WO2023142383A1 - 一种高强度植入物及其制备方法 - Google Patents

一种高强度植入物及其制备方法 Download PDF

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WO2023142383A1
WO2023142383A1 PCT/CN2022/103062 CN2022103062W WO2023142383A1 WO 2023142383 A1 WO2023142383 A1 WO 2023142383A1 CN 2022103062 W CN2022103062 W CN 2022103062W WO 2023142383 A1 WO2023142383 A1 WO 2023142383A1
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implant
spinning
water
cross
strength
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PCT/CN2022/103062
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English (en)
French (fr)
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王志伟
陈雄伟
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爱美客技术发展股份有限公司
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Publication of WO2023142383A1 publication Critical patent/WO2023142383A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/222—Gelatin
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • 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
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/045—Gelatin
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/048—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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

Definitions

  • the invention relates to the technical field of medical materials and implant devices, in particular to a high-strength implant and its preparation method and application.
  • tubular objects With the development of science and technology, surgical implantation of tubular objects is used as a method to treat diseases.
  • the properties of the tubular objects required are different according to different diseases. For example, when a certain part of the human body cannot When the blood supply is normal, the blood circulation is maintained by artificial blood vessel replacement.
  • the ideal artificial blood vessel has the characteristics of stable performance, certain strength and flexibility, no bleeding and easy suturing and anticoagulation; For glaucoma, more and more doctors choose to control intraocular pressure and reduce postoperative complications by implanting a catheter. This type of catheter can control the flow rate of the fluid and maintain a fixed shape for a long time.
  • the present invention provides a high-strength implant, which includes a dense layer formed by post-treatment of polymer threads, so that the spaces (or gaps) between the polymer threads are reduced, and the high-strength implant It has accurate size control, good biocompatibility, high strength and toughness, and is suitable for surgical operations.
  • the first aspect of the present invention provides a high-strength implant.
  • the high-strength implant includes a dense layer formed by post-treatment of polymer wires, and the post-treatment makes the spaces (or gaps) between the polymer wires ) decreases.
  • the post-treatment includes but not limited to steam humidification, electrothermal humidification, electrode humidification or high-pressure spray humidification.
  • the post-treatment is steam humidification.
  • the post-treatment time is any value in the range of 5-50 minutes. More preferably, it is any value in 10-30min.
  • the post-processing time can be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50min .
  • the porosity of the dense layer formed after post-treatment is lower than the porosity (or porosity) of the polymer filaments before treatment.
  • the polymer filaments are prepared by spinning and cross-linking water-soluble polymers.
  • the water-soluble polymer may be an ionic, non-ionic or amphiphilic water-soluble polymer.
  • the water-soluble polymer may be a natural water-soluble polymer, a semi-synthetic water-soluble polymer or a synthetic water-soluble polymer.
  • natural water-soluble polymers include but not limited to water-soluble polymers extracted from starch, protein, bovine vitreous or seaweed, such as gelatin and sodium hyaluronate.
  • Semi-synthetic water-soluble polymers include, but are not limited to, cellulose, methylcellulose, hydroxymethylcellulose, or carboxymethylchitosan, among others.
  • Synthetic water-soluble polymers include, but are not limited to, polyacrylic acid, polyacrylamide, or polyvinyl alcohol, among others.
  • the water-soluble polymer is selected from one or more of polyvinyl alcohol, gelatin, carboxymethyl chitosan, cellulose or sodium hyaluronate.
  • the crosslinking uses a crosslinking agent.
  • the crosslinking agent can be epoxy compound, polyethylene glycol-epoxy compound or multi-arm-polyethylene glycol-epoxy compound.
  • Described epoxy compound can be oxirane, propylene oxide, 1,2-epoxybutane or 1,4-epoxybutane, also can be two epoxy compounds (for example 1,4-butanedi Alcohol diglycidyl ether, 1,2,3,4, butylene oxide) or polyepoxides (mostly 3 or more, such as tris(1,2-epoxy)propyl ether).
  • the multi-arm-polyethylene glycol-epoxy compound (mostly 3 or more) includes but not limited to three-arm-polyethylene glycol-epoxy, four-arm-polyethylene glycol-epoxy base, five-arm-polyethylene glycol-epoxy, six-arm-polyethylene glycol-epoxy, seven-arm-polyethylene glycol-epoxy, eight-arm-polyethylene glycol-epoxy, Nine-arm-polyethylene glycol-epoxy or ten-arm-polyethylene glycol-epoxy, etc.
  • the crosslinking agent is selected from diepoxy compounds, polyepoxy compounds or multi-arm-polyethylene glycol-epoxy compounds.
  • the crosslinking agent is selected from 1,4-butanediol diglycidyl ether, 1,2,3,4,-diepoxybutane, glycerol tri(1, One or more of 2-epoxy)propyl ether, four-arm-polyethylene glycol-epoxy or three-arm-polyethylene glycol-epoxy.
  • the added mass of the crosslinking agent is any numerical multiple of 0.01-0.10 of the added mass of the water-soluble polymer, more preferably 0.01-0.05, 0.01-0.07, 0.01-0.02, 0.02-0.07, 0.01-0.035 or 0.02-0.05 times, such as 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 times.
  • the high-strength implant comprises mixing a water-soluble polymer with water to obtain a water-soluble polymer solution (the concentration of the water-soluble polymer solution is 0.05-0.2 g/mL), Then add a cross-linking agent to form a spinning solution, and then spin-cross-link to obtain.
  • the implant is obtained by mixing a water-soluble polymer with water, adding a cross-linking agent and a catalyst, and then spinning and cross-linking.
  • the catalyst is selected from alkali metal hydroxides or alkali metal carbonates.
  • the alkali metal is selected from lithium, sodium, potassium, rubidium, cesium or francium.
  • the hydroxide of the alkali metal is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide or francium hydroxide.
  • the carbonate may be normal salt, acid salt or basic salt, such as sodium carbonate, potassium carbonate, zinc carbonate, calcium carbonate, magnesium carbonate, iron carbonate, copper carbonate and the like.
  • the catalyst is selected from sodium hydroxide, potassium hydroxide or sodium carbonate.
  • the catalyst is added according to a mass ratio of catalyst to water-soluble polymer of 0.01-0.5:1 (preferably 0.25-0.5:1 or 0.01-0.25:1).
  • it can be added according to the mass ratio of the catalyst to the water-soluble polymer (0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4, 0.5):1.
  • the spinning in the spinning-crosslinking is phase separation spinning, flash spinning, electrospinning, liquid crystal spinning or reaction spinning. Electrospinning is further preferred.
  • the implant may be a cosmetic product or a product for treating diseases.
  • the cosmetic products include but not limited to nasal implants, eye implants, contact lenses, subcutaneous implants (for example, facial or neck injections can reduce and smooth wrinkles).
  • the products for treating diseases include but are not limited to eye implants (such as drainage tubes, artificial tear ducts), cardiac implants (such as heart valves), oral protection, denture pads, tissue replacement implants, ureteral prostheses, tendon and ligament substitutes, bandages, sutures, vascular implants (such as artificial blood vessels), orthopedic plates or staples, artificial joints or staplers.
  • the staplers are, for example, skin staplers, digestive tract (esophagus, gastrointestinal, etc.) circular staplers, rectal staplers, circular hemorrhoid staplers, circumcision staplers, blood vessel staplers, hernia staplers, lung Cutting staplers, etc.
  • the high-strength implant is preferably a tubular implant. According to the needs of use, it can also be made into implants of other shapes such as sheet, ring, rod, etc.
  • the second aspect of the present invention provides a tubular implant.
  • the tubular implant includes a tube body, and the tube body includes a cavity in the tube and a tube wall.
  • the cavity in the tube is hollow cylindrical.
  • the diameter of the cavity in the tube is any value in the range of 20-4000 ⁇ m (preferably 30-3000 ⁇ m).
  • the diameter of the cavity in the tube can be 20, 50, 100, 500, 1000, 1500, 2000, 2500, 3000, 3500 or 4000 ⁇ m
  • the average thickness of the tube wall is any value in the range of 100-2000 ⁇ m.
  • the average thickness of the tube wall may be 100, 200, 500, 1000, 1500 or 2000 ⁇ m.
  • the pipe body further includes an outer structure.
  • the shape of the outer tube structure can be adjusted according to the implantation site. In order to reduce shedding, etc., all or part of it can preferably be a cylindrical structure, an annular structure, a conical structure, a rectangular parallelepiped structure, a cube structure or a spherical structure.
  • the average diameter of the outer tube structure is any value in the range of 50-7000 ⁇ m (preferably any value in the range of 200-6500 ⁇ m).
  • the average diameter of the outer structure of the tube may be 50, 100, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000 ⁇ m.
  • the tubular implant includes a dense layer of polymer wires after post-treatment, and the post-treatment reduces the spaces between the polymer wires.
  • the tubular implant may be a cosmetic product or a product for treating diseases.
  • the cosmetic products include but not limited to nasal implants, eye implants, contact lenses, subcutaneous implants (for example, facial or neck injections can reduce and smooth wrinkles).
  • the products for treating diseases include but are not limited to eye implants (such as drainage tubes, artificial tear ducts), cardiac implants (such as heart valves), oral protection, denture pads, tissue replacement implants, ureteral prostheses, tendon and ligament substitutes, bandages, sutures, vascular implants (such as artificial blood vessels), orthopedic plates or staples, artificial joints or staplers.
