WO2022028397A1 - 一种可再生修复的血管支架覆膜及其制备方法 - Google Patents

一种可再生修复的血管支架覆膜及其制备方法 Download PDF

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WO2022028397A1
WO2022028397A1 PCT/CN2021/110229 CN2021110229W WO2022028397A1 WO 2022028397 A1 WO2022028397 A1 WO 2022028397A1 CN 2021110229 W CN2021110229 W CN 2021110229W WO 2022028397 A1 WO2022028397 A1 WO 2022028397A1
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silk
silk fibroin
bombyx mori
vascular stent
regenerative
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French (fr)
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王建南
郑昌懂
宋广州
裔洪根
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Suzhou University
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Suzhou University
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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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • 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
    • 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • C07K14/43563—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from insects
    • C07K14/43586—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from insects from silkworms
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers

Definitions

  • the invention relates to the technical field of preparation of vascular stent covering, in particular to a regenerative repairable vascular stent covering and a preparation method thereof.
  • Cardiovascular and cerebrovascular diseases such as embolism, vascular stenosis, and vascular aneurysms are a serious threat to human health, and have become the death rate of human beings. highest cause.
  • minimally invasive endovascular isolation has gradually become the main treatment method for various arterial diseases due to its small surgical trauma.
  • Vascular stent-graft is the main body of endovascular isolation, and its performance directly affects the clinical treatment effect.
  • the silk fibroin is the silk core, which accounts for 70% to 80% of the silk quality, and the purification is simple and convenient.
  • Silk fibroin has excellent mechanical properties and excellent biocompatibility.
  • Silk fibroin is composed of 20 kinds of amino acids.
  • Silk fibroin is an absorbable material that does not cause obvious immune response.
  • a large number of literature studies have shown that silk fibroin materials can support the growth of a variety of cells, and there are many studies on anticoagulant properties, and research on tissue engineering materials has also received great attention. the preferred material.
  • the existing publicly reported covering materials for vascular stents are mainly synthetic polymers such as polytetrafluoroethylene, polyester, polyamide, polyethylene, polypropylene, polyurethane, etc. into a film.
  • the lack of histocompatibility of synthetic polymers is an important cause of postoperative complications.
  • the inner surface of the membrane is difficult to endothelialize, and immune rejection will occur after being implanted in the body for a period of time. Long-term medication will induce other more serious diseases. happened.
  • the purpose of the present invention is to provide a regenerative repairable vascular stent coating and a preparation method thereof, which are used to produce a regenerative repairable vascular stent that can be absorbed, rapidly endothelialized in situ, and induce the reconstruction of healthy vascular tissue.
  • a technical scheme of the present invention is:
  • regenerable and repairable vascular stent covering with axial tensile strength>2MPa, elongation at break>40%, circumferential tensile strength>6MPa, elongation at break>140%, and overall water leakage Less than 2ml/min.cm 2 under 120mmHg water pressure, hemolysis rate ⁇ 0.1%.
  • the preparation method of the above-mentioned regenerative and repairable vascular stent coating comprises the following steps:
  • Bombyx mori silk fibroin and cooked silk thread after preparing degumming choose 40 ⁇ 160D silk thread and silk monofilament, described silk thread is obtained by twisting and merging Bombyx mori raw silk, and the silk monofilament adopts boiling water, sodium carbonate, hydrogen carbonate Any one of sodium or biological enzymes is degummed to obtain degummed Bombyx mori silk fibroin fibers, and any one of sodium carbonate, sodium bicarbonate or biological enzymes is used for degumming the silk threads to obtain degummed cooked silk threads;
  • the dialysis bag perfused with the Bombyx mori fibroin solution is placed in a container filled with deionized water, and the liquid in the container is replaced with new deionized water every 2 hours, and the dialysis is continued for 3 days to obtain purified Bombyx mori Vegetarian protein aqueous solution;
  • modified silk fibroin solution using a rotary evaporator to concentrate, adjust and measure the purified silk fibroin aqueous solution so that the mass fraction of the purified silk fibroin aqueous solution is 1-10% , adding polyethylene glycol diglycidyl ether with a mass ratio of 0.6 to silk fibroin, stirring evenly and defoaming to obtain a modified silk fibroin solution;
  • the cooked silk thread is braided on a stainless steel rod by knitting technology into a tubular structure with a linear density of 4 to 10 pieces/cm and an inner diameter of 2 to 20 mm.
  • the preparation of degummed Bombyx mori silk fibroin fibers and cooked silk threads in step (1) includes: selecting 40-160 D silk threads and silk monofilaments, the silk threads are obtained by twisting and combining the silkworm raw silk, and the silk monofilaments are obtained by twisting and merging the silk threads. And silk thread is put into sodium carbonate aqueous solution with a concentration of 0.1-0.6% at a bath ratio of 1:50 (g/mL), and treated three times at a temperature of 98-100 ° C for 30 minutes each time, deionized The silk monofilament and the silk thread are fully cleaned with water, and then the silk monofilament and the silk thread are dried in an oven with a temperature of 60° C. to obtain degummed silk fibroin fibers and cooked silk threads.
  • preparing the degummed Bombyx mori silk fibroin fiber and cooked silk thread in step (1) includes: selecting 40-160D silk thread and silk monofilament, the silk thread is obtained by twisting and combining the silkworm raw silk, and pressing the silk thread according to 1 :
  • the bath ratio of 50 (g/mL) is put into the sodium carbonate aqueous solution with a concentration of 0.1 to 0.6%, and the temperature is 98 to 100 °C.
  • the silk thread is fully cleaned, and then the silk thread is dried in an oven with a temperature of 60 ° C to obtain the cooked silk thread after degumming; the silk monofilament is put into deionized water at a bath ratio of 1:50 (g/mL).
