersed in water and / or an organic solvent first, and then the other may be dissolved or dispersed. Also good.
  • a silk fibroin solution obtained by dissolving silk fibroin fibers in water or an organic solvent as described above may be mixed with a polyurethane resin.
  • an organic solvent the same thing as the above is mentioned.
  • the coated tubular structure of the present invention is produced by preparing a coating liquid containing silk fibroin and polyurethane resin, and coating the innermost wall and / or outermost wall of the tubular structure with the coating liquid.
  • the coating liquid can appropriately contain arbitrary components.
  • an antithrombotic agent such as heparin, endothelial cell growth factor and the like can be contained.
  • the tubular structure in the present invention is not particularly limited, and tubular structures composed of various materials can be used.
  • the thing made from PET, PTFE, silk fibroin, etc. are mentioned.
  • a tubular structure made of silk fibroin is preferable.
  • tubular structure made of silk fibroin examples include a tubular structure in which silk fibroin fibers are wound by one or more methods selected from knitting, braiding, weaving and entanglement.
  • a known knitting method, braiding method, weaving method, and entanglement method can be used.
  • the method for braiding silk fibroin fiber is not particularly limited, and for example, known braiding techniques such as eight punching, twelve punching, and sixteen punching can be used. Specifically, it is carried out by winding a silk thread or refined thread unraveled from boiled rice cake around a thermoplastic resin core rod and the like and assembling silk fibroin fibers.
  • a thermoplastic resin core rod having an outer diameter of 1 to 5 mm, preferably 2 to 5 mm can be used according to the size of the target tubular structure.
  • the thermoplastic resin is not particularly limited, and examples thereof include polyolefin, polyester, fluororesin, and vinyl chloride resin.
  • silk fibroin fibers are knit knitted to form a tubular structure, it can be made into a tubular structure that is highly elastic, flexible, excellent in tensile strength, and difficult to fray at the cut end.
  • knit knitting include round knitting (horizontal knitting), vertical knitting, full fashion, raschel, tricot and the like.
  • the knit machine is not particularly limited.
  • the obtained silk cloth may be wound around the thermoplastic resin core rod or the like to form a tubular shape.
  • the method for coating the tubular structure with the coating composition of the present invention is not particularly limited, but it is preferable to immerse the tubular structure in the coating solution, freeze, heat-treat, and then dry.
  • the immersion treatment is not particularly limited, but is performed at room temperature, normal pressure, or reduced pressure.
  • the immersion time is preferably 5 to 30 minutes, particularly 10 to 20 minutes.
  • the heat treatment is preferably performed at a temperature of 100 ° C. or higher, more preferably 120 ° C. or higher.
  • a closed pressure device such as an autoclave may be used.
  • an autoclave it is preferably at 120 ° C. or higher for 20 to 40 minutes.
  • drying treatment examples include natural drying, heat drying, and vacuum drying.
  • the drying temperature is 15 ° C. to 150 ° C., preferably 50 ° C. to 80 ° C., and the time is preferably 30 minutes to 1 hour. In this way, the innermost wall and / or the outermost wall of the tubular structure is coated.
  • the coating layer formed on the tubular structure may be a single layer, or may be a coated tubular structure having a multilayer coating layer such as two layers, three layers, or four layers.
  • the thickness of the coating layer is not particularly limited, but the innermost wall portion is preferably 0.005 to 0.5 mm, and the outermost wall portion is preferably 0.1 to 1.0 mm.
  • the innermost wall and the outermost wall of the tubular structure may be coated with a coating composition containing silk fibroin and polyurethane resin, and both are coated. It may be.
  • the innermost wall of the tubular structure is preferably coated with the coating composition.
  • the other may be coated with an arbitrary coating agent. Examples of such other coating agents include general coating agents such as polyurethane resins and gelatin.
  • coated tubular structure of the present invention can be used, for example, as a substitute for an artificial blood vessel, an artificial trachea, a stent graft, and other animal biological tubular structures.
  • an artificial blood vessel an artificial trachea, a stent graft, and other animal biological tubular structures.
