WO2023125434A1 - 一种覆膜支架系统及其制备方法 - Google Patents

一种覆膜支架系统及其制备方法 Download PDF

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Publication number
WO2023125434A1
WO2023125434A1 PCT/CN2022/142006 CN2022142006W WO2023125434A1 WO 2023125434 A1 WO2023125434 A1 WO 2023125434A1 CN 2022142006 W CN2022142006 W CN 2022142006W WO 2023125434 A1 WO2023125434 A1 WO 2023125434A1
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Prior art keywords
stent
coating
receiving device
diameter
layer
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PCT/CN2022/142006
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English (en)
French (fr)
Inventor
张贵
张德元
肖潇
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元心科技(深圳)有限公司
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Publication of WO2023125434A1 publication Critical patent/WO2023125434A1/zh

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    • 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
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • 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

Definitions

  • the invention belongs to the technical field of medical devices, and in particular relates to a covered stent and a preparation method thereof.
  • the covered stent is an implanted medical device that is covered with a flow-blocking film on the support frame so that it has the dual functions of opening the lumen and sealing the breach.
  • the diameter of the covered stent ranges from several millimeters to several ten millimeters.
  • covered stents are mainly used to treat aneurysms, pseudoaneurysms, vascular rupture, vascular stenosis, vascular occlusion and other arteriovenous malformations caused by various reasons.
  • Small-diameter covered stents are also often used in PCI (Percutaneous Coronary Intervention, percutaneous coronary intervention) emergency use in case of coronary artery perforation.
  • the methods of stent coating mainly include woven cloth suture coating, adhesive bonding coating, heating and sintering bonding coating, support skeleton dip coating, electrospinning coating and other methods, among which electrospinning coating Membrane technology is a mature and simple coating process, which is widely used in the preparation of various covered stents, and the coated membrane prepared by electrospinning has large specific surface area, high porosity, and easy film thickness. control features. Because the membrane surface prepared by electrospinning is easy to imitate the composition and structure design of the extracellular matrix, it is beneficial for cell endothelialization and control of neointimal hyperplasia, reducing the thrombosis of the membrane stent, and the prognosis is good.
  • a double-layer electrospun stent graft is disclosed in the patent CN108136078B.
  • Adhesives are used to bond the outer films together to improve the bonding strength of the inner and outer films.
  • the use of adhesives to bond the film increases the difficulty of process operations, and at the same time, the use of adhesives increases the use of redundant materials and increases biological risks.
  • Another invention patent application CN113151980A discloses an electrospinning film-covered stent, the film-covered stent is the inner and outer film of the support frame prepared by electrospinning and then sintered at 360°C-400°C. 1.
  • the outer coating is melted and bonded together by an adhesive.
  • this method can greatly improve the bonding strength between the coating and the supporting frame, the subsequent high-temperature heating of the electrospinning coating will change the pores of the electrospinning coating. rate and coating structure, which destroys the unique advantages of electrospinning coating.
  • the thickness of the final prepared PTFE tubular coating stent is 0.08-0.14mm, and the supporting skeleton coating is thicker, and the transport performance in the body is poor, increasing Risk of vascular injury.
  • the present invention provides a method that does not introduce additional adhesives, does not require subsequent high-temperature heating and fusion bonding, and has the advantages of thin coating, small outer diameter of crimping, and bonding strength of the coating layer.
  • the stent graft and the preparation method thereof have the characteristics of high mechanical properties of the film, etc., and the stent graft provided by the present invention also has the advantages of fast endothelialization of the lumen, rapid growth of tissue cells in the film layer, and no stent graft. Inflammatory reaction, neointimal hyperplasia, low lumen stenosis rate and other advantages.
  • the technical solution of the present invention provides a covered stent, including an inner covering, an outer covering, and a supporting framework between the inner and outer coverings.
  • the inner film and the outer film are bonded to each other in the supporting skeleton grid.
  • the "supporting skeleton" described in the present invention is a tubular body designed with any pattern structure; further, the “supporting skeleton” described in the present invention is a tubular body composed of independent corrugations or corrugations and connecting rods connected to each other . That is, in some embodiments, the support skeleton described in the present invention is a tubular body composed of a plurality of independent wave coils, while in other embodiments, the support skeleton is composed of a plurality of wave coils and a plurality of connecting rods interconnected Tubular body formed by connection.
  • the “stent grid” mentioned in the present invention refers to the area covered by the material on the side surface of the cylinder surrounded by the support, that is, on the pattern structure of the support; the “in the support grid”, “stent The “grid area” refers to the void of the stent, that is, the area not covered by the material on the side surface of the cylinder surrounded by the stent.
  • the “inner coating and the outer coating are bonded to each other in the supporting skeleton grid” in the present invention refers to the multi-layer spinning of the inner coating and the outer coating in the grid of the supporting skeleton.
  • Mutual bonding between the inner and outer coatings enhances the bonding force between the inner and outer coatings, thereby increasing the peel strength between the inner and outer coatings.
  • the multi-layer spinning room of the inner film and the multi-layer spinning room of the outer film are also bonded to each other, so that the film layers form adhesion areas in the thickness direction, and the mechanical properties of the film layer are enhanced.
  • the total arc length ⁇ L of the gap between the inner layer coating and the outer layer coating on any cross section along the circumferential direction of the supporting frame occupies the arc length L of the circumference of the entire cross section.
  • 0.1%-5% of the circumference the ratio of the L gap to the L circumference , that is, the ratio of the gaps in any section in the circumferential direction of the stent graft, that is, the void ratio A, can be calculated by the following method:
  • the circle and arc length mentioned in the present invention refer to the circle where the support frame is located and the arc length on the circle.
  • the arc length of the gap part refers to the corresponding arc length projected onto the circumference of the bracket
  • the arc length of the circumference of the entire section refers to the midpoint of the cross section of the support rod with the support skeleton on the cross section.
  • the porosity of the inner coating and the outer coating are both 70-90%, and the porosity of the further inner coating and the outer coating are both 70-85% or 75%-88%.
  • the thickness of the outer coating is greater than the thickness of the inner coating; the thickness of the outer coating is 1.1-5 times the thickness of the inner coating.
  • the thickness of the inner coating is 10-100 ⁇ m; the total wall thickness of the inner and outer coatings in the supporting skeleton grid is 30-500 ⁇ m, that is, the inner coating in the supporting skeleton grid + The total thickness of the outer coating is 30-500 ⁇ m.
  • the depth of the inner layer covered film in the support skeleton grid is 10 ⁇ m-350 ⁇ m, including but not limited to 20 ⁇ m, 30 ⁇ m, 40 ⁇ m, 50 ⁇ m, 60 ⁇ m, 70 ⁇ m, 80 ⁇ m, 90 ⁇ m, 100 ⁇ m, 110 ⁇ m , 120 ⁇ m, 130 ⁇ m, 140 ⁇ m, 150 ⁇ m, 160 ⁇ m, 170 ⁇ m, 200 ⁇ m, 230 ⁇ m, 250 ⁇ m, 280 ⁇ m, 300 ⁇ m, 350 ⁇ m, 500 ⁇ m, etc.
  • the depth of the inner coating film sinking into the support skeleton grid is 10 ⁇ m-300 ⁇ m, further, the depth of the inner coating film sinking into the support skeleton grid is 20 ⁇ m-300 ⁇ m, 30 ⁇ m-300 ⁇ m, 40 ⁇ m-300 ⁇ m or 50 ⁇ m -300 ⁇ m.
  • the crimping diameter on the expansion balloon catheter is 0.9-6mm, further 0.9-4.5mm, 0.9-5.0mm or 1.0-5.5mm.
  • the materials used for the inner layer coating and the outer layer coating are selected from cellulose, chitin, hyaluronic acid, collagen, gelatin, sodium alginate, polyurethane (PU, Polyurethane) , Polytetrafluoroethylene (PTFE, Poly tetrafluoroethylene), expanded polytetrafluoroethylene (E-PTFE, Expanded PTFE), polylactic acid (PAL, Polylactic acid), L-polylactic acid (PLLA, Poly(l-lactic acid) ), D-polylactic acid (PDLLA, Poly(D-lactide)), polyglycolic acid (PGA, Polyglycolic acid), polycaprolactone (PCL, Polycaprolactone), polyamide (PA, Polyamide), polyterephthalic acid At least one of ethylene glycol esters (PET, Polyethylene terephthalate).
  • PU Polyurethane
  • PTFE Polytetrafluoroethylene
  • E-PTFE Expanded PTFE
  • polylactic acid
  • the material used for the inner coating and the outer coating is one of the above materials, such as gelatin for the inner coating and sodium alginate for the outer coating; in some embodiments,
  • the inner and outer coatings are prepared from at least two of the above-mentioned materials, which can be a blend and/or copolymer of at least two or more of the above-mentioned materials, that is, can be a simple blend of at least two materials , it can also be a pure copolymer of at least two materials, or a blend and a copolymer of at least two materials above, such as the inner coating is a blend of gelatin and sodium alginate, and the outer coating It is a copolymer of polytetrafluoroethylene and polyamide, or part of the outer coating is a copolymer of polytetrafluoroethylene and polyamide, and part of it is a blend of polytetrafluoroethylene and polyamide; in some embodiments , the material of the inner layer coating can be the same
  • the support frame in the covered stent provided by the present invention can be ball-expandable or self-expandable; it can also be degradable or non-degradable.
  • the inner film covers the support frame completely, and the outer film covers 10-100% of the radial length of the support frame.
  • the stent graft provided by the present invention carries drugs or imaging materials on its inner coating, outer coating, or between the inner coating and the outer coating, wherein the drugs include anticoagulant drugs and/or Or anti-cell proliferation drugs;
  • the imaging material is selected from at least one of barium sulfate, niobium trioxide, titanium oxide, zirconia, iodine compounds, elemental iodine, gold, platinum, osmium, rhenium, tungsten, iridium, rhodium, and tantalum ;
  • anticoagulant drugs are selected from one or more of heparin, hirudin, sodium citrate, ethylenediaminetetraacetic acid, aspirin, warfarin, rivaroxaban;
  • anti-cell proliferation drugs are selected from Western One or more of rolimus, tacrolimus, pimecrolimus, paclitaxel, colchicine, dexamethasone, prednisone, and hydrocor
  • the wall thickness of the support frame is 30-300 ⁇ m, and the radial support force can reach 90-180 kpa.
  • “carrying” in the present invention refers to the dissolution or/melting of drugs or developing materials into the coating material, and then spraying together to form a coating; The side of the coating and the outer coating close to the supporting frame is coated with medicine or developing material.
  • the peel strength between the spun fiber layers in the inner layer or the outer layer of the film is 0.01-0.2N/mm, that is, the inner and outer layers of the respective multi-layer
  • the peeling strength between spinning is 0.01-0.2N/mm; the peeling strength between the inner layer coating and the outer layer coating is 0.1-0.5N/mm.
  • the peel strength between the inner and outer coatings of the stent graft in which the inner and outer coatings are bonded to each other provided by the present invention is greater than that between the respective spinning fiber layers in the inner coating or the outer coating Peel strength, that is, the bonding force between the inner and outer coatings in the technical solution provided by the present invention is significantly enhanced by the preparation method provided by the present invention.
  • Another aspect of the present invention provides a preparation method of the above-mentioned covered stent, the preparation method is simple and easy to operate, and specifically includes the following steps:
  • S2 Install the supporting frame on the receiving device spun with the inner film, adjust the diameter of the receiving device, expand the inner film until part of the inner film is embedded in the grid of the supporting frame;
  • the diameter of the receiving device in step S1 and/or S3 can gradually expand during the preparation process of the inner layer coating, and the rate of expansion is 0.1-10mm/h. Further, the receiving device is coated with the inner layer
  • the rate of diameter expansion during membrane preparation can be 0.1-1mm/h, 1-8mm/h, 1-6mm/h, 1-4mm/h, 3-10mm/h, 5-10mm/h, 7-10mm/h
  • the value of the new interval range composed of any two values in 0.1-10 such as h.
  • the original diameter of the receiving device is 1-50mm, further can be 1-30mm.
  • receiving devices of corresponding specifications can be matched according to brackets of different specifications.
  • the maximum diameter of the receiving device is 1.2-10 times the minimum diameter (original diameter).
  • the diameter of the device can be its smallest diameter, or any value between the smallest diameter and the largest diameter, but it must meet the total diameter of the receiving device and the inner layer film after the inner layer film is woven in step S1 It is smaller than the inner diameter of the supporting frame, and at the same time, the diameter of the receiving device must be 1.2-10 times that of the diameter before the inner film coating (that is, before the S1 step operation) when the outer coating is prepared, that is, when the S3 step operation is completed.
  • the depth of the inner film covering in the support skeleton grid during spinning is 10 ⁇ m-900 ⁇ m, including but not limited to 20 ⁇ m, 30 ⁇ m, 40 ⁇ m, 50 ⁇ m, 60 ⁇ m, 70 ⁇ m, 80 ⁇ m, 90 ⁇ m, 100 ⁇ m, 110 ⁇ m, 120 ⁇ m, 130 ⁇ m, 140 ⁇ m, 150 ⁇ m, 160 ⁇ m, 170 ⁇ m, 200 ⁇ m, 230 ⁇ m, 250 ⁇ m, 280 ⁇ m, 300 ⁇ m, 350 ⁇ m, 500 ⁇ m, 600 ⁇ m, 700 ⁇ m, 800 ⁇ m, 900 ⁇ m, etc.
  • the depth of the inner coating film sinking into the supporting skeleton grid is 10 ⁇ m-300 ⁇ m, 10 ⁇ m-500 ⁇ m, 10 ⁇ m-600 ⁇ m, 10 ⁇ m-700 ⁇ m, 10 ⁇ m-650 ⁇ m, further, the inner coating film is sinking into the supporting framework grid
  • the depth in the medium is 20 ⁇ m-300 ⁇ m, 30 ⁇ m-300 ⁇ m, 40 ⁇ m-300 ⁇ m or 50 ⁇ m-300 ⁇ m.
  • the spinning solution used in the spinning process can be a polymer solution formed by dispersing polymers in a solvent, or a polymer in a molten state after high-temperature melting.
  • step S3 also includes the step of spraying a solvent to dissolve the inner film before weaving the outer film, and multiple nozzles can be used to work simultaneously when weaving the outer film, as in some embodiments
  • one nozzle sprays polymer solution, and one nozzle sprays solvent In some other embodiments, one nozzle sprays solvent, and another nozzle sprays the polymer of molten state; In some other embodiments, one nozzle sprays polymer solution, The other sprays the polymer in the molten state; in still other embodiments, one sprays the polymer solution, another sprays the polymer in the molten state, and one sprays the solvent.
  • the solvent all arrives on the inner layer film earlier than the polymer, so that the spinning in the inner layer coating is dissolved and softened, and then further combined with the outer coating spinning film.
  • the polymer sprayed during the film further interacts with the dissolved or softened polymer on the inner film, and even rearranges the molecules to achieve the effect between the multi-layer spinning of the inner film and the spinning of the outer film.