  • the silk thread in step (1) is 60D-120D.
  • the molecular weight cut-off of the dialysis bag in step (2) is 50kDa.
  • the mass fraction of the purified silk fibroin aqueous solution in step (3) is 3%.
  • step (4) the cooked silk thread is braided on the stainless steel rod into a tubular structure with a linear density of 4 to 12 pieces/cm and an inner diameter of 2 to 20 mm on a stainless steel rod by using a knitting technique.
  • step (4) the soaking time is 5-15 seconds, and the number of times of repeating this step is 3-5 times.
  • the invention provides a regenerative and repairable vascular stent covering and a preparation method thereof.
  • the composite blood vessel is obtained by adjusting the core layer of degummed silk fibroin fiber textile structure, infiltrating low-concentration and high-viscosity macromolecular silk fibroin solution inside and outside, and self-assembling layer by layer.
  • Stent covering, the vascular stent covering has excellent toughness, and in situ induces vascular intimal regeneration that regulates the balance of the blood system. It can be prepared into in vivo grafts with various morphologies for the treatment of cardiovascular diseases (such as heart repair sheets, vascular stent coverings, artificial heart valves), and can also be extended to other medical devices such as tissue engineering stents.
  • the purpose of the present invention is to address the complications such as vascular stent-graft migration, endoleak, and stent-derived new breaks that occur after endovascular isolation for cardiovascular and cerebrovascular diseases, as well as device failure and restenosis caused by long-term fatigue damage
  • vascular stent covering with natural polymer silk fibroin protein material molecular weight ⁇ 50kDa
  • the axial tensile strength of the film is>2MPa, the elongation at break>40%, the circumferential tensile strength>6MPa, the elongation at break>140%, and the overall water leakage is less than 2ml/min under 120mmHg water pressure .cm 2 , hemolysis rate ⁇ 0.1%.
  • the film layer of the film is fully welded to the wire, and does not slip even when stretched. Controlling the self-assembly of the nanoscale layer by layer makes the film have excellent flexibility, the film does not have endoleak, and is closely combined with the lesion tissue after implantation without slipping.
  • the stent coating provided by the present invention has excellent cytocompatibility, histocompatibility and rapid endothelialization ability, and at the same time, the coating is degraded and absorbed in a gradient manner, and the in-situ repair of vascular intimal tissue will not be troublesome for implantation into the human body. Later, the device failed due to long-term fatigue damage. Moreover, rapid endothelialization is the fundamental factor to inhibit thrombosis and restenosis, and the rapid formation of intimal tissue will completely restore the regulation function of the blood coagulation system balance in blood vessels.
  • one embodiment or “an embodiment” refers to a particular feature, structure, or characteristic that may be included in at least one implementation of the present invention.
  • the appearances of "in one embodiment” in various places in this specification are not all referring to the same embodiment, nor are they separate or selectively mutually exclusive from other embodiments.
  • This example demonstrates a method for preparing a regeneratively repairable vascular stent covering, including:
  • the silkworm raw silk is twisted and merged to obtain a 120D silk thread group, and the other group is a silk monofilament group.
  • the silk monofilament and the silk thread are put into carbonic acid with a concentration of 0.1 to 0.6% at a liquor ratio of 1:50 (g/mL).
  • sodium aqueous solution treated at 98-100 °C three times for 30 minutes each time, then the silk was fully cleaned with deionized water, and dried in an oven at 60 °C to obtain degummed silk fibroin fibers and cooked silk threads.
  • the 120D cooked silk thread is braided into a tubular fabric with a linear density of 10 ⁇ 2 and an inner diameter of 2 to 20 mm on a stainless steel rod with a 90° interlace using the braiding technique, and immersed in the modified silk fibroin solution in the third step above. Take it out for about 10 seconds, place it in a hot air drying box below 50°C and rotate in the circumferential direction to form a film, and control the surface of the film to keep wet. The dipping coating was repeated 4 times to obtain the silk fibroin composite vascular stent covering, which can be regenerated and repaired.
  • the above-mentioned regenerative and repairable vascular stent coating has excellent mechanical properties.
  • the axial tensile strength is >2.5MPa
  • the elongation at break is >45%
  • the circumferential tensile strength is >8MPa.
  • Elongation at break >140%.
  • the overall water leakage is less than 12ml/min.cm 2 under 120mmHg water pressure.
  • the hemolysis rate is less than 0.1%, which fully meets the standard of non-hemolytic material (0-2%) by measuring the hemolysis rate of the regenerable and repaired vascular stent coating according to the hemolysis rate test method.
  • the regenerative and repairable vascular stent covering has no sensitization through animal experiments, and the cytotoxicity is less than or equal to 1.5.
  • the stent covering is prepared according to the national standard.
  • This example demonstrates a method for preparing a regeneratively repairable vascular stent covering, including:
  • the silkworm raw silk is twisted and merged to obtain a 120D silk thread group, and the other group is a silk monofilament group.
  • the silk monofilament and the silk thread are put into carbonic acid with a concentration of 0.1 to 0.6% at a liquor ratio of 1:50 (g/mL).
  • sodium aqueous solution treated at 98-100 °C three times for 30 minutes each time, then the silk was fully cleaned with deionized water, and dried in an oven at 60 °C to obtain degummed silk fibroin fibers and cooked silk threads.
  • the 120D cooked silk thread is braided on a stainless steel rod into a tubular fabric with a linear density of 6 ⁇ 1 and an inner diameter of 2 to 20 mm, 90° interlacing, and dipped in the modified silk fibroin solution in the third step above. Take it out for about 15 seconds, put it in a hot air drying box below 50 °C and rotate it in the circumferential direction to form a film, and control the surface of the film to keep wet. The dipping coating was repeated 4 times to obtain the silk fibroin composite vascular stent covering, which can be regenerated and repaired.