  • it is suitable for small-diameter artificial blood vessels having a diameter of 5 mm or less, preferably 1 to 5 mm or less.
  • Production Example 1 ⁇ Preparation of dissolved silk fibroin solution> A silk fibroin fiber from which a protein (sericin) covering fibroin and other fats were removed was obtained by finely cutting the rabbit with a scissors (about 2 mm ⁇ 10 mm) or spinning the rabbit. Next, this silk fibroin fiber was dissolved in 9M lithium bromide aqueous solution so as to be 15 w / v%. This aqueous solution is dialyzed with pure water using a cellulose dialysis membrane (Seamless Cellulose Tubing 36/32 manufactured by VISKASESELES COAP) for 3 days to remove lithium chloride, and further centrifuged to remove undissolved residue and dust. Then, a silkworm silk fibroin lysate was obtained. The silk fibroin concentration in the rabbit silk fibroin lysate was 3-8 w / v%.
  • Production Example 2 ⁇ Creating silkworm silk artificial blood vessels> 1. Fabrication of small-diameter silk graft using an assembling machine For the fabrication of an artificial blood vessel, a braided string production device (16 strokes) (manufactured by Kokbun Limited) was used. The bobbin was wrapped with silk fibroin fiber refined by the above-mentioned standard method. A vinyl chloride or polytetrafluoroethylene core rod with an outer diameter of 1 to 5 mm is attached to the center of the machine, and silk fibroin fibers are assembled around the core rod, and a silkworm artificial blood vessel with an inner diameter of 1.5 to 5 mm ⁇ )
  • Production Example 3 Preparation of coating composition> Rabbit silk fibroin melt (SI) obtained in Production Example 1 and water-dispersible polyurethane (PU, Neo Sticker 100c, manufactured by Nikka Chemical Co., Ltd., polyurethane concentration 30 w / v%) in a volume ratio of 1:10, 10 Were mixed at a ratio of 1:10, 1: 4 and 1: 2, respectively, to obtain coating compositions (1), (2), (3) and (4). Further, a coating composition (5) using only the water-dispersible polyurethane and a coating composition (6) using only a rabbit silk fibroin solution were obtained.
  • Example 1 ⁇ Rabbit silk artificial blood vessel coating>
  • a silkworm silk artificial blood vessel (inner diameter: 4 mm ⁇ ) with a core rod attached was immersed for 10 minutes under normal pressure, and then immersed in liquid nitrogen for 1 minute to freeze. This operation was repeated once more.
  • the frozen silkworm artificial blood vessel was autoclaved at 120 ° C. for 20 minutes, separated from the core rod, and dried in a dryer set at 50 ° C. for 1 hour to thereby remove the outer wall of the silkworm silk artificial blood vessel. Two layers of coated rabbit silk artificial blood vessel were obtained.
  • the coating composition (1) was flowed on the inner wall of the silkworm artificial blood vessel using a syringe, and then immersed in liquid nitrogen for 1 minute to freeze. This operation was repeated once more. Next, after drying at room temperature for 30 minutes, it was dried in a dryer set at 120 ° C. for 2 hours to obtain a coated rabbit silk artificial blood vessel in which the inner wall of the rabbit silk artificial blood vessel was coated in two layers.
  • the coating conditions are shown in Table 1 (hereinafter the same).
  • Comparative Example 1 ⁇ Rabbit silk artificial blood vessel coating>
  • a coated rabbit silk artificial blood vessel in which the outermost wall of the rabbit silk artificial blood vessel was coated in two layers with the coating composition (5) was obtained.
  • the coated rabbit silk artificial blood vessel which coated the inner wall of the rabbit silk artificial blood vessel in two layers was obtained in the same manner as in Example 1 except that the coating composition (1) was replaced with the coating composition (6).
  • Examples 2 to 3 and Comparative Examples 2 to 3 ⁇ Rabbit silk artificial blood vessel coating>
  • a silkworm silk artificial blood vessel (inner diameter: 4 mm ⁇ ) with a core rod attached is immersed for 10 minutes under normal pressure, and then immersed in liquid nitrogen for 1 minute. Frozen. It was stored in a freezer at ⁇ 80 ° C. for 1 hour, and treated by freeze vacuum drying for 12 hours. The 10-minute immersion to lyophilization was repeated twice.