  • the solvent used for dissolving the inner and outer coating spinning is dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, ethanol, isopropanol, dimethyl sulfoxide , dimethylacetamide, dimethylformamide, hexafluoroisopropanol, trifluoroacetic acid, hexafluoroisopropanol trifluoroethanol or a mixture of one or more, as in some embodiments, adopted
  • the solvent for dissolving the inner coating is dichloromethane, and in some other embodiments, the solvent for dissolving the inner coating is a combination of dichloromethane, ethyl acetate and hexafluoroisopropanol.
  • the mass ratio of the solvent to the polymer in the polymer solution dispersed in the solvent is 80:20-99:1, and further can be 80:20-50:1, 80:1 20-30:1, 80:20-25:1, 80:20-20:1, 80:20-15:1 and other value intervals.
  • the spinning viscosity is controlled at 10-100 Pa.s, thereby improving the spinning efficiency and reducing the spinning diameter , so that the thickness of the final woven inner layer coating or outer layer coating is relatively thin.
  • the diameters of the spun fibers of the inner film and the outer film are 1-5 ⁇ m.
  • a small amount of inorganic salts can be mixed in the polymer to reduce the viscosity of the solution, wherein the selected inorganic salts are sodium chloride, sodium phosphate, potassium chloride, Sodium chloride, magnesium chloride, aluminum chloride, sodium hydrogen phosphate, disodium hydrogen phosphate, calcium phosphate, sodium carbonate, sodium bicarbonate of sodium, calcium carbonate, calcium carbonate, ferric chloride, aluminum chloride, ferric hydroxide, trichloro One or more of iron oxide and ferrous gluconate.
  • step S1 and step S3 according to the difference in polymer concentration, viscosity and conductivity, the electrospinning voltage is controlled at 5-100kv, and the polymer injection flow rate is 0.01-1ml/min , the distance between the receiving device and the nozzle is 2-15cm, and the rotating speed of the receiving device is 100-2000/min.
  • the profile of the stent-graft in the present invention refers to the size of the outer diameter of the stent-graft system after the stent-graft is pressed onto the support.
  • the technical solution of the present invention also provides a receiving device for the above preparation method, wherein the diameter of the receiving device is adjustable, and its maximum diameter is 1.2-10 times of the minimum diameter.
  • the surface of the receiving device is coated with a conductive coating and/or a release agent.
  • the surface of the receiving device is provided with a microporous structure, the diameter of the micropores is 10-100 ⁇ m, and the distance between the micropores is 0.1-10 mm.
  • the shape of the receiving device is cylindrical.
  • the receiving device provided by the above technical solution is equipped with a heating assembly, that is, the receiving device is also equipped with a heating function, which can heat the spinning or coating placed on it, thereby accelerating the bonding between spinning , At the same time, it makes the bonding strength between the spinning larger and has a larger bonding force.
  • the shape of the pores on the surface of the receiving device is one or a combination of strips, grids or random scattered points.
  • the symbol “/” in the present invention means “or”, such as “A/B” means “A or B”; and “A and/or B” means “A and B, Or A or B", as described in the present invention, "the drug includes anticoagulant drugs and/or anti-cell proliferation drugs” means that the drugs carried on the covered stent include anticoagulant drugs and anti-cell proliferation drugs , or the drug carried on the stent graft is one of anticoagulant drugs and anti-cell proliferation drugs. That is, at least one of anticoagulant drugs and anti-cell proliferation drugs carried on the stent graft.
  • the support frame is tightly sandwiched between the inner layer film and the outer layer film, and in the area covered by the support frame rod, the outer wall side of the inner layer film layer is bonded to the inner wall of the support frame lumen, The inner wall side of the outer coating layer is bonded to the outer wall of the support frame.
  • the outer wall side of the inner film is closely bonded to the inner wall side of the outer film, and forms a continuous or discontinuous bonding area, which enhances the bonding between the inner film and the outer film strength.
  • the film-grafted stent prepared by this method does not require subsequent high-temperature heating, fusion bonding, or adhesive bonding for the bonding of the spinning and the supporting frame, and the film retains the thin diameter of the electrospun fiber, the thin spinning film,
  • the porosity is easy to adjust, and the coating has a high specific surface area, high porosity and good elasticity.
  • the structure of the coating layer is easy to imitate the composition and structure of the extracellular matrix, which is conducive to endothelialization and control of neointimal hyperplasia, reducing Thrombosis, improving the long-term effect of covered stents and other technical advantages. It also has the following advantages:
  • the inner film under the strong support and extrusion of the receiving device, the inner film remains immersed in the support skeleton grid to a depth of 10-900 ⁇ m.
  • the inner coating is trapped in the grid of the supporting skeleton so that when the outer coating is spun, the spun fibers can be well adhered to the inner coating, and the inner coating can be further dissolved or melted by the coating liquid or solvent.
  • the interaction force between the inner and outer films in the preparation process is enhanced, and the contact area of the inner and outer films is increased, so as to improve the bonding force of the inner and outer films the goal of.
  • the covered stent provided by the invention has a very thin covered film.
  • certain measures are taken during the preparation process to ensure that the spinning has a smaller diameter;
  • thirdly, in the process of preparing the inner and outer coatings increase the diameter of the receiving device while spinning, combined with the control of the diameter increase speed of the receiving device, let the inner and outer coatings spin While in close contact, increase the solution spraying step to dissolve the spinning between different spinning layers again.
  • the spinning spinning that is in contact with each other is solidified and bonded together again, so that the partial area of the coating layer is spun in the thickness direction.
  • the silk fibers are bonded to each other, which increases the strength of the spinning coating layer, thereby further reducing the wall thickness of the inner and outer coatings. Combining the above three factors, it is finally ensured that the covered stent has a small crimped outer diameter after crimping, which improves the delivery capacity of the stent in the body and reduces the risk of damage to human blood vessels.
  • FIG. 1 is a structural diagram of a stent graft, wherein 100 is a stent graft, 111 is a membrane, 101 is a supporting frame, 102 is an inner membrane, and 103 is an outer membrane.
  • Fig. 2 is the longitudinal sectional view of the absorbable stent graft in Example 1, wherein 101 is the absorbable iron-based stent, 102 is the inner coating, 103 is the outer coating, 2 is the inner wall of the absorbable iron-based stent, 3 It is the outer wall of absorbable iron-based stent.
  • Fig. 3 is a flow chart of the preparation of the absorbable stent graft.
  • Fig. 4 is a device structure diagram of an electrospinning machine.
  • Example 5 is a transverse cross-sectional view of the inner layer of the absorbable stent graft on the receiving device in Example 1.
  • Example 6 is a transverse cross-sectional view of the stent-graft in Example 1 after installing an absorbable iron-based stent outside the stent-graft.
  • Figure 7 is a transverse cross-sectional view of the absorbable stent graft in Example 1, where 2 is the inner surface of the absorbable iron-based support framework, 4 is the grid area of the support framework, and 3 is the outer surface of the absorbable iron-based support framework , 101 is an absorbable iron-based stent, 102 is an inner coating of the stent, and 103 is an outer coating of the stent.
  • FIG. 8 is an electron microscope image of the membrane morphology of the absorbable stent graft in Example 1.
  • FIG. 9 is a scanning electron micrograph of the endothelialization of the absorbable stent graft in Example 1 after it is implanted into a human body.
  • FIG. 10 is a histopathological diagram of the absorbable covered stent implanted in the human body in Example 1.
  • FIG. 10 is a histopathological diagram of the absorbable covered stent implanted in the human body in Example 1.
  • Figure 11 is a transverse cross-sectional view of the covered stent in Example 2, wherein 2 is the inner surface of the supporting frame, 4 is the grid area of the supporting frame, 3 is the outer surface of the supporting frame, 201 is a cobalt-chromium alloy stent, and 202 is a stent
  • the bottom coating, 203 is the coating of the inner layer of the stent, and 204 is the coating of the outer layer of the stent.
  • the structure diagram of a stent-graft device is a lumen structure formed by a membrane covering the surface of a hollow support skeleton.
  • 100 is composed of a supporting frame 101 and a coating 111 on the supporting frame
  • the coating 111 is composed of an inner layer coating 102 of the supporting frame and an outer coating 103 of the supporting frame.
  • the inner coating 102 is positioned in the lumen on the inner wall side of the supporting frame 101
  • the outer coating 103 is positioned on the outer surface of the supporting frame 101
  • the inner coating 102 and the outer coating 103 are in the grid area 4 of the supporting frame. In this way, the support frame 101 is firmly embedded in the middle of the membrane layer 111 .
  • the supporting frame 101 can be made of any material; in other embodiments, the supporting frame is made of bioabsorbable materials.
  • the supporting frame 101 is made of iron, iron-based alloy, magnesium, magnesium-based alloy, zinc, zinc-based alloy, or absorbable polymer material.
  • the support frame 101 is made of a non-bioabsorbable material.
  • the supporting frame 101 is made of medical materials such as nickel-titanium alloy, cobalt-chromium alloy or stainless steel.
  • the material used for the inner coating and the outer coating is selected from cellulose, chitin, hyaluronic acid, collagen, gelatin, sodium alginate, polyurethane (PU, Polyurethane), polytetrafluoroethylene (PTFE, Poly tetrafluoroethylene), expanded polytetrafluoroethylene (E-PTFE, Expanded PTFE), polylactic acid (PAL, Polylactic acid), L-polylactic acid (PLLA, Poly(l-lactic acid)), D-polylactic acid (PDLLA, Poly(D-lactide)), polyglycolic acid (PGA, Polyglycolic acid), polycaprolactone (PCL, Polycaprolactone), polyamide (PA, Polyamide), polyethylene terephthalate (PET, Polyethylene terephthalate) at least one.
  • PU Polyurethane
  • PTFE Polytetrafluoroethylene
  • E-PTFE Expanded PTFE
  • polylactic acid PAL, Polylactic acid
  • the material used for the inner coating and the outer coating is one of the above materials, such as gelatin for the inner coating and sodium alginate for the outer coating; in some embodiments,
  • the inner and outer coatings are prepared from at least two of the above-mentioned materials, which can be a blend and/or copolymer of at least two or more of the above-mentioned materials, that is, can be a simple blend of at least two materials , it can also be a pure copolymer of at least two materials, or a blend and a copolymer of at least two materials above, such as the inner coating is a blend of gelatin and sodium alginate, and the outer coating It is a copolymer of polytetrafluoroethylene and polyamide, or part of the outer coating is a copolymer of polytetrafluoroethylene and polyamide, and part of it is a blend of polytetrafluoroethylene and polyamide; in some embodiments , the material of the inner layer coating can be the same
  • the stent coating is prepared by solution electrospinning.
  • the solvents used are dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, ethanol, isopropanol,
  • dimethylsulfoxide, dimethylacetamide, dimethylformamide, hexafluoroisopropanol, trifluoroacetic acid, hexafluoroisopropanol and trifluoroethanol are mixed and dissolved polymers.
  • the mass ratio of the solvent to the polymer in the polymer solution dispersed in the solvent is 80:20-99:1, further it can be 80:20-50:1, 80:20-30:1, 80:20- 25:1, 80:20-20:1, 80:20-15:1 and other value intervals.
  • the stent cover is prepared using melt electrospinning. Further, during electrospinning of the melt, the viscosity of the melt is controlled at 10-100 Pa.s. Specifically, the viscosity of the melt is selected from sodium chloride, sodium phosphate, potassium chloride, sodium chloride, magnesium chloride, aluminum chloride, sodium hydrogen phosphate, disodium hydrogen phosphate, calcium phosphate, sodium carbonate, sodium hydrogen carbonate, Calcium carbonate, calcium carbonate, ferric chloride, aluminum chloride, ferric hydroxide, ferric chloride, one or more organic salts in ferrous gluconate to adjust.
  • melt electrospinning is used for the inner coating
  • solution electrospinning is used for the outer coating. Further, whether it is the inner coating or the outer coating, melt spinning and solution spinning can be used to blend, or alternatively weaving the coating.
  • the bottom layer is added to the inner wall layer to improve the blood compatibility of the stent graft.
  • an anticoagulant substance is loaded on the inner layer of the stent to prevent thrombus formation in the covered stent.
  • the anticoagulant substance is selected from one or more of heparin, hirudin, sodium citrate, ethylenediaminetetraacetic acid, aspirin, warfarin, and rivaroxaban. Specifically, a sufficient amount of anticoagulant substance is mixed into the coating material, and liquid electrospinning or melt electrospinning is carried out together, and the anticoagulant substance is loaded in the spinning fiber, so as to achieve slow release and inhibition in the coating stent. The purpose of thrombosis.
  • the outer coating is loaded with anti-cell proliferation drugs selected from sirolimus, tacrolimus, pimecrolimus, paclitaxel, colchicine, dexamethasone, prednisone, One or more of hydrocortisone.
  • anti-cell proliferation drugs selected from sirolimus, tacrolimus, pimecrolimus, paclitaxel, colchicine, dexamethasone, prednisone, One or more of hydrocortisone.
  • a sufficient amount of anti-cell proliferation drug is mixed into the coating material, and liquid electrospinning or melt electrospinning is carried out together, and the anti-cell proliferation drug is loaded in the spun fiber, so as to achieve slow release and inhibit the growth of new cells.
  • the purpose of membrane hyperplasia is a sufficient amount of anti-cell proliferation drug is mixed into the coating material, and liquid electrospinning or melt electrospinning is carried out together, and the anti-cell proliferation drug is loaded in the spun fiber, so as to achieve slow release and inhibit the growth of
  • the outer covering film completely covers the supporting frame. In another embodiment, the outer covering film only partially covers the supporting frame, and the outer covering film covers 10%-100% of the radial length of the supporting frame. area.
  • the preparation process of the covered stent device includes the following steps:
  • the viscosity of the solvent in the solvent nozzle is lower than that of the polymer spinning solution, when subjected to the same electrostatic attraction, the solvent will form tiny solvent droplets and fly to the electrostatic spinning beam on the receiving device, and the spinning around the solvent droplets will be dissolved again , after the solvent volatilizes and solidifies again, the spun filaments in contact with each other at the droplet will adhere to each other, and the spun-bonded filaments are arranged in disorder, forming a stent inner layer coating that is mutually bonded in the thickness direction. Further, the distance between the solvent nozzle and the receiving device can also be reduced, so that the solvent jet is directly and continuously sprayed on the spinning bundle to form a continuously oriented spinning bonding zone.
  • the diameter-adjustable receiving device is a mechanically designed adjustment mechanism or a balloon expansion adjustment, and the mechanically designed receiving device can realize diameter adjustment only by rotating the expansion mechanism.
  • the balloon expansion adjustment receiving device only needs to inject the same volume of liquid or gas into the balloon to realize the adjustment of the diameter of the balloon.
  • the diameter adjustment method may be step-by-step or step-by-step increase.
  • the original diameter of the cylindrical receiving device with adjustable diameter is 1-50mm, and the diameter adjustment range is 1.01-10 times of the original diameter, preferably 1.5 times. Its diameter increases by 0.05-1 mm per step when it is increased step by step, preferably 0.1 mm. When increasing step by step, its diameter increase rate is 0.1-10mm/h, preferably 1mm/h.
  • the diameter-adjustable receiving device can also have a microporous structure on the surface, the perimeter of the micropore projected inner coating is 30-300 ⁇ m, preferably 100 ⁇ m, and the spacing between the micropores is 0.1-10 mm, preferably 1 mm.
  • the micropores are selected from one or more combinations of circular, elliptical, polygonal, and irregular shapes.
