WO2023046044A1 - 表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料及其制备方法 - Google Patents

表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料及其制备方法 Download PDF

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WO2023046044A1
WO2023046044A1 PCT/CN2022/120718 CN2022120718W WO2023046044A1 WO 2023046044 A1 WO2023046044 A1 WO 2023046044A1 CN 2022120718 W CN2022120718 W CN 2022120718W WO 2023046044 A1 WO2023046044 A1 WO 2023046044A1
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membrane material
polymer membrane
solution
heparin
modified polymer
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PCT/CN2022/120718
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English (en)
French (fr)
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胡艳飞
刘欢
胡蝶
陈金婷
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宁波健世科技股份有限公司
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Priority to CN202280058209.6A priority Critical patent/CN117940174A/zh
Publication of WO2023046044A1 publication Critical patent/WO2023046044A1/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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • A61L33/068—Use of 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • A61L33/0041—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate characterised by the choice of an antithrombatic agent other than heparin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
    • C08J5/18—Manufacture of films or sheets
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C08J7/12—Chemical modification
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C08J7/12—Chemical modification
    • C08J7/16—Chemical modification with polymerisable compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/23—Carbohydrates
    • A61L2300/236—Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2375/00—Characterised by the use of polyureas or polyurethanes; Derivatives of such polymers
    • C08J2375/04—Polyurethanes

Definitions

  • the present application relates to the field of biomedical polymer materials, in particular to a polyurethane film grafted with a heparin coating on the surface and a preparation method thereof.
  • Polymer materials are widely used in materials in contact with body fluids or blood because of their good mechanical properties, wear resistance and processing properties.
  • polyurethane is widely used in artificial heart and artificial blood vessel.
  • Polyurethane biomaterials can currently be used in medical devices such as catheters for interventional operations, ureteral catheters, wound dressings, artificial hearts, artificial heart valves, and intravenous infusion ports.
  • Polyester polyurethane is a polyurethane material synthesized based on polyester polyol, but the ester bond is also susceptible to degradation by water, which limits its application in long-term implant materials; polyether polyurethane is based on poly The polyurethane material synthesized based on ether polyol is easy to decompose its polyether chain, which limits its application in implant materials; in addition, due to the flexibility of the polyether chain, the polyether polyurethane material is resistant to water and The water vapor transmission rate is high.
  • polycarbonate polyurethane PCU
  • PCU polycarbonate polyurethane
  • heparin and phosphorylcholine are research hotspots.
  • Heparin can inhibit the activity of thromboplastin, thereby inhibiting the conversion of prothrombin into thrombin, so that it cannot play the role of promoting fibrinogen into fibrin, and prevents the aggregation of platelets, thus possessing anticoagulant properties.
  • Phosphorylcholine is the hydrophilic end group of the basic unit of the cell membrane.
  • the phosphorylcholine group contains a quaternary ammonium group and a phosphoryl group, and has both positive and negative charges. It is a zwitterionic structure and has a strong ability to bind water. By imitating the structure of the extracellular phospholipid bilayer membrane, the material rich in phosphorylcholine groups is modified into a natural component in the body, so that it has excellent biocompatibility, the surface is not easy to adsorb platelets, and the anticoagulation of the material is improved. Blood performance.
  • Patent CN104629058A discloses a method for preparing a heparinized polyurethane film.
  • the polyurethane film with carboxyl groups is used as the base, and the carboxyl groups on the surface of the polyurethane are activated by 1-ethyl-3-(dimethylpropylamine) carbodiimide (WSC), and then Heparin was grafted to prepare heparinized polyurethane membranes.
  • WSC 1-ethyl-3-(dimethylpropylamine) carbodiimide
  • Heparin was grafted to prepare heparinized polyurethane membranes.
  • the amount of carboxyl groups on the surface of the polyurethane membrane is limited and the active groups are less, resulting in a low grafting efficiency of heparin.
  • Patent CN101967235A discloses a phosphorylcholine-modified polyurethane biomaterial and its preparation method, in which the method of plasma surface modification is adopted to introduce functional molecules or groups on the surface of the material to reduce the contact angle and improve the anticoagulant performance .
  • the surface grafting of plasma-treated membranes is not reliable and cannot meet the time requirement for surface modification.
  • Patent CN112316218A discloses a zwitterionic polymer and heparin composite coating and its preparation method and application, wherein a dopamine solution is used to form a mediation layer, and then amide bonds are grafted to heparin by immersion in the zwitterionic polymer solution.
  • a dopamine solution is used to form a mediation layer, and then amide bonds are grafted to heparin by immersion in the zwitterionic polymer solution.
  • the content of amino or carboxyl groups on the surface of the membrane formed by this method is limited, resulting in low heparin grafting efficiency; at the same time, this method of dopamine adhesion may affect the mechanical properties of the membrane.
  • a modified polymer membrane material and a preparation method thereof are provided which are compounded with grafted phosphorylcholine and heparin anticoagulant coating on the surface.
  • the application provides a modified polymer membrane material with surface composite grafted phosphorylcholine and heparin anticoagulant coating, and the preparation method of the modified polymer membrane material comprises the following steps:
  • the surface of the modified polymer membrane material is the coating on which the phosphorylcholine and the heparin are chemically grafted with two anticoagulant substances.
  • the unsaturated phosphorylcholine comprises dimethylacryloyloxyethylphosphorylcholine (MPC).
  • the thickness of the modified polymer membrane material is 0.01-2 mm.
  • the polymer film material includes polyurethane film, polyethylene terephthalate film, polytetrafluoroethylene film, polyether ether ketone film, polyimide, polyamide, super polyurethane film One or more of polyethylene film and polystyrene elastomer film.
  • the preparation method of the modified polymer membrane material includes the following steps:
  • the polymer membrane material is washed in isopropanol solution, then washed with purified water, dried, and placed in a solution containing N-(3-aminopropyl)methacrylamide hydrochloride and dimethylacryloyloxy
  • the polymer membrane material containing polyphosphorylcholine zwitterions and multiple heparin binding sites is obtained, and the heparin binding
  • the site is the amino group of poly N-(3-aminopropyl) methacrylamide hydrochloride;
  • the polymer membrane material grafted with polyphosphorylcholine zwitterions and N-(3-aminopropyl)methacrylamide is placed in a cleaning solution for cleaning, soaking, and drying;
  • the polymer film material of the grafted polyphosphorylcholine zwitterion and N-(3-aminopropyl) methacrylamide after drying is placed in 1-(3-dimethylaminopropyl)-3 -In the heparin solution of ethyl carbodiimide and N-hydroxysuccinimide, react, wash, and dry to obtain surface composite grafted zwitterions and heparin-coated polymer membrane materials.
  • the present application also provides a preparation method for the modified polymer membrane material of the surface composite grafted phosphorylcholine and heparin anticoagulant coating, comprising the following steps:
  • the polymer membrane material is placed in an isopropanol solution for cleaning, then washed with purified water, dried, and placed in a solution containing N-(3-aminopropyl)methacrylamide hydrochloride and dimethyl
  • a polyphosphorylcholine zwitterion and a plurality of heparin binding sites are obtained.
  • the membrane material of the amino group of methacrylamide hydrochloride is obtained.