  • the silkworm artificial blood vessel was autoclaved at 120 ° C. for 20 minutes, then immersed in pure water for 15 minutes, separated from the core rod, and dried in a dryer set at 50 ° C. for 1 hour.
  • a coated rabbit silk artificial blood vessel was obtained in which the outer wall of the silk artificial blood vessel was coated in two layers. Thereafter, 6 mL of the coating composition (1), (2), (5), or (6) was flowed on the inner wall of the silkworm silk artificial blood vessel using a syringe, and immersed in liquid nitrogen for 1 minute to freeze. . It was stored in a freezer at ⁇ 80 ° C. for 1 hour, and treated by freeze vacuum drying for 12 hours. Then, an autoclave treatment was performed at 120 ° C. for 20 minutes. Subsequently, the operation of immersing the silkworm silk artificial blood vessel in pure water at 50 ° C. and allowing it to stand for 12 hours was repeated 6 times while changing the water. Subsequently, it dried at 50 degreeC and the coated rabbit silk artificial blood vessel which coated the innermost wall of the rabbit silk artificial blood vessel with a single layer was obtained.
  • Example 4 ⁇ Rabbit silk artificial blood vessel coating>
  • a silkworm silk artificial blood vessel (inner diameter 4 mm ⁇ ) with a core rod attached was immersed for 10 minutes under normal pressure, and then immersed in liquid nitrogen for 1 minute to freeze. It was stored in a freezer at ⁇ 80 ° C. for 1 hour, and treated by freeze vacuum drying for 12 hours.
  • the silkworm artificial blood vessel was autoclaved at 120 ° C. for 20 minutes, then immersed in pure water for 15 minutes, separated from the core rod, and dried in a dryer set at 50 ° C. for 1 hour.
  • a coated rabbit silk artificial blood vessel having a single layer coating on the outermost wall of the silk artificial blood vessel was obtained.
  • Test Example 1 Morphological Observation Test Morphological observation of each coated rabbit silk artificial blood vessel obtained in Examples 1 to 4 and Comparative Examples 1 to 3 was performed using a scanning electron microscope (VE7800 manufactured by Keyence Corporation). As shown in FIG. 2, the outer surface, inner surface, and cross section of each coated rabbit silk artificial blood vessel formed a structure covered with a fine porous material along the tubular structure. In particular, by placing a vacuum drying operation in the middle of the coating, it was possible to produce an artificial blood vessel with almost no holes. On the other hand, what coated the inner wall of the artificial blood vessel only with silk fibroin (Comparative Example 1) had a large hole.
  • Test Example 2 Measurement of Water Permeability
  • tests were conducted in accordance with ISO 7198 guidance. Water was dropped on the side wall of each coated rabbit silk artificial blood vessel so that a water pressure of 120 mmHg was applied, and the amount of water leakage (permeability) per unit area discharged from the fixing jig through the artificial blood vessel was measured. . The test was performed 5 times, and the average value was obtained. The results are shown in FIG.
  • the amount of water leakage was 90.64 (mL / cm 2 / min) in Example 1, 3.12 (mL / cm 2 / min) in Example 2, and 0.24 (mL / cm 2 / min in Example 3). ) And 7.32 (mL / cm 2 / min) in Example 4.
  • the amount of water leakage was greatly reduced.
  • it was 647.2 (mL / cm 2 / min) in Comparative Example 1.
  • the water permeability of Dacron artificial blood vessels that do not require pre-clotting (pre-blood treatment) with commercially available artificial blood vessels is a published value of 1 to 10 mL / cm 2 / min.
  • Test Example 3 Measurement of Compression Elastic Modulus
  • Each coated rabbit silk artificial blood vessel obtained in Examples 2 to 3 and Comparative Examples 2 to 3 was cut to a length of 0.5 cm, and a compressive force was applied in the circumferential direction.