  • the micropore arrangement can be one of strips, grids, or random scattered points.
  • the micropores can conduct away the charge on the electrospinning, reduce the accumulation of charges on the spinning, and reduce the mutual repulsion between spinning.
  • the diameter-adjustable cylindrical receiving device is covered with a flexible material.
  • the flexible material on the receiving device surface and the inner layer of the receiving device are depressed in the area bound by the support skeleton rods, and the stent grid is formed.
  • the flexible material on the surface of the receiving device and the inner film of the stent are pressed and protruded into the grid of the support frame, and the inner wall film is embedded on the support frame.
  • the flexible material is selected from natural rubber, butyl rubber, butadiene rubber, neoprene rubber, EPDM rubber, acrylic rubber, polyurethane rubber, conductive silicone rubber, nylon, polyester, acrylic polyester fiber, aramid fiber , Polypropylene fiber, PET, PTFE. Further, the flexible material on the surface of the receiving device is depressed by the support skeleton rods to a depth of 10-200 ⁇ m, and the grid area of the support skeleton protrudes into the grid to a height of 10-900 ⁇ m.
  • rigid projections of different shapes are provided on the surface of the adjustable-diameter cylindrical receiving device.
  • the rigid projections When the diameter of the receiving device expands, the rigid projections will press the inner membrane of the stent to protrude into the grid in the area of the stent grid.
  • the height of the rigid protrusions is 1-100 ⁇ m, and the pattern area of the rigid protrusions accounts for 10%-90% of the total rod surface.
  • the rigid protrusion patterns can be uniformly or unevenly distributed in the form of points, or continuous strips, grid shape, and can also be a raised pattern matching the grid shape of the bracket.
  • the diameter of the cylindrical receiving device can be increased by a certain size, so that the film-coated spun fibers on the cylindrical receiving device are in the circumferential direction At this time, the spun fibers of the outer layer of the coating layer will exert pressure on the spun fibers of the inner layer, reducing the gap between the spun fibers, and facilitating the re-dissolving of the spun fibers to stick together.
  • step S1 depending on the polymer concentration, viscosity, and conductivity, the electrospinning voltage is 5-100kv, the injection flow rate is 0.01-1ml/min, the distance between the receiving device and the nozzle is 2-15cm, and the receiving device rotates Speed 100-2000/min.
  • step S1 there may be one or more polymer nozzles, it may be a solution spinning nozzle alone, it may also be a melt spinning nozzle, or it may be a solution spinning and a melt spinning mutual Combined blending nozzles.
  • the distance between the solvent nozzle and the receiving device is 1-5 cm
  • the liquid directly forms a jet and sprays to the spinning, forming a continuous solvent imprint on the spinning film layer, and can also enlarge the solvent nozzle and the receiving device.
  • the distance between the receiving devices is 5-10cm
  • the solvent liquid forms dispersed droplets and sprays to the spinning beam on the coating layer
  • the solvent injection flow rate is 0.01-0.5ml/min
  • the solvent injection can be selected continuously or at intervals of a certain period of time Pulse injection, pulse time interval 0.1-100s.
  • the supporting frame of the required film is placed on the above-mentioned receiving device covered with the inner layer of the film, and the diameter of the receiving device is enlarged, and the inner layer of the film is squeezed tightly by the receiving device
  • the inner wall of the supporting frame, the film under the supporting frame rod is in close contact with the inner wall side of the supporting frame rod, and the inner film of the grid part of the supporting frame rod is extruded and protruded into the bracket grid.
  • a scanning electron microscope (abbreviation: SEM) was used to observe the morphology of the stent-graft membrane, and the diameter of the wire was measured by magnification to 2000 times.
  • SEM was a JSM6510 scanning electron microscope of JEOL Ltd.
  • the stent graft was cut longitudinally and cut to a certain width, and the peel strength of the inner and outer layers of the stent graft was measured using a universal tensile machine. Taking the peel strength test of the inner and outer layers of the superficial femoral artery stent graft as an example, it specifically includes the following steps:
  • the microscope is Keyence, VHX-700F or SENSOFAR, Q6).
  • the microscope is Keyence, VHX-700F or SENSOFAR, Q6.
  • 3 superficial femoral artery stent-grafts were implanted in the superficial femoral artery of 3 minipigs weighing 30-35 kg, and the animals were euthanized 28 days after implantation to take out the stent-grafts.
  • Use 10% formaldehyde to fix for 7 days then use 70%, 80%, 90% and 100% gradient alcohol to dehydrate successively, use methyl methacrylate to carry out resin embedding, and use a precision cutting machine (U.S.
  • BUEHLER company Lsomet5000 after curing) Slice with a thickness of about 150 ⁇ m, throw it thinly with a grinding and polishing machine (Ecomet 250 from BUEHLER, USA) to a thickness of about 10-20 ⁇ m, stain with hematoxylin for 30 minutes, differentiate with differentiating fluid for 1 minute, reverse blue with ammonia water for 10 minutes, and stain with eosin for 5 minutes to prepare disease volume slices.
  • the longitudinal sectional view of the absorbable stent-graft 100 provided in this embodiment is shown in FIG. membrane composition.
  • the inner membrane 102 is positioned in the lumen of the supporting framework 101 , and the outer wall of the inner membrane is in close contact with the inner wall 2 of the supporting framework 101 .
  • the outer coating 103 is positioned on the outer surface of the supporting frame 101 and its inner wall is in close contact with the outer wall 3 of the supporting frame 101 .
  • the inner covering film 102 and the outer covering film 103 are bonded to each other at the support frame mesh area 4 , in this way, the support frame 101 is firmly embedded in the middle of the film layer 111 .
  • the support frame 101 is an absorbable iron-based alloy stent, which is made of 99% nitrided pure iron through nitriding and laser engraving, the nitrogen content of nitrided pure iron is ⁇ 0.25%, and the nominal expansion diameter of the stent is 6mm , consisting of 10 groups of wave coils and connecting rods, the wall thickness of the bracket rod is 80 ⁇ m, and the radial support force is 120kPa.
  • the inner coating 102 and the outer coating 103 of the stent are made of electrospun PLLA liquid, and the total thickness of the inner and outer coatings is 69.8 ⁇ m.
  • the absorbable coated stent is pressed on the expansion balloon, and the outer diameter of the pressing grip is 1.8mm.
  • the fabrication steps of the stent graft are shown in Figure 3.
  • Step S1 To prepare the inner wall layer coating 102, add 10 g of PLLA with a molecular weight of 500,000 to 190 ml of ethyl acetate, and stir at room temperature for 8 hours to completely dissolve it to obtain a polylactic acid spinning solution with a mass fraction of 5%.
  • PLLA polylactic acid spinning solution
  • Step S1 To prepare the inner wall layer coating 102, add 10 g of PLLA with a molecular weight of 500,000 to 190 ml of ethyl acetate, and stir at room temperature for 8 hours to completely dissolve it to obtain a polylactic acid spinning solution with a mass fraction of 5%.
  • the above-mentioned polylactic acid spinning solution is sucked into the micro-injection pump 35 and connected to the spinning solution nozzle 37 through a microcatheter.
  • the distance between the spinning solution nozzle 37 and the cylindrical receiving device 30 is set to 10 cm, and the rotating speed of the receiving device 30 is 200.
  • the reciprocating speed of the axial direction is 0.1mm/s
  • the pump flow rate of the spinning solution 35 is 0.05ml/min
  • another chloroform is taken in the solvent injector 36
  • the pump flow rate is adjusted to be 0.1ml/min
  • the injection pulse interval time is 10s
  • the duration is 6s
  • the distance between the solvent nozzle 41 and the receiving device 30 is 5cm
  • the voltage of the electrospinning power supply 40 is adjusted to 15kV
  • the equipment is turned on to prepare the inner film of the stent.
  • the spun fibers that have been spun on the surface will be radially tightened, and the spun fibers will be squeezed each other, reducing the gap between the spun fibers.
  • the solvent falls on the spun fiber bundles that are in close contact with each other, and the spun fibers at the solvent droplet are dissolved under the action of solvent dissolution, and the spun fibers that are in close contact with each other are bonded together after the solvent is completely volatilized. Electrospinning was performed for 60 minutes to obtain a 27.6 ⁇ m thick oriented spinning coating, that is, the stent inner wall layer coating 102 , as shown in FIG. 5 .
  • the diameter-variable cylindrical receiving device 30 is a balloon ( FIG. 5 ).
  • the balloon has a simple structure and is easy to operate. It only needs to inject different volumes of liquid to change the diameter. Inject a small amount of saturated sodium chloride solution into the receiving device 30, so that the filling diameter of the receiving device 30 is 4.5mm, connect the negative electrode 39 of the power supply of the electrospinning machine 40 with the saturated sodium chloride solution 29 in the balloon, and connect the positive electrode of the power supply 38 is connected with the polymer solution nozzle 37 and the solvent nozzle 41, an electric field E2 is formed between the liquid in the balloon and the polymer nozzle 37, for the polymer to form electrospinning, and an electric field is formed between the liquid in the balloon and the solvent nozzle 41 E1, for solvent injection to form power.
  • Step S2 loads the absorbable iron-based alloy stent, installs the absorbable iron-based alloy stent 101 on the outer periphery of the inner coating film 102 of the stent, and continues to inject saturated sodium chloride solution 29 into the receiving device 30, and the outer diameter of the receiving device 30 gradually increases.
  • the stent inner coating 102 is squeezed toward the inner cavity of the stent, the outer side of the inner coating 102 is closely attached to the inner surface 2 of the absorbable iron-based alloy stent 101, and the inner layer at the 4 grid areas of the stent The coating 102 is pressed by the balloon and protrudes into the stent grid area 4, and is 80 ⁇ m higher than the inner wall of the stent rod, as shown in FIG. 6 ;
  • Step S3 Prepare the outer layer coating, and then electrospin the outer wall layer of the absorbable iron-based alloy stent 101 referring to the preparation method of the inner wall layer coating to obtain the outer wall layer coating 103, because the solvent droplets sprayed by the solvent nozzle when the outer layer of the stent is coated Dissolving part of the spinning fibers in the inner coating and the outer coating, after the solvent volatilizes, the inner coating 102 and the outer coating 103 are in contact with each other at the stent mesh structure unit 4 to form a firm bond.
  • the inner side of 103 is in close contact with the outer surface 3 of the absorbable iron-based alloy stent 101 to achieve the purpose of firmly embedding the absorbable iron-based stent in the middle of the film layer.
  • the coating conditions of the outer layer of the stent were the same as those of the inner wall of the stent, and the total film thickness was 69.8 ⁇ m obtained by electrospinning for 120 minutes, as shown in Figure 7 .
  • step S4 the membrane is trimmed, and the saturated sodium chloride liquid 29 in the balloon 30 is drawn out, the diameter of the balloon 30 becomes smaller and separated from the inner membrane, the stent graft 100 is removed from the balloon, and the excess at both ends is trimmed Then compress the covered stent on the balloon dilatation catheter, the outer diameter of the grip is 1.8mm, pack it in a dialysis bag and sterilize it with EO (Epoxy ethane, ethylene oxide) to get the final absorbable covered stent Product 100.
  • EO epoxy ethane, ethylene oxide
  • the above-mentioned detection method shows that the spinning orientation of the absorbable stent graft is good, the spinning diameter is uniform, the spinning diameter is 1.5-2 ⁇ m, and the spinning can be seen to be bonded to each other, as shown in Figure 8.
  • the coating layer maintains a relatively high porosity, and the porosity of the coating layer is 82% through testing.
  • the inner and outer coatings have strong bonding force, and the absorbable iron-based stent is firmly fixed in the coating layer.
  • the total thickness of the inner and outer coatings is 72 ⁇ m, and the diameter of the crimping grip on the expansion balloon is 2.3 mm.
  • the bonding strength of the inner and outer coatings is 0.3N/mm, and the peeling strength of the spinning layer of the outer coating is 0.12N/mm. Between the inner and outer coatings, the total arc length of gaps is very small, and the total arc length of gaps accounts for only 1.2% of the arc length of the circumference of the entire section.
  • the rate of endothelialization and tissue response of absorbable stent-grafts was assessed after implantation in the superficial femoral artery of minipigs.
  • the neointima coverage rate was 67 ⁇ 15% at 7 days after implantation, and the morphology of endothelial cells on the surface of the membrane was not typical.
  • the coverage rate of neointima was 90 ⁇ 5%, with typical endothelial cells.
  • the neointima coverage rate was 100%, and the lumen surface of the stent graft was covered with typical endothelial cells, as shown in Figure 9 .
  • Histopathology at 28 days after implantation showed that all tissue cells had grown into the membrane, and there was no inflammatory reaction or cell necrosis around the membrane.
  • the stenosis rate of blood vessels measured by the detection method was 21%, as shown in FIG. 10 .
  • FIG. 11 is a cross-section of a stent graft 200 with good blood compatibility.
  • the stent graft 200 is made of cobalt
  • the chromium alloy support frame is composed of a stent 201 , a stent bottom coating 202 , a stent inner coating 203 and a stent outer coating 204 .
  • the underlying coating 202 is positioned on the inner wall of the lumen of the stent inner coating 203, and the inner coating 203 is positioned on the inner wall of the cobalt-chromium alloy support frame 201 and the outer wall of the underlying coating 202, and is combined with the cobalt-chromium alloy
  • the inner surface 2 of the support frame bracket 201 is in close contact.
  • the outer coating 204 is positioned on the outer surface of the cobalt-chromium alloy supporting skeleton stent 201 and is in close contact with the outer surface 3 of the stent 201 .
  • the inner wall coating 203 and the outer coating 204 are bonded to each other at the stent grid area 4, in this way, the cobalt-chromium alloy supporting skeleton stent 201 is firmly embedded in the middle of the outer coating and the inner coating,
  • the outer film covers 100% of the cobalt-chromium alloy supporting frame 201 .
  • the nominal expansion diameter of the covered stent 200 is 10 mm
  • the wall thickness of the cobalt-chromium alloy supporting frame 201 is 120 ⁇ m
  • the thickness of the bottom coating 202 is 5 ⁇ m
  • the inner coating 203 and The outer wall coating 204 is made by electrospinning PET (Polyethylene terephthalate, polyethylene terephthalate) melt
  • the total thickness of the inner and outer coatings is 120 ⁇ m
  • the spinning diameter is about 4 ⁇ m.
  • the production steps are to cover the PTFE film with a thickness of 5 ⁇ m on the diameter-adjustable receiving device, and then use melt spinning to prepare the inner and outer coatings of the stent.
  • the preparation process is as follows:
  • the diameter of the adjustable receiving device is set to 9.0 mm, and then covered with a PTFE film with a thickness of 5 ⁇ m, and then the inner coating is prepared.
  • the diameter of the adjustable receiving device is adjusted by means of mechanical structure adjustment.
  • S1 Inner coating preparation Weigh 20 mg of PET raw material slices, add them into the spinneret material tube with heating, extrusion, and stirring, and mix in sodium chloride powder with a mass fraction of 5% to reduce the viscosity of the melt. Electric heating is used to heat the raw material to melt, the melt heating temperature is set to 270°C, the spinning environment temperature is set to 65°C, the distance between the spinneret and the receiving device is 7cm, and the rotating speed of the receiving device is 100/min.