  • step (2) placing the membrane material in step (1) in a cleaning solution for cleaning, soaking, and drying;
  • step (3) Place the dried membrane material in step (2) in heparin containing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and N-hydroxysuccinimide reacting in the solution, washing and drying to obtain the modified polymer membrane material with the phosphorylcholine and the heparin anticoagulant coating compositely grafted on the surface.
  • the polymer membrane material in step (1) is prepared by one or more methods of weaving, electrospinning, solution coagulation, extraction and spraying.
  • the concentration of the isopropanol solution in step (1) is 2.5-25%; the washing time of the isopropanol solution and the purified water is 10-30 minutes.
  • the concentration of the N-(3-aminopropyl)methacrylamide hydrochloride in step (1) is 5-25% w/v; the dimethylacryloyloxyethyl The concentration of phosphorylcholine is 5-25% w/v.
  • the pretreatment solution in step (1) needs to remove oxygen in the solution before adding the cerium-containing compound; the concentration of cerium ions in the cerium-containing compound is 0.01-0.1M.
  • the reaction temperature in step (1) is 40-60° C.
  • the reaction time is 12-24 hours, and oxygen cannot participate in the reaction throughout the process.
  • the cerium-containing compound includes one or more of cerium trioxide, cerium chloride, cerium fluoride, cerium carbonate, cerium phosphate, cerium nitrate, and cerium ammonium nitrate.
  • the cleaning solution in step (2) is one of purified water, phosphate buffer saline, and Triton X-100 solution; the soaking time is 12 to 24 hours; the drying method is room temperature drying or vacuum drying .
  • the heparin solution in step (3) can be prepared from heparin or heparin sodium; the concentration of the heparin solution is 0.5-5 mg/ml.
  • the molar ratio of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to N-hydroxysuccinimide in step (3) is 0.5-10 ;
  • the concentration of N-hydroxysuccinimide is 0.02-0.04M.
  • the reaction in step (3) is carried out at a temperature of 37° C. and protected from light for 12-24 hours.
  • the cleaning in step (3) is performed with purified water, phosphate buffer, purified water, and 30-95% ethanol; and the drying is room temperature drying or vacuum drying.
  • Fig. 1 is a schematic diagram of the reaction process of the preparation method of the modified polymer membrane material in various embodiments of the present application.
  • Fig. 2 is the water contact angle of the unmodified polyurethane film in Example 1 of the present application.
  • Fig. 3 is the water contact angle of the modified polyurethane membrane grafted with phosphorylcholine and heparin anticoagulant coating on the surface in Example 1 of the present application.
  • Fig. 4 is a scanning electron microscope image of platelet adhesion on the unmodified polyurethane membrane in Example 1 of the present application.
  • Fig. 5 is a scanning electron micrograph of platelet adhesion on a modified polyurethane film composited with grafted phosphorylcholine and heparin anticoagulant coating in Example 1 of the present application.
  • Fig. 6 is a scanning electron microscope image of platelet adhesion of the modified polyurethane membrane grafted with phosphorylcholine and heparin anticoagulant coating on the surface in Example 1 of the present application after being washed with PBS solution for 30 days.
  • an embodiment of the present application provides a modified polymer membrane material with surface composite grafted phosphorylcholine and heparin anticoagulation coating, the modified polymer membrane material
  • the preparation method comprises the following steps:
  • step S4 Grafting the cleaned grafted polymer membrane material obtained in step S3 with heparin using a carbodiimide (EDC) chemical method.
  • EDC carbodiimide
  • the surface of the modified polymer membrane material is coated with two anticoagulant substances, phosphorylcholine and heparin, which are chemically grafted.
  • the unsaturated phosphorylcholine comprises dimethylacryloyloxyethylphosphorylcholine (MPC).
  • the thickness of the modified polymer membrane material is 0.01-2 mm.
  • the polymer film material includes polyurethane (PU) film, polyethylene terephthalate (PET) film, polytetrafluoroethylene (PTFE) film, polyether ether ketone (PEEK) film, poly One or more combination of imide (PI), polyamide (PA), ultra polyurethane weight polyethylene (UMWPE) film, polystyrene elastomer (SIBS) film.
  • PU polyurethane
  • PET polyethylene terephthalate
  • PTFE polytetrafluoroethylene
  • PEEK polyether ether ketone
  • the preparation method of modified polymer membrane material comprises the following steps:
  • the polymer membrane material in the step S100 of the preparation method of the above-mentioned modified polymer membrane material is prepared by one or more of weaving method, electrospinning method, solution coagulation method, leaching method and spraying method. Method preparation.
  • the concentration of the isopropanol solution in step S100 of the method for preparing the modified polymer membrane material is 2.5-25%; the washing time of the isopropanol solution and purified water is 10-30 minutes.
  • the concentration of N-(3-aminopropyl)methacrylamide hydrochloride (APMA) in step S100 of the method for preparing the modified polymer membrane material is 5-25% w/v;
  • the concentration of dimethylacryloyloxyethylphosphorylcholine is 5-25% w/v.
  • the pretreatment solution in step S100 of the method for preparing the modified polymer membrane material needs to remove oxygen in the solution before adding the cerium-containing compound; the concentration of cerium ions in the cerium-containing compound is 0.01-0.1M.
  • the reaction temperature in step S100 of the above method for preparing the modified polymer membrane material is 40-60° C.
  • the reaction time is 12-24 hours, and oxygen cannot participate in the reaction throughout the process.
  • the cerium-containing compound in step S100 of the method for preparing the modified polymer membrane material includes cerium trioxide, cerium chloride, cerium fluoride, cerium carbonate, cerium phosphate, cerium nitrate, and cerium ammonium nitrate. one or more of .
  • the cleaning solution in step S200 of the preparation method of the above-mentioned modified polymer membrane material is one of purified water, phosphate buffer, and Triton X-100 solution; the soaking time is 12 to 24 hours; the drying method Dry at room temperature or vacuum.
  • the heparin solution in step S300 of the method for preparing a modified polymer membrane material can be prepared from heparin or heparin sodium; the concentration of the heparin solution is 0.5-5 mg/ml.
  • the combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and N-hydroxysuccinimide in step S300 of the preparation method of the above-mentioned modified polymer membrane material The molar ratio is 0.5-10; the concentration of N-hydroxysuccinimide is 0.02-0.04M.
  • the reaction in step S300 of the method for preparing the modified polymer membrane material is carried out at a temperature of 37° C. and protected from light for 12 to 24 hours.
  • the cleaning in step S300 of the method for preparing the modified polymer membrane material is performed with purified water, phosphate buffer, purified water, and 30-95% ethanol; and the drying is room temperature drying or vacuum drying.
  • Another embodiment of the present application provides a method for preparing the above-mentioned modified polymer membrane material grafted with phosphorylcholine and heparin anticoagulant coating on the surface, including the following steps:
  • step (1) The membrane material in step (1) is placed in the cleaning solution for cleaning, soaking, and drying;
  • step (3) The membrane material in step (2) is placed in a mixture containing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and N-hydroxysuccinimide (NHS) react in the heparin solution, wash, and dry to obtain a modified polymer film material with a composite grafted phosphorylcholine and heparin anticoagulant coating on the surface.
  • EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • NHS N-hydroxysuccinimide
  • the phosphorylcholine and heparin anticoagulant coating are only combined on the surface of the polymer membrane material.
  • the polymer membrane material in step (1) is prepared by one or more methods of weaving, electrospinning, solution coagulation, leaching, and spraying.
  • the concentration of the isopropanol solution in step (1) is 2.5-25%; the washing time of the isopropanol solution and purified water is 10-30 minutes.
  • the concentration of N-(3-aminopropyl)methacrylamide (APMA) in step (1) is 5-25% w/v;
  • the concentration of base (MPC) is 5-25% w/v.
  • the pretreatment solution in step (1) needs to remove oxygen in the solution before adding the cerium-containing compound; the concentration of cerium ions in the cerium-containing compound is 0.01-0.1M.
  • the cerium-containing compound includes one or more combinations of cerium trioxide, cerium chloride, cerium fluoride, cerium carbonate, cerium phosphate, cerium nitrate, and cerium ammonium nitrate.
  • the reaction temperature in step (1) is 40-60° C.
  • the reaction time is 12-24 hours
  • no oxygen can participate in the reaction throughout the process, and the reaction is protected by argon.
  • the cleaning solution in step (2) is one of purified water, phosphate buffered saline (PBS solution), and Triton X-100 solution; the soaking time is 12 to 24 hours; the drying method is room temperature drying or Vacuum dry.
  • PBS solution phosphate buffered saline
  • Triton X-100 solution Triton X-100 solution
  • MES 2-morpholinoethanesulfonic acid buffer
  • the heparin solution in step (3) can be prepared from heparin or heparin sodium; the concentration of the heparin solution is 0.5-5 mg/ml.
  • the molar ratio of EDC to NHS in step (3) is 0.5-10; the concentration of NHS is 0.02-0.04M.
  • step (3) is reacted at a temperature of 37° C. and protected from light for 12 to 24 hours.
  • the cleaning in step (3) is performed with purified water, PBS solution, purified water, and 30-95% ethanol; the drying is room temperature drying or vacuum drying.
  • the polymer membrane material is a polyurethane membrane.
  • the pretreatment solution is prepared in step (1), and argon gas is introduced to remove oxygen in the solution; when the temperature of the pretreatment solution reaches a specified temperature, a cerium-containing compound is added, and the film is added to react.
  • the preparation method of the polyurethane film comprises the following steps: dissolving the polyurethane pellets in one of dimethylacetamide (DMAc), dimethylformamide (DMF), tetrahydrofuran, dioxane, or A variety of mixed solutions are prepared with a mass concentration of 10-15% polyurethane solution, the polyurethane solution is poured into a polytetrafluoroethylene mold, and the solvent is completely evaporated by vacuum drying to obtain a polyurethane film; after the polyurethane film is cleaned, room temperature or vacuum Dry and set aside.
  • DMAc dimethylacetamide
  • DMF dimethylformamide
  • tetrahydrofuran dioxane
  • a variety of mixed solutions are prepared with a mass concentration of 10-15% polyurethane solution, the polyurethane solution is poured into a polytetrafluoroethylene mold, and the solvent is completely evaporated by vacuum drying to obtain a polyurethane film; after the polyurethane film is cleaned, room temperature
  • the above-mentioned modified polymer membrane material or the modified polymer membrane material prepared by the above-mentioned preparation method introduces phosphorylcholine zwitterions and N-(3 -aminopropyl) methacrylamide, while having an anticoagulant effect, provides a large number of heparin grafting sites (amino groups), and then adopts 1-(3-dimethylaminopropyl)-3-ethylcarbodiethylene Amine (EDC) chemically grafted heparin, through the combination of polyphosphorylcholine zwitterions and biologically active heparin, the anticoagulant effect of the modified polymer membrane material is more efficient and durable.
  • EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiethylene Amine
  • APMA and MPC are grafted to the surface of the polyurethane membrane through the initiation of cerium-containing compounds, and anticoagulant phosphorylcholine is introduced to create multiple amino groups for heparin grafting at the same time. site, increased the amount of grafted heparin, and enhanced the anticoagulant performance of the polyurethane membrane.
  • phosphorylcholine zwitterions and heparin are grafted onto the surface of the polyurethane membrane, which can effectively reduce platelet adhesion and improve anticoagulant performance.
  • phosphorylcholine zwitterions and heparin are immobilized on the surface of the polyurethane membrane by chemical grafting, which can ensure the firmness of heparin, and the prepared material can meet the requirements of in vivo anticoagulation To achieve long-acting anticoagulation.
  • the preparation method of the modified polyurethane film in some embodiments of the present application is simple, the preparation condition is mild and environmentally friendly, and has a good market application prospect; in addition, in addition to the polyurethane film, other materials that are in contact with blood and body fluids Improvements can also be made using this technique.
  • the polymer membrane material is polyurethane membrane.
  • the preparation steps of the unmodified polyurethane film include: dissolving polyurethane pellets in dimethylacetamide to prepare a polyurethane solution with a mass concentration of 12%, pouring the polyurethane solution into a polytetrafluoroethylene mold, and spreading Open it, put it into a vacuum drying oven, dry it in vacuum at 50°C for 24 hours, take out the mold, wait for the temperature to drop to room temperature, add purified water, take out the film, wash it, and dry it at room temperature or in vacuum for later use to obtain a flat polyurethane film, and put the polyurethane
  • the membranes were divided into two groups, the control group and the test group, with 3 pieces in each group; among them,
  • Control group the flat polyurethane film was washed in PBS solution and cut into 10*10mm sheets for contact angle and platelet adhesion tests;
  • the modified polyurethane membrane of the test group was washed with 1X PBS solution at 37° C. for 30 days at a rotation speed of 500 rpm. After taking it out, it was washed with deionized water for platelet adhesion test.
  • Example 1 of the present application heparin can be effectively grafted onto the surface of the polyurethane membrane, and the contact angle can be effectively reduced, thereby greatly improving the anticoagulant performance of the polyurethane membrane.
  • the preparation steps of the unmodified polyurethane film include: dissolving the polyurethane pellets in dioxane to prepare a polyurethane solution with a mass concentration of 15%, pouring the polyurethane solution into a polytetrafluoroethylene mold, and spreading it evenly , put it into a vacuum drying oven, dry it in vacuum at 50°C for 24 hours, take out the mold, wait until the temperature drops to room temperature, add purified water, take out the film, wash it, dry it at room temperature or in vacuum for later use, obtain a flat polyurethane film, and put the polyurethane film Divided into two groups of control group and test group, each group has 3 tablets;
  • Control group the flat polyurethane film was washed in PBS solution and cut into 10*10mm sheets for contact angle and platelet adhesion tests;
  • Test group In the first step, prepare 100ml of a pretreatment solution containing 15% w/v APMA and 15% w/v MPC, pour the solution into a three-necked flask, pass argon gas at a rate of 1.5L/min for 20min, and remove the
  • the second step when the solution reaches 50°C, add 0.03M cerium nitrate, stir evenly, add the membrane, and react for 18 hours under the protection of argon
  • Example 2 of the present application heparin can be effectively grafted to the surface of the polyurethane membrane, and the contact angle can be effectively reduced, thereby greatly improving the anticoagulant performance of the polyurethane membrane.