  • the staplers are, for example, skin staplers, digestive tract (esophagus, gastrointestinal, etc.) circular staplers, rectal staplers, circular hemorrhoid staplers, circumcision staplers, blood vessel staplers, hernia staplers, lung Cutting staplers, etc.
  • the third aspect of the present invention provides a method for preparing a high-strength implant.
  • the method includes spinning-crosslinking the spinning solution to obtain polymer filaments, and post-processing to form a dense layer.
  • the post-treatment either dissolves and cross-links the polymer threads together to form a void-free whole or reduces the voids (or gaps) between the threads. Thereby forming a dense layer pipe wall structure with better strength.
  • the post-treatment is selected from steam humidification, electrothermal humidification, electrode humidification or high-pressure spray humidification.
  • the present invention can realize the dynamic controllability of polymer crosslinking degree by adding a small amount of crosslinking agent and controlling the spinning time and process conditions, and has the advantages of simple process, controllable product shape, crosslinking degree and strength. Advantages, suitable for industrial promotion.
  • the preparation method includes passing the spinning solution through the filaments on the electrospinning device to form a spinning-crosslinking layer.
  • the diameter of the filaments obtained by the spinning-crosslinking is any value in the range of 20-4000 ⁇ m, preferably 30-3000 ⁇ m. More preferably, it is 30-1000 ⁇ m, 50-1000 ⁇ m, 100-1000 ⁇ m, 30-100 ⁇ m or 50-100 ⁇ m.
  • the diameter of the wire may be 20, 50, 100, 500, 1000, 1500, 2000, 2500, 3000, 3500 or 4000 ⁇ m.
  • the wires can be made of any material, preferably metal wires.
  • steel wire such as stainless steel wire
  • tungsten wire gold wire
  • platinum wire platinum wire or copper wire, etc.
  • the spinning solution contains water-soluble polymer and water.
  • the water-soluble polymer is dissolved in water and completely dissolved to obtain a water-soluble polymer solution.
  • the concentration of the water-soluble polymer solution is any value in the range of 0.05-0.2 g/mL, preferably 0.05-0.15 g/mL.
  • the concentration can be 0.05, 0.1, 0.11, 0.15, 0.17, 0.18, 0.19, 0.2, etc. g/mL. If the polymer concentration is too high (as in Comparative Example 1), the viscosity is too high and spinning cannot be performed.
  • the water-soluble polymer may be an ionic, non-ionic or amphiphilic water-soluble polymer.
  • the water-soluble polymer may be a natural water-soluble polymer, a semi-synthetic water-soluble polymer or a synthetic water-soluble polymer.
  • natural water-soluble polymers include but not limited to water-soluble polymers extracted from starch, protein, bovine eye vitreous or seaweed, such as gelatin, sodium hyaluronate.
  • Semi-synthetic water-soluble polymers include, but are not limited to, cellulose, methylcellulose, hydroxymethylcellulose, or carboxymethylchitosan, among others.
  • Synthetic water-soluble polymers include, but are not limited to, polyacrylic acid, polyacrylamide, or polyvinyl alcohol, among others.
  • the water-soluble polymer is selected from one or more of polyvinyl alcohol, gelatin, carboxymethyl chitosan, cellulose or sodium hyaluronate.
  • the spinning solution also contains a crosslinking agent.
  • the crosslinking agent can be epoxy compound, polyethylene glycol-epoxy compound or multi-arm-polyethylene glycol-epoxy compound. Described epoxy compound can be oxirane, propylene oxide, 1,2-epoxybutane or 1,4-epoxybutane, also can be two epoxy compounds (for example 1,4-butanedi Alcohol diglycidyl ether, 1,2,3,4,-diepoxybutane) or polyepoxides (mostly 3 or more, such as glycerol tri(1,2-epoxy)propyl ether) .
  • the multi-arm-polyethylene glycol-epoxy compound (mostly 3 or more) includes but not limited to three-arm-polyethylene glycol-epoxy, four-arm-polyethylene glycol-epoxy base, five-arm-polyethylene glycol-epoxy, six-arm-polyethylene glycol-epoxy, seven-arm-polyethylene glycol-epoxy, eight-arm-polyethylene glycol-epoxy, Nine-arm-polyethylene glycol-epoxy or ten-arm-polyethylene glycol-epoxy, etc.
  • the crosslinking agent is selected from diepoxy compounds, polyepoxy compounds or multi-arm-polyethylene glycol-epoxy compounds.
  • the crosslinking agent is selected from 1,4-butanediol diglycidyl ether, 1,2,3,4,-diepoxybutane, glycerol tri(1, One or more of 2-epoxy)propyl ether, four-arm-polyethylene glycol-epoxy or three-arm-polyethylene glycol-epoxy.
  • the added mass of the crosslinking agent is any number of times in 0.01-0.10 of the added mass of the water-soluble polymer, more preferably 0.01-0.05, 0.01-0.02 or 0.02-0.05 times, for example, it can be 0.01, 0.02, 0.03, 0.04, 0.05 times.
  • the post-treatment includes but not limited to steam humidification, electrothermal humidification, electrode humidification or high-pressure spray humidification.
  • the post-treatment is steam humidification.
  • the post-treatment time is any value in the range of 5-50 minutes. More preferably, it is any value in 10-30min.
  • post-processing time can be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50min .
  • the porosity of the dense layer formed after the post-treatment is lower than the porosity (or porosity) of the polymer filaments before the treatment.
  • the preparation method includes transferring the spinning solution to a receiving device of an electrospinning device, performing spinning-crosslinking, and then performing steam humidification and densification treatment.
  • the steam humidification is preferably water vapor humidification.
  • the temperature of the steam humidification is from room temperature to 125°C.
  • the steam humidification time is any value in 5-50min. More preferably, it is any value in 10-30min.
  • steam humidification time can be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50min .
  • the spinning time is any value in 10-150 min, preferably any value in 20-120 min.
  • the spinning time can be 10, 20, 40, 50, 60, 100, 120, 130, 150 min.
  • the preparation method includes transferring the spinning liquid to the receiving device of the electrospinning equipment, and the injection speed is preferably any value in 0.1-3mL/h (preferably 0.1-3mL/h). 2mL/h, 0.2-0.5mL/h or 0.1-1mL/h or 1-2mL/h, such as 0.1, 0.2, 0.5, 1, 1.5, 2, 2.5, 3mL/h), the voltage is preferably 5-50kV Any value (preferably 10-30kV or 10-25kV or 10-22kV or 22-30kV or 22-25kV or 25-30kV, such as 5, 10, 20, 30, 40, 45, 50), the receiving distance is preferably Any value in 0.1-20cm (preferably 0.5-15cm or 0.5-10cm or 10-15cm, such as 5, 10, 15, 20), install silk thread, carry out spinning-crosslinking; then carry out steam humidification 5 -50min, obtain high-strength implants.
  • the voltage is preferably 5-50kV Any value (preferably 10-30kV or 10-25kV or 10-22kV
  • the preparation method further includes the steps of spinning-crosslinking or steam humidification, repeated freezing-thawing. Preferably repeated freeze-thaw 5-8 times. Specifically, the polymer thread is frozen in an environment below 0°C (such as 0-70°C), and then placed in an environment above 0°C (such as 0-40°C) to melt.
  • 0°C such as 0-70°C
  • 0°C such as 0-40°C
  • the preparation method further includes the steps of pickling, cleaning, demoulding, drying and/or sterilizing.
  • the acid leaching is soaking in an acidic solution (i.e. a solution with pH ⁇ 7)
  • the acidic solution can be a strong acidic aqueous solution such as sulfuric acid solution, hydrochloric acid solution, etc., or an organic acid aqueous solution, such as acetic acid solution, formic acid solution, etc. .
  • described preparation method comprises:
  • the spinning solution is transferred to the receiving device of the electrospinning equipment, the injection speed is preferably 0.1-3mL/h (preferably 0.1-2mL/h or 0.1-1mL/h or 1-2mL/h), and the voltage is preferably 5 -50kV (preferably 10-30kV or 10-25kV or 10-22kV or 22-30kV or 22-25kV or 25-30kV), the receiving distance is preferably 0.1-20cm (preferably 0.5-15cm or 0.5-10cm or 10- 15cm), the silk thread is installed, and the spinning solution is formed on the silk thread for spinning-crosslinking layer;
  • the fourth aspect of the present invention provides a high-strength implant obtained by the above preparation method.
  • the fifth aspect of the present invention provides an application of the above-mentioned high-strength implant, tubular implant or high-strength implant obtained by the above-mentioned preparation method in the preparation of cosmetic products or products for treating diseases.
  • the cosmetic products include but not limited to nasal implants, eye implants, contact lenses, subcutaneous implants (for example, facial or neck injections can reduce and smooth wrinkles).
  • the products for treating diseases include but are not limited to eye implants (such as drainage tubes, artificial tear ducts), cardiac implants (such as heart valves), oral protection, denture pads, tissue replacement implants, ureteral prostheses, tendon and ligament substitutes, bandages, sutures, vascular implants (such as artificial blood vessels), orthopedic plates or staples, artificial joints or staplers.
  • the staplers are, for example, skin staplers, digestive tract (esophagus, gastrointestinal, etc.) circular staplers, rectal staplers, circular hemorrhoid staplers, circumcision staplers, blood vessel staplers, hernia staplers, lung Cutting staplers, etc.