  • the above-mentioned regenerative and repairable vascular stent coating has excellent mechanical properties.
  • the axial tensile strength is >2.0MPa
  • the elongation at break is >40%
  • the circumferential tensile strength is >6MPa.
  • Elongation at break >140%.
  • the overall water leakage is less than 3 ml/min.cm 2 under 120 mmHg water pressure.
  • the hemolysis rate is less than 0.1%, which fully meets the standard of non-hemolytic material (0-2%) by measuring the hemolysis rate of the regenerable and repaired vascular stent coating according to the hemolysis rate test method.
  • the regenerative and repairable vascular stent coating has no sensitization through animal experiments, and the cytotoxicity is less than or equal to 1 according to the national standard.
  • This example demonstrates a method for preparing a regeneratively repairable vascular stent covering, including:
  • the silkworm raw silk is twisted and merged to obtain a 120D silk thread group, and the other group is a silk monofilament group.
  • the 120D cooked silk thread is braided into a tubular fabric with a linear density of 10 ⁇ 2 and an inner diameter of 2 to 20 mm on a stainless steel rod with a 90° interlace using the braiding technique, and immersed in the modified silk fibroin solution in the third step above. Take it out for about 5 seconds, place it in a hot air drying box below 50°C and rotate it in the circumferential direction to form a film, and control the surface of the film to keep wet. The dipping coating was repeated 4 times to obtain the silk fibroin composite vascular stent covering, which can be regenerated and repaired.
  • the above-mentioned regenerative and repairable vascular stent coating has excellent mechanical properties.
  • the axial tensile strength is >3.0MPa
  • the elongation at break is >70%
  • the circumferential tensile strength is >12MPa. Elongation at break>200%.
  • the overall water leakage is less than 2 ml/min.cm 2 under 120 mmHg water pressure.
  • the hemolysis rate is less than 0.1%, which fully meets the standard of non-hemolytic material (0-2%) by measuring the hemolysis rate of the regenerable and repaired vascular stent coating according to the hemolysis rate test method.
  • the regenerative and repairable vascular stent coating has no sensitization through animal experiments, and the cytotoxicity is less than or equal to 1 according to the national standard.
  • This example demonstrates a method for preparing a regeneratively repairable vascular stent covering, including:
  • the silkworm raw silk is twisted and merged to obtain a 60D silk thread group, and the other group is a silk monofilament group.
  • the 60D cooked silk thread is braided on a stainless steel rod into a tubular fabric with a linear density of 10 ⁇ 2 and an inner diameter of 2 to 20 mm, 90° interlacing, and immersed in the modified silk fibroin solution in the third step above. Take it out for about 5 seconds, place it in a hot air drying box below 50°C and rotate it in the circumferential direction to form a film, and control the surface of the film to keep wet. The dipping coating was repeated 4 times to obtain the silk fibroin composite vascular stent covering, which can be regenerated and repaired.
  • the above-mentioned regenerative and repairable vascular stent coating has excellent mechanical properties.
  • the axial tensile strength is >2.5MPa
  • the elongation at break is >45%
  • the circumferential tensile strength is >8MPa. Elongation at break>150%.
  • the overall water leakage is less than 3 ml/min.cm 2 under 120 mmHg water pressure.
  • the hemolysis rate is less than 0.1%, which fully meets the standard of non-hemolytic material (0-2%) by measuring the hemolysis rate of the regenerable and repaired vascular stent coating according to the hemolysis rate test method.
  • the regenerative and repairable vascular stent coating has no sensitization through animal experiments, and the cytotoxicity is less than or equal to 1 according to the national standard.
  • This example demonstrates a method for preparing a regeneratively repairable vascular stent covering, including:
  • the silkworm raw silk is twisted and merged to obtain a 60D silk thread group, and the other group is a silk monofilament group.
  • the 60D cooked silk thread is braided on the stainless steel rod into a tubular fabric with a linear density of 10 ⁇ 2 and an inner diameter of 2-20 mm, 60° interlacing, and immersed in the modified silk fibroin solution in the third step above. Take it out for about 5 seconds, place it in a hot air drying box below 50°C and rotate it in the circumferential direction to form a film, and control the surface of the film to keep wet. The dipping coating was repeated 4 times to obtain the silk fibroin composite vascular stent covering, which can be regenerated and repaired.
  • the above-mentioned regenerative and repairable vascular stent coating has excellent mechanical properties.
  • the axial tensile strength is >2.0MPa
  • the elongation at break is >50%
  • the circumferential tensile strength is >6MPa. Elongation at break>150%.
  • the overall water leakage is less than 3 ml/min.cm 2 under 120 mmHg water pressure.
  • the hemolysis rate is less than 0.1%, which fully meets the standard of non-hemolytic material (0-2%) by measuring the hemolysis rate of the regenerable and repaired vascular stent coating according to the hemolysis rate test method.
  • the prepared stent coating has no sensitization through animal experiments, and the cytotoxicity is less than or equal to 1 according to the national standard.