  • Control group the flat polyurethane film was washed in PBS solution and cut into 10*10mm sheets for contact angle and platelet adhesion tests;
  • Test group the first step, prepare 100ml of pretreatment solution containing 20% w/v APMA and 20% w/v MPC, pour the solution into a three-necked flask, pass argon gas at a rate of 1.5L/min for 20min, and remove the
  • the second step when the solution reaches 50°C, add 0.1M cerium nitrate, stir evenly, add the membrane, and react for 24 hours under the protection of argon
  • Example 3 of the present application heparin can be effectively grafted onto the surface of the polyurethane membrane, and the contact angle can be effectively reduced, thereby greatly improving the anticoagulant performance of the polyurethane membrane.

Abstract

本申请涉及一种表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料，该改性高分子膜材料的制备方法包括以下步骤：S1、制备高分子膜材料；S2、在高分子膜材料表面化学接枝不饱和磷酰胆碱和N-(3-氨基丙基)甲基丙烯酰胺；S3、将步骤S2得到的接枝高分子膜材料进行清洗；S4、将步骤S3得到的清洗后的接枝高分子膜材料采用碳二亚胺化学法接枝肝素。

Description

表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料及其制备方法
相关申请
本申请要求2021年9月24日申请的，申请号为202111123851.1，名称为“一种改性高分子膜材料及其制备方法”的中国专利申请的优先权，在此将其全文引入作为参考。
技术领域
本申请涉及生物医用高分子材料领域，尤其涉及一种表面接枝肝素涂层的聚氨酯膜及其制备方法。
背景技术
高分子材料因其良好的机械性能、耐磨性和加工性能被广泛应用于与体液或血液接触的材料。聚氨酯作为其中一种重要的医用材料，在人工心脏、人工血管方面应用十分广泛。聚氨酯生物材料目前可用于介入类手术的导管、输尿管导管、伤口敷料、人工心脏、人工心脏瓣膜、静脉输液港等医疗器械。
医用聚氨酯材料可以根据化学组成分为聚酯型聚氨酯、聚醚型聚氨酯以及聚碳酸酯型聚氨酯等。聚酯型聚氨酯是以聚酯多元醇为基础合成的聚氨酯材料，但酯键同样容易受到水的影响发生降解反应，从而限制了其在长期植入材料方面的应用；聚醚型聚氨酯是以聚醚多元醇为基础合成的聚氨酯材料，由于其聚醚链易发生分解，这限制了其在植入材料方面的应用；此外，由于聚醚链的柔顺性，使聚醚型聚氨酯材料对水和水蒸气的透过率高，当作为医疗设备材料应用时，这对设备的金属部件有很大的威胁；聚碳酸酯型聚氨酯(PCU)相对其他聚氨酯材料具有更好的生物相容性，同时，其化学结构决定了其在生物体内更加稳定，可以满足长期植入型应用对材料提出的要求。
虽然聚氨酯材料具有良好的生物相容性，但当其与血液直接接触时，仍会发生凝血和溶血现象，从而引起血栓。为解决这一问题，研究者通过表面改性的方法对材料进行抗凝的研究。其中，肝素和磷酰胆碱(PC)是研究的热点。肝素可以抑制凝血活酶的活力，从而抑制凝血酶原变成凝血酶，使之不能发挥促进纤维蛋白原变成纤维蛋白的作用，组织血小板的聚集，从而具备抗凝血性能。磷酰胆碱是组成细胞膜的基本单元的亲水端基，在外层细胞膜中占重要地位，直接影响生物体细胞与外界发生作用。磷酰胆碱基团含有季铵基团和磷酰基团，同时带有正负两种电荷，是两性离子结构，具有很强的结合水能力。通过 模仿细胞外磷脂双层膜的构造，富含磷酰胆碱基团的材料在生物体内将其修饰成天然成分，使其具有优良的生物相容性，表面不易吸附血小板，提高材料抗凝血性能。
专利CN104629058A公开了一种肝素化聚氨酯膜制备方法，以带羧基的聚氨酯膜为基底，通过1-乙基-3-(二甲基丙胺)碳二亚胺(WSC)对聚氨酯表面羧基活化，然后接枝肝素，制备肝素化的聚氨酯膜。然而聚氨酯膜表面的羧基量有限，活性基团较少，导致肝素的接枝效率很低。
专利CN101967235A公开了一种磷酰胆碱改性聚氨酯生物材料及其制备方法，其中采用等离子体表面改性的方法，在材料表面引入功能性分子或基团，降低接触角，提高抗凝血性能。但是经过等离子体处理的膜表面接枝并不牢靠，不能满足表面改性的时长要求。
专利CN112316218A公开了一种两性离子聚合物与肝素复合涂层和制备方法及应用，其中采用多巴胺溶液形成介导层，随后通过浸入两性离子聚合物溶液形成酰胺键接枝肝素。但是这种方法形成的膜表面氨基或羧基含量有限，导致肝素接枝效率较低；同时这种多巴胺粘附的方法可能会影响膜的力学性能。
发明内容
根据本申请的各种实施例，提供一种表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料及其制备方法。
本申请所采用的技术方案如下：
本申请提供了一种表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料，所述改性高分子膜材料的制备方法包括以下步骤：
S1、制备高分子膜材料；
S2、在高分子膜材料表面化学接枝不饱和磷酰胆碱和N-(3-氨基丙基)甲基丙烯酰胺；
S3、将步骤S2得到的接枝高分子膜材料进行清洗；
S4、将步骤S3得到的清洗后的接枝高分子膜材料采用碳二亚胺化学法接枝肝素。
在一些实施方式中，所述改性高分子膜材料的表面为化学接枝所述磷酰胆碱和所述肝素两种具有抗凝作用物质的所述涂层。
在一些实施方式中，所述不饱和磷酰胆碱包括二甲基丙烯酰氧乙基磷酰胆碱(MPC)。
在一些实施方式中，所述改性高分子膜材料的厚度为0.01～2mm。
在一些实施方式中，所述高分子膜材料包括聚氨酯膜、聚对苯二甲酸乙二醇酯膜、聚四氟乙烯膜、聚醚醚酮膜、聚酰亚胺、聚酰胺、超聚氨酯量聚乙烯膜和聚苯乙烯弹性体膜中的一种或多种。
在一些实施方式中，所述改性高分子膜材料的制备方法，包括以下步骤：