  • the product is an artificial blood vessel, an artificial lacrimal duct or a drainage tube.
  • the present invention has the following prominent features:
  • Epoxy compounds are used as cross-linking agents, which can be used for cross-linking reactions of various water-soluble polymers such as polyvinyl alcohol, gelatin, carboxymethyl chitosan, cellulose or sodium hyaluronate. Wide range; and avoid the use of boron and other heavy metal toxic elements commonly used in the prior art and aldehyde crosslinking agents with high cytotoxicity to ensure the biological safety of the implant; in addition, the epoxy group in the epoxy compound
  • the reaction rate with the amino group or hydroxyl group in the polymer is relatively slow, which ensures the stability of the performance of the spinning solution during the spinning process, facilitates the spinning process, and provides guarantee for the subsequent crosslinking and densification treatment.
  • the carbon-nitrogen bond or ether bond structure formed by the joint reaction is a single bond and is not easy to break, which improves the strength and stability of the implant.
  • the present invention forms a spinning solution by adding a small amount of cross-linking agent into the water-soluble polymer solution, and the solvent can evaporate as the spinning proceeds,
  • concentration of solute such as cross-linking agent
  • the concentration of solute increases to form cross-linked silk threads.
  • the post-treatment such as steam humidification, all or part of the silk threads are dissolved with each other, and the degree of cross-linking is further increased, so that uniform cross-linking and dense layer tubes are obtained. High-strength implants for the wall.
  • the reduction in the amount of the cross-linking agent reduces the residual amount of the cross-linking agent in the implant, further ensuring the safety of its application.
  • the present invention ensures the stability and uniformity of cross-linking in spinning and post-treatment by adjusting the amount of water-soluble polymer and cross-linking agent in the spinning solution, and the degree of cross-linking is controllable, which optimizes the implant
  • the shape and structure of the invention; the process of the invention is simple, the operation is convenient, and it is beneficial to the promotion of industrialization.
  • the surface and tube wall of the high-strength implant prepared by the present invention are dense and uniform, with good strength (up to 20MPa) and elasticity, and can exist stably after implantation, reducing the time of implantation. There is a risk of bending and breaking, and the high-strength implant has the characteristics of good toughness, easy-to-control volume expansion rate, and stable structure after rehydration, and is more suitable for use as an implant for eye surgery to control tear drainage or retention.
  • Fig. 1 Field emission scanning electron microscope (FESEM) observes the implant prepared in Example 6, wherein, the left figure is the morphology structure of the implant surface, and the right figure is a further enlarged view of the implant surface.
  • FESEM Field emission scanning electron microscope
  • Figure 2 Field emission scanning electron microscope (FESEM) observation of the implant prepared in Comparative Example 6, wherein the left figure is the topography of the implant surface, and the right figure is a further enlarged view of the implant surface.
  • FESEM Field emission scanning electron microscope
  • Fig. 3 Observation of the implant prepared in Example 6 by a field emission scanning electron microscope (FESEM), wherein, the left figure is the morphology and structure of the implant cross-section, and the right figure is a further enlarged view of the implant cross-section.
  • FESEM field emission scanning electron microscope
  • the "implant” mentioned in the present invention is an implantable article placed in a body cavity caused by surgical operation or physiologically existing, and retained for a certain period of time. It can adjust its shape, length, thickness, etc. arbitrarily according to the type of disease or the shape caused by surgical operation or the shape of body cavity.
  • Cross-linking in the present invention is a process in which linear or branched polymer chains are covalently connected to form a network or body-shaped polymer, including chemical cross-linking and physical cross-linking.
  • Cross-linking-spinning or “spinning-cross-linking” in the present invention means that cross-linking and spinning are carried out simultaneously, wherein the “simultaneously” means that the process of cross-linking and the process of spinning partly overlap , does not only include starting at the same moment, and/or, ending at the same moment, and/or, the complete overlap of the crosslinking process and the spinning process time.
  • the total time of spinning is not necessarily the same as the total time of crosslinking.
  • the spinning time can be longer than the crosslinking time, the spinning time can be shorter than the crosslinking time, or the time can be the same.
  • the voids or interstices of the present invention reflect the degree of densification of the implant surface.
  • the Remove the silk thread from the rotor humidify it with steam at 100°C for 10 minutes, seal it and transfer it to an environment of 25°C, and place it for 12 hours.
  • Transfer the silk thread to 10% acetic acid solution and soak for 1 hour, wash it with normal saline for several times, remove the catheter from the silk thread, put it in a vacuum drying oven, set the temperature at 40°C, dry it for 24 hours, and irradiate it with 25kGy after packaging.
  • the product is obtained by bacteria, and the average inner diameter of the prepared catheter is 30-40 ⁇ m, and the average outer diameter is 220-230 ⁇ m.
  • the prepared high-strength implants can be used for ocular implants (such as drainage tubes, artificial lacrimal ducts).
  • the Remove the silk thread from the rotor After running for 60min, the Remove the silk thread from the rotor, humidify with steam at 60°C for 30 minutes, transfer to a sealed environment at 40°C, and place it for 24 hours. After the thread is transferred to 10% hydrochloric acid solution and soaked for 1 hour, the process steps of cleaning, drying and sterilization adopt the operation method of Example 1, and the average inner diameter of the obtained catheter is 2990-3000 ⁇ m, and the average diameter of the outer diameter is 6400-3000 ⁇ m. 6500 ⁇ m.
  • the prepared high-strength implant can be used in reconstruction surgery of blood vessels.
  • the Remove the silk thread from the rotor After running for 120min, the Remove the silk thread from the rotor, humidify with steam at 25°C for 30 minutes, transfer to a sealed environment at 30°C, and place it for 18 hours. After the thread is transferred to 10% sulfuric acid solution and soaked for 1 hour, the process steps of cleaning, drying and sterilization adopt the operation method of Example 1, and the average inner diameter of the obtained implant catheter is 1000-1100 ⁇ m, and the average diameter of the outer diameter is 1000 ⁇ m. It is 3200 ⁇ 3300 ⁇ m.
  • the process steps of cleaning, drying and sterilization adopt the operation method of Example 1, and the average inner diameter of the obtained implant catheter is 100-110 ⁇ m, and the average diameter of the outer diameter is 100 ⁇ m. It is 280-290 ⁇ m.
  • the Remove the silk thread from the rotor humidify with steam at 30°C for 30 minutes, seal and transfer to an environment of 30°C, and place it for 16 hours.
  • the silk thread is transferred to 10% sulfuric acid solution and soaked for 1 hour, the process steps of cleaning, drying and sterilization adopt the operation method of Example 1, and the average inner diameter of the obtained implant catheter is 50-60 ⁇ m, and the average diameter of the outer diameter is 50 ⁇ m. 250-260 ⁇ m.
  • the inner diameter is 55-65 ⁇ m, and the average diameter of the outer diameter is 190-220 ⁇ m.
  • the silk on the rotor is removed, and the temperature is 121°C, humidify with steam for 30 minutes, seal and transfer to an environment of 35°C, place for 14 hours, place the silk thread in an environment of -20°C to freeze, then place it in an environment of 25°C to thaw, repeat freezing-thawing for 5-8 Second-rate.
  • the process steps of cleaning, drying and sterilizing the silk thread adopt the operation method of Example 1, and the average inner diameter of the obtained implant catheter is 100-110 ⁇ m, and the average diameter of the outer diameter is 280-290 ⁇ m.
  • the silk thread on the rotor was removed, sealed and transferred to an environment of 25° C., and placed for 12 hours. Transfer the silk thread to 10% acetic acid solution and soak it for 1 hour, wash it with normal saline several times, remove the catheter from the silk thread, put it in a vacuum drying oven, set the temperature at 40°C, dry it for 24 hours, and irradiate it with 25kGy after packaging.
  • the product is obtained by bacteria, and the average inner diameter of the prepared implant catheter is 30-40 ⁇ m, and the average diameter of the outer diameter is 220-230 ⁇ m.
  • the inner diameter is 55-65 ⁇ m, and the average diameter of the outer diameter is 190-220 ⁇ m. Density test
  • the surface morphology of the implants prepared in Example 6 and Comparative Example 6 was observed by FESEM. It can be seen from Figure 2 that the surface structure of the implant without steam humidification is a multi-fiber overlapping porous structure, and the gaps between the threads are large; while Figure 1 shows that the surface structure of the implant after steam humidification is multi-fiber overlapping porous structure The structure becomes an overall homogeneous shape without voids and fibers, and the surface is relatively smooth, indicating that the surface of a high-density layer can be formed after steam humidification, and its porosity is much lower than that of the implant silk before treatment (or gap rate).
  • FIG. 3 shows that the cross-section of the steam-humidified implant is dense, indicating that the prepared implant tube wall forms a dense and uniform structure, and further shows that the post-treatment of the silk thread after steam humidification can make the inside of the silk tube wall, The outer cross-linking reaction is more uniform, making the surface of the implant and the wall of the tube more dense and uniform, and it is more suitable for implants used as eye surgery to control tear discharge or retention.