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Abstract

本发明公开了一种可再生修复的血管支架覆膜及其制备方法，将家蚕蚕丝分为两组，一组加捻合并丝线组，另一组为单丝组，丝线组采用碳酸钠、碳酸氢钠或生物酶进行脱胶，单丝组采用沸水、碳酸钠、碳酸氢钠或生物酶进行脱胶，脱胶后溶解于溴化锂中性盐溶液制备丝素蛋白溶解液，将丝素溶解液灌注于透析袋内透析，得到纯化后的家蚕丝素蛋白水溶液，再采用旋转蒸发器浓缩丝素蛋白至合适的质量分数。在丝素蛋白水溶液中加入亲水性的柔性分子的交联剂混合均匀并脱气泡，得到改性丝素蛋白溶液，然后将单丝编结管状结构，浸入改性丝素蛋白溶液，风干，得到可再生修复的血管支架覆膜。该覆膜具有卓越的韧性，且原位诱导调节血液系统平衡的血管内膜再生。

Description

一种可再生修复的血管支架覆膜及其制备方法
本申请要求于2020年08月06日提交中国专利局、申请号为202010781023.6、发明名称为“一种可再生修复的血管支架覆膜及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及血管支架覆膜制备技术领域，具体涉及一种可再生修复的血管支架覆膜及其制备方法。
背景技术
随着生活水平的提高和老龄化进程的加快，心脑血管疾病的发病率正逐年显著升高，栓塞、血管狭窄、血管动脉瘤等心脑血管疾病严重威胁着人类健康，已成为人类死亡率最高的病因。随着医学的发展，微创的腔内隔绝术由于手术创伤小逐渐成为动脉多种病变的主要治疗方式，血管覆膜支架是腔内隔绝术治疗的主体，其性能直接影响着临床治疗效果，但术后中、远期仍然会出现如血管覆膜支架的滑移、内漏和支架源性新破口等并发症，以及仍然会出现血栓和再狭窄，这些临床问题值得密切关注。血管覆膜支架本身的生物相容性(尤其是组织相容性和血液相容性)差、生物力学性能不相配及不降解材料长期被血液里的成分包裹是诱发术后并发症的主要原因，因此迫切需要开发出与宿主血管间生物学性能匹配的血管覆膜支架。
腔内修复术的关键在于血管支架系统的研制，其中包括支架、覆膜和输送系统，目前我国在覆膜+支架的设计及加工制作方面的研究不够深入，临床运用的覆膜支架依赖进口，价格昂贵。覆膜是腔内隔绝的重要承担者，其生物学性能及其重要。现在临床应用的覆膜材料没有优异的组织相容性，术后远期易发生再狭窄，也发生滑移等并发症。对于发病率越来越高的中青年人群来说，长期靠药物来维持抗血栓是不合适的选择。家蚕蚕丝是天然动物蛋白，来源广泛，纯度高，其中丝素即丝芯，占蚕丝质量的70％～80％，纯化简单方便。丝素纤维具有卓越的力学性能，又具有优异的生物 相容性，丝素蛋白由20种氨基酸组成，丝素是可吸收材料，不会引起明显的免疫反应。已有大量的文献研究表明丝素蛋白材料能够支持多种细胞的生长，在抗凝血性方面也有较多的研究，在组织工程材料方面的研究也受到极大的关注，是作为可吸收覆膜的优选材料。
现有公开报导的血管支架的覆膜材料主要是聚四氟乙烯、聚酯、聚酰胺、聚乙烯、聚丙烯、聚氨酯等合成高分子，还有采用涤纶丝与镍钛合金丝编织或交替编织成覆膜。合成高分子缺乏组织相容性，是引起术后并发症的重要原因，覆膜内表面难以内皮化，置入体内一段时间后会产生免疫排异，依靠长期服药，会诱发其它更为严重疾病的发生。针对现有临床应用瓶颈问题和越来越年轻化(甚至活产婴儿)的发病现象，有必要研发一种再生修复的血管支架覆膜解决上述问题。
发明内容
有鉴于此，本发明的目的在于提供一种可再生修复的血管支架覆膜及其制备方法，用于生产可吸收、原位快速内皮化、诱导健康血管组织重建的可再生修复的血管支架。
本发明的一种技术方案是：
提供一种可再生修复的血管支架覆膜，轴向抗拉伸强度>2MPa，断裂伸长率>40％，圆周向抗拉伸强度>6MPa，断裂伸长率>140％，整体水渗漏在120mmHg水压下小于2ml/min.cm 2，溶血率<0.1％。
上述可再生修复的血管支架覆膜的制备方法，该方法包括如下步骤：
(1)制备脱胶后的家蚕丝素纤维和熟丝线：选取40～160D丝线和蚕丝单丝，所述丝线由家蚕生丝加捻合并获得，将所述蚕丝单丝采用沸水、碳酸钠、碳酸氢钠或生物酶中的任意一种进行脱胶，获得脱胶后的家蚕丝素纤维，将所述丝线采用碳酸钠、碳酸氢钠或生物酶中的任意一种进行脱胶，获得脱胶后的熟丝线；
(2)制备家蚕丝素蛋白水溶液：将所述脱胶后的家蚕丝素纤维按1:10(g/mL)的浴比溶解于9.3M的溴化锂水溶液中，在温度为65±10℃的条件下处理直至家蚕丝素纤维完全溶解，得到家蚕丝素溶解液，将所述家蚕 丝素溶解液灌注于透析袋内，所述透析袋的材质为半透膜，截留分子量为10～50kDa，将灌注了所述家蚕丝素溶解液的透析袋置于盛有去离子水的容器内，每隔2小时用新的去离子水更换容器内的液体，持续透析3天，得到纯化后的家蚕丝素蛋白水溶液；