将所述高分子膜材料置于异丙醇溶液中清洗，随后用纯化水清洗，干燥，置于含N-(3-氨基丙基)甲基丙烯酰胺盐酸盐和二甲基丙烯酰氧乙基磷酰胆碱的前处理溶液中，在含铈化合物的引发下，得到含有聚磷酰胆碱两性离子和多个所述肝素结合位点的所述高分子膜材料，所述肝素结合位点为聚N-(3-氨基丙基)甲基丙烯酰胺盐酸盐的氨基；
将接枝聚磷酰胆碱两性离子和N-(3-氨基丙基)甲基丙烯酰胺的所述高分子膜材料置于清洗液中清洗，浸泡，干燥；
将干燥后的接枝聚磷酰胆碱两性离子和N-(3-氨基丙基)甲基丙烯酰胺的所述高分子膜材料置于含1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基丁二酰亚胺的肝素溶液中，反应，清洗，干燥后得到表面复合接枝两性离子和肝素涂层高分子膜材料。
本申请还提供了上述表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料的制备方法，包括以下步骤：
(1)将所述高分子膜材料置于异丙醇溶液中清洗，随后用纯化水清洗，干燥，置于含N-(3-氨基丙基)甲基丙烯酰胺盐酸盐和二甲基丙烯酰氧乙基磷酰胆碱的前处理溶液中，在含铈化合物的引发下，得到含有聚磷酰胆碱两性离子和多个所述肝素结合位点(聚N-(3-氨基丙基)甲基丙烯酰胺盐酸盐)的氨基的膜材料；
(2)将步骤(1)中的所述膜材料置于清洗液中清洗，浸泡，干燥；
(3)将步骤(2)中干燥后的所述膜材料置于含1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基丁二酰亚胺的肝素溶液中反应，清洗，干燥后得到表面复合接枝所述磷酰胆碱和所述肝素抗凝涂层的所述改性高分子膜材料。
在一些实施方式中，步骤(1)中的所述高分子膜材料由编织法、静电纺丝法、溶液凝固法、浸提法和喷涂法中的一种或多种方法制备。
在一些实施方式中，步骤(1)中的所述异丙醇溶液的浓度为2.5～25％；所述异丙醇溶液和所述纯化水的清洗时间为10～30min。
在一些实施方式中，步骤(1)中的所述N-(3-氨基丙基)甲基丙烯酰胺盐酸盐的浓度为5～25％w/v；所述二甲基丙烯酰氧乙基磷酰胆碱的浓度为5～25％w/v。
在一些实施方式中，步骤(1)中的所述前处理溶液需要先去除溶液中的氧气再加入所述含铈化合物；所述含铈化合物中铈离子浓度为0.01～0.1M。
在一些实施方式中，步骤(1)中的反应温度为40～60℃，反应时间为12～24h，全程不能有氧气参与反应。
在一些实施方式中，所述含铈化合物包括三氧化二铈、氯化铈、氟化铈、碳酸铈、磷 酸铈、硝酸铈和硝酸铈铵中的一种或多种。
在一些实施方式中，步骤(2)中的所述清洗液为纯化水、磷酸盐缓冲液、Triton X-100溶液中的一种；浸泡时间为12～24h；干燥方式为室温干燥或真空干燥。
在一些实施方式中，步骤(3)中所述肝素溶液的溶剂为pH＝5-6的2-吗啉代乙磺酸缓冲液，所述2-吗啉代乙磺酸缓冲液的含量为0.05～0.5M。
在一些实施方式中，步骤(3)中所述肝素溶液可以由肝素或者肝素钠制备；所述肝素溶液的浓度为0.5～5mg/ml。
在一些实施方式中，步骤(3)中所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺与所述N-羟基丁二酰亚胺的摩尔比0.5～10；N-羟基丁二酰亚胺的浓度为0.02～0.04M。
在一些实施方式中，步骤(3)中的反应在温度37℃下避光反应12～24h。
在一些实施方式中，步骤(3)中清洗采用纯化水、磷酸盐缓冲液、纯化水、30～95％的乙醇清洗；干燥为室温干燥或真空干燥。
本申请的一个或多个实施例的细节在下面的附图和描述中提出。本申请的其它特征、目的和优点将从说明书、附图以及权利要求书变得明显。
附图说明
为了更清楚地说明本申请实施例或传统技术中的技术方案，下面将对实施例或传统技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据公开的附图获得其他的附图。
图1为本申请多种实施例中改性高分子膜材料制备方法的反应流程示意图。
图2为本申请实施例1中未改性聚氨酯膜的水接触角。
图3为本申请实施例1中表面复合接枝磷酰胆碱和肝素抗凝涂层的改性聚氨酯膜的水接触角。
图4为本申请实施例1中未改性聚氨酯膜血小板黏附扫描电镜图。
图5为本申请实施例1中表面复合接枝磷酰胆碱和肝素抗凝涂层的改性聚氨酯膜血小板黏附扫描电镜图。
图6为本申请实施例1中表面复合接枝磷酰胆碱和肝素抗凝涂层的改性聚氨酯膜经过PBS溶液清洗30天后的血小板黏附扫描电镜图。
具体实施方式
下面将结合本申请实施例中的附图，对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。
下面描述和附图中所阐明的一些具体细节解释了本申请指导下的各个实施方式，相关领域技术人员能够在缺少本文所描述的一个或多个细节的情况下实施本申请指导下的其他实施方式。因此，申请人的意图并不是将所附权利要求的范围限定或以任何方式限制至细节的具体描述中。虽然下文参照附图有序地对各步骤的实施过程进行了详尽的描述，但所描述的步骤和步骤顺序及其术语不应该认为是实施本申请教导的所有实施方式所必须的。
同样，可以理解，本文中所使用的词组和用语是出于描述的目的，而不应当被认为是限制性的。本文中的“包括”、“包含”或“具有”及其变型的使用，旨在开放式地包括其后列出的项及其等同项以及附加的项。
为解决背景技术部分提到的技术问题之一，本申请一实施方式提供一种表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料，该改性高分子膜材料的制备方法包括以下步骤：
S1、制备高分子膜材料；
S2、在高分子膜材料表面化学接枝不饱和磷酰胆碱和N-(3-氨基丙基)甲基丙烯酰胺(APMA)；
S3、将步骤S2得到的接枝高分子膜材料进行清洗；
S4、将步骤S3得到的清洗后的接枝高分子膜材料采用碳二亚胺(EDC)化学法接枝肝素。
在一些实施方式中，改性高分子膜材料的表面为化学接枝磷酰胆碱和肝素两种具有抗凝作用物质的涂层。
在一些实施方式中，不饱和磷酰胆碱包括二甲基丙烯酰氧乙基磷酰胆碱(MPC)。
在一些实施方式中，改性高分子膜材料的厚度为0.01～2mm。
在一些实施方式中，高分子膜材料包括聚氨酯(PU)膜、聚对苯二甲酸乙二醇酯(PET)膜、聚四氟乙烯(PTFE)膜、聚醚醚酮(PEEK)膜、聚酰亚胺(PI)、聚酰胺(PA)、超聚氨酯量聚乙烯(UMWPE)膜、聚苯乙烯弹性体(SIBS)膜中的一种或多种组合。
在一些实施方式中，改性高分子膜材料的制备方法，包括以下步骤：
S100、将高分子膜材料置于异丙醇溶液中清洗，随后用纯化水清洗，干燥，置于含 N-(3-氨基丙基)甲基丙烯酰胺盐酸盐(APMA)和二甲基丙烯酰氧乙基磷酰胆碱(MPC)的前处理溶液中，在含铈化合物的引发下，得到含有聚磷酰胆碱两性离子(PMPC)和多个肝素结合位点的高分子膜材料，肝素结合位点为聚N-(3-氨基丙基)甲基丙烯酰胺盐酸盐(PAPMA)的氨基；