  • Example 1 Tensile strength (MPa) Example 1 19
  • Example 2 twenty two Example 3 twenty one
  • Example 4 twenty three
  • Example 5 twenty two
  • Example 6 22.8 Comparative example 1 /(The sample failed to form a conduit and could not be measured) Comparative example 2 0.3 Comparative example 3 17.5
  • Comparative example 4 16 Comparative example 5 /(The sample failed to form a conduit and could not be determined) Comparative example 6 18.5
  • the tensile strength of the cross-linked implant catheter that is, Examples 1 to 6 is greater than that of the non-cross-linked implant catheter, that is, Comparative Example 2, which is Since the non-cross-linked nanofibers will partially swell or even dissolve when they are dissolved in water, the structure of the catheter will be destroyed, thereby losing its strength.
  • the amount of crosslinking agent used in Comparative Example 4 (1000 mg) is much greater than the amount of crosslinking agent used in Example 6 (100 mg), which further illustrates that the present invention forms a spinning solution by adding a small amount of crosslinking agent to the water-soluble polymer solution.
  • the spinning process can reduce the amount of cross-linking agent, improve the cross-linking uniformity of the implant, improve its mechanical strength, and maintain its structural stability.
  • the samples of Examples and Comparative Examples were completely submerged in physiological saline at 37°C, and the changes in shape were observed after soaking for 30 minutes.
  • the samples of Examples 1 to 6 still maintained the shape of the catheter, and the whole was in a transparent gel state, and the implant The surface is smooth, but the rehydration rate of Comparative Example 2 is slow, and the surface of the catheter no longer presents a smooth surface, and obvious swelling occurs, and it is easy to adhere to the contact surface; the surface of the catheter after rehydration of the sample of Comparative Example 4 is not smooth, Poor stability.
  • the samples of Comparative Examples 3 and 6 were loose after rehydration, but the structure was relatively stable. It can be seen from the above comparison that the surface structure of the implant prepared by the present invention is smooth and more stable after rehydration.
  • Example 1 Sample name Loss rate (%) Example 1 1.2
  • Example 2 1.5
  • Example 3 Example 4
  • Example 5 1.1
  • Example 6 0.8 Comparative example 2 98.3 Comparative example 3 5.5 Comparative example 4 13.4 Comparative example 6 6.2
  • the samples of Examples 1 to 6 are soaked at a temperature at which the water-soluble polymer can be dissolved, and the loss rate of the samples in the solution is lower than that of the samples of Comparative Examples 2 to 4 and Comparative Example 6, which is Since the samples treated by electrospinning and steam humidification have a higher degree of crosslinking, the degree of crosslinking is more uniform, the part of non-crosslinking in the sample is very low, and the crosslinked gel has better stability in the solution , so the sample loss rate is low. Since Comparative Examples 3 and 6 were not post-treated by steam humidification, the degree of crosslinking was lower than that of the implants of Examples 1 and 6 after post-treatment, so the loss rate was higher than that of Examples 1 and 6.
  • Comparative Example 2 was almost completely dissolved without cross-linking reaction, and the loss rate was as high as 98.3%.
  • the loss rate of Comparative Example 4 was 13.4%. This was because the cross-linking reaction only occurred on the surface of the tube wall, and almost no cross-linking reaction occurred inside the tube wall. During the soaking treatment, the uncross-linked part would be dissolved, and the loss rate higher and less stable. Therefore, the implant prepared by the present invention has high cross-linking degree and good cross-linking uniformity, and can improve the stability of the catheter.
  • the implant disclosed by the present invention which uses cross-linked polymers as components, has high strength after rehydration after post-treatment process, controllable size, stable structure, and the polymer itself has a good biophase Capacitive, suitable as an implant for therapeutic or non-therapeutic purposes.