  • the voltage is 25kv
  • the feeding pressure is 2kpa
  • the stent inner layer coating 203 is prepared on the outer wall of the stent bottom layer coating 202
  • the diameter of the receiving device is increased by 0.1mm every 15 minutes of spinning
  • the oriented stent inner wall with a thickness of 51.3 ⁇ m is obtained by electrospinning for 60 minutes Thick coating
  • the temperature of the receiving device is set to 90° C., which increases the adhesion between spinning and the underlying coating 202 and between spinning and spinning.
  • Preparation of the outer layer coating refer to the preparation method of the inner wall layer coating 203 outside the cobalt-chromium alloy support frame 201, and perform melt electrospinning to obtain the outer wall layer coating, and the thickness of the outer layer coating is 98.5 ⁇ m.
  • the outer layer coating completely covers the cobalt-chromium alloy support skeleton. During the weaving process, the extrusion of the receiving device on the inner wall of the coating, the increase of the ambient temperature and the increase of the temperature of the receiving device will cause the inner coating of the cobalt-chromium alloy stent grid area Bonding with the outer covering film finally obtains the covered stent graft 200 with good blood compatibility.
  • the total thickness of the inner and outer coatings of the stent is 149.6 ⁇ m
  • the fiber diameter of the inner and outer coatings of the stent is 3.8 ⁇ m
  • the peel strength between the inner coating and the outer coating is 0.23 N/mm.
  • the peel strength between the respective spinning layers of the inner coating layer and the outer coating layer of the stent is 0.11N/mm
  • the total arc length of the gap between the inner and outer coating layers accounts for the arc length of the circumference of the entire section Only 3%, the porosity of the membrane is 75%.
  • the crimping diameter of the covered stent on the expansion balloon is 3.5 mm.
  • the stent-graft is an absorbable stent-graft whose support frame is composed of several corrugated rings that are not connected to each other, wherein the support frame only maintains the radial diameter in the stent-graft and does not affect the stent-graft axially.
  • Constrained when the stent-graft is implanted into a curved blood vessel, the stent-graft has good compliance, the stent-graft has strong adaptability to the curved blood vessel, and the inner layer of the stent-graft is not easy to wrinkle, which also improves the stent-graft in the curved blood vessel.
  • the specific preparation method is as follows.
  • the initial diameter of the receiving device will be set to 2.5 mm
  • the rotation speed will be 100 rpm
  • the axial reciprocating speed will be 0.1 mm/s.
  • the solution pump flow rate was 0.05ml/min
  • the distance between the spinning nozzle and the receiving device was 10cm
  • the voltage was set to 8kv
  • a 19.9 ⁇ m-thick inner film was obtained after spinning for 120min.
  • the corrugated rings of the absorbable supporting frame are placed outside the inner coating.
  • the distance between two adjacent corrugated rings of the supporting frame is 4mm.
  • adjust the diameter of the receiving device to 3mm.
  • the inner film of other parts protrudes from the supporting frame rod and is higher than the supporting frame rod.
  • the inner wall of the skeleton is at least 70 ⁇ m.
  • melt spinning method to prepare the outer coating of the stent take 10 mg of PLA raw material slices, add them to the spinneret material tube with heating, extrusion, and stirring, use electric heating to heat the raw materials to melt, and set the melt temperature 200°C, mixed with sodium phosphate at the same time to adjust the viscosity of PLA melt to 20Pa.s, the ambient temperature is set to 45°C, the distance between the spinneret and the receiving device is 7cm, the spinning voltage is 15kv, and the feeding pressure is 5kpa.
  • the 30.3 ⁇ m-thick stent outer coating was obtained by electrospinning the layer coating for 60 minutes, and finally the blended stent graft of this embodiment was obtained.
  • the support skeleton in the coating was discontinuous, and the stent graft had good flexibility.
  • the total thickness of the stent coating is 50.1 ⁇ m
  • the peel strength between the inner and outer coatings of the stent is 0.11N/mm
  • the peel strength between the spinning layers of the inner and outer coatings of the stent is 0.02N/mm
  • the total arc length of the gap between the inner and outer coating accounts for only 0.7% of the arc length of the circle where the entire section is located
  • the porosity of the coating is 90%.
  • the crimping diameter of the covered stent on the expansion balloon is 1.5 mm.
  • the inner layer of the stent is loaded with anticoagulant substances to prevent thrombus formation in the covered stent, and the outer layer of the covered layer is loaded with anti-cell proliferation drugs to inhibit excessive neointimal hyperplasia.
  • the specific implementation process of this embodiment is:
  • the surface of the cylindrical receiving device is covered with a flexible PTFE gasket, the distance between the receiving device and the spinning nozzle is set to 12cm, the diameter of the receiving device is 2.5mm, the rotation speed is 2000 rpm, and the spinning solution pump flow rate is 0.05ml/min , and a spinning voltage of 7 kv was used for electrospinning to prepare the inner layer of the stent graft, and the inner layer of the stent graft was obtained after 120 minutes with a thickness of 27.5 ⁇ m.
  • the flexible PTFE gasket under the absorbable iron-based stent grid pushes the inner film into the stent grid , the flexible PTFE gasket under the stent rod is compressed and dented into the receiving device together with the inner membrane.
  • the depth of the depression is 30 ⁇ m, and the height of the grid area protruding into the grid is greater than 75 ⁇ m.
  • the total thickness of the stent coating is 78.3 ⁇ m
  • the peel strength between the inner and outer coatings of the covered stent is 0.13N/mm
  • the peeling strength between the respective multi-layer textiles of the inner and outer coatings of the stent The strength is 0.14N/mm
  • the total arc length of the gap between the inner and outer coating accounts for only 0.5% of the arc length of the circle where the entire section is located
  • the porosity of the coating is 80%.
  • the covered stent is held by the expansion ball
  • the diameter of the crimp grip on the capsule is 1.5 mm.
  • the X-ray imaging material is loaded in the film layer to enhance the visualization of the stent graft. Its preparation process is as follows:
  • the polylactic acid spinning solution After configuring the polylactic acid spinning solution with a mass fraction of 8%, set the diameter of the receiving device to 9.5 mm, the rotation speed to 100 rpm, and the axial reciprocating speed to 0.1 mm/s, and then set the spinning solution pump The flow rate was 0.05ml/min, the distance between the spinning nozzle and the receiving device was 10cm, and the voltage was set at 8kv. After spinning for 120min, a 19.5 ⁇ m thick inner film was obtained.