S200、将接枝聚磷酰胆碱两性离子(PMPC)和N-(3-氨基丙基)甲基丙烯酰胺(APMA)的高分子膜材料置于清洗液中清洗，浸泡，干燥；
S300、将干燥后的接枝聚磷酰胆碱两性离子(PMPC)和N-(3-氨基丙基)甲基丙烯酰胺(APMA)的高分子膜材料置于含1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)和N-羟基丁二酰亚胺(NHS)的肝素溶液中，反应，清洗，干燥后得到表面复合接枝两性离子和肝素涂层高分子膜材料。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S100中的高分子膜材料由编织法、静电纺丝法、溶液凝固法、浸提法和喷涂法中的一种或多种方法制备。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S100中的异丙醇溶液的浓度为2.5～25％；异丙醇溶液和纯化水的清洗时间为10～30min。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S100中的N-(3-氨基丙基)甲基丙烯酰胺盐酸盐(APMA)的浓度为5～25％w/v；二甲基丙烯酰氧乙基磷酰胆碱的浓度为5～25％w/v。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S100中的前处理溶液需要先去除溶液中的氧气再加入含铈化合物；含铈化合物中铈离子浓度为0.01～0.1M。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S100中的反应温度为40～60℃，反应时间为12～24h，全程不能有氧气参与反应。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S100中的含铈化合物包括三氧化二铈、氯化铈、氟化铈、碳酸铈、磷酸铈、硝酸铈和硝酸铈铵中的一种或多种。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S200中的清洗液为纯化水、磷酸盐缓冲液、Triton X-100溶液中的一种；浸泡时间为12～24h；干燥方式为室温干燥或真空干燥。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S300中的肝素溶液的溶剂为pH＝5-6的2-吗啉代乙磺酸缓冲液，2-吗啉代乙磺酸缓冲液的含量为0.05～0.5M。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S300中的肝素溶液可以由肝素或者肝素钠制备；肝素溶液的浓度为0.5～5mg/ml。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S300中的1-(3-二甲氨基 丙基)-3-乙基碳二亚胺与N-羟基丁二酰亚胺的摩尔比0.5～10；N-羟基丁二酰亚胺的浓度为0.02～0.04M。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S300中的反应在温度37℃下避光反应12～24h。
在一些实施方式中，上述改性高分子膜材料的制备方法步骤S300中的清洗采用纯化水、磷酸盐缓冲液、纯化水、30～95％的乙醇清洗；干燥为室温干燥或真空干燥。
本申请另一实施方式提供了上述表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料的制备方法，包括以下步骤：
(1)将高分子膜材料置于异丙醇溶液中清洗，随后用纯化水清洗，干燥，置于含N-(3-氨基丙基)甲基丙烯酰胺盐酸盐(APMA)和二甲基丙烯酰氧乙基磷酰胆碱(MPC)的前处理溶液中，在含铈化合物的引发下，得到含有聚磷酰胆碱两性离子(PMPC)和多个肝素结合位点(聚N-(3-氨基丙基)甲基丙烯酰胺盐酸盐的氨基(PAPMA)的氨基)的膜材料；
(2)将步骤(1)中的膜材料置于清洗液中清洗，浸泡，干燥；
(3)将步骤(2)中的膜材料置于含1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)和N-羟基丁二酰亚胺(NHS)的肝素溶液中反应，清洗，干燥后得到表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料。
上述表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料的制备方法中，磷酰胆碱和肝素抗凝涂层仅在高分子膜材料表面结合。
在一些实施方式中，步骤(1)中的高分子膜材料由编织法、静电纺丝法、溶液凝固法、浸提法、喷涂法中的一种或多种方法制备。
在一些实施方式中，步骤(1)中的异丙醇溶液的浓度为2.5～25％；异丙醇溶液和纯化水的清洗时间为10～30min。
在一些实施方式中，步骤(1)中的N-(3-氨基丙基)甲基丙烯酰胺(APMA)的浓度为5～25％w/v；二甲基丙烯酰氧乙基磷酰胆碱(MPC)的浓度为5～25％w/v。
在一些实施方式中，步骤(1)中的前处理溶液需要先去除溶液中的氧气再加入含铈化合物；含铈化合物中铈离子浓度为0.01～0.1M。
在一些实施方式中，含铈化合物包括三氧化二铈、氯化铈、氟化铈、碳酸铈、磷酸铈、硝酸铈、硝酸铈铵中的一种或多种组合。
在一些实施方式中，步骤(1)中的反应温度为40～60℃，反应时间为12～24h，全程不能有氧气参与反应，反应为氩气保护。
在一些实施方式中，步骤(2)中的清洗液为纯化水、磷酸盐缓冲液(PBS溶液)、Triton  X-100溶液中的一种；浸泡时间为12～24h；干燥方式为室温干燥或真空干燥。
在一些实施方式中，步骤(3)中肝素溶液的溶剂为pH＝5-6的2-吗啉代乙磺酸缓冲液(MES)溶液，MES的含量为0.05～0.5M。
在一些实施方式中，步骤(3)中肝素溶液可以由肝素或者肝素钠制备；肝素溶液的浓度为0.5～5mg/ml。
在一些实施方式中，步骤(3)中EDC与NHS的摩尔比0.5～10；NHS的浓度为0.02～0.04M。
在一些实施方式中，步骤(3)在温度37℃下避光反应12～24h。
在一些实施方式中，步骤(3)中清洗采用纯化水、PBS溶液、纯化水、30～95％的乙醇清洗；干燥为室温干燥或真空干燥。
在一个优选的实施方式中，高分子膜材料为聚氨酯膜。
在一些实施方式中，步骤(1)中配制前处理液，通入氩气，去除溶液中的氧气；待前处理液温度达到指定温度，加入含铈化合物，将膜加入，反应。