Abstract

本发明提供了一种高强度植入物，所述的高强度植入物包括由水溶性聚合物经纺丝-交联制备得到聚合物丝线，再经后处理形成的致密层，所述后处理使聚合物丝线间空隙减小。该高强度植入物强度高、结构更加致密，可以作为美容产品或治疗疾病的产品。

Description

一种高强度植入物及其制备方法 技术领域
本发明涉及医用材料及植入器械技术领域，具体涉及一种高强度植入物及其制备方法和应用。
背景技术
随着科学技术的发展，通过手术植入管状物作为治疗疾病的一种方法，依据疾病的不同所需要的的管状物性质并不相同，例如，当人体某部位因血管老化、栓塞或破损不能正常供血时，通过人造血管置换来维持血液流通，理想的人造血管具有性能稳定、一定的强度和柔韧度以及无渗血易缝合抗凝血的特点；在治疗由于顽固性的高眼压引起的青光眼时，通过植入导流管来控制眼压、降低术后并发症成为越来越多医生选择的治疗的手段，该类型的导管具有控制流出液体速度的同时，长时间保持固定形态也是一项重要的标准；对于泪道阻塞引起的溢泪症治疗过程中，通过激光探通联合插入人造泪管是较好的治疗方法，较强的力学性能和生物相容性是保证泪液畅流的前提。因此，制造一种机械强度高的、生物相容性好的植入物，特别是应用于小口径的人工血管置换、眼科类疾病治疗过程中使用到的毫米级甚至微米级导管显得尤为重要。
现有技术中制备管状植入物，存在采用先纺丝，再交联的工艺过程，通过该工艺得到的管状植入物，交联反应只发生在植入物的表面，造成交联程度不均匀，从而强度较低等缺陷，无法满足临床的应用需求。
发明内容
为解决现有技术的不足，本发明提供了一种高强度植入物，其包括聚合物丝线经后处理形成的致密层，使聚合物丝线间空隙(或间隙)减小，该高强度植入物尺寸控制准确、生物相容性好、强度高、有韧性，适用于手术操作。
本发明的第一方面，提供了一种高强度植入物，所述的高强度植入物包括聚合物丝线经后处理形成的致密层，所述后处理使聚合物丝线间空隙(或间隙)减小。
所述的后处理包括但不限于蒸汽加湿、电热式加湿、电极式加湿或高压喷雾加湿。优 选的，所述的后处理为蒸汽加湿。
优选的，后处理时间为5-50min中的任一数值。进一步优选为10-30min中的任一数值。例如，后处理时间可以为5、6、7、8、9、10、11、12、13、14、15、20、25、26、27、28、29、30、35、40、45、50min。
优选的，后处理形成的致密层的空隙率低于处理前聚合物丝线的空隙率(或间隙率)。
所述的聚合物丝线由水溶性聚合物纺丝-交联制备得到。
优选的，所述的水溶性聚合物可以为离子型、非离子型或两亲性水溶性聚合物。
优选的，所述的水溶性聚合物可以为天然水溶性聚合物、半合成水溶性聚合物或合成水溶性聚合物。其中，天然水溶性聚合物包括但不限于从淀粉、蛋白质、牛眼玻璃体或海藻等中提取的水溶性聚合物，例如明胶、透明质酸钠。半合成水溶性聚合物包括但不限于纤维素、甲基纤维素、羟甲基纤维素或羧甲基壳聚糖等。合成水溶性聚合物包括但不限于聚丙烯酸、聚丙烯酰胺或聚乙烯醇等。
在本发明的一个具体实施方式中，所述的水溶性聚合物选自聚乙烯醇、明胶、羧甲基壳聚糖、纤维素或透明质酸钠中的一种或两种以上。
所述交联使用交联剂。
优选的，所述的交联剂可以为环氧化合物、聚乙二醇-环氧化合物或多臂-聚乙二醇-环氧化合物。所述的环氧化合物可以为环氧乙烷、环氧丙烷、1,2-环氧丁烷或1,4-环氧丁烷，也可以为双环氧化合物(例如1，4-丁二醇二缩水甘油醚、1,2,3,4,二环氧丁烷)或多环氧化合物(多为3个或3个以上，例如甘油三(1,2-环氧)丙醚)。所述的多臂-聚乙二醇-环氧化合物(多为3个或3个以上)包括但不限于三臂-聚乙二醇-环氧基、四臂-聚乙二醇-环氧基、五臂-聚乙二醇-环氧基、六臂-聚乙二醇-环氧基、七臂-聚乙二醇-环氧基、八臂-聚乙二醇-环氧基、九臂-聚乙二醇-环氧基或十臂-聚乙二醇-环氧基等。
进一步优选的，所述的交联剂选自双环氧化合物、多环氧化合物或多臂-聚乙二醇-环氧化合物。
在本发明的一个具体实施方式中，所述的交联剂选自1，4-丁二醇二缩水甘油醚、 1,2,3,4,-二环氧丁烷、甘油三(1,2-环氧)丙醚、四臂-聚乙二醇-环氧基或三臂-聚乙二醇-环氧基中的一种或两种以上。
优选的，交联剂的加入质量为水溶性聚合物加入质量的0.01-0.10中的任一数值倍，进一步优选为0.01-0.05、0.01-0.07、0.01-0.02、0.02-0.07、0.01-0.035或0.02-0.05倍，例如可以为0.01、0.015、0.02、0.025、0.03、0.035、0.04、0.045、0.05、0.06、0.07、0.08、0.09、0.1倍。
在本发明的一个具体实施方式中，所述的高强度植入物包括将水溶性聚合物与水混合后获得水溶性聚合物溶液(水溶性聚合物溶液浓度为0.05-0.2g/mL)，再加入交联剂，形成纺丝液，然后纺丝-交联获得。
在本发明的一个具体实施方式中，所述的植入物为水溶性聚合物与水混合后加入交联剂和催化剂，然后纺丝-交联获得。其中，所述的催化剂选自碱金属的氢氧化物或碱金属的碳酸盐。其中，所述的碱金属选自锂、钠、钾、铷、铯或钫。所述的碱金属的氢氧化物选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铷、氢氧化铯或氢氧化钫。所述的碳酸盐可以为正盐、酸式盐或碱式盐，例如碳酸钠、碳酸钾、碳酸锌、碳酸钙、碳酸镁、碳酸铁、碳酸铜等。
在本发明的一个具体实施方式中，所述的催化剂选自氢氧化钠、氢氧化钾或碳酸钠。
优选的，所述的催化剂按照催化剂与水溶性聚合物的质量比为0.01-0.5:1(优选0.25-0.5:1或0.01-0.25:1)加入。例如可以按照催化剂与水溶性聚合物的质量比为(0.01、0.05、0.1、0.15、0.2、0.25、0.3、0.4、0.5)：1加入。
优选的，所述的纺丝-交联中的纺丝为相分离纺丝、闪蒸纺丝、静电纺丝、液晶纺丝或反应纺丝。进一步优选为静电纺丝。
优选的，所述的植入物可以为美容产品或治疗疾病的产品。
优选的，所述的美容产品包括但不限于鼻腔植入物、眼部植入物、隐形眼镜、皮下植入物(例如面部或颈部注射后可以减少抚平皱纹)。
优选的，所述的治疗疾病的产品包括但不限于眼部植入物(例如导流管、人造泪管)、 心脏植入物(例如心脏瓣膜)、口腔防护物、假牙垫料、组织替代物、输尿管修补物、筋和韧带代用物、绷带、缝线、血管植入物(例如人造血管)、骨科的板或钉、人工关节或吻合器。其中，所述吻合器例如皮肤吻合器、消化道(食道、胃肠等)圆形吻合器、直肠吻合器、圆形痔吻合器、包皮环切吻合器、血管吻合器、疝气吻合器、肺切割缝合器等。
所述的高强度植入物优选为管状植入物。根据使用需要，也可以制成片状、环状、棒状等其他形状的植入物。
本发明的第二方面，提供了一种管状植入物，所述的管状植入物包含管体，所述的管体包含管内空腔和管壁。
优选的，所述的管内空腔为空心圆柱形。
所述的管内空腔的直径为20-4000μm中的任一数值(优选30-3000μm)。例如所述的管内空腔的直径可以为20、50、100、500、1000、1500、2000、2500、3000、3500或4000μm
优选的，所述的管壁的平均厚度为100-2000μm中的任一数值。例如所述的管壁的平均厚度可以为100、200、500、1000、1500或2000μm。
优选的，所述的管体还包括管外结构。
所述的管外结构可以根据植入部位调整形状，为了减少脱落等，其可以全部或部分优选为圆柱形结构、环纹结构、圆锥形结构、长方体结构、正方体结构或球形结构等。
优选的，所述的管外结构平均直径为50-7000μm中的任一数值(优选200-6500μm中的任一数值)。例如管外结构平均直径可以为50、100、500、1000、1500、2000、2500、3000、3500、4000、4500、5000、5500、6000、6500、7000μm。
优选的，所述的管状植入物包括聚合物丝线经后处理形成的致密层，所述后处理使聚合物丝线间空隙减小。
优选的，所述的管状植入物可以为美容产品或治疗疾病的产品。
优选的，所述的美容产品包括但不限于鼻腔植入物、眼部植入物、隐形眼镜、皮下植入物(例如面部或颈部注射后可以减少抚平皱纹)。
优选的，所述的治疗疾病的产品包括但不限于眼部植入物(例如导流管、人造泪管)、 心脏植入物(例如心脏瓣膜)、口腔防护物、假牙垫料、组织替代物、输尿管修补物、筋和韧带代用物、绷带、缝线、血管植入物(例如人造血管)、骨科的板或钉、人工关节或吻合器。其中，所述吻合器例如皮肤吻合器、消化道(食道、胃肠等)圆形吻合器、直肠吻合器、圆形痔吻合器、包皮环切吻合器、血管吻合器、疝气吻合器、肺切割缝合器等。
本发明的第三方面，提供了一种高强度植入物的制备方法，所述的制备方法包括将纺丝液进行纺丝-交联获得聚合物丝线，后处理形成致密层。所述后处理使聚合物丝线相互溶和并交联到一起形成无空隙的整体或将丝线间空隙(或间隙)减小。从而形成强度更好的致密层管壁结构。
优选的，所述的后处理选自蒸汽加湿、电热式加湿、电极式加湿或高压喷雾加湿。
因此，本发明可以通过加入少量交联剂，同时通过控制纺丝的时间和工艺条件，实现聚合物交联度的动态可控，具有工艺简单，产品形貌、交联度、强度均可控的优势，适合产业化推广。
优选的，所述的制备方法包括将纺丝液通过静电纺丝设备上的丝线形成纺丝-交联层。优选的，所述纺丝-交联得到的丝线的直径为20-4000μm中的任一数值，优选30-3000μm。进一步优选为30-1000μm、50-1000μm、100-1000μm、30-100μm或50-100μm。例如丝线的直径可以为20、50、100、500、1000、1500、2000、2500、3000、3500或4000μm。
优选的，所述的丝线可以为任何材质，优选为金属丝线。例如钢丝(例如不锈钢丝)、钨丝、金丝、铂金丝或铜丝等。
优选的，所述的纺丝液包含水溶性聚合物和水。具体来说，将水溶性聚合物溶于水，完全溶解得到水溶性聚合物溶液。所述水溶性聚合物溶液浓度为0.05-0.2g/mL中的任一数值，优选0.05-0.15g/mL。例如浓度可以为0.05、0.1、0.11、0.15、0.17、0.18、0.19、0.2、等g/mL。若聚合物浓度过大(如对比例1)，粘度过高导致无法进行纺丝。