  • the compression elastic modulus (N / mm 2 ) until the diameter of the artificial blood vessel was reduced by 10% (the change in diameter was plotted on the horizontal axis and the compressive force was plotted on the vertical axis and obtained from the slope) was determined.
  • the test was performed 5 times, and the average value was obtained.
  • the results are shown in FIG. From FIG. 4, the elastic modulus of the coated rabbit silk artificial blood vessels obtained in Examples 2 and 3 is more flexible in the circumferential direction than that of the artificial blood vessel coated only with silk fibroin (Comparative Example 2). The improvement was confirmed.
  • Test Example 4 Measurement of anastomotic thread retention strength
  • Each coated rabbit silk artificial blood vessel obtained in Examples 2-3 and Comparative Examples 2-3 was tested according to the guidance of ISO 7198. The test was performed 5 times, and the average value was obtained. The results are shown in FIG. FIG. 5 shows that the coated rabbit silk artificial blood vessels obtained in Examples 2 and 3 have anastomotic thread holding strength equivalent to that obtained by coating the inner wall of the artificial blood vessel only with silk fibroin (Comparative Example 2). confirmed.
  • Example 5 ⁇ Rabbit silk artificial blood vessel coating>
  • a silkworm silk artificial blood vessel (inner diameter 4 mm ⁇ ) with a core rod attached was immersed for 10 minutes under normal pressure, and then immersed in liquid nitrogen for 1 minute to freeze. It was stored in a freezer at ⁇ 80 ° C. for 1 hour, and treated by freeze vacuum drying for 12 hours.
  • the steps from 10 minutes immersion to freeze-drying were repeated 4 times.
  • the silkworm artificial blood vessel was autoclaved at 120 ° C. for 20 minutes, then immersed in pure water for 15 minutes, separated from the core rod, and dried in a dryer set at 50 ° C. for 1 hour.
  • a coated rabbit silk artificial blood vessel in which the outer wall of the silk artificial blood vessel was coated in four layers was obtained.
  • Test Example 5 Canine transplantation test ⁇ operative method> Anesthesia for dogs (beagle dogs, female, 1 year old) is atropine (0.1 ml / kg, atropine injection), midazolam (0.04 ml / kg, midazolam injection 10 mg “sand”), butorphanol (0.04 ml / lg) After pretreatment with Betolfal Note), it was introduced and intubated using Propofol (Betolfal), and maintenance of anesthesia was performed using isoflurane. After shaving the operative field, it was disinfected with alcohol and chlorhexidine and draped.
  • Betolfal Propofol
  • heparin 100 IU / kg, heparin injection
  • ACT activated coagulation time
  • the electronic linear probe used was UST-5524-7.5 for superficial superficial part, peak systolic velocity (PSV), end-diastolic velocity (EDV), pulsation Index (Pulsatility index: PI), resistance index (RI), systolic acceleration time (Acceleration time: AT), and measurement of the inner diameter of the artificial blood vessel, including before and after the artificial blood vessel, a total of 7 locations (1. common carotid artery) Proximal part, 2. proximal anastomosis part, 3. artificial blood vessel proximal part, 4. artificial blood vessel middle part, 5. artificial blood vessel distal part, 6. distal anastomosis part, 7. common carotid artery distal part) went. At the same time, ultrasonic modeling inspection using color Doppler, e-flow, and sonazoid was also used to evaluate turbulence, stenosis, and plaque formation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)

Abstract

La présente invention porte sur une composition de revêtement de structure tubulaire contenant de la fibroïne et de la résine de polyuréthane.
PCT/JP2011/069691 2010-12-28 2011-08-31 Procédé de fabrication de vaisseau sanguin artificiel WO2012090553A1 (fr)

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JP2010291983A JP2014050412A (ja) 2010-12-28 2010-12-28 人工血管の製造方法

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WO2012090553A1 true WO2012090553A1 (fr) 2012-07-05

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CN109069699A (zh) * 2016-04-14 2018-12-21 澳大利亚耳科学研究所 改善的丝纤蛋白生物相容性聚氨酯膜

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