在一些实施方式中，聚氨酯膜的制备方法包括以下步骤：将聚氨酯粒料溶于二甲基乙酰胺(DMAc)、二甲基甲酰胺(DMF)、四氢呋喃、二氧六环中的一种或多种混合液，制备质量浓度为10-15％的聚氨酯溶液，将聚氨酯溶液倒入聚四氟乙烯模具中，通过真空干燥使溶剂完全蒸发，获得聚氨酯膜；聚氨酯膜经过清洗后，室温或者真空干燥备用。
上述改性高分子膜材料或者采用上述制备方法制得的改性高分子膜材料，通过在高分子膜材料的表面化学接枝磷酰胆碱，引入磷酰胆碱两性离子和N-(3-氨基丙基)甲基丙烯酰胺，在具有抗凝效果的同时，提供大量肝素接枝位点(氨基)，然后采用1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)化学接枝肝素，通过聚磷酰胆碱两性离子与生物活性的肝素两种抗凝血作用的结合，使改性高分子膜材料的抗凝血效果更高效持久。
与传统技术相比，本申请的优点在于：
1.区别于传统技术，本申请的一些实施方式中通过含铈化合物的引发，将APMA和MPC接枝到聚氨酯膜表面，引入抗凝的磷酰胆碱同时为肝素接枝创建多个氨基结合位点，提高了肝素的接枝量，提升了聚氨酯膜的抗凝血性能。
2.区别于传统技术，本申请的一些实施方式中通过将磷酰胆碱两性离子和肝素接枝到聚氨酯膜表面，可以有效减小血小板黏附，提高抗凝血性能。
3.区别于传统技术，本申请的一些实施方式中通过化学接枝的方法，将磷酰胆碱两性离子和肝素固定在聚氨酯膜表面，可保证肝素牢固度，制备的材料可满足体内抗凝的需求，实现长效抗凝。
4.区别于传统技术，本申请的一些实施方式中改性聚氨酯膜的制备方法简单，制备条件温和环保，具有良好的市场应用前景；此外，除聚氨酯膜外，其他与血液和体液接触的材料也可采用此技术进行改进。
下面将参考本申请的若干方面的不同的实施例和示例对本申请进行更详细的描述。
实施例1：
本实施例中，高分子膜材料为聚氨酯膜。
本实施例中，未改性的聚氨酯膜的制备步骤包括:将聚氨酯粒料溶于二甲基乙酰胺制备质量浓度为12％的聚氨酯溶液，将聚氨酯溶液倒入聚四氟乙烯模具，均匀铺开，放入真空干燥箱，50℃真空干燥24h后，取出模具，待温度降至室温，加入纯化水，将膜取出经过清洗后，室温或者真空干燥备用，获取平整的聚氨酯膜，并将聚氨酯膜分为对照组和试验组两组，每组3片；其中，
对照组：将平整的聚氨酯膜在PBS溶液中清洗后切割成10*10mm的片状进行接触角、血小板黏附测试；
试验组：第一步，配制100ml含有10％w/vAPMA和10％w/v MPC的前处理溶液，将溶液倒入三口烧瓶，以1L/min的速度通入氩气10min，去除溶液中的氧气；第二步，待溶液达到50℃，加入0.02M硝酸铈铵，搅拌均匀后加入膜，氩气保护下反应18h；第三步，将经过前处理的膜用纯化水润洗，配制pH＝7.4±0.2的PBS溶液，将膜浸入PBS溶液，室温下浸泡24h，之后将膜用纯化水清洗，并在空气中干燥；第四步，配制pH＝5.5±0.5的MES溶液，其中，MES的摩尔浓度为0.05M，在MES溶液中加入1.25mg/ml的肝素钠，并加入0.03M的EDC和NHS，搅拌均匀，将膜浸入，37℃避光反应24h；第五步，将反应后的膜取出，依次用纯化水，PBS溶液，纯化水，70％乙醇清洗，并在空气中干燥，改性聚氨酯膜的制备反应流程如图1所示；将试验组改性的聚氨酯膜切成10mm*10mm的片状进行接触角、肝素接枝密度、血小板黏附测试。
本实施例中，将试验组改性的聚氨酯膜用1X PBS溶液37℃清洗30天，转速为500转，取出后用去离子水清洗，进行血小板黏附测试。
结果分析：如图2和图4所示，聚氨酯膜经过不同处理后，对照组聚氨酯膜的水接触角α为96°，血小板黏附极多；如图3和图5所示，试验组改性的聚氨酯膜的水接触角β为40°，血小板黏附几乎为零，肝素接枝密度为6.3μg/cm 2,具有显著差异性；如图6所示，试验组改性的聚氨酯膜经过30天PBS溶液清洗后，血小板黏附仍保持极少的状态。
结论：利用本申请实施例1的方法可以有效接枝肝素到聚氨酯膜表面，并有效减小接触角，从而极大提升聚氨酯膜的抗凝血性能。
实施例2：
与实施例1的不同之处在于：
本实施例中，未改性的聚氨酯膜的制备步骤包括:将聚氨酯粒料溶于二氧六环制备质量浓度为15％的聚氨酯溶液，将聚氨酯溶液倒入聚四氟乙烯模具，均匀铺开，放入真空干燥箱，50℃真空干燥24h后，取出模具，待温度降至室温，加入纯化水，将膜取出经过清洗后，室温或者真空干燥备用，获取平整的聚氨酯膜，并将聚氨酯膜分为对照组和试验组两组，每组3片；其中，
对照组：将平整的聚氨酯膜在PBS溶液中清洗后切割成10*10mm的片状进行接触角、血小板黏附测试；
试验组：第一步，配制100ml含有15％w/vAPMA和15％w/v MPC的前处理溶液，将溶液倒入三口烧瓶，以1.5L/min的速度通入氩气20min，去除溶液中的氧气；第二步，待溶液达到50℃，加入0.03M硝酸铈，搅拌均匀后加入膜，氩气保护下反应18h；第三步，将经过前处理的膜用纯化水润洗，配制pH＝7.4±0.2的PBS溶液，将膜浸入PBS溶液，室温下浸泡12h，之后将膜用纯化水清洗，并在空气中干燥；第四步，配制pH＝5.5±0.5的MES溶液，其中，MES的摩尔浓度为0.1M，在MES溶液中加入2mg/ml的肝素钠，并加入0.06M的EDC和0.03M的NHS，搅拌均匀，将膜浸入，37℃避光反应18h；第五步，将反应后的膜取出，依次用纯化水，PBS溶液，纯化水，75％乙醇清洗，并在空气中干燥，改性聚氨酯膜的制备反应流程如图1所示；将试验组的改性聚氨酯膜切成10mm*10mm的片状进行接触角、肝素接枝密度、血小板黏附测试。
结果分析：未改性的聚氨酯膜经过不同处理后，对照组聚氨酯膜的水接触角为102°，血小板黏附极多；试验组改性的聚氨酯膜的水接触角为50°，血小板黏附几乎为零，肝素接枝密度为4.3μg/cm 2,具有显著差异性。
结论：利用本申请实施例2的方法可以有效接枝肝素到聚氨酯膜表面，并有效减小接触角，从而极大提升聚氨酯膜的抗凝血性能。
实施例3：
与实施例1的不同之处在于：
本实施例中，未改性的聚氨酯膜的制备步骤包括:将聚氨酯粒料溶于四氢呋喃/二氧六环＝1：1的溶剂中制备质量浓度为15％的聚氨酯溶液，将聚氨酯溶液倒入聚四氟乙烯模具，均匀铺开，放入真空干燥箱，50℃真空干燥24h后，取出模具，待温度降至室温，加入纯化水，将膜取出经过清洗后，室温或者真空干燥备用，获取平整的聚氨酯膜，并将聚氨酯膜分为对照组和试验组两组，每组3片；其中，
对照组：将平整的聚氨酯膜在PBS溶液中清洗后切割成10*10mm的片状进行接触角、血小板黏附测试；