优选的，所述的水溶性聚合物可以为离子型、非离子型或两亲性水溶性聚合物。
优选的，所述的水溶性聚合物可以为天然水溶性聚合物、半合成水溶性聚合物或合成水溶性聚合物。其中，天然水溶性聚合物包括但不限于从淀粉、蛋白质、牛眼玻璃体或海 藻等中提取的水溶性聚合物，例如明胶、透明质酸钠。半合成水溶性聚合物包括但不限于纤维素、甲基纤维素、羟甲基纤维素或羧甲基壳聚糖等。合成水溶性聚合物包括但不限于聚丙烯酸、聚丙烯酰胺或聚乙烯醇等。
在本发明的一个具体实施方式中，所述的水溶性聚合物选自聚乙烯醇、明胶、羧甲基壳聚糖、纤维素或透明质酸钠中的一种或两种以上。
优选的，所述的纺丝液中还包含交联剂。优选的，所述的交联剂可以为环氧化合物、聚乙二醇-环氧化合物或多臂-聚乙二醇-环氧化合物。所述的环氧化合物可以为环氧乙烷、环氧丙烷、1,2-环氧丁烷或1,4-环氧丁烷，也可以为双环氧化合物(例如1，4-丁二醇二缩水甘油醚、1,2,3,4,-二环氧丁烷)或多环氧化合物(多为3个或3个以上，例如甘油三(1,2-环氧)丙醚)。所述的多臂-聚乙二醇-环氧化合物(多为3个或3个以上)包括但不限于三臂-聚乙二醇-环氧基、四臂-聚乙二醇-环氧基、五臂-聚乙二醇-环氧基、六臂-聚乙二醇-环氧基、七臂-聚乙二醇-环氧基、八臂-聚乙二醇-环氧基、九臂-聚乙二醇-环氧基或十臂-聚乙二醇-环氧基等。
进一步优选的，所述的交联剂选自双环氧化合物、多环氧化合物或多臂-聚乙二醇-环氧化合物。
在本发明的一个具体实施方式中，所述的交联剂选自1，4-丁二醇二缩水甘油醚、1,2,3,4,-二环氧丁烷、甘油三(1,2-环氧)丙醚、四臂-聚乙二醇-环氧基或三臂-聚乙二醇-环氧基中的一种或两种以上。
优选的，交联剂的加入质量为水溶性聚合物加入质量的0.01-0.10中的任一数值倍，进一步优选为0.01-0.05、0.01-0.02或0.02-0.05倍，例如可以为0.01、0.02、0.03、0.04、0.05倍。
优选的，所述的后处理包括但不限于蒸汽加湿、电热式加湿、电极式加湿或高压喷雾加湿。优选的，所述的后处理为蒸汽加湿。
优选的，后处理时间为5-50min中的任一数值。进一步优选为10-30min中的任一数值。例如，后处理时间可以为5、6、7、8、9、10、11、12、13、14、15、20、25、26、27、 28、29、30、35、40、45、50min。
优选的，后处理形成的致密层的空隙率低于处理前聚合物丝线间空隙率(或间隙率)。
在本发明的一个具体实施方式中，所述的制备方法包括将纺丝液转移至静电纺丝设备的接收装置，纺丝-交联后再进行蒸汽加湿致密化处理。
所述蒸汽加湿优选水蒸气加湿。
所述蒸汽加湿的温度为室温～125℃。
所述蒸汽加湿的时间为5-50min中的任一数值。进一步优选为10-30min中的任一数值。例如，蒸汽加湿时间可以为5、6、7、8、9、10、11、12、13、14、15、20、25、26、27、28、29、30、35、40、45、50min。
所述纺丝的时间为10-150min中的任一数值，优选20-120min中的任一数值。例如纺丝的时间可以为10、20、40、50、60、100、120、130、150min。
在本发明的一个具体实施方式中，所述的制备方法包括将纺丝液转移至静电纺丝设备的接收装置，推注速度优选为0.1-3mL/h中的任一数值(优选为0.1-2mL/h、0.2-0.5mL/h或0.1-1mL/h或1-2mL/h，例如0.1、0.2、0.5、1、1.5、2、2.5、3mL/h)，电压优选为5-50kV中的任一数值(优选为10-30kV或10-25kV或10-22kV或22-30kV或22-25kV或25-30kV，例如5、10、20、30、40、45、50)，接收距离优选为0.1-20cm中的任一数值(优选为0.5-15cm或0.5-10cm或10-15cm，例如5、10、15、20)，安装丝线，进行纺丝-交联；然后再进行蒸汽加湿5-50min，获得高强度植入物。
为提高交联程度，当使用聚乙烯醇作为水溶性聚合物时，所述的制备方法还包括纺丝-交联后或蒸汽加湿后、反复冷冻-融化的步骤。优选反复冷冻-融化5-8次。具体为将聚合物丝线在0℃以下(如0～-70℃)的环境中冷冻，再将其置于0℃以上(如0-40℃)的环境中融化。
优选的，所述的制备方法还包括酸浸、清洗、脱模、干燥和/或灭菌的步骤。其中，所述酸浸为在酸性溶液(即pH＜7的溶液)中浸泡，所述酸性溶液可以为强酸性水溶液例如硫酸溶液、盐酸溶液等，或有机酸水溶液，例如醋酸溶液、甲酸溶液等。
在本发明的一个具体实施方式中，所述的制备方法包括：
将水溶性聚合物与水混合，加入交联剂、催化剂，获得纺丝液；
将纺丝液转移至静电纺丝设备的接收装置，推注速度优选为0.1-3mL/h(优选为0.1-2mL/h或0.1-1mL/h或1-2mL/h)，电压优选为5-50kV(优选为10-30kV或10-25kV或10-22kV或22-30kV或22-25kV或25-30kV)，接收距离优选为0.1-20cm(优选为0.5-15cm或0.5-10cm或10-15cm)，安装丝线，将纺丝液在丝线上形成纺丝-交联层；
然后，蒸汽加湿，酸浸、清洗(优选生理盐水清洗)、脱模、干燥和/或灭菌，获得高强度植入物。
本发明的第四方面，提供了一种上述的制备方法获得的高强度植入物。
本发明的第五方面，提供了一种上述的高强度植入物、管状植入物或上述的制备方法获得的高强度植入物在制备美容产品或治疗疾病的产品中的应用。
优选的，所述的美容产品包括但不限于鼻腔植入物、眼部植入物、隐形眼镜、皮下植入物(例如面部或颈部注射后可以减少抚平皱纹)。
优选的，所述的治疗疾病的产品包括但不限于眼部植入物(例如导流管、人造泪管)、心脏植入物(例如心脏瓣膜)、口腔防护物、假牙垫料、组织替代物、输尿管修补物、筋和韧带代用物、绷带、缝线、血管植入物(例如人造血管)、骨科的板或钉、人工关节或吻合器。其中，所述吻合器例如皮肤吻合器、消化道(食道、胃肠等)圆形吻合器、直肠吻合器、圆形痔吻合器、包皮环切吻合器、血管吻合器、疝气吻合器、肺切割缝合器等。
在本发明的一个具体实施方式中，所述的产品为人造血管、人造泪管或导流管。
与现有技术相比，本发明具有以下突出特点：
1、采用环氧类化合物作为交联剂，可以用于聚乙烯醇、明胶、羧甲基壳聚糖、纤维素或透明质酸钠等多种不同的水溶性聚合物的交联反应，适用范围广；并避免了使用现有技术中常用的硼等重金属有毒元素以及细胞毒性较高的醛类交联剂，保障植入物的生物安全性；另外，环氧化合物中的环氧基团与聚合物中的氨基或羟基的反应速率较慢，确保纺丝液在纺丝的过程中性能的稳定，利于纺丝的进行，并为后续的交联、致密化的处理提供 保障，同时交联反应形成的碳氮键或醚键结构为单键且不容易断裂，提高了植入物的强度及稳定性。
2、相较于现有技术中先纺丝再交联的工艺而言，本发明通过在水溶性聚合物溶液中加入少量交联剂形成纺丝液，可以随着纺丝进行，溶剂挥发，溶质(如交联剂)浓度增加，形成交联的丝线，随着蒸汽加湿等后处理的进行，丝线全部或部分相互溶和，交联程度进一步增加，从而得到交联均匀、包含致密层管壁的高强度植入物。另外，交联剂用量的减少，使植入物中交联剂的残留量低，进一步保证了其应用的安全性。
3、本发明通过调整纺丝液中水溶性聚合物与交联剂的用量，保证了纺丝和后处理中交联的稳定性和均匀性，并且交联程度可控，优化了植入物的形貌及结构；本发明的工艺简单，操作方便，利于产业化推广。
4、通过本发明制备得到的高强度植入物的表面、管壁均为致密、均匀的结构，具有良好的强度(高达20MPa)、弹性，植入体内后可稳定存在，降低了植入时出现弯曲、断裂的风险，并且该高强度植入物复水后具有韧性好、体积膨胀率易控、结构稳定等特点，更适用于作为眼部手术使用控制泪液排出或留存的植入物。
附图说明
图1：场发射扫描电子显微镜(FESEM)观察实施例6制备的植入物，其中，左图为植入物表面的形貌结构，右图为植入物表面的进一步放大图。
图2：场发射扫描电子显微镜(FESEM)观察对比例6制备的植入物，其中，左图为植入物表面的形貌结构，右图为植入物表面的进一步放大图。
图3：场发射扫描电子显微镜(FESEM)观察实施例6制备的植入物，其中，左图为植入物横截面的形貌结构，右图为植入物横截面的进一步放大图。
具体实施方式
通过以下实施例对本发明作进一步的详细说明，这并不限制本发明的保护范围。
本发明所述的“植入物”是放置于外科操作造成的或者生理存在的体腔中，留存一定时间的可植入型物品。其可以根据疾病的类型或者外科操作造成的形状或体腔形状任意调 整其形状、长短、薄厚等。
本发明所述的“交联”是线型或支型高分子链间以共价键连接成网状或体型高分子的过程，包括化学交联和物理交联。
本发明所述的“交联-纺丝”或者“纺丝-交联”代表交联与纺丝同时进行，其中，所述的“同时”代表交联的过程与纺丝的过程部分时间重叠，并不仅仅包括同一个时刻开始，和/或，同一个时刻结束，和/或，交联的过程与纺丝的过程时间的完全重叠。当然，纺丝的总时间与交联的总时间并不一定一致，可以纺丝时间长于交联，可以纺丝时间短于交联，也可以时间一致。
本发明的空隙或称为间隙，可反应出植入物表面的致密化程度。
实施例中未注明具体条件的实验方法，通常按照常规条件以及手册中所述的条件，或按照制造厂商所建议的条件；所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1
取5.0g纤维素加到95mL水里，90℃下搅拌，直至完全溶解。向水溶液中加入10mL的氢氧化钠溶液(25wt.％)，加入50mg的1，4-丁二醇二缩水甘油醚，搅拌均匀，将溶液转移到静电纺丝装置的注射器中，离心脱泡后，开启静电纺丝机，设置推注速度为0.1mL/h，加速电压为10KV，并安装不锈钢丝接收装置，设置接收距离为10cm，不锈钢丝的直径为30μm进行纺丝，运行20min后，将转子上的丝线取下，经温度为100℃，蒸汽加湿10min，密封转移到25℃的环境中，放置12h。将丝线转移到10％的醋酸溶液中浸泡1h后，用生理盐水多次清洗，将导管从丝线上取下，放于真空干燥箱内，设置温度为40℃，干燥24h，包装后25kGy辐射灭菌获得产品，制得导管的平均内径为30～40μm，外径的平均直径为220～230μm。制备的高强度植入物可用于眼部植入物(例如导流管、人造泪管)。