  • the iron-based absorbable supporting bone sleeve outside the inner coating, and then adjust the diameter of the receiving device to 10mm. All protrude from the supporting framework rods, and are at least 150 ⁇ m higher than the inner wall of the supporting framework.
  • melt spinning method to prepare the outer coating of the stent, take 10 mg of PLA raw material slices, add them to the spinneret material tube with heating, extrusion, and stirring, use electric heating to heat the raw materials to melt, and set the melt temperature 200°C, while mixing barium sulfate powder with a mass fraction of 4% into the melt, the ambient temperature is set to 50°C, the distance between the spinneret and the receiving device is 7cm, the spinning voltage is 15kv, and the feeding pressure is 10kpa.
  • the outer coating was electrospun for 80 minutes to obtain a 43.4 ⁇ m thick developable outer coating of the stent, and finally the X-ray imaging stent of this embodiment was obtained.
  • the stent coating is clearly visible under X-rays.
  • the total thickness of the stent coating is 62.8 ⁇ m.
  • the peel strength between the inner and outer coatings of the covered stent is 0.10N/mm.
  • the peel strength between the respective multi-layer textiles of the coating is 0.02N/mm, the total arc length of the gap between the inner and outer coatings accounts for only 1% of the arc length of the entire cross-section circle, and the porosity of the coating is 75 %, the crimping diameter of the covered stent on the expansion balloon is 3.6mm.
  • This comparative example adopts the same spinning conditions as in Example 1 to prepare the stent inner layer coating and the outer layer coating.
  • the difference from the embodiment is that no matter whether it is the textile stent inner layer coating or the weaving outer layer coating, the receiving The diameter of the device is always fixed, and the solvent spray droplets are not added to dissolve the spinning fibers when weaving the film.
  • other conditions are the same.
  • the final preparation has a nominal diameter of 5mm and an inner film thickness of 31.5mm. ⁇ m, the covered stent graft of Comparative Example 1 with an outer coating thickness of 42.3 ⁇ m was crimped on the expansion catheter for subsequent comparison tests.
  • the inner and outer layers of the stent graft of Comparative Example 1 were separated from the support frame after being pressed, and the total arc length of the gap between the inner layer and the outer layer of the stent graft accounted for the entire circumference of the section.
  • the porosity of the coating is 87%
  • the peel strength of the multi-layer spinning layer of the outer coating is only 0.0052N/mm
  • the adhesion strength of the coating layer is extremely low.
  • the peel strength of the inner and outer layers of the absorbable stent-graft of Comparative Example 1 are far lower than the absorbable stent-graft of Example 1.
  • This comparative example adopts the same spinning conditions as in Example 2, and uses the melt spinning method to prepare a coated stent with a bottom coating.
  • the difference from Example 2 is that whether it is the inner coating of the textile stent or the outer coating of the textile During the filming process, the diameter of the receiving device remained constant.
  • other conditions were the same as in Example 2, and finally a comparative example 2 covered stent with a bottom film was prepared.
  • the peel strength between the inner and outer layers of the stent graft of Comparative Example 1 is 0.007/mm, and the peel strength between the respective multi-layer spinning of the inner and outer layers is 0.009 N/mm,
  • the total arc length of the stent gap accounts for 67% of the arc length of the circumference of the entire cross section, and the porosity of the covering film is 80%.
  • the crimping diameter of the covered stent graft on the expansion balloon is 2.3 mm.
  • the membrane binding force and membrane layer peeling strength of the covered stent graft in Comparative Example 2 are both lower than those prepared in Example 2.
  • the porosity of the stent graft prepared in Example 2 is significantly larger than that of the stent graft prepared in Example 2.

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Abstract

一种覆膜支架及其制备方法,该覆膜支架包括内层覆膜、外层覆膜以及位于内、外层覆膜之间的支撑骨架，内层覆膜与外层覆膜在支撑骨架网格中的区域相互粘结。该覆膜支架未引入额外的粘合剂，也无需后续加热熔融来粘结支撑骨架的内、外层覆膜，且具有覆膜薄、压握外径小、内外层覆膜的结合强度高、覆膜力学性能好等优点。

Description

一种覆膜支架系统及其制备方法 技术领域
本发明属于医疗器械技术领域，具体涉及一种覆膜支架及其制备方法。
背景技术
覆膜支架是一种在支撑骨架上覆上阻流膜使其同时具备开通管腔和封堵破口双重功能的植入医疗器械，根据使用部位不同，覆膜支架的直径从几毫米到几十毫米不等。在临床上覆膜支架主要用于治疗各种原因引起的动脉瘤、假性动脉瘤、血管破裂、血管狭窄、血管闭塞和其它动静脉畸形，小直径的覆膜支架也常在PCI(Percutaneous Coronary Intervention，经皮冠状动脉介入治疗术)中冠状动脉穿孔时急救使用。
目前，支架覆膜的方法主要有编织布缝合覆膜、粘合剂粘合覆膜、加热烧结粘合覆膜、支撑骨架浸涂覆膜、静电纺丝覆膜等方法，其中静电纺丝覆膜技术是一种成熟而简便的覆膜工艺，被广泛的应用于各种覆膜支架的制备中，并且静电纺丝法所制备的覆膜具有比表面积大、孔隙率高、膜层厚度容易控制等特点。由于静电纺丝所制备的覆膜表面易于模仿细胞外基质的组成和结构设计，从而利于细胞内皮化和控制新生内膜增生，减少覆膜支架血栓形成，预后良好。因此目前市场上采用该方法制备覆膜支架的相对较多。但由于静电纺丝覆膜方法在纺丝时聚合物溶液喷嘴到纺丝接收支撑骨架需要足够的距离，因此，直径过小的支撑骨架内径空间不足以产生静电纺丝所需要的距离，从而加大了从支撑骨架内壁静电纺丝覆支撑骨架内层覆膜的技术难度，导致静电纺丝覆小直径支撑骨架时，无法同时从支撑骨架内、外壁一起静电纺，通常只能在支撑骨架外壁覆盖上单层的覆膜。或者需事先在一根模具杆上静电纺上支撑骨架内层覆膜，再在内层覆膜外安装支撑骨架后，静电纺支撑骨架外层覆膜，这样也能达到支撑骨架内、外壁覆膜的目的，但单纯的分成两步进行支撑骨架内、外壁覆膜，会导致支撑骨架内、外层覆膜不能粘结在一起，覆膜与支撑骨架结合力低，限制了该方法的应用。
目前已有一些有关提高覆膜支架内、外膜连接强度的相关研究公开，如在专利CN108136078B中公开了一种双层静电纺丝覆膜支架，该覆膜支架是在支 撑骨架内层膜与外层膜之间使用粘合剂粘合在一起，提升内、外层覆膜的结合强度。但使用粘合剂粘接覆膜，增加了工艺操作的难度，同时由于粘合剂的使用增加了多余的材料使用，增加了生物学风险。另发明专利申请CN113151980A中公开了一种静电纺丝覆膜支架，该覆膜支架是将静电纺丝制备好的支撑骨架内、外层覆膜经过360℃-400℃下烧结之后将支撑骨架内、外层覆膜熔融并通过粘合剂粘合在一起，该方法虽然可以大幅度提高覆膜与支撑骨架结合强度，但后续高温加热静电纺丝覆膜，会改变静电纺丝覆膜的孔隙率及覆膜结构，破坏了静电纺丝覆膜特有的优点，同时最终制备的PTFE管状覆膜支架的厚度为0.08-0.14mm，支撑骨架覆膜较厚，在体内的输送性能较差，增加血管损伤的风险。
发明内容
为了克服上述现有技术中存在的缺陷与不足，本发明提供了一种未引入额外粘合剂，无需后续高温加热熔融粘合，具有覆膜薄、压握外径小、覆膜层结合强度高、覆膜力学性能好等特点的覆膜支架及其制备方法，且本发明所提供的覆膜支架还具有管腔内皮化速度快、覆膜层中组织细胞长入迅速、覆膜支架无炎性反应、新生内膜无过度增生，管腔狭窄率低等优点。
本发明的技术方案一方面提供了一种覆膜支架，包括内层覆膜、外层覆膜，以及位于内、外层覆膜之间的支撑骨架。且内层覆膜与外层覆膜在支撑骨架网格中相互粘结。
本发明中所述的“支撑骨架”为由任意花纹结构设计的管状体；进一步的，本发明中所述的“支撑骨架”为独立的波圈或波圈与连接杆相互连接组成的管状体。即本发明中所述的支撑骨架在一些实施例中，是由多个独立的波圈组成的管状体，而在另外一些实施例中，支撑骨架是由多个波圈和多个连接杆相互连接形成的管状体。
本发明中所述的“支架网格”是指支架所围成的圆柱体的侧表面上被材料覆盖的区域，也即支架的花纹结构上；所述的“支架网格中”、“支架网格区域”均指支架空隙中，即在支架所围成的圆柱体的侧表面上未被材料覆盖的区域。
本发明中所述的“内层覆膜与外层覆膜在支撑骨架网格中相互粘结”是指在 支撑骨架的网格中，内层覆膜和外层覆膜的多层纺丝间相互粘结，增强了内、外层覆膜间的结合力，从而使内外、层覆膜之间的剥离强度增加。同时内层覆膜的多层纺丝间、外层覆膜的多层纺丝间也各自相互粘结，使覆膜层在厚度方向上相互形成粘连区域，增强覆膜层的力学性能。
本发明所提供的覆膜支架，沿支撑骨架的周向方向任意一截面上内层覆膜与外层覆膜之间存在的空隙部分的总弧长∑L 空隙占整个截面所在圆周弧长L 圆周的0.1％-5％，L 空隙与L 圆周的比值也即覆膜支架周向方向任意一截面上所存在空隙的占比即空隙率A，可以通过以下方式计算得到：
Figure PCTCN2022142006-appb-000001
需要说明的是，本发明中所述的圆周和弧长为支撑骨架所在圆周及圆周上的弧长。进一步的，空隙部分的弧长是指其投影到支架所在圆周上所对应的相应的弧长，而整个截面所在圆周的弧长是指该截面上有支撑骨架的支撑杆截面上的中点相互连接所形成的圆周的弧长。
本发明所提供的覆膜支架，其中内层覆膜和外层覆膜的孔隙率均为70-90％，进一步的内层覆膜和外层覆膜的孔隙率均为70-85％或75％-88％。
本发明所提供的覆膜支架，外层覆膜的厚度大于内层覆膜的厚度；外层覆膜的厚度为内层覆膜厚度的1.1-5倍。
本发明所提供的覆膜支架，内层覆膜的厚度为10-100μm；支撑骨架网格中内、外层覆膜的总壁厚为30-500μm，即支撑骨架网格中内层覆膜+外层覆膜的总厚度为30-500μm。本发明所提供的覆膜支架，所述内层覆膜陷入支撑骨架网格中的深度10μm-350μm，包括但不限于20μm、30μm、40μm、50μm、60μm、70μm、80μm、90μm、100μm、110μm、120μm、130μm、140μm、150μm、160μm、170μm、200μm、230μm、250μm、280μm、300μm、350μm、500μm等。进一步的，内层覆膜陷入支撑骨架网格中的深度为10μm-300μm，更进一步的，内层覆膜陷入支撑骨架网格中的深度为20μm-300μm、30μm-300μm、40μm-300μm或50μm-300μm。