(3)制备改性丝素蛋白溶液：采用旋转蒸发器浓缩、调整并测定所述纯化后的家蚕丝素蛋白水溶液，使所述纯化后的家蚕丝素蛋白水溶液的质量分数为1～10％，添加与丝素蛋白质量比为0.6的聚乙二醇二缩水甘油醚，搅拌均匀并脱气泡，得到改性丝素蛋白溶液；
(4)制备丝素蛋白管状覆膜：将所述熟丝线采用编结技术在不锈钢棒上编成30～90°交织、线密度为4～10根/厘米、内径为2～20mm的管状结构，将所述管状结构放入所述改性丝素蛋白溶液中浸渍3～30秒取出，置于热风干燥箱内在温度小于50℃的条件下沿圆周方向旋转成膜，并控制所述膜表面保持润湿，重复本步骤2～10次，获得可再生修复的血管支架覆膜。
进一步的，步骤(1)中所述制备脱胶后的家蚕丝素纤维和熟丝线包括：选取40～160D丝线和蚕丝单丝，所述丝线由家蚕生丝加捻合并获得，将所述蚕丝单丝和丝线按1:50(g/mL)的浴比放入浓度为0.1～0.6％的碳酸钠水溶液中，在温度为98～100℃的条件下处理三次，每次处理30分钟，用去离子水将所述蚕丝单丝和丝线充分清洗干净，然后将所述蚕丝单丝和丝线置于温度为60℃烘箱内干燥，获得脱胶后的家蚕丝素纤维和熟丝线。
进一步的，步骤(1)中所述制备脱胶后的家蚕丝素纤维和熟丝线包括：选取40～160D丝线和蚕丝单丝，所述丝线由家蚕生丝加捻合并获得，将所述丝线按1:50(g/mL)的浴比放入浓度为0.1～0.6％的碳酸钠水溶液中，在温度为98～100℃的条件下处理三次，每次处理30分钟，用去离子水将所述丝线充分清洗干净，然后将所述丝线置于温度为60℃烘箱内干燥，得到脱胶后的熟丝线；将所述蚕丝单丝按1:50(g/mL)的浴比放入去离子水中，在温度为98～100℃的条件下沸煮7小时，期间多次更换去离子水，然后用去离子水将蚕丝单丝充分清洗干净，置于温度为60℃烘箱内干燥，得到脱胶后的家蚕丝素纤维。
进一步的，步骤(1)中所述丝线为60D～120D。
进一步的，步骤(2)中所述透析袋的截留分子量为50kDa。
进一步的，步骤(3)中所述纯化后的家蚕丝素蛋白水溶液的质量分数为3％。
进一步的，步骤(4)中将所述熟丝线采用编结技术在不锈钢棒上编成60°～90°交织、线密度为4～12根/厘米、内径为2～20mm的管状结构。
进一步的，步骤(4)中浸渍时间为5～15秒，重复本步骤次数为3～5次。
本发明提供了一种可再生修复的血管支架覆膜及其制备方法，通过调节脱胶丝素纤维纺织结构芯层、内外渗透低浓高粘大分子丝素蛋白溶液并层层自组装获得复合血管支架覆膜，该血管支架覆膜具有卓越的韧性，且原位诱导调节血液系统平衡的血管内膜再生。可以制备成各种形貌应用于心血管疾病治疗(如心脏修补片、血管支架覆膜、人工心脏瓣膜)的体内移植物，也可以拓展用于其它一些组织工程支架等医疗器械。
具体实施方式
本发明的目的是针对目前心脑血管疾病腔内隔绝术治疗术后出现的血管覆膜支架移、内漏和支架源性新破口等并发症，以及长期疲劳损坏而导致装置失效、再狭窄等严峻的临床问题，而开发的一种天然高分子丝素蛋白质材料(分子量≥50kDa)的血管支架覆膜的制备技术，以促进病变和缺损血管的组织再生与功能恢复。该覆膜轴向抗拉伸强度>2MPa，断裂伸长率>40％，圆周向抗拉伸强度>6MPa，断裂伸长率>140％，整体水渗漏在120mmHg水压下小于2ml/min.cm 2，溶血率<0.1％。具有卓越的拉伸性能、爆破强度、顺应性和耐疲劳性，覆膜的膜层与丝线完全焊接，即使拉伸断裂时也不滑移。控制纳米级层层自组装，使覆膜具有卓越的柔韧性，覆膜不发生内漏，植入后与病灶组织结合紧密不滑移。控制丝素蛋白分子量，采用低浓度和低层次涂覆便获得优异的力学性能。通过调节丝素蛋白浓度、管状织构的几何参数和自组装层数等制备参数获得生物体不同部位 物理尺寸和物理性能要求的血管支架覆膜。另一方面，本发明提供的支架覆膜具有优异细胞相容性、组织相容性及快速内皮化能力，同时覆膜梯度降解吸收，原位修复血管内膜组织，不会困扰于植入人体后因长期的疲劳损坏而导致装置失效。而且快速内皮化是抑制血栓形成和再狭窄的根本因素，内膜组织快速形成将彻底恢复血管血液凝血系统平衡的调节功能。
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合实施例进一步说明本发明的技术方案。但是本发明不限于所列出的实施例，还应包括在本发明所要求的权利范围内其他任何公知的改变。
首先，此处所称的“一个实施例”或“实施例”是指可包含于本发明至少一个实现方式中的特定特征、结构或特性。在本说明书中不同地方出现的“在一个实施例中”并非均指同一个实施例，也不是单独的或选择性的与其他实施例互相排斥的实施例。
实施例1
本实施案例展示一种可再生修复的血管支架覆膜的制备方法，包括：