实施例2
取6.0g明胶加到34mL水里，50℃下搅拌，直至完全溶解。向水溶液中加入10mL的氢氧化钾溶液(15wt.％)，加入300mg的甘油三(1,2-环氧)丙醚，搅拌均匀，将溶液转移到静电纺丝装置的注射器中，离心脱泡后，开启静电纺丝机，设置推注速度为2mL/h，加 速电压为20KV，并安装钨丝接收装置，设置接收距离为15cm，钨丝的直径为3000μm进行纺丝，运行60min后，将转子上的丝线取下，经温度为60℃，蒸汽加湿30min，密封转移到40℃的环境中，放置24h。将丝线转移到10％的盐酸溶液中浸泡1h后，清洗、干燥和灭菌的工艺步骤采用实施例1的操作方法，制得导管的平均内径为2990～3000μm，外径的平均直径为6400～6500μm。制备的高强度植入物可用于血管的重建手术。
实施例3
取10.0g羧甲基壳聚糖加到90mL水里，搅拌直至完全溶解。向水溶液中加入2mL的氢氧化钠溶液(5wt.％)，加入200mg的四臂-聚乙二醇-环氧基，搅拌均匀，将溶液转移到静电纺丝装置的注射器中，离心脱泡后，开启静电纺丝机，设置推注速度为0.5mL/h，加速电压为30KV，并安装金丝接收装置，设置接收距离为20cm，金丝的直径为1000μm进行纺丝，运行120min后，将转子上的丝线取下，经温度为25℃，蒸汽加湿30min，密封转移到30℃的环境中，放置18h。将丝线转移到10％的硫酸溶液中浸泡1h后，清洗、干燥和灭菌的工艺步骤采用实施例1的操作方法，制得植入物导管的平均内径为1000～1100μm，外径的平均直径为3200～3300μm。
实施例4
取6.0g聚乙烯醇加到34mL水里，90℃下搅拌，直至完全溶解。向水溶液中加入10mL的氢氧化钾溶液(30wt.％)，加入300mg的三臂-聚乙二醇-环氧基，搅拌均匀，将溶液转移到静电纺丝装置的注射器中，离心脱泡后，开启静电纺丝机，设置推注速度为0.5mL/h，加速电压为20KV，并安装钨丝接收装置，设置接收距离为15cm，钨丝的直径为100μm进行纺丝，运行20min后，将转子上的丝线取下，经温度为121℃，蒸汽加湿30min，密封转移到35℃的环境中，放置14h，将丝线置于-20℃的环境中冷冻，再将其置于25℃的环境中融化，反复冷冻-融化5～8次。将丝线转移到10％的盐酸溶液中浸泡1h后，清洗、干燥和灭菌的工艺步骤采用实施例1的操作方法，制得植入物导管的平均内径为100～110μm，外径的平均直径为280～290μm。
实施例5
取20.0g透明质酸钠加到90mL水里，搅拌直至完全溶解。向水溶液中加入10mL的碳酸钠溶液(20wt.％)，加入700mg的1,2,3,4-二环氧丁烷，搅拌均匀，将溶液转移到静电纺丝装置的注射器中，离心脱泡后，开启静电纺丝机，设置推注速度为2mL/h，加速电压为40KV，并安装铂金丝接收装置，设置接收距离为10cm，铂金丝的直径为50μm进行纺丝，运行20min后，将转子上的丝线取下，经温度为30℃，蒸汽加湿30min，密封转移到30℃的环境中，放置16h。将丝线转移到10％的硫酸溶液中浸泡1h后，清洗、干燥和灭菌的工艺步骤采用实施例1的操作方法，制得植入物导管的平均内径为50～60μm，外径的平均直径为250～260μm。
实施例6
取10.0g聚乙烯醇加到90mL水里，90℃下搅拌，直至完全溶解。向水溶液中加入100mg的1，4-丁二醇二缩水甘油醚，搅拌均匀，将溶液转移到静电纺丝装置的注射器中，离心脱泡后，开启静电纺丝机，设置推注速度为0.2mL/h，加速电压为5KV，并安装不锈钢接收装置，设置接收距离为5cm，不锈钢的直径为60μm进行纺丝，运行60min后，将转子上的丝线取下，经温度为90℃，蒸汽加湿10min，密封转移到25℃的环境中，放置24h。将丝线用生理盐水多次清洗，将导管从丝线上取下，放于真空干燥箱内，设置温度为40℃，干燥24h，包装后25kGy辐射灭菌获得产品，制得植入物导管的平均内径为55～65μm，外径的平均直径为190～220μm。
对比例1
取25.0g聚乙烯醇加到75mL水里，90℃下搅拌，直至完全溶解。向水溶液中加入10mL的氢氧化钠溶液(15wt.％)，加入250mg的1，4-丁二醇二缩水甘油醚，搅拌均匀，将溶液转移到静电纺丝装置的注射器中，设置推注速度为2mL/h，加速电压为40KV，并安装铂金丝接收装置，设置接收距离为10cm，在纺丝的过程中发现溶液的粘度高，在静电场里的作用下，溶液经针头挤出后在针头的Taylor锥顶点无法被加速形成丝束在接收金属丝表面形成纤维层。
对比例2
取6.0g聚乙烯醇加到34mL水里，90℃下搅拌，直至完全溶解，搅拌均匀，将溶液转移到静电纺丝装置的注射器中，离心脱泡后，开启静电纺丝机，设置推注速度为0.5mL/h，加速电压为20KV，并安装钨丝接收装置，设置接收距离为15cm，钨丝的直径为100μm进行纺丝，运行20min后，将转子上的丝线取下，经温度为121℃，蒸汽加湿30min，密封转移到35℃的环境中，放置14h，将丝线置于-20℃的环境中冷冻，再将其置于25℃的环境中融化，反复冷冻-融化5～8次。将丝线清洗、干燥和灭菌的工艺步骤采用实施例1的操作方法，制得植入物导管的平均内径为100～110μm，外径的平均直径为280～290μm。
对比例3
取5.0g纤维素加到95mL水里，90℃下搅拌，直至完全溶解。向水溶液中加入10mL的氢氧化钠溶液(15wt.％)，加入50mg的1，4-丁二醇二缩水甘油醚，搅拌均匀，将溶液转移到静电纺丝装置的注射器中，离心脱泡后，开启静电纺丝机，设置推注速度为0.1mL/h，加速电压为10KV，并安装不锈钢丝接收装置，设置接收距离为10cm，不锈钢丝的直径为30μm进行纺丝，运行20min后，将转子上的丝线取下，密封转移到25℃的环境中，放置12h。将丝线转移到10％的醋酸溶液中浸泡1h后，用生理盐水多次清洗，将导管从丝线上取下，放于真空干燥箱内，设置温度为40℃，干燥24h，包装后25kGy辐射灭菌获得产品，制得植入物导管的平均内径为30～40μm，外径的平均直径为220～230μm。
对比例4
取10.0g聚乙烯醇加到90mL水里，90℃下搅拌，直至完全溶解。将溶液转移到静电纺丝装置的注射器中，离心脱泡后，开启静电纺丝机，设置推注速度为0.2mL/h，加速电压为5KV，并安装不锈钢丝接收装置，设置接收距离为5cm，不锈钢丝的直径为60μm进行纺丝，运行60min后，将转子上的丝线取下，将其浸泡于含有1000mg 1，4-丁二醇二缩水甘油醚的氢氧化钠的溶液(30wt.％)中进行交联。丝线清洗、干燥和灭菌的工艺步骤采用实施例6的操作方法相同。
对比例5
取6.0g聚乙烯醇加到34mL水里，90℃下搅拌，直至完全溶解。加入300mg的戊二醛， 搅拌均匀，试验过程中发现溶液在搅拌时粘度增加，形成凝胶化的固体，无法进行静电纺丝。
对比例6
取10.0g聚乙烯醇加到90mL水里，90℃下搅拌，直至完全溶解。向水溶液中加入100mg的1，4-丁二醇二缩水甘油醚，搅拌均匀，将溶液转移到静电纺丝装置的注射器中，离心脱泡后，开启静电纺丝机，设置推注速度为0.2mL/h，加速电压为5KV，并安装不锈钢接收装置，设置接收距离为5cm，不锈钢的直径为60μm进行纺丝，运行60min后，将转子上的丝线取下，密封转移到25℃的环境中，放置24h。将丝线用生理盐水多次清洗，将导管从丝线上取下，放于真空干燥箱内，设置温度为40℃，干燥24h，包装后25kGy辐射灭菌获得产品，制得植入物导管的平均内径为55～65μm，外径的平均直径为190～220μm。致密度检测
通过FESEM观察实施例6、对比例6制备得到的植入物表面形态。从图2可以看出，未经过蒸汽加湿的植入物表面结构为多纤维重叠多孔结构，丝线间的空隙大；而图1表明，经过蒸汽加湿后的植入物表面结构由多纤维重叠多孔结构变为无空隙、无纤维丝状的整体均一形态，表面较为光滑，表明经过蒸汽加湿后处理可形成高致密层的表面，其空隙率远低于处理前植入物丝线的空隙率(或间隙率)。
进一步地，通过FESEM观察实施例6制备得到的植入物横截面形态。图3表明，经过蒸汽加湿的植入物，其横截面呈致密形态，说明制备的植入物管壁形成致密、均一的结构，进一步表明丝线经过蒸汽加湿的后处理可以使丝线管壁内、外的交联反应更为均匀，使得植入物表面、管壁更加致密、均匀，更适用于作为眼部手术使用控制泪液排出或留存的植入物。
拉伸强度性能的检测
将实施例和对比例中获得的样品，放于设置温度为37℃的生理盐水中浸泡60min，取出吸去表面游离的水，采用深圳三思纵横科技股份有限公司的UTM6202电子万能拉力试验机，测定拉伸强度。样品的检测结果如表1所示：
表1样品的拉伸强度检测结果
样品 拉伸强度(MPa)
实施例1 19
实施例2 22
实施例3 21
实施例4 23
实施例5 22
实施例6 22.8
对比例1 /(样品未能形成导管无法测定)
对比例2 0.3
对比例3 17.5
对比例4 16
对比例5 /(样品未能形成导管无法测定)
对比例6 18.5
由表1中的拉伸强度的检测结果可以看出，交联后的植入物导管即实施例1～6的拉伸强度均大于非交联的植入物导管即对比例2，这是由于非交联的纳米纤维在水溶时会发生部分的溶胀甚至溶解，破坏了导管的结构，从而使其强度丧失。通过对比表1中的对比例3和实施例1，对比例6和实施例6的数据，可以看出，采用蒸汽加湿后处理的导管，拉伸强度高于未蒸汽加湿后处理的导管，这是由于导管经蒸汽加湿的后处理，降低了丝线间的空隙，提高了导管的致密性，从而提高其拉伸强度。对比表中的对比例4和实施例6可以看出，静电纺丝后再交联处理，其拉伸强度低于经蒸汽加湿的后处理的实施例6的导管，这是由于，静电纺丝后再进行交联，此时的交联反应主要发生在导管表面，交联不均匀，导致其强度较低，而本发明的交联可以均匀的发生在导管的内壁及表面，形成致密层，进一步提高其强度。上述结果说明，本发明中的蒸汽加湿后处理能够提高导管的机械强度， 特别是在将管状物复水浸湿后，经过后处理的导管拉伸强度远高于非交联的。