本发明所提供的覆膜支架，压握于扩张球囊导管上的压握直径为0.9-6mm，进一步的为0.9-4.5mm、0.9-5.0mm或1.0-5.5mm。
本发明所提供的覆膜支架，内层覆膜与外层覆膜所用材料选自纤维素、甲 壳素、透明质酸、胶原蛋白、明胶、海藻酸钠、聚氨基甲酸脂(PU，Polyurethane)、聚四氟乙烯(PTFE，Poly tetra fluoroethylene)、膨体聚四氟乙烯(E-PTFE，Expanded PTFE)、聚乳酸(PAL，Polylactic acid)、左旋聚乳酸(PLLA，Poly(l-lactic acid))、右旋聚乳酸(PDLLA，Poly(D-lactide))、聚羟基乙酸(PGA，Polyglycolic acid)、聚已内酯(PCL，Polycaprolactone)、聚酰胺(PA，Polyamide)，聚对苯二甲酸乙二酯(PET，Polyethylene terephthalate)中的至少一种。在一些实施方式中，内层覆膜与外层覆膜所用的材料是上述材料中的某一种，如内层覆膜为明胶，外层覆膜为海藻酸钠；在一些实施方式中，内、外层覆膜是由上述的至少两种的材料制备而成的，可以是上述至少两种以上材料的共混体和/或共聚体，即可以是至少两种材料的单纯共混体，也可以是至少两种材料单纯的共聚体，还可以是上述至少两种材料的共混体和共聚体，如内层覆膜为明胶和海藻酸钠的共混体，而外层覆膜为聚四氟乙烯与聚酰胺的共聚体，亦或者外层覆膜部分为聚四氟乙烯与聚酰胺的共聚体，部分为聚四氟乙烯与聚酰胺的共混体；在一些实施例中，内层覆膜的材质可以与外层覆膜一样，如内层覆膜和外层覆膜均为明胶和海藻酸钠的共混体；在一些实施例中，内层覆膜的材质也可以与外层覆膜不一样，如内层覆膜为明胶，而外层覆膜为海藻酸钠和聚氨基甲酸脂的共聚体；在还有一些实施例中，内层覆膜和外层覆膜各自都可以是由不同材料纺成的多层膜，如内层覆膜的底层为胶原蛋白或海藻酸钠与聚氨基甲酸脂的共聚体，内层覆膜的外层为明胶或左旋聚乳酸与聚酰胺的共聚体或共混体等。
本发明所提供的覆膜支架中的支撑骨架可以为球扩式的或自膨式的；也可以为可降解或不可降解。
本发明所提供的覆膜支架，其内层覆膜完全覆盖支撑骨架，外层覆膜覆盖沿支撑骨架径向长度的10-100％的区域。
本发明所提供的覆膜支架，在其内层覆膜、外层覆膜或者内层覆膜与外层覆膜之间携带有药物或显影材料，其中所述药物包括抗凝血药物和/或抗细胞增殖药物；显影材料选自硫酸钡、三氧化二铌、氧化钛、氧化锆、碘化合物、单质碘、金、铂、锇、铼、钨、铱、铑、钽中的至少一种；进一步的，抗凝血药物选自肝素、水蛭素、柠檬酸钠、乙二胺四乙酸、阿司匹林、华法林、利伐沙班中的一种或几种；抗细胞增殖药物选自西罗莫司、他克莫司、吡美莫司、紫 杉醇、秋水仙碱、地塞米松、泼尼松、氢化可的松中的一种或几种。
在本发明所提供的覆膜支架，支撑骨架的壁厚为30-300μm，径向支撑力能达到90-180kpa。
需要说明的是，本发明中的“携带”是指药物或显影材料溶解或/熔融到覆膜材料中，再一起喷涂形成覆膜；也可以是将每层覆膜制备完成后，在内层覆膜、外层覆膜靠近支撑骨架的一侧涂覆上药物或者显影材料。
本发明所提供的覆膜支架，所述内层覆膜或外层覆膜中纺丝纤维层之间的剥离强度为0.01-0.2N/mm，也即内、外层覆膜各自的多层纺丝之间的剥离强度为0.01-0.2N/mm；所述内层覆膜与外层覆膜之间的剥离强度为0.1-0.5N/mm。本发明所提供的内、外层覆膜相互粘结的覆膜支架的内、外层覆膜之间的剥离强度大于内层覆膜或外层覆膜中各自的纺丝纤维层之间的剥离强度，也即本发明所提供的技术方案中内外层覆膜之间的结合力通过本发明所提供的制备方法得到了明显的增强。
本发明另一方面提供了上述覆膜支架的制备方法，该制备方法简单易操作，具体包括以下步骤：
S1：将纺丝液静电纺到直径可调的接收装置外壁上，形成内层覆膜；
S2：将支撑骨架安装在纺有内层覆膜的接收装置上调节接收装置直径，扩大内层覆膜至部分内层覆膜嵌入支撑骨架的网格中；
S3：将纺丝液静电纺到支撑骨架外壁上形成外层覆膜；
S4：待外层覆膜纺织完成后，停止静电纺丝，将圆柱形接收装置直径调小并从覆膜支架管腔中抽出，得到覆膜支架。
根据上述技术方案提供的制备方法，步骤S1和/或S3中接收装置在内层覆膜制备过程中直径可以逐渐扩大，扩大的速率为0.1-10mm/h，进一步的，接收装置在内层覆膜制备过程中直径扩大的速率可以为0.1-1mm/h、1-8mm/h、1-6mm/h、1-4mm/h、3-10mm/h、5-10mm/h、7-10mm/h等由0.1-10中任意两值组成的新的区间范围的取值。其中接收装置的原始直径为1-50mm，进一步的可以为1-30mm。在实际生产中，可以根据不同规格的支架匹配对应规格的接收装置，一般接收装置的最大直径是最小直径(原始直径)的1.2-10倍，在S1中刚开始纺织内层覆膜时，接收装置的直径可以是其最小直径，也可以是介于 最小直径和最大直径之间的任意一值，但是其必须满足步骤S1中内层覆膜纺织完成后接收装置和内层覆膜的总直径小于支撑骨架的内径，同时也得满足接收装置在外层覆膜制备完成时即S3步骤操作完成时的直径为内层膜覆膜前(即S1步骤操作前)直径的1.2-10倍。
根据上述技术方案提供的制备方法，纺织时内层覆膜陷入支撑骨架网格中的深度为10μm-900μm，包括但不限于20μm、30μm、40μm、50μm、60μm、70μm、80μm、90μm、100μm、110μm、120μm、130μm、140μm、150μm、160μm、170μm、200μm、230μm、250μm、280μm、300μm、350μm、500μm、600μm、700μm、800μm、900μm等。进一步的，内层覆膜陷入支撑骨架网格中的深度为10μm-300μm、10μm-500μm、10μm-600μm、、10μm-700μm、10μm-650μm，更进一步的，内层覆膜陷入支撑骨架网格中的深度为20μm-300μm、30μm-300μm、40μm-300μm或50μm-300μm。
根据上述技术方案提供的制备方法，纺织过程中的所采用的纺丝液可以是聚合物分散于溶剂中所形成的聚合物溶液，也可以是经过高温熔化后的熔融状态的聚合物。
上述技术方案所提供的制备方法中，步骤S3中在纺织外层膜之前还包括喷涂溶剂溶解内层覆膜的步骤，在纺织外层膜时可以采用多个喷头同时工作，如在一些实施例中，一个喷头喷聚合物溶液，一个喷头喷溶剂；在另外一些实施例中，一个喷头喷溶剂，另一个喷头喷熔融状态的聚合物；在其他一些实施例中，一个喷头喷聚合物溶液，另一个喷头喷熔融状态的聚合物；在还有一些实施例中，一个喷头喷聚合物溶液，另一个喷头喷熔融状态的聚合物，还有一个喷头喷溶剂。但不论是哪种实施方案中，溶剂都先于聚合物到达内层膜上，达到先使内层覆膜中纺丝溶解、软化之后再与外层覆膜纺丝膜进一步结合，由于纺织外膜时喷的聚合物进一步的与内膜上溶解或软化后的聚合物作用，甚至进行分子间的重排，达到内层覆膜的多层纺丝之间、外层覆膜的纺丝之间以及内层覆膜与外层覆膜的多层纺丝之间相互粘结的效果。
上述技术方案所提供的制备方法中，所采用的溶解内、外层覆膜纺丝的溶剂为二氯甲烷、三氯甲烷、四氢呋喃、乙酸乙酯、乙醇、异丙醇、二甲基亚砜、二甲基乙酰胺、二甲基甲酰胺、六氟异丙醇、三氟乙酸、六氟异丙醇三氟乙醇 中的一种或多种的混合，如在一些实施例中，所采用的溶解内层覆膜的溶剂为二氯甲烷，而在另外一些实施例中，所采用的溶解内层覆膜的溶剂为二氯甲烷、乙酸乙酯与六氟异丙醇的结合。
上述技术方案所提供的制备方法中，分散于溶剂中的聚合物溶液中溶剂与聚合物的质量比为80∶20-99∶1，进一步的也可以为80∶20-50∶1、80∶20-30∶1、80∶20-25∶1、80∶20-20∶1、80∶20-15∶1等取值区间。
上述技术方案所提供的制备方法中，纺丝液为熔融状态的聚合物熔体纺丝时，纺丝的粘度控制在10-100Pa.s，从而提高纺丝的效率，减小纺丝的直径，使得最终所纺织出的内层覆膜或者外层覆膜的厚度较薄。
本发明所提供的制备方法中，内层覆膜与外层覆膜纺丝纤维的直径为1-5μm。
在本发明的一些实施例中为了控制熔融纺丝的黏度，可以在聚合物中混入少量的无机盐来降低溶体的黏度，其中所选用的无机盐为氯化钠、磷酸钠、氯化钾、氯化钠、氯化镁、氯化铝、磷酸氢钠、磷酸氢二钠、磷酸钙、碳酸钠、碳酸钠氢钠、碳酸钙、碳酸钙、氯化铁、氯化铝、氢氧化铁、三氯化铁，葡萄糖酸亚铁中的一种或多种。
在本发明所提供的覆膜支架的制备方法中，步骤S1和步骤S3中根据聚合物浓度、黏度、导电率不同，静电纺丝电压控制在5-100kv，聚合物注射流速0.01-1ml/min，接收装置与喷嘴之间距离为2-15cm，接收装置旋转速度为100-2000/min。
本发明中所述的覆膜支架的轮廓是指覆膜支架压握到支撑件上后覆膜支架系统外径的大小。
本发明的技术方案还提供了一种上述制备方法用的接收装置，其中该接收装置的直径可调，其最大直径为最小直径的1.2-10倍。
上述技术方案所提供的接收装置，该接收装置的表面涂有导电涂层和/或脱模剂。
上述技术方案所提供的接收装置，所述接收装置的表面设有微孔结构，微孔的直径为10-100μm，微孔间距0.1-10mm。
上述技术方案所提供的接收装置，接收装置的形状为圆柱形的。
上述技术方案所提供的接收装置，所述接收装置上装有加热组件，即接收 装置上还附带有加热功能，可以对置于上面的纺丝或者覆膜进行加热，从而加快纺丝间的粘结，同时使纺丝间的粘结力度较大，具有较大的结合力。
上述技术方案所提供的接收装置，所述接收装置表面的微孔形状为条状、网格状或无序的散点状中的一种或多种的组合。
应理解的是，文中使用的术语仅出于描述特定示例实施方式的目的，而无意于进行限制。除非上下文另外明确地指出，否则如文中使用的单数形式“一”、“一个”以及“所述”也可以表示包括复数形式。术语“包括”、“包含”、“含有”以及“具有”是包含性的，并且因此指明所陈述的特征、步骤、操作、元件和/或部件的存在，但并不排除存在或者添加一个或多个其它特征、步骤、操作、元件、部件、和/或它们的组合。文中描述的方法步骤、过程、以及操作不解释为必须要求它们以所描述或说明的特定顺序执行，除非明确指出执行顺序。还应当理解，可以使用另外或者替代的步骤。
需要说明的是，本发明中的符号“/”代表“或”的意思，如“A/B”是指“A或者B”；又如“A和/或B”是指“A和B，或者A或B”，又如本发明中所述的“所述药物包括抗凝血药物和/或抗细胞增殖药物”是指覆膜支架上携带的药物包括抗凝血药物和抗细胞增殖药物，或者覆膜支架上携带的药物为抗凝血药物和抗细胞增殖药物中的一种。也即，覆膜支架上携带的药物抗凝血药物和抗细胞增殖药物中的至少一种。
本发明的有益效果：
本发明所制备的覆膜支架，支撑骨架紧密的夹在内层覆膜和外层覆膜之中，在支撑骨架杆覆盖区域，内层覆膜层外壁侧与支撑骨架管腔内壁粘合，外层覆膜层内壁侧与支撑骨架外壁粘合。在支撑骨架网格中，内层覆膜外壁侧与外层覆膜内壁侧紧密粘合，并形成连续或不连续的粘结区域，增强了内层覆膜与外层覆膜之间的结合强度。与此同时，为了增强内、外覆膜层之间的力学性能，静电纺丝纤维层之间也有部分区域相互接触的纺丝被溶剂再次溶解、再次凝固粘结在一起，增强纺丝纤维层之间结合力及覆膜力学性能，使得静电纺丝层不容易分层。使用该方法制备的覆膜支架，纺丝与支撑骨架接合无需后续高温加热熔融粘结，也无需使用粘合剂粘结，覆膜保留了静电纺丝纤维丝径细、纺丝覆膜薄、孔隙率易于调节，覆膜具有较高的比表面积、较高孔隙率和良好的弹 性，覆膜层结构易于模仿细胞外基质的组成和结构，有利于内皮细胞化和控制新生内膜增生，减少血栓形成，提升覆膜支架远期效果等技术优点。同时还具有以下优点：
本发明中内层覆膜在接收装置的强力支撑挤压下，保持陷入支撑骨架网格中的深度10-900μm。内层覆膜陷入支撑骨架的网格中后使得在纺织外层覆膜时，纺丝纤维可以很好的黏附到内层覆膜上，通过覆膜液或溶剂进一步的溶解或者熔化内层覆膜，使得支撑骨架内、外层覆膜的覆膜纤维相互粘结，增强内、外覆膜之间的结合强度；同时接收装置直径的扩大，使装置上的纺丝纤维拉伸，外层纺丝对内层纺丝会产生向圆心上的挤压力，使得纺丝纤维层结合更为紧密，空隙更小，从而大幅的增加纺丝纤维层之间的结合力。
本发明通过改变内、外层膜之间的结合方式，增强内、外层覆膜在制备过程中的相互作用力，以及增加内外覆膜的接触面积，从而达到提升内、外覆膜结合力的目的。
本发明所提供的覆膜支架具有很薄的覆膜。首先，在制备过程中采用一定的措施确保纺丝具有较小的直径；其次，在内、外覆膜紧密结合的同时，减少内、外覆膜间的空隙，增加内外覆膜的密度，从而降低覆膜的厚度；最后，在制备内、外层覆膜的过程中，边纺织边增大接收装置的直径，结合对接收装置直径增大速度的控制，让内、外层覆膜纺丝紧密接触的同时、增加溶液喷涂步骤，使不同纺丝层之间的纺丝再次溶解，溶剂挥发后，相互接触的纺丝再次凝固粘合在一起，使得覆膜层部分区域在厚度方向上纺丝纤维相互粘结，增加了纺丝覆膜层的强度，从而进一步降低内、外层覆膜的壁厚。结合以上三方面的因素，最终确保覆膜支架在压握后具有很小的压握外径，提升了支架在体内的输送能力，降低了对人体血管的损伤风险。
附图说明
通过阅读下文优选实施方式的详细描述，各种其它的优点和益处对于本领域普通技术人员将变得清楚明了。附图仅用于示出优选实施方式的目的，而并不认为是对本发明的限制。而且在整个附图中，用相同的附图标记表示相同的部件。其中：
图1为覆膜支架结构图，其中，100为覆膜支架，111为覆膜，101为支撑骨架，102为内层覆膜，103为外层覆膜。
图2为实施例1中可吸收覆膜支架的纵向剖面图，其中101为可吸收铁基支架，102为内层覆膜，103为外层覆膜，2为可吸收铁基支架内壁，3为可吸收铁基支架外壁。
图3为可吸收覆膜支架的制备流程图。
图4为静电纺丝机的设备结构图。
图5为实施例1中接收装置上的可吸收覆膜支架内层覆膜横向截面图。
图6为实施例1中覆膜支架内层覆膜外安装可吸收铁基支架之后的横向截面图。
图7为实施例1中可吸收覆膜支架的横向截面图，其中2为可吸收铁基支撑骨架的内表面，4为支撑骨架的网格区域，3为可吸收铁基支撑骨架的外表面，101为可吸收铁基支架，102为支架内层覆膜，103为支架外层覆膜。
图8为实施例1中可吸收覆膜支架覆膜形貌电镜图。
图9为实施例1中可吸收覆膜支架植入人体后的内皮化扫描电镜图。
图10为实施例1中可吸收覆膜支架植入人体后的组织病理图。
图11为实施例2中覆膜支架横向截面图，其中2为支撑骨架的内表面，4为支撑骨架的网格区域，3为支撑骨架的外表面，201为钴铬合金支架，202为支架底层覆膜，203为支架内层覆膜，204为支架外层覆膜。
具体实施方式
下面将参照附图更详细地描述本发明的示例性实施方式。虽然附图中显示了本发明的示例性实施方式，然而应当理解，可以以各种形式实现本发明而不应被这里阐述的实施方式所限制。相反，提供这些实施方式是为了能够更透彻地理解本发明，并且能够将本发明的范围完整的传达给本领域的技术人员。
请参见图1覆膜支架器械结构图，覆膜支架器械100为镂空的支撑骨架表面覆膜形成的管腔结构。100由支撑骨架101和支撑骨架上的覆膜111组成，覆膜111由支撑骨架内层覆膜102和支撑骨架外层覆膜103组成。内层覆膜102被定位于支撑骨架101内壁侧的管腔内，外层覆膜103定位于支撑骨架101的 外表面，内层覆膜102与外层覆膜103在支撑骨架网格区域4处相互粘结在一起，以此方式，支撑骨架101牢固的嵌于膜层111中间。
在一实施方式中，支撑骨架101可以是任意材质的；在另一些实施例中，支撑骨架由生物可吸收的材料的制成。例如，支撑骨架101由铁、铁基合金、镁、镁基合金、锌、锌基合金或可吸收的高分子材料等材料制成。
在一实施方式中，支撑骨架101由生物不可吸收的材料制成。例如，支撑骨架101由镍钛合金、钴铬合金或不锈钢等医用材料制成。