1.将家蚕生丝加捻合并得120D丝线组，另一组为蚕丝单丝组，将蚕丝单丝和丝线按1:50(g/mL)的浴比放入浓度为0.1～0.6％的碳酸钠水溶液中，于98～100℃处理三次，每次处理30分钟，然后用去离子水将丝充分清洗干净，置于60℃烘箱内干燥，得到脱胶后的家蚕丝素纤维和熟丝线。
2.称取脱胶后的家蚕丝素纤维按1:10(g/mL)的浴比溶解于9.3M的溴化锂水溶液中，65℃处理直至家蚕丝素纤维完全溶解，得家蚕丝素溶解液。将家蚕丝素溶解液灌注于透析袋内，透析袋壁是半透膜，截留分子量为50kDa范围，将灌注了家蚕丝素溶解液的透析袋置于盛有去离子水的容器内，每隔2小时用新的去离子水或纯水更换容器内的水，持续透析3天，得到纯化后的家蚕丝素蛋白水溶液。
3.采用旋转蒸发器浓缩、调整纯化后的家蚕丝素蛋白水溶液质量分数为3％，然后添加与丝素蛋白质量比为0.6的聚乙二醇二缩水甘油醚(纯化后的家蚕丝素蛋白水溶液中的丝素蛋白与聚乙二醇二缩水甘油醚的质量比是10：6)，搅拌均匀并脱气泡，得到改性丝素蛋白溶液。
4.将120D的熟丝线采用编结技术在不锈钢棒上编成90°交织、线密 度为10±2、内径为2～20mm的管状织物，于上述第3步的改性丝素蛋白溶液中浸渍约10秒取出，置于50℃以下的热风干燥箱内圆周方向旋转成膜，并控制覆膜表面保持润湿。重复浸渍涂层4次，获得蚕丝丝素复合血管支架覆膜，即可再生修复的血管支架覆膜。
经检测，上述可再生修复的血管支架覆膜具有卓越的机械性能，按照国标检测方法测定轴向抗拉伸强度>2.5MPa，断裂伸长率>45％，圆周向抗拉伸强度>8MPa，断裂伸长率>140％。整体水渗漏在120mmHg水压下小于12ml/min.cm 2。
通过对可再生修复的血管支架覆膜按照溶血率测试方法测定溶血率<0.1％，完全符合非溶血性材料的标准(0～2％)。可再生修复的血管支架覆膜通过动物实验无致敏性，按照国标检测细胞毒性≤1.5.制备的支架覆膜。
实施例2
本实施案例展示一种可再生修复的血管支架覆膜的制备方法，包括：
1.将家蚕生丝加捻合并得120D丝线组，另一组为蚕丝单丝组，将蚕丝单丝和丝线按1:50(g/mL)的浴比放入浓度为0.1～0.6％的碳酸钠水溶液中，于98～100℃处理三次，每次处理30分钟，然后用去离子水将丝充分清洗干净，置于60℃烘箱内干燥，得到脱胶后的家蚕丝素纤维和熟丝线。
2.称取脱胶后的家蚕丝素纤维按1:10(g/mL)的浴比溶解于9.3M的溴化锂水溶液中，65℃处理直至脱胶后的家蚕丝素纤维完全溶解，得家蚕丝素溶解液。将家蚕丝素溶解液灌注于透析袋内，透析袋壁是半透膜，截留分子量为50kDa范围，将灌注了家蚕丝素溶解液的透析袋置于盛有去离子水的容器内，每隔2小时用新的去离子水或纯水更换容器内的水，持续透析3天，得到纯化后的家蚕丝素蛋白水溶液。
3.采用旋转蒸发器浓缩、调整纯化后的家蚕丝素蛋白水溶液质量分数为3％，然后添加与丝素蛋白质量比为0.6的聚乙二醇二缩水甘油醚，搅拌均匀并脱气泡，得到改性丝素蛋白溶液。
4.将120D的熟丝线采用编结技术在不锈钢棒上编成90°交织、线密度为6±1、内径为2～20mm的管状织物，于上述第3步的改性丝素蛋白 溶液中浸渍约15秒取出，置于50℃以下的热风干燥箱内圆周方向旋转成膜，并控制覆膜表面保持润湿。重复浸渍涂层4次，获得蚕丝丝素复合血管支架覆膜，即可再生修复的血管支架覆膜。
经检测，上述可再生修复的血管支架覆膜具有卓越的机械性能，按照国标检测方法测定轴向抗拉伸强度>2.0MPa，断裂伸长率>40％，圆周向抗拉伸强度>6MPa，断裂伸长率>140％。并且，整体水渗漏在120mmHg水压下小于3ml/min.cm 2。
通过对可再生修复的血管支架覆膜按照溶血率测试方法测定溶血率<0.1％，完全符合非溶血性材料的标准(0～2％)。可再生修复的血管支架覆膜通过动物实验无致敏性，按照国标检测细胞毒性≤1。
实施例3
本实施案例展示一种可再生修复的血管支架覆膜的制备方法，包括：
1.将家蚕生丝加捻合并得120D丝线组，另一组为蚕丝单丝组，将丝线按1:50(g/mL)的浴比放入浓度为0.1～0.6％的碳酸钠水溶液中，于98～100℃处理三次，每次处理30分钟，然后用去离子水将丝线充分清洗干净，置于60℃烘箱内干燥，得到脱胶后的熟丝线。将蚕丝单丝按1:50(g/mL)的浴比放入去离子水中，于98～100℃沸煮7小时，期间多次更换去离子水，然后用去离子水将丝充分清洗干净，置于60℃烘箱内干燥，得到脱胶后的家蚕丝素纤维。
2.称取脱胶后的家蚕丝素纤维按1:10(g/mL)的浴比溶解于9.3M的溴化锂水溶液中，65℃处理直至家蚕丝素纤维完全溶解，得家蚕丝素溶解液。将家蚕丝素溶解液灌注于透析袋内，透析袋壁是半透膜，截留分子量为50kDa范围，将灌注了家蚕丝素溶解液的透析袋置于盛有去离子水的容器内，每隔2小时用新的去离子水或纯水更换容器内的水，持续透析3天，得到纯化后的家蚕丝素蛋白水溶液。