此外，对比例4的交联剂用量(1000mg)远大于实施例6中交联剂用量(100mg)，也进一步说明，本发明通过在水溶性聚合物溶液中加入少量交联剂形成纺丝液进行纺丝的工艺，可以在减少交联剂用量的同时，提高植入物的交联均匀性，提高其机械强度，从而保持其结构稳定性。
复水后植入物导管形态检测
将实施例和对比例样品完全浸没于37℃的生理盐水中，浸泡30min后观察形态的变化，实施例1～6样品依然保持导管的形态，整体呈现透明的凝胶态，并且植入物的表面光滑，但对比例2复水速率较慢，并且导管表面不再呈现光滑的表面，出现明显的溶胀现象，容易与接触面发生粘连；对比例4的样品复水后的导管表面不光滑，稳定性差。对比例3、6的样品复水后导管表面疏松，但结构相对稳定。通过上述比较可知，通过本发明制备得到的植入物的表面结构光滑、复水后更稳定。
植入物导管稳定性测试
分别称取实施例及对比例的样品0.1g，精密称定，记录样品质量(m 1)，将称取的样品完全浸没于设置一定温度装有纯化水的恒温水浴锅中，设置水温与实施例及对比例中水溶性聚合物原料溶解时的温度相同，浸泡30min，取出烘干至恒重，记录烘干后的质量(m 2)，计算样品的损失率＝(m 1-m 2)/m 1×100％，其检测结果如下表2所示：
表2样品损失率的检测结果
样品名称 损失率(％)
实施例1 1.2
实施例2 1.5
实施例3 1.3
实施例4 0.8
实施例5 1.1
实施例6 0.8
对比例2 98.3
对比例3 5.5
对比例4 13.4
对比例6 6.2
由表2可以看出，实施例1～6的样品在水溶性聚合物可溶解的温度下浸泡处理，溶液中样品的损失率均低于对比例2～4和对比例6的样品，这是由于通过静电纺丝和蒸汽加湿处理后的样品拥有更高的交联程度，交联程度更均匀，样品中非交联的部分很低，而交联的凝胶在溶液中具有更好的稳定性，因此样品损失率低。对比例3、6由于未经过蒸汽加湿后处理，交联度低于经过后处理的实施例1、6的植入物，故损失率高于实施例1、6。而对比例2未经过交联反应，几乎完全溶解，损失率高达98.3％。另外，对比例4的损失率为13.4％，这是由于交联反应只发生在管壁表面，管壁内部几乎没有发生交联反应，浸泡处理中，未发生交联部分会被溶解，损失率较高，稳定性较差。因此，通过本发明制备得到的植入物交联程度高、交联均匀性好，能够提高导管的稳定性。
综上所述，本发明所公开的以交联聚合物作为组成成分的植入物，经过后处理工艺后复水后强度高，尺寸可控，结构稳定，聚合物本身具有很好的生物相容性，适用作为植入物来实现治疗或非治疗的目的。

Claims (11)

  1. 一种高强度植入物，其特征在于，所述的高强度植入物包括聚合物丝线经后处理形成的致密层，所述后处理使聚合物丝线间空隙减小；
    所述的后处理选自蒸汽加湿、电热式加湿、电极式加湿或高压喷雾加湿。
  2. 根据权利要求1所述的高强度植入物，其特征在于，所述的后处理时间为5-50min。
  3. 根据权利要求1所述的高强度植入物，其特征在于，所述的聚合物丝线由水溶性聚合物纺丝-交联制备得到；优选的，所述的纺丝为静电纺丝。
  4. 根据权利要求1所述的高强度植入物，其特征在于，所述的水溶性聚合物选自聚乙烯醇、明胶、羧甲基壳聚糖、纤维素或透明质酸钠中的一种或两种以上；
    优选的，交联使用交联剂，所述的交联剂选自双环氧化合物、多环氧化合物或多臂-聚乙二醇-环氧化合物；进一步优选的，所述的交联剂选自1，4-丁二醇二缩水甘油醚、1,2,3,4,-二环氧丁烷、甘油三(1,2-环氧)丙醚、四臂-聚乙二醇-环氧基或三臂-聚乙二醇-环氧基中的一种或两种以上。
  5. 根据权利要求1-4任一所述的高强度植入物，其特征在于，所述的高强度植入物为管状植入物、片状植入物或环状植入物；
    优选的，所述的管状植入物包含管体，所述的管体包含管内空腔和管壁，所述的管内空腔的直径为20-4000μm；
    优选的，所述的管壁的平均厚度为100-2000μm。
  6. 根据权利要求5所述的高强度植入物，其特征在于，所述的管体还包括管外结构，所述的管外结构平均直径为50-7000μm。
  7. 一种高强度植入物的制备方法，其特征在于，所述的制备方法包括将纺丝液进行纺丝-交联，后处理形成致密层；
    所述的后处理选自蒸汽加湿、电热式加湿、电极式加湿或高压喷雾加湿。
  8. 根据权利要求7所述的制备方法，其特征在于，所述纺丝液包含水溶性聚合物、水和交联剂；所述纺丝-交联得到的丝线直径为20～4000μm。
  9. 根据权利要求7或8所述的制备方法，其特征在于，所述的制备方法包括：
    所述的制备方法包括将纺丝液转移至静电纺丝设备的接收装置，纺丝-交联后再进行蒸汽加湿；优选的，蒸汽加湿时间为5-50min；优选的，所述的水溶性聚合物的浓度为0.05-0.2g/mL；所述的交联剂的加入质量为水溶性聚合物加入质量的0.01-0.10倍，优选为0.01-0.05倍。
  10. 根据权利要求7-9任一所述的制备方法，其特征在于，所述的制备方法还包括酸浸、清洗、脱模、干燥和/或灭菌的步骤。
  11. 一种权利要求1-6任一所述的高强度植入物或权利要求7-10任一所述的制备方法获得的高强度植入物，在制备美容产品或治疗疾病的产品中的应用；
    优选的，所述的美容产品选自鼻腔植入物、眼部植入物、隐形眼镜、皮下植入物；
    优选的，所述的治疗疾病的产品选自眼部植入物、口腔防护物、假牙垫料、组织替代物、输尿管修补物、筋和韧带代用物、绷带、缝线、心脏植入物或血管植入物。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106110371A (zh) * 2016-07-19 2016-11-16 江西省科学院应用化学研究所 一种高吸水性海藻酸钠复合纳米纤维创伤敷料的制备方法
US20180251596A1 (en) * 2012-12-21 2018-09-06 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Methods of electrospinning and compositions made therefrom
CN108904858A (zh) * 2018-07-27 2018-11-30 西北师范大学 一种聚乙烯醇/三氟乙酸高乌甲素复合纤维膜及其制备和应用

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2592420B2 (ja) * 1988-01-25 1997-03-19 日本合成化学工業株式会社 ポリビニルアルコール系繊維の製造法
IN187510B (zh) * 1995-05-22 2002-05-11 Kuraray Co
WO2007112446A2 (en) * 2006-03-28 2007-10-04 University Of Washington Alginate-based nanofibers and related scaffolds
CN101260570A (zh) * 2008-04-29 2008-09-10 东华大学 一种高吸水聚乙烯醇纤维及其制备
CN111686593A (zh) * 2019-03-13 2020-09-22 西陇科学股份有限公司 一种新型可调控超薄有机聚合物复合膜及其制备方法
CN112481711B (zh) * 2020-11-20 2023-06-16 齐鲁工业大学 一种静电纺丝制备抗菌明胶膜的方法
CN113914016A (zh) * 2021-11-05 2022-01-11 青岛大学 耐水性纳米纤维膜及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180251596A1 (en) * 2012-12-21 2018-09-06 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Methods of electrospinning and compositions made therefrom
CN106110371A (zh) * 2016-07-19 2016-11-16 江西省科学院应用化学研究所 一种高吸水性海藻酸钠复合纳米纤维创伤敷料的制备方法
CN108904858A (zh) * 2018-07-27 2018-11-30 西北师范大学 一种聚乙烯醇/三氟乙酸高乌甲素复合纤维膜及其制备和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FAN ZHIHAI, ZONGGANG XIE, FENG ZHANG, BAOQI ZUO: "Influence of Ethanol-Water Vapor Treatment on Structural Performance of Electrospun Fibroin Nanofiber", SICHOU = JOURNAL OF SILK, SICHOU ZAZHISHE - ZHEJIANG UNIVERSITY OF TECHNOLOGY; CHINA SILK ASSOCIATION; CHINA TEXTILE INFORMATION CENTER, CN, vol. 50, no. 6, 20 June 2013 (2013-06-20), CN , pages 1 - 5, XP093082123, ISSN: 1001-7003, DOI: 10.3969/j.issn.1001-7003.2013.06.001 *

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