进一步的，内层覆膜与外层覆膜所用材料选自纤维素、甲壳素、透明质酸、胶原蛋白、明胶、海藻酸钠、聚氨基甲酸脂(PU，Polyurethane)、聚四氟乙烯(PTFE，Poly tetra fluoroethylene)、膨体聚四氟乙烯(E-PTFE，Expanded PTFE)、聚乳酸(PAL，Polylactic acid)、左旋聚乳酸(PLLA，Poly(l-lactic acid))、右旋聚乳酸(PDLLA，Poly(D-lactide))、聚羟基乙酸(PGA，Polyglycolic acid)、聚已内酯(PCL，Polycaprolactone)、聚酰胺(PA，Polyamide)，聚对苯二甲酸乙二酯(PET，Polyethylene terephthalate)中的至少一种。在一些实施方式中，内层覆膜与外层覆膜所用的材料是上述材料中的某一种，如内层覆膜为明胶，外层覆膜为海藻酸钠；在一些实施方式中，内、外层覆膜是由上述的至少两种的材料制备而成的，可以是上述至少两种以上材料的共混体和/或共聚体，即可以是至少两种材料的单纯共混体，也可以是至少两种材料单纯的共聚体，还可以是上述至少两种材料的共混体和共聚体，如内层覆膜为明胶和海藻酸钠的共混体，而外层覆膜为聚四氟乙烯与聚酰胺的共聚体，亦或者外层覆膜部分为聚四氟乙烯与聚酰胺的共聚体，部分为聚四氟乙烯与聚酰胺的共混体；在一些实施例中，内层覆膜的材质可以与外层覆膜一样，如内层覆膜和外层覆膜均为明胶和海藻酸钠的共混体；在一些实施例中，内层覆膜的材质也可以与外层覆膜不一样，如内层覆膜为明胶，而外层覆膜为海藻酸钠和聚氨基甲酸脂的共聚体；在还有一些实施例中，内层覆膜和外层覆膜各自都可以是由不同材料纺成的多层膜，如内层覆膜的底层为胶原蛋白或海藻酸钠与聚氨基甲酸脂的共聚体，内层覆膜的外层为明胶或左旋聚乳酸与聚酰胺的共聚体或共混体等。
在一实施方式中，支架覆膜使用溶液静电纺丝制备，近一步地，溶液静电纺丝时，采用的溶剂为二氯甲烷、三氯甲烷、四氢呋喃、乙酸乙酯、乙醇、异 丙醇、二甲基亚砜、二甲基乙酰胺、二甲基甲酰胺、六氟异丙醇、三氟乙酸、六氟异丙醇三氟乙醇中的一种或多种混合溶解聚合物。分散于溶剂中的聚合物溶液中溶剂与聚合物的质量比为80∶20-99∶1，进一步的也可以为80∶20-50∶1、80∶20-30∶1、80∶20-25∶1、80∶20-20∶1、80∶20-15∶1等取值区间。
在一实施方式中，支架覆膜使用熔体静电纺丝制备。进一步的，熔体静电纺丝时，熔体的粘度控制在10-100Pa.s。具体地说，熔体的粘度选用氯化钠、磷酸钠、氯化钾、氯化钠、氯化镁、氯化铝、磷酸氢钠、磷酸氢二钠、磷酸钙、碳酸钠、碳酸钠氢钠、碳酸钙、碳酸钙、氯化铁、氯化铝、氢氧化铁、三氯化铁，葡萄糖酸亚铁中的一种或多种物机盐进行调节。
在一实施方式中，内层覆膜使用熔体静电纺丝覆膜、外层覆膜使用溶液静电纺丝覆膜。进一步的，无论是内层覆膜，还是外层覆膜，都可以使用熔体纺丝与溶液纺丝共混，或者交替纺织覆膜。
在一实施方式中，在内壁层覆膜中增加底层覆膜，用于提高覆膜支架的血液相容性。
在一实施方式中，在支架内层覆膜中载上抗凝血物质，防止覆膜支架内血栓形成。抗凝物质选自肝素、水蛭素、柠檬酸钠、乙二胺四乙酸、阿司匹林、华法林、利伐沙班中的一种或几种。具体地，是将足量的抗凝物质掺入覆膜材料中，一同进行液体静电纺丝或者熔体静电纺丝，将抗凝物质载于纺丝纤维中，达到缓慢释放抑制覆膜支架内血栓形成的目的。
在一实施方式中，外层覆膜中载有抗细胞增殖的药物，选自西罗莫司、他克莫司、吡美莫司、紫杉醇、秋水仙碱、地塞米松、泼尼松、氢化可的松中的一种或几种。具体地，是将足量的抗细胞增殖药物掺入覆膜材料中，一同进行液体静电纺丝或者熔体静电纺丝，将抗细胞增殖药物载于纺丝纤维中，达到缓慢释放抑制新生内膜过度增生的目的。
在一实施方式中，外层覆膜完全覆盖支撑骨架，在另一实施例中，外层覆膜只部分覆盖支撑骨架，外层覆膜覆盖沿支撑骨架径向长度的10％-100％的区域。
覆膜支架器械的制备流程包括如下步骤：
S1.以一根直径可调节的圆柱形接收装置作为静电纺丝接收装置，在其外径 上使用静电纺丝法制备支架内层覆膜，纺丝前先将接收装置直径调节至所需大小，并确保接收装置加上内层覆膜厚度后总直径小于所需覆膜的支撑骨架内径。在圆柱形接收装置上方布置至少一个聚合物溶液纺丝喷嘴和一个溶剂喷嘴，静电纺丝时，将聚合物溶液喷嘴和溶剂喷嘴与电源发生器正极接通，负极与圆柱形接收装置连接，开启电源调节电压，调节注射器流速、圆柱形接收装置与喷嘴之间距离、接收装置旋转速度，最终聚合物溶液在静电力作用下，形成静电纺丝喷射到旋转的圆柱形接收装置上。溶剂喷嘴内溶剂由于黏度比聚合物纺丝溶液低，受相同静电引力作用时，溶剂会形成微小溶剂液滴飞向接收装置上的静电纺丝束，溶剂液滴周围的纺丝会被再次溶解，待溶剂挥发后再次凝固，液滴处相互接触的纺丝会相互粘连在一起，纺丝粘连呈无序排列，形成厚度方向上相互粘结的支架内层覆膜。进一步地，也可缩小溶剂喷嘴与接收装置之间距离，让溶剂射流直接连续喷于纺丝束上，形成连续取向的纺丝粘连区。
具体地，直径可调的接收装置为机械结构设计的调节机构或球囊扩张调节，机械结构设计的接收装置只需旋转扩张机构时就可实现直径调节。球囊扩张调节接收装置只需向球囊中注同等体积的液体或气体，就可实现球囊直径调节。进一步地，直径调节方式可以是步进，也可是逐级递增。直径可调的圆柱形接收装置原始直径为1-50mm，直径调节范围为原直径的1.01-10倍，优选1.5倍。步进递增时其直径每一步增加0.05-1mm，优选0.1mm。逐级递增时其直径增加速率为0.1-10mm/h，优选1mm/h。
在一实施方式中，直径可调的接收装置还可以在表面设置微孔结构，微孔投影内层覆膜的周长为30-300μm，优选100μm，微孔间距0.1-10mm，优选1mm。具体地，微孔选自圆形、椭圆形、多边形、不规则形的一种或多种组合，进一步地，微孔排列可为条状、网格状或无序的散点状中的一种或其组合，静电纺丝时微孔可将静电纺丝上的电荷导走，减少纺丝上电荷累积，降低纺丝之间相互排斥力。
在一实施方式中，直径可调的圆柱形接收装置表面覆盖有柔性材料，在增加直径时，有支撑骨架杆束缚的区域接收装置表面柔性材料连同内层覆膜被压凹陷，在支架网格区域，接收装置表面柔性材料连同支架内层覆膜被压迫凸入支撑骨架网格中，将内壁层覆膜镶嵌于支撑骨架上。具体地，柔性材料选自天 然橡胶、丁基橡胶、顺丁橡胶、氯丁橡胶、三元乙丙橡胶、丙烯酸酯橡胶、聚氨酯橡胶、导电硅橡胶、尼龙、涤纶、腈纶聚酯纤维、芳纶、丙纶纤维、PET、PTFE。进一步地，接收装置表面的柔性的材料被支撑骨架杆压迫的凹陷深度10-200μm，支撑骨架网格区域凸入网格中高度10-900μm。
在一实施方式中，直径可调的圆柱形接收装置表面设置不同形状的刚性凸起，接收装置直径扩大时，在支架网格区域，刚性凸起将支架内层覆膜压迫凸入网格中，刚性凸起高度1-100μm，刚性凸起的花纹面积占总杆表面的10％-90％，进一步地，刚性凸起花纹可以是点状均匀或不均匀分布，也可以是连续的条状、网格状，还可以是支架网格形状相匹配的凸起花纹。
在一些实施例中，进一步地，步骤S1中，还可以每纺数层纺丝纤维后，圆柱形接收装置直径即增加一定大小，使圆柱形接收装置上的覆膜纺丝纤维在周长方向上处于绷紧状态，此时覆膜层外层纺丝纤维会对内层纺丝纤维产生压力，减小纺丝纤维之间的空隙，利于再次溶解的纺丝相互粘连在一起。
进一步地，在S1步骤中，根据聚合物浓度、黏度、导电率不同，静电纺丝电压为5-100kv，注射流速0.01-1ml/min，接收装置与喷嘴之间距离2-15cm，接收装置旋转速度100-2000/min。
进一步地，在S1步骤中，聚合物喷嘴可以是一个，也可以是多个，可以单独是溶液纺丝喷嘴，也可以是熔体纺丝喷嘴，还可以是溶液纺丝和熔体纺丝相互组合的混纺喷嘴。
进一步地，在S1步骤中溶剂喷嘴与接收装置之间的距离为1-5cm，液体直接形成射流喷向纺丝，在纺丝覆膜层上形成连续的溶剂印迹，也可拉大溶剂喷嘴与接收装置之间距离至5-10cm，溶剂液体形成分散液滴喷向覆膜层上的纺丝束，溶剂注射流速0.01-0.5ml/min，溶剂注射可选择连续注射，也可是间隔一定时间段脉冲注射，脉冲时间间隔0.1-100s。
S2.待支架内层覆膜制备完成后，将所需覆膜的支撑骨架套装于上述覆有内层覆膜的接收装置上，扩大接收装置直径，内层覆膜被接收装置挤压紧贴支撑骨架内壁，支撑骨架杆下方的覆膜紧密的与支撑骨架杆内壁侧接触，支撑骨架杆的网格部位内层覆膜被挤压凸入支架网格中。
S3.使用S1所述的方法继续在支撑骨架外制备外壁层覆膜。
S4.待外层覆膜完成后，停止纺丝设备，将圆柱形接收接收装置直径调小并从覆膜支架中抽出，得到所述的内、外壁同时覆膜的覆膜支架。
以下通过具体实施例对上述覆膜支架器械及其制备方法进一步阐述。
实施例中采用的测试方法如下：
1.形貌分析
使用扫描电镜(简称：SEM)对覆膜支架覆膜进行形貌观察，放大至2000倍测量丝直径，SEM为日本电子株式会社的JSM6510型扫描电镜。
2.孔隙率测试
参考GB/T33052-2016《微孔功能薄膜孔隙率测定方法十六烷吸收法》标准测试覆膜支架孔隙率。
3.内、外覆膜层间的空隙率：
将覆膜支架扩张到标称直径，然后镶嵌在有机玻璃中，横向切断，使用不同粒径的金刚石沙纸将截面打磨光滑，利用显微镜测量内、外层覆膜之间所有支架杆两侧存在空隙的弧长之和∑L 空隙，和支撑骨架所在的圆周弧长L 圆周。然后根据下列公式计算出覆膜层空隙率A，显微镜为基恩士，VHX-700F。
Figure PCTCN2022142006-appb-000002
4.覆膜剥离强度测试
覆膜支架纵向剪开并裁切一定宽度，使用万能拉力机测量覆膜支架内外层覆膜剥离强度。以股浅动脉覆膜支架内外、层覆膜剥离强度测试为例，具体包括以下步骤：
将覆膜支架纵向剪开后，裁成宽10mm，长10cm的条，再从一端将支架内壁层覆膜和外壁层覆膜剥离，长度为5cm左右，将万能拉力机上、下夹具间距调整至5cm左右，将剥离的支架内壁层覆膜夹于拉力机的上夹具，支架外层覆膜夹于万能拉力机的下夹具，设置拉伸移动速度为10mm/min，试验结束参数设置(定力衰减)50％，启动测试覆膜剥离最大力N，按下列公式计算覆膜支架内、外壁覆膜剥离强度P。P＝N/L，式中P为剥离强度，单位为N/mm；N为覆膜剥离最大拉伸力，单位为N；L为试样宽度，单位为mm。
5.覆膜支架的压握外径
利用显微镜测试覆膜支架的压握外径。显微镜为基恩士，VHX-700F或 SENSOFAR，Q6)。
6.覆膜层厚度测试
将覆膜支架镶嵌在有机玻璃中，横向或纵向切开，使用不同粒径的金刚石沙纸打磨光滑后，利用显微镜测试各层覆膜的厚度。显微镜为基恩士，VHX-700F或SENSOFAR，Q6。
7.可吸收覆膜支架内皮化速度测试
以股浅动脉覆膜支架植入小型猪评估内皮化为例，将股浅动脉覆膜支架植入6只体重30-35kg的小型猪股浅动脉，植入7天、14天和28天后安乐处死后取出植入支架段血管，使用2.5％戊二醛固定72h后，纵向剪成两半，再依次用80％、90％、95％、95％和100％浓度乙醇梯度脱水，二氧化碳临界点干燥，喷金后SEM扫描计算整个覆膜支架被新生内膜覆盖的面积比，内皮覆盖率＝(有内皮覆盖区域的面积/支架总表面积)×100％。
8.体内植入病理反应
以股浅动脉覆膜支架植入小型猪评估组织反应为例，将股浅动脉覆膜支架植入3只体重30-35kg的小型猪股浅动脉，植入28天后安乐处死动物取出覆膜支架，使用10％甲醛固定7天，然后依次用70％、80％、90％和100％梯度酒精脱水，使用量甲基丙烯酸甲酯进行树脂包埋，固化后使用精密切割机(美国BUEHLER公司Lsomet5000)切片，切片厚度约150μm，用磨抛机(美国BUEHLER公司Ecomet250)抛薄，厚度约10-20μm，苏木素染色30min，分化液分化1min，氨水反蓝10min，伊红染色5min制备成病量切片，使用德国LEICA公司的DM2500型显微镜观察组织病理，并测量支架段血管所在截面的管腔面积及原始管腔面积。则，管腔狭窄率＝(原始管腔面积-现有管腔面积)/原始管腔面积×100％
实施例1
本实施例中所提供的可吸收覆膜支架100的纵向剖面图如图2所示，可吸收覆膜支架100由支撑骨架101和支撑骨架上的内层覆膜102及支撑骨架外层103覆膜组成。内层覆膜102被定位于支撑骨架101的管腔内，且内层覆膜的外壁面与支撑骨架101的内壁2紧密接触。外层覆膜103定位于支撑骨架101 的外表面且其内壁面与支撑骨架101外壁面3紧密接触。内层覆膜102与外层覆膜103在支撑骨架网格区域4处相互粘结在一起，以此方式，支撑骨架101牢固的嵌于膜层111中间。本实施例中支撑骨架101为可吸收铁基合金支架，其使用99％的渗氮纯铁经渗氮和激光雕刻而成，渗氮纯铁的氮含量≤0.25％，支架标称扩张直径6mm，由10组波圈和连接杆件组成，支架杆壁厚80μm，径向支撑力120kPa。支架内层覆膜102和外层覆膜103由PLLA液体静电纺丝制成，内、外层覆膜总厚度69.8μm，可吸收覆膜支架压握于扩张球囊上，压握外径为1.8mm。覆膜支架制作步骤如图3所示。
步骤S1：制备内壁层覆膜102，将10g分子量为50万的PLLA加入到190ml的乙酸乙酯中，室温密闭搅拌8h完全溶解，得到质量分数为5％的聚乳酸纺丝液。参照图4搭建静电纺丝机。首先将上述聚乳酸纺丝液吸入微量注射泵35中并通过微导管与纺丝溶液喷嘴37连接，纺丝溶液喷嘴37与圆柱形接收装置30距离设定为10cm，接收装置30旋转速度为200转/min，轴向上往复移动速度为0.1mm/s，纺丝溶液35泵流速度为0.05ml/min，另取三氯甲烷于溶剂注射器36中，调节泵流速为0.1ml/min，设置注射脉冲间隔时间为10s，持续时间为6s，溶剂喷嘴41与接收装置30的距离5cm，调节静电纺丝电源40电压为15kV，开启设备进行支架内层覆膜的制备，在纺织过程中每纺30min将接收装置30的直径增加0.1mm，接收装置30直径增加后，表面已纺上的纺丝纤维会被径向拉紧，纺丝纤维之间相互形成挤压，减小了纺丝纤维间的间隙，溶剂落在相互紧密接触的纺丝纤维束上，在溶剂溶解作用下，溶剂液滴处的纺丝被溶解，待溶剂完全挥发后相互紧密接触的纺丝纤维粘结在一起。静电纺丝60min得到27.6μm厚的取向纺丝覆膜，即支架内壁层覆膜102，如图5所示。
在本实施例中，直径可变的圆柱形接收装置30为球囊(图5)，球囊结构简单操作容易，只需注入不同体积的液体，即可改变直径。在接收装置30内注入少量的饱和氯化钠溶液，使接收装置30充盈直径为4.5mm，将静电纺丝机40的电源负极39与球囊内的饱和氯化钠溶液29接通，电源正极38与聚合物溶液喷嘴37和溶剂喷嘴41连接，球囊中的液体与聚合物喷嘴37之间形成电场E2，供聚合物形成静电纺丝，球囊中的液体与溶剂喷嘴41之间形成电场E1，供溶剂喷射形成动力。
步骤S2加载可吸收铁基合金支架，在支架内层覆膜102外周安装上可吸收铁基合金支架101，向接收装置30里继续注入饱和的氯化钠溶液29，接收装置30外径逐渐增大至5.0mm，将支架内层覆膜102向支架内腔挤压，内层覆膜102外侧与可吸收铁基合金支架101的内表面2紧密贴合，支架网格区域4处的内层覆膜102，被球囊压迫凸入支架网格区域4中，并高出支架杆内壁80μm，如图6所示；
步骤S3外层覆膜制备，再在可吸收铁基合金支架101外壁层参照内壁层覆膜制备方法静电纺丝得到外壁层覆膜103，因支架外层覆膜时溶剂喷嘴喷洒的溶剂液滴溶解部分内层覆膜和外层覆膜中的纺丝纤维，溶剂挥发后内层覆膜102与外层覆膜103在支架网眼结构单元4处相互接触粘结在一起形成牢固结合，覆膜103内侧与可吸收铁基合金支架101的外表面3紧密贴合，达到将可吸收支铁基支架牢固的嵌于膜层中间目的。支架外层覆膜条件同支架内壁覆膜，静电纺丝120min得到总膜厚度为69.8μm，如图7所示。
步骤S4覆膜修剪，抽出球囊30中的饱和氯化钠液体29，球囊30的直径变小并与内层覆膜脱离，将覆膜支架100从球囊上取下，修剪两端多余的覆膜，再将覆膜支架压缩于球囊扩张导管上，压握外径为1.8mm，透析袋包装后经EO(Epoxy ethane，环氧乙烷)灭菌后得到最终可吸收覆膜支架产品100。临床使用时只需将覆膜支架输送至病变血管，向球囊内加压扩起覆膜支架后，完成覆膜支架植入治疗，覆膜支架在体内、聚乳酸覆膜和铁基合金支架都会缓慢降解和吸收，最终血管恢复自然弯曲和舒缩，血管内无残留植入物。
通过前述的检测方法测得可吸收覆膜支架纺丝取向性好，纺丝直径均匀性好，纺丝直径1.5-2μm，纺丝与纺丝之间可见相互粘合，如图8所示。覆膜层保持较高的孔隙率，通过测试覆膜层的孔隙率为82％。内、外层覆膜结合力强，可吸收铁基支架被牢固的固定于覆膜层中，内、外层覆膜总厚度72μm，压握于扩张球囊上的压握直径为2.3mm。内、外层覆膜结合强度0.3N/mm，外层覆膜纺丝层剥离强度0.12N/mm。内、外层覆膜之间，存在空隙的总弧长占比很少，空隙的总弧长占整个截面所在圆周的弧长仅为1.2％。