3.采用旋转蒸发器浓缩、调整纯化后的家蚕丝素蛋白水溶液质量分数为3％，然后添加与丝素蛋白质量比为0.6的聚乙二醇二缩水甘油醚，搅拌均匀并脱气泡，得到改性丝素蛋白溶液。
4.将120D的熟丝线采用编结技术在不锈钢棒上编成90°交织、线密 度为10±2、内径为2～20mm的管状织物，于上述第3步的改性丝素蛋白溶液中浸渍约5秒取出，置于50℃以下的热风干燥箱内圆周方向旋转成膜，并控制覆膜表面保持润湿。重复浸渍涂层4次，获得蚕丝丝素复合血管支架覆膜，即可再生修复的血管支架覆膜。
经检测，上述可再生修复的血管支架覆膜具有卓越的机械性能，按照国标检测方法测定轴向抗拉伸强度>3.0MPa，断裂伸长率>70％，圆周向抗拉伸强度>12MPa，断裂伸长率>200％。并且，整体水渗漏在120mmHg水压下小于2ml/min.cm 2。
通过对可再生修复的血管支架覆膜按照溶血率测试方法测定溶血率<0.1％，完全符合非溶血性材料的标准(0～2％)。可再生修复的血管支架覆膜通过动物实验无致敏性，按照国标检测细胞毒性≤1。
实施例4
本实施案例展示一种可再生修复的血管支架覆膜的制备方法，包括：
1.将家蚕生丝加捻合并得60D丝线组，另一组为蚕丝单丝组，将丝线按1:50(g/mL)的浴比放入浓度为0.1～0.6％的碳酸钠水溶液中，于98～100℃处理三次，每次处理30分钟，然后用去离子水将丝线充分清洗干净，置于60℃烘箱内干燥，得到脱胶后的熟丝线。将蚕丝单丝按1:50(g/mL)的浴比放入去离子水中，于98～100℃沸煮7小时，期间多次更换去离子水，然后用去离子水将丝充分清洗干净，置于60℃烘箱内干燥，得到脱胶后的家蚕丝素纤维。
2.称取脱胶后的家蚕丝素纤维按1:10(g/mL)的浴比溶解于9.3M的溴化锂水溶液中，65℃处理直至家蚕丝素纤维完全溶解，得家蚕丝素溶解液。将家蚕丝素溶解液灌注于透析袋内，透析袋壁是半透膜，截留分子量为50kDa范围，将灌注了家蚕丝素溶解液的透析袋置于盛有去离子水的容器内，每隔2小时用新的去离子水或纯水更换容器内的水，持续透析3天，得到纯化后的家蚕丝素蛋白水溶液。
3.采用旋转蒸发器浓缩、调整纯化后的家蚕丝素蛋白水溶液的质量分数为3％，然后添加与丝素蛋白质量比为0.6的聚乙二醇二缩水甘油醚，搅拌均匀并脱气泡，得到改性丝素蛋白溶液。
4.将60D的熟丝线采用编结技术在不锈钢棒上编成90°交织、线密度为10±2、内径为2～20mm的管状织物，于上述第3步的改性丝素蛋白溶液中浸渍约5秒取出，置于50℃以下的热风干燥箱内圆周方向旋转成膜，并控制覆膜表面保持润湿。重复浸渍涂层4次，获得蚕丝丝素复合血管支架覆膜，即可再生修复的血管支架覆膜。
经检测，上述可再生修复的血管支架覆膜具有卓越的机械性能，按照国标检测方法测定轴向抗拉伸强度>2.5MPa，断裂伸长率>45％，圆周向抗拉伸强度>8MPa，断裂伸长率>150％。并且，整体水渗漏在120mmHg水压下小于3ml/min.cm 2。
通过对可再生修复的血管支架覆膜按照溶血率测试方法测定溶血率<0.1％，完全符合非溶血性材料的标准(0～2％)。可再生修复的血管支架覆膜通过动物实验无致敏性，按照国标检测细胞毒性≤1。
实施例5
本实施案例展示一种可再生修复的血管支架覆膜的制备方法，包括：
1.将家蚕生丝加捻合并得60D丝线组，另一组为蚕丝单丝组，将丝线按1:50(g/mL)的浴比放入浓度为0.1～0.6％的碳酸钠水溶液中，于98～100℃处理三次，每次处理30分钟，然后用去离子水将丝线充分清洗干净，置于60℃烘箱内干燥，得到脱胶后的熟丝线。将蚕丝单丝按1:50(g/mL)的浴比放入去离子水中，于98～100℃沸煮7小时，期间多次更换去离子水，然后用去离子水将蚕丝单丝充分清洗干净，置于60℃烘箱内干燥，得到脱胶后的家蚕丝素纤维。
2.称取脱胶后的家蚕丝素纤维按1:10(g/mL)的浴比溶解于9.3M的溴化锂水溶液中，65℃处理直至家蚕丝素纤维完全溶解，得家蚕丝素溶解液。将家蚕丝素溶解液灌注于透析袋内，透析袋壁是半透膜，截留分子量为50kDa范围，将灌注了家蚕丝素溶解液的透析袋置于盛有去离子水的容器内，每隔2小时用新的去离子水或纯水更换容器内的水，持续透析3天，得到纯化后的家蚕丝素蛋白水溶液。
3.采用旋转蒸发器浓缩、调整纯化后的家蚕丝素蛋白水溶液的质量分数为3％，然后添加与丝素蛋白质量比为0.6的聚乙二醇二缩水甘油醚，搅 拌均匀并脱气泡，得到改性丝素蛋白溶液。
4.将60D的熟丝线采用编结技术在不锈钢棒上编成60°交织、线密度为10±2、内径为2～20mm的管状织物，于上述第3步的改性丝素蛋白溶液中浸渍约5秒取出，置于50℃以下的热风干燥箱内圆周方向旋转成膜，并控制覆膜表面保持润湿。重复浸渍涂层4次，获得蚕丝丝素复合血管支架覆膜，即可再生修复的血管支架覆膜。