试验组：第一步，配制100ml含有20％w/vAPMA和20％w/v MPC的前处理溶液，将溶液倒入三口烧瓶，以1.5L/min的速度通入氩气20min，去除溶液中的氧气；第二步，待溶液达到50℃，加入0.1M硝酸铈，搅拌均匀后加入膜，氩气保护下反应24h；第三步，将经过前处理的膜用纯化水润洗，配制pH＝7.4±0.2的PBS溶液，将膜浸入PBS溶液，室温下浸泡24h，之后将膜用纯化水清洗，并在空气中干燥；第四步，配制pH＝5.5±0.5的MES溶液，其中，MES的摩尔浓度为0.5M，在MES溶液中加入2mg/ml的肝素钠，并加入0.3M的EDC和0.03M的NHS，搅拌均匀，将膜浸入，37℃避光反应24h；第五步，将反应后的膜取出，依次用纯化水，PBS溶液，纯化水，75％乙醇清洗，并在空气中干燥，改性聚氨酯膜的制备反应流程如图1所示；将试验组的膜切成10mm*10mm的片状进行接触角、肝素接枝密度、血小板黏附测试。
结果分析：未改性的聚氨酯膜经过不同处理后，对照组聚氨酯膜的水接触角为98°，血小板黏附极多；试验组改性聚氨酯膜的水接触角为45°，血小板黏附几乎为零，肝素接枝密度为5.8μg/cm 2,具有显著差异性。
结论：利用本申请实施例3的方法可以有效接枝肝素到聚氨酯膜表面，并有效减小接触角，从而极大提升聚氨酯膜的抗凝血性能。
以上实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上实施例仅表达了本申请的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对申请专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。因此，本申请专利的保护范围应以所附权利要求为准。

Claims (14)

  1. 一种表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料，其特征在于，所述改性高分子膜材料的制备方法包括以下步骤：
    S1、制备高分子膜材料；
    S2、在高分子膜材料表面化学接枝不饱和磷酰胆碱和N-(3-氨基丙基)甲基丙烯酰胺；
    S3、将步骤S2得到的接枝高分子膜材料进行清洗；
    S4、将步骤S3得到的清洗后的接枝高分子膜材料采用碳二亚胺化学法接枝肝素。
  2. 根据权利要求1所述的改性高分子膜材料，其特征在于，所述改性高分子膜材料的厚度为0.01～2mm。
  3. 根据权利要求1～2任一项所述的改性高分子膜材料，其特征在于，所述高分子膜材料包括聚氨酯膜、聚对苯二甲酸乙二醇酯膜、聚四氟乙烯膜、聚醚醚酮膜、聚酰亚胺、聚酰胺、超聚氨酯量聚乙烯膜和聚苯乙烯弹性体膜中的一种或多种。
  4. 根据权利要求1～3任一项所述的改性高分子膜材料，其特征在于，所述改性高分子膜材料的制备方法，包括以下步骤：
    将所述高分子膜材料置于异丙醇溶液中清洗，随后用纯化水清洗，干燥，置于含N-(3-氨基丙基)甲基丙烯酰胺盐酸盐和二甲基丙烯酰氧乙基磷酰胆碱的前处理溶液中，在含铈化合物的引发下，得到含有聚磷酰胆碱两性离子和多个所述肝素结合位点的所述高分子膜材料，所述肝素结合位点为聚N-(3-氨基丙基)甲基丙烯酰胺盐酸盐的氨基；
    将接枝聚磷酰胆碱两性离子和N-(3-氨基丙基)甲基丙烯酰胺的所述高分子膜材料置于清洗液中清洗，浸泡，干燥；
    将干燥后的接枝聚磷酰胆碱两性离子和N-(3-氨基丙基)甲基丙烯酰胺的所述高分子膜材料置于含1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基丁二酰亚胺的肝素溶液中，反应，清洗，干燥后得到表面复合接枝两性离子和肝素涂层高分子膜材料。
  5. 如权利要求1～4任一项所述的表面复合接枝磷酰胆碱和肝素抗凝涂层的改性高分子膜材料的制备方法，其特征在于，包括以下步骤：
    (1)将所述高分子膜材料置于异丙醇溶液中清洗，随后用纯化水清洗，干燥，置于含N-(3-氨基丙基)甲基丙烯酰胺盐酸盐和二甲基丙烯酰氧乙基磷酰胆碱的前处理溶液中，在含铈化合物的引发下，得到含有聚磷酰胆碱两性离子和多个所述肝素结合位点(聚N-(3-氨基丙基)甲基丙烯酰胺盐酸盐)的氨基的膜材料；
    (2)将步骤(1)中的所述膜材料置于清洗液中清洗，浸泡，干燥；
    (3)将步骤(2)中干燥后的所述膜材料置于含1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基丁二酰亚胺的肝素溶液中反应，清洗，干燥后得到表面复合接枝所述磷酰胆碱和所述肝素抗凝涂层的所述改性高分子膜材料。
  6. 根据权利要求5的所述改性高分子膜材料的制备方法，其特征在于，步骤(1)中的所述高分子膜材料由编织法、静电纺丝法、溶液凝固法、浸提法和喷涂法中的一种或多种方法制备。
  7. 根据权利要求5～6任一项所述的改性高分子膜材料的制备方法，其特征在于，步骤(1)满足如下条件中的至少一个：
    1)步骤(1)中的所述异丙醇溶液的浓度为2.5～25％；所述异丙醇溶液和所述纯化水的清洗时间为10～30min；
    2)步骤(1)中的所述N-(3-氨基丙基)甲基丙烯酰胺盐酸盐的浓度为5～25％w/v；所述二甲基丙烯酰氧乙基磷酰胆碱的浓度为5～25％w/v；
    3)步骤(1)中的所述前处理溶液需要先去除溶液中的氧气再加入所述含铈化合物；所述含铈化合物中铈离子浓度为0.01～0.1M；
    4)步骤(1)中的反应温度为40～60℃，反应时间为12～24h，全程不能有氧气参与反应。
  8. 根据权利要求5～7任一项所述的改性高分子膜材料的制备方法，其特征在于，所述含铈化合物包括三氧化二铈、氯化铈、氟化铈、碳酸铈、磷酸铈、硝酸铈和硝酸铈铵中的一种或多种。
  9. 根据权利要求5～8任一项所述的改性高分子膜材料的制备方法，其特征在于，步骤(2)中的所述清洗液为纯化水、磷酸盐缓冲液、Triton X-100溶液中的一种；浸泡时间为12～24h；干燥方式为室温干燥或真空干燥。
  10. 根据权利要求5～9任一项所述的改性高分子膜材料的制备方法，其特征在于，步骤(3)中所述肝素溶液的溶剂为pH＝5-6的2-吗啉代乙磺酸缓冲液，所述2-吗啉代乙磺酸缓冲液的含量为0.05～0.5M。
  11. 根据权利要求5～10任一项所述的改性高分子膜材料的制备方法，其特征在于，步骤(3)中所述肝素溶液可以由肝素或者肝素钠制备；所述肝素溶液的浓度为0.5～5mg/ml。
  12. 根据权利要求5～11任一项所述的改性高分子膜材料的制备方法，其特征在于，步骤(3)中所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺与所述N-羟基丁二酰亚胺的摩尔比0.5～10；N-羟基丁二酰亚胺的浓度为0.02～0.04M。
  13. 根据权利要求5～12任一项所述的改性高分子膜材料的制备方法，其特征在于， 步骤(3)中的反应在温度37℃下避光反应12～24h。
  14. 根据权利要求5～13任一项所述的改性高分子膜材料的制备方法，其特征在于，步骤(3)中清洗采用纯化水、磷酸盐缓冲液、纯化水、30～95％的乙醇清洗；干燥为室温干燥或真空干燥。
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