通过在小型猪股浅动脉中植入后评估可吸收覆膜支架的内皮化速度和组织反应。植入7天新生内膜覆盖率为67±15％，覆膜表面内皮细胞形态不典型， 植入14天时新生内膜覆盖率为90±5％，可见形态典型的内皮细胞，植入28天时新生内膜覆盖率为100％，覆膜支架管腔表面布满形态典型的内皮细胞，见图9所示。
植入28天组织病理显示，覆膜中全部长入组织细胞，覆膜周围无炎性反应、细胞坏死，可吸收覆膜支架组织相容性好，无明显的新生内膜增生，通过前述的检测方法测得血管的狭窄率为21％，如图10所示。
实施例2
在本实施例中，在内层覆膜上增加底层覆膜来提升覆膜支架的抗血栓能力，图11为具有良好血液相容性的覆膜支架200的横截面，覆膜支架200由钴铬合金支撑骨架支架201、支架底层覆膜202、支架内层覆膜203和支架外层覆膜204组成。底层覆膜202被定位于支架内层覆膜203的管腔内壁，内层覆膜203被定位于钴铬合金支撑骨架201的管腔内和底层覆膜202的外壁面，并且与钴铬合金支撑骨架支架201的内表面2紧密接触。外层覆膜204定位于钴铬合金支撑骨架支架201的外表面并且与支架201的外表面3紧密接触。内壁层覆膜203与外层覆膜204在支架网格区域4处相互粘合在一起，以此方式，钴铬合金支撑骨架支架201牢固的嵌于外层覆膜和内层覆膜中间，外层覆膜100％覆盖钴铬合金支撑骨架201。本实施例中覆膜支架200标称扩张直10mm，钴铬合金支撑骨架201壁厚120μm，有5组波圈和连接杆组成的管状体，底层覆膜202厚5μm，内层覆膜203和外壁层覆膜204由PET(Polyethylene terephthalate，聚对苯二甲酸乙二醇酯)熔体静电纺丝制成，内、外层覆膜总厚度120μm，纺丝直径4μm左右。制作步骤是先在直径可调节的接收装置上覆盖厚度为5μm的PTFE薄膜，然后再在外面使用熔体纺丝制备支架内层覆膜和外层覆膜，其制备过程如下：
先将直径可调节的接收装置直径设定为9.0mm，再覆盖厚度为5μm的PTFE薄膜，再进行内层覆膜制备，本实施例中直径可调的接收装置直径调节为机械结构调节方式。
S1内层覆膜制备：称取20mg的PET原料切片，加入具备加热、挤压、 搅拌的喷丝嘴料管中，同时混入质量分数为5％的氯化钠粉末来降低熔体的粘度，采用电加热方式加热原料至熔融，熔体加热温度设定270℃，纺丝环境温度设置为65℃，喷丝嘴与接收装置之间距离为7cm，接收装置旋转速度为100/min，纺丝电压为25kv，供料压力2kpa，在支架底层覆膜202外壁进行支架内层覆膜203的制备，每纺15min将接收装置直径增加0.1mm，静电纺丝60min得到51.3μm厚的取向的支架内壁厚覆膜，在本实施例中将接收装置温度设置为90℃，增加了纺丝与底层覆膜202的粘结性及纺丝与纺丝的粘结性。
S2支撑骨架安装：支架内层覆膜203纺织完后，将钴铬合金支撑骨架201扩至10mm内径，安装于内层覆膜203外周，再继续将接收装置直径增加，直到内层覆膜203被压迫凸入支架网格区域4中，并高出支架杆内壁150μm为止。
S3外层覆膜制备：再在钴铬合金支撑骨架201外参照内壁层覆膜203制备方法，进行熔体静电纺丝得到外壁层覆膜，外层覆膜厚度为98.5μm。本实施例外层覆膜完全覆盖钴铬合金支撑骨架，在纺织过程中，覆膜内壁接收装置的挤压、环境温度提高和接收装置的温度提高，钴铬合金支架网格区域的内层覆膜与外层覆膜粘结，最终得到具有良好血液相容性的覆膜支架200。
经检测，支架内、外层覆膜的总厚度为149.6μm，支架内、外层覆膜纤维直径为3.8μm，内层覆膜与外层覆膜之间的剥离强度为0.23N/mm，支架内层覆膜层、外层覆膜层各自的纺丝层之间的剥离强度为0.11N/mm，内、外层覆膜之间存在空隙的总弧长占整个截面所在圆周的弧长仅为3％，覆膜的孔隙率为75％。覆膜支架压握于扩张球囊上的压握直径为3.5mm。
实施例3
本实施例中，覆膜支架为支撑骨架由数个相互不相连接的波圈环组成的可吸收覆膜支架，其中支撑骨架在覆膜中只是维持径向直径，不对覆膜支架轴向产生束缚，使得覆膜支架植入弯曲的血管时，覆膜支架顺应性好，覆膜支架对弯曲的血管适应能力强，内层覆膜不容易产生皱褶，也提升了覆膜支架在弯曲血管中的疲劳性能，具体制备方法如下。
配置好质量分数为8％的聚乳酸纺丝溶液后，将设置接收装置的初始直径为2.5mm，旋转速度为100转/min，轴向上往复移动速度为0.1mm/s，另设置纺丝溶液泵流速度为0.05ml/min，纺丝喷嘴与接收装置的距离为10cm，电压设置为8kv，纺织120min后得到19.9μm厚的内层覆膜。
内层覆膜制备完后，再将可吸收支撑骨架的波圈环套在内层覆膜外，支撑骨架的两个相邻的波圈环之间的距离为4mm，待所有支撑骨架波圈环安装完成后，再将接收装置直径调至3mm，此时，除支撑骨架波圈环杆区域下的内层覆膜外，其它部位的内层覆膜均凸出支撑骨架杆，高出支撑骨架内壁至少70μm。
使用熔体纺丝法制备支架外层覆膜，取10mg的PLA原料切片，加入具备加热和挤压、搅拌的喷丝嘴料管中，采用电加热方式加热原料至熔融，熔体温度设定200℃，同时混入磷酸钠将PLA熔体粘度调节至20Pa.s，环境温度设置为45℃，喷丝嘴与接收装置之间距离为7cm，纺丝电压为15kv，供料压力5kpa，纺织外层覆膜静电纺丝60min得到30.3μm厚的支架外层覆膜，最终得到本实施例的混纺覆膜支架，覆膜中支撑骨架不连续，覆膜支架柔顺性好。
通过前述的检测方法检测，支架覆膜总厚度50.1μm，支架内、外层覆膜之间的剥离强度为0.11N/mm，支架内、外层覆膜各自的纺丝层之间的剥离强度0.02N/mm，内、外层覆膜之间空隙的总弧长占整个截面所在圆周的弧长仅为0.7％，覆膜的孔隙率为90％。覆膜支架压握于扩张球囊上的压握直径为1.5mm。
实施例4
本实施例的覆膜支架，是在支架内层覆膜载有抗凝血物质，防止覆膜支架内血栓形成，外层覆膜中载有抗细胞增殖的药物，达到抑制新生内膜过度增生的目的。本实施例的具体实施过程为：
首先将10g分子量为30万的PLLA加入到190ml的乙酸乙酯中，再加入500U肝素钠注射液，室温密闭搅拌8h完全溶解，得到质量分数为5％的聚乳酸-肝素纺丝溶液。圆柱形接收装置表面覆盖有柔性的PTFE垫片，接收装置与纺丝喷嘴距离设定为12cm，接收装置的直径为2.5mm，旋转速度为2000转，纺丝溶液泵流速度为0.05ml/min，纺丝电压7kv进行静电纺丝制备覆膜支架内层 覆膜，120min后得到27.5μm内层覆膜。
将可吸收铁基支架安装于内层覆膜外，将接收装置直径调至3.4mm，此时，可吸收铁基支架网格下柔性的PTFE垫片将内层覆膜顶出凸入支架网格中，支架杆下的柔性的PTFE垫片连同内层覆膜被压缩凹陷进接收装置。凹陷的深度30μm，网格区域凸入网格中高度大于75μm。
再在支架外壁纺织载有雷帕霉素的外层覆膜，外层覆膜纺织前，将10g分子量为30万的PLLA加入到190ml的乙酸乙酯中，再加入5mg的雷帕霉素，室温密闭搅拌8h完全溶解，得到质量分数为5％的聚乳酸-雷帕霉纺丝溶液，将丝溶液泵流速度为0.09ml/min，电压调至14kv，其它条件与支架内层覆膜纺丝条件相同，继续纺织备支架外层覆膜，75min后得到50.7μm厚的载有雷帕霉素的外层覆膜。
通过前述的检测方法检测，支架覆膜总厚度78.3μm，覆膜支架内、外层覆膜之间的剥离强度为0.13N/mm，支架内、外层覆膜各自的多层纺织间的剥离强度为0.14N/mm，内、外层覆膜之间空隙的总弧长占整个截面所在圆周的弧长仅为0.5％，覆膜的孔隙率为80％，覆膜支架压握于扩张球囊上的压握直径为1.5mm。
实施例5
本实施例的覆膜支架，覆膜层中载有X射线显影材料，增强覆膜支架的显影性。其制备过程如下：
配置质量分数为8％的聚乳酸纺丝溶液后，设定接收装置直径为9.5mm，旋转速度为100转/min，轴向上往复移动速度为0.1mm/s，再设定纺丝溶液泵流速度为0.05ml/min，纺丝喷嘴与接收装置为10cm，电压设置为8kv，纺织120min后得到19.5μm厚的内层覆膜。
将铁基可吸收支撑骨套在内层覆膜外，再将接收装置直径调至10mm，此时，除支撑骨架波圈环杆区域下的内层覆膜外，其它部位的内层覆膜均凸出支撑骨架杆，高出支撑骨架内壁至少150μm。
使用熔体纺丝法制备支架外层覆膜，取10mg的PLA原料切片，加入具备加热和挤压、搅拌的喷丝嘴料管中，采用电加热方式加热原料至熔融，熔体温度设定200℃，同时混入质量分数为4％的硫酸钡粉末于熔体中，环境温度设置为50℃，喷丝嘴与接收装置之间距离为7cm，纺丝电压为15kv，供料压力10kpa，纺织外层覆膜静电纺丝80min得到43.4μm厚的可显影的支架外层覆膜，最终得到本实施例具有X射线显影性的覆膜支架。
通过前述的检测方法检测，支架覆膜在X射线下清晰可见，支架覆膜总厚度62.8μm，覆膜支架内、外层覆膜之间的剥离强度为0.10N/mm，支架内、外层覆膜各自的多层纺织间的剥离强度为0.02N/mm，内、外层覆膜之间空隙的总弧长占整个截面所在圆周的弧长仅为1％，覆膜的孔隙率为75％，覆膜支架压握于扩张球囊上的压握直径为3.6mm。
对比例1
本对比例采用与实施例1相同纺丝条件，制备支架内层覆膜和外层覆膜，与实施例的不同的是，无论是纺织支架内层覆膜还是编制外层覆膜时，接收装置的直径始终固定不变，纺织覆膜时，也不增加溶剂喷射液滴溶解纺丝纤维，除此之外，其它条件均相同，最终制备得到标称直径为5mm，内层覆膜厚31.5μm，外层覆膜厚42.3μm的对比例1的覆膜支架，将其压握于扩张导管上进行后续对比测试。
通过前述的检测方法，对比例1的覆膜支架内、外层覆膜压握后即与支撑骨架分离，内层覆膜与外层覆膜之间空隙的总弧长占整个截面所在圆周上，覆膜的孔隙率为87％，外层覆膜的多层纺丝层剥离强度仅为0.0052N/mm，覆膜层粘合强度极低。与实施例1的可吸收覆膜支架比较，对比例1的可吸收覆膜支架的内、外层覆膜剥离强度、覆膜层剥离强度远远低于实施例1的可吸收覆膜支架。
对比例2
本对比例采用与实施例2相同纺丝条件，使用熔体纺丝法制备具有底层覆 膜的覆膜支架，与实施例2不同的是，无论是纺织支架内层覆膜还是纺织外层覆膜时，接收装置的直径始终固定不变，除此之外，其它条件均与实施例2相同，最终制备得到具有底层覆膜的对比例2覆膜支架。
通过前述的检测方法检测，对比例1的覆膜支架内、外层覆膜间的剥离强度为0.007/mm，内、外覆膜各自的多层纺丝间的剥离强度为0.009N/mm，支架空隙的总弧长占整个截面所在圆周的弧长为67％，覆膜的孔隙率为80％。覆膜支架压握于扩张球囊上的压握直径为2.3mm，与实施2例所制备的覆膜支架比较，对比例2的覆膜支架覆膜结合力、覆膜层剥离强度均小于实施例2中制备的覆膜支架，空隙率明显大于实施例2中制备的覆膜支架。
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以权利要求的保护范围为准。

Claims (22)

  1. 一种覆膜支架，包括内层覆膜、外层覆膜，以及位于内、外层覆膜之间的支撑骨架，其特征在于，所述覆膜支架内层覆膜与外层覆膜在支撑骨架网格中的区域相互粘结。
  2. 根据权利要求1所述的覆膜支架，其特征在于，沿支撑骨架的周向方向任意一截面，内层覆膜与外层覆膜之间存在的空隙总弧长占整个截面所在圆周弧长的0.1％-5％。
  3. 根据权利要求1所述的覆膜支架，其特征在于，所述内层覆膜与外层覆膜之间的剥离强度为0.1-0.5N/mm；所述内层覆膜或外层覆膜中纺丝纤维层之间的剥离强度为0.01-0.2N/mm。
  4. 根据权利要求1所述的覆膜支架，其特征在于，所述外层覆膜的厚度大于内层覆膜的厚度；所述外层覆膜的厚度为内层覆膜厚度的1.1-5倍。
  5. 根据权利要求1所述的覆膜支架，其特征在于，所述内层覆膜的厚度为10-100μm；所述支撑骨架网格中内、外层覆膜的总壁厚为30-500μm。
  6. 根据权利要求1所述的覆膜支架，其特征在于，所述覆膜支架压握于扩张球囊导管上的压握外径为0.9-6mm；所述内层覆膜和外层覆膜的孔隙率为70％-90％。
  7. 根据权利要求1所述的覆膜支架，其特征在于，所述内层覆膜陷入支撑骨架网格中的深度为10-350μm。
  8. 根据权利要求1所述的覆膜支架，其特征在于，所述内层覆膜与外层覆膜用材料选自纤维素、甲壳素、透明质酸、胶原蛋白、明胶、海藻酸钠、聚氨基甲酸脂、聚乳酸、左旋聚乳酸、右旋聚乳酸、聚羟基乙酸、聚已内酯、聚酰胺、聚对苯二甲酸乙二酯中的至少一种。
  9. 根据权利要求1所述的覆膜支架，其特征在于，所述覆膜支架的内层覆膜完全覆盖支撑骨架；所述外层覆膜覆盖沿支撑骨架径向长度的10％-100％的区域。
  10. 根据权利要求1所述的覆膜支架，其特征在于，所述覆膜支架上携带有药物或显影材料。
  11. 一种权利要求1-10所述覆膜支架的制备方法，其特征在于，包括以下步骤：
    S1：将纺丝液静电纺到直径可调的接收装置外壁上，形成内层覆膜；
    S2：将支撑骨架安装在纺有内层覆膜的接收装置上，调节接收装置直径，扩大内层覆膜至部分内层覆膜嵌入支撑骨架的网格中；
    S3：将纺丝液静电纺到支撑骨架外壁上形成外层覆膜；
    S4：待外层覆膜纺织完成后，停止静电纺丝，将接收装置直径调小并从覆膜支架管腔中抽出，得到覆膜支架。
  12. 根据权利要求11所述的覆膜支架的制备方法，其特征在于，所述步骤S1和/或S3中接收装置在覆膜制备过程中直径逐渐扩大；步骤S1和/或S3中接收装置扩大的速率为0.1-10mm/h。
  13. 根据权利要求11所述的覆膜支架的制备方法，其特征在于，所述内、外层覆膜纺丝的直径为1-5μm；所述步骤S3中内层覆膜陷入支撑骨架网格中的深度10-900μm。
  14. 根据权利要求11所述的覆膜支架的制备方法，其特征在于，所述步骤S1中内层覆膜纺织完成后接收装置与内层覆膜的总直径小于支撑骨架的标称内径；所述接收装置在外层覆膜制备完成时的直径为S1步骤中接收装置初始直径的1.2-10倍。
  15. 根据权利要求11所述的覆膜支架的制备方法，其特征在于，所述步骤S3中在纺织外层覆膜之前还包括喷涂溶剂溶解内层覆膜纺丝纤维的步骤；所述步骤S1和步骤S3中所采用的纺丝液为熔融状态的聚合物熔体和/或分散于溶剂中的聚合物溶液。
  16. 根据权利要求15所述的覆膜支架的制备方法，其特征在于，所述溶剂选自乙酸乙酯、丙酮、四氢呋喃、二氯甲烷、三氯甲烷、二甲基甲酰胺、二甲基乙酰胺、异丙醇、六氟异丙醇、乙醇、三氟乙酸中的一种或多种混合。
  17. 根据权利要求15所述的覆膜支架的制备方法，其特征在于，所述聚合物溶液中溶剂与聚合物的质量比为80:20-99:1；所述聚合物熔体粘度为10-100Pa.s；所述聚合物熔体中还包括无机盐。
  18. 根据权利要求17所述的覆膜支架的制备方法，其特征在于，所述无机盐选自氯化钠、磷酸钠、氯化钾、氯化钠、氯化镁、氯化铝、磷酸氢钠、磷酸氢二钠、磷酸钙、碳酸钠、碳酸钠氢钠、碳酸钙、碳酸钙、氯化铁、氯化铝、 氢氧化铁、三氯化铁，葡萄糖酸亚铁中的一种或多种。
  19. 根据权利要求11所述的覆膜支架的制备方法，其特征在于，所述步骤S1和步骤S3纺织过程中的电压为5-100kv，聚合物注射流速为0.01-1ml/min，接收装置与喷嘴之间距离为2-15cm，接收装置旋转的速度为100-2000/min。
  20. 一种权利要求11-19所述覆膜支架制备方法用接收装置，其特征在于，所述接收装置的直径可调，其最大直径为最小直径的1.2-10倍。
  21. 根据权利要求20所述的覆膜支架制备方法用接收装置，其特征在于，所述接收装置表面涂有导电涂层和/或脱模剂。所述接收装置的表面设有微孔结构，微孔的直径为10-100μm，微孔间距0.1-10mm；所述接收装置的表面的微孔形状为条状、网格状或无序的散点状中的一种或多种的组合。
  22. 根据权利要求20所述的覆膜支架制备方法用接收装置，其特征在于，所述接收装置上接有加热组件。
PCT/CN2022/142006 2021-12-31 2022-12-26 一种覆膜支架系统及其制备方法 WO2023125434A1 (zh)

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CN118319553B (zh) * 2024-06-13 2024-09-17 北京阿迈特医疗器械有限公司 一种人工血管及其制备方法

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