经检测，上述可再生修复的血管支架覆膜具有卓越的机械性能，按照国标检测方法测定轴向抗拉伸强度>2.0MPa，断裂伸长率>50％，圆周向抗拉伸强度>6MPa，断裂伸长率>150％。并且，整体水渗漏在120mmHg水压下小于3ml/min.cm 2。
通过对可再生修复的血管支架覆膜按照溶血率测试方法测定溶血率<0.1％，完全符合非溶血性材料的标准(0～2％)。制备的支架覆膜通过动物实验无致敏性，按照国标检测细胞毒性≤1。
应说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围当中。

Claims (9)

  1. 一种可再生修复的血管支架覆膜，其特征在于：轴向抗拉伸强度>2MPa，断裂伸长率>40％，圆周向抗拉伸强度>6MPa，断裂伸长率>140％，整体水渗漏在120mmHg水压下小于2ml/min.cm 2，溶血率<0.1％。
  2. 一种可再生修复的血管支架覆膜的制备方法，其特征在于，该方法包括如下步骤：
    (1)制备脱胶后的家蚕丝素纤维和熟丝线：选取40～160D丝线和蚕丝单丝，所述丝线由家蚕生丝加捻合并获得，将所述蚕丝单丝采用沸水、碳酸钠、碳酸氢钠或生物酶中的任意一种进行脱胶，获得脱胶后的家蚕丝素纤维，将所述丝线采用碳酸钠、碳酸氢钠或生物酶中的任意一种进行脱胶，获得脱胶后的熟丝线；
    (2)制备家蚕丝素蛋白水溶液：将所述脱胶后的家蚕丝素纤维按1:10(g/mL)的浴比溶解于9.3M的溴化锂水溶液中，在温度为65±10℃的条件下处理直至家蚕丝素纤维完全溶解，得到家蚕丝素溶解液，将所述家蚕丝素溶解液灌注于透析袋内，所述透析袋的材质为半透膜，截留分子量为10～50kDa，将灌注了所述家蚕丝素溶解液的透析袋置于盛有去离子水的容器内，每隔2小时用新的去离子水更换容器内的液体，持续透析3天，得到纯化后的家蚕丝素蛋白水溶液；
    (3)制备改性丝素蛋白溶液：采用旋转蒸发器浓缩、调整并测定所述纯化后的家蚕丝素蛋白水溶液，使所述纯化后的家蚕丝素蛋白水溶液的质量分数为1～10％，添加与丝素蛋白质量比为0.6的聚乙二醇二缩水甘油醚，搅拌均匀并脱气泡，得到改性丝素蛋白溶液；
    (4)制备丝素蛋白管状覆膜：将所述熟丝线采用编结技术在不锈钢棒上编成30～90°交织、线密度为4～12根/厘米、内径为2～20mm的管状结构，将所述管状结构放入所述改性丝素蛋白溶液中浸渍3～30秒取出，置于热风干燥箱内在温度小于50℃的条件下沿圆周方向旋转成膜，并控制所述膜表面保持润湿，重复本步骤2～10次，获得可再生修复的血管支架覆膜。
  3. 根据权利要求2所述的一种可再生修复的血管支架覆膜的制备方法， 其特征在于，步骤(1)中所述制备脱胶后的家蚕丝素纤维和熟丝线包括：选取40～160D丝线和蚕丝单丝，所述丝线由家蚕生丝加捻合并获得，将所述蚕丝单丝和丝线按1:50(g/mL)的浴比放入浓度为0.1～0.6％的碳酸钠水溶液中，在温度为98～100℃的条件下处理三次，每次处理30分钟，用去离子水将所述蚕丝单丝和丝线充分清洗干净，然后将所述蚕丝单丝和丝线置于温度为60℃烘箱内干燥，获得脱胶后的家蚕丝素纤维和熟丝线。
  4. 根据权利要求2所述的一种可再生修复的血管支架覆膜的制备方法，其特征在于，步骤(1)中所述制备脱胶后的家蚕丝素纤维和熟丝线包括：选取40～160D丝线和蚕丝单丝，所述丝线由家蚕生丝加捻合并获得，将所述丝线按1:50(g/mL)的浴比放入浓度为0.1～0.6％的碳酸钠水溶液中，在温度为98～100℃的条件下处理三次，每次处理30分钟，用去离子水将所述丝线充分清洗干净，然后将所述丝线置于温度为60℃烘箱内干燥，得到脱胶后的熟丝线；将所述蚕丝单丝按1:50(g/mL)的浴比放入去离子水中，在温度为98～100℃的条件下沸煮7小时，期间多次更换去离子水，然后用去离子水将蚕丝单丝充分清洗干净，置于温度为60℃烘箱内干燥，得到脱胶后的家蚕丝素纤维。
  5. 根据权利要求2～4中任意一项所述的一种可再生修复的血管支架覆膜的制备方法，其特征在于：步骤(1)中所述丝线为60D～120D。
  6. 根据权利要求2所述的一种可再生修复的血管支架覆膜的制备方法，其特征在于：步骤(2)中所述透析袋的截留分子量为50kDa。
  7. 根据权利要求2所述的一种可再生修复的血管支架覆膜的制备方法，其特征在于：步骤(3)中所述纯化后的家蚕丝素蛋白水溶液的质量分数为3％。
  8. 根据权利要求2所述的一种可再生修复的血管支架覆膜的制备方法，其特征在于：步骤(4)中将所述熟丝线采用编结技术在不锈钢棒上编成60°～90°交织、线密度为4～12根/厘米、内径为2～20mm的管状结构。
  9. 根据权利要求2所述的一种可再生修复的血管支架覆膜的制备方法，其特征在于：步骤(4)中浸渍时间为5～10秒，重复本步骤次数为3～5次。
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