WO2015188716A1 - 一种抗凝血涂层及其涂覆方法 - Google Patents

一种抗凝血涂层及其涂覆方法 Download PDF

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Publication number
WO2015188716A1
WO2015188716A1 PCT/CN2015/080662 CN2015080662W WO2015188716A1 WO 2015188716 A1 WO2015188716 A1 WO 2015188716A1 CN 2015080662 W CN2015080662 W CN 2015080662W WO 2015188716 A1 WO2015188716 A1 WO 2015188716A1
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Prior art keywords
charged polyelectrolyte
solution
negatively charged
positively charged
anticoagulant
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PCT/CN2015/080662
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English (en)
French (fr)
Inventor
陈大凯
杜广武
梁灿权
闫冬环
刘鹏
罗七一
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上海微创医疗器械（集团）有限公司
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Priority claimed from CN201410253582.4A external-priority patent/CN105233348A/zh
Priority claimed from CN201410254131.2A external-priority patent/CN105199125A/zh
Application filed by 上海微创医疗器械（集团）有限公司 filed Critical 上海微创医疗器械（集团）有限公司
Publication of WO2015188716A1 publication Critical patent/WO2015188716A1/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
    • A61L33/08—Polysaccharides
    • 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
    • C08J7/04—Coating

Definitions

  • the invention relates to a biological material and a preparation method thereof, in particular to an anticoagulant coating and a coating method thereof.
  • Biomaterials are materials that have special properties and special functions and are used in medical and health care fields such as artificial organs, surgical repair, diagnosis, examination, and treatment of diseases, and have no adverse effects on human tissues and blood. As a biomaterial, it must have good biocompatibility, including blood compatibility and histocompatibility. Among them, blood compatibility is more demanding on biomaterials than tissue compatibility.
  • Blood compatibility is particularly important for devices that come into contact with blood, such as extracorporeal circulation devices, interventional treatment systems, artificial blood vessels, and artificial organs.
  • extracorporeal circulation devices When these devices and related materials come into contact with blood, they induce protein adsorption or activation of coagulation factors on the surface of the material, leading to the formation of fibrin gel and the formation of platelet thrombus, which eventually leads to blood coagulation.
  • biomaterials with good anticoagulant properties are mainly prepared by synthesizing new anticoagulant materials and modifying the surface of existing materials. Since various existing biological materials generally have good physical and mechanical properties and low prices, and have been widely used in various types of biomedical devices, the surface materials are modified by existing materials to maintain good materials. On the basis of physical and mechanical properties, improving the anticoagulant properties of materials is a cost-effective way. People mainly improve the anticoagulant properties of materials by adjusting the surface charge, hydrophobicity or grafting bioactive macromolecules on the surface of materials by means of surface chemical grafting, surface photochemical grafting, plasma treatment and other technical methods. Good results. However, these surface modification methods generally have weaknesses such as solvent toxicity, complicated preparation process, and poor controllability, which not only greatly limit the designability of the material surface, but also cannot modify the medical device with complex geometric shape. Meet the needs of the rapid development of medical devices.
  • the technical problem to be solved by the present invention is to provide an anticoagulant coating and a method for applying an anticoagulant coating to a surface of a carrier.
  • the coating method is simple, solvent-free, environmentally friendly, and prepared separately. Coagulation biomaterials and medical devices have good anticoagulant properties.
  • the technical solution adopted by the present invention to solve the above technical problems is to provide an anticoagulant coating for forming on a surface of a carrier which is alternately adsorbed by a positively charged polyelectrolyte and a negatively charged polyelectrolyte. form.
  • the positively charged polyelectrolyte and the negatively charged polyelectrolyte are crosslinked together by a crosslinking agent.
  • the crosslinking agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, glutaraldehyde or periodic acid.
  • the carrier is a biomaterial.
  • the carrier is polyethylene, polypropylene, polyurethane, cellulose acetate, polyether sulfone or polyvinyl chloride.
  • the carrier is a medical device.
  • the carrier is an extracorporeal circulation device, an interventional treatment system or an artificial organ.
  • the positively charged polyelectrolyte is serum protein, human fibrinogen, anti-human chorionic gonadotropin, collagen, ovalbumin, soy protein or whey protein.
  • the negatively charged polyelectrolyte is sodium heparin, hirudin, sodium alginate or dextran sulfate.
  • Another technical solution of the present invention to solve the above technical problems is to provide a method of applying an anticoagulant coating to the surface of a carrier, comprising the steps of: a) providing a carrier; and b) providing the carrier The surface alternately adsorbs the positively charged polyelectrolyte and the negatively charged polyelectrolyte to form an anticoagulant coating.
  • the coating method further comprises subjecting the alternately adsorbed positively and negatively charged polyelectrolyte to a crosslinking reaction by a crosslinking agent.
  • the crosslinking agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, glutaraldehyde or periodic acid.
  • the coating method further comprises, after the crosslinking reaction, rinsing with a purified water. Said carrier of an anticoagulant coating.
  • the crosslinker has a pH of from 4.6 to 5.0.
  • the carrier is a biomaterial
  • the step b) comprises: b1) formulating the positively charged polyelectrolyte solution and the negatively charged polyelectrolyte solution to the positively charged polyelectrolyte solution And the negatively charged polyelectrolyte solution are separately sonicated; and, b2) alternately placing the biological material in the positively charged polyelectrolyte solution and the negatively charged under vacuuming conditions The electrolytic solution is concentrated to form the anticoagulant coating on the surface of the biomaterial.
  • step b2) further comprises the following steps:
  • the step b2) comprises alternately flowing the positively charged polyelectrolyte solution and the negatively charged polyelectrolytic solution through the surface of the biomaterial.
  • the vacuuming condition is a vacuum ranging from -0.02 MPa to -0.08 MPa.
  • the biomaterial is polyethylene, polypropylene, polyurethane, cellulose acetate, polyether sulfone or polyvinyl chloride.
  • the carrier is a medical device
  • the step b) comprises: b1) formulating a positively charged polyelectrolyte solution and a negatively charged polyelectrolyte solution, the positively charged polyelectrolyte solution and the strip
  • the negatively charged polyelectrolyte solution is separately sonicated; and b2) alternately flowing the positively charged polyelectrolyte solution and the negatively charged polyelectrolytic solution through the surface of the medical device, thereby The surface of the device forms the anticoagulant coating.
  • the step b2) further comprises:
  • the medical device is an extracorporeal circulation device, an interventional treatment system or an artificial organ.
  • the positively charged polyelectrolyte solution has a pH of from 3.5 to 4.5
  • the negatively charged polyelectrolyte solution has a pH of from 2.5 to 4.5.
  • the sonication has an operating frequency of 25 kHz and an ultrasonic time of 2-5 minutes.
  • the positively charged polyelectrolyte is serum protein, human fibrinogen, anti-human chorionic gonadotropin, collagen, ovalbumin, soy protein or whey protein.
  • the negatively charged polyelectrolyte is sodium heparin, hirudin, sodium alginate or dextran sulfate.
  • the preparation method of the invention has simple process, can be realized by a simple solution circulation device, and can obtain a relatively stable coating structure by cross-linking; 2)
  • the invention is manufactured.
  • the method is carried out in a mild aqueous environment without solvent toxicity, and is an environmentally friendly preparation method; 3)
  • the preparation method of the present invention after the ultrasonic treatment of the polyelectrolyte solution, the polyelectrolyte solute has good dispersibility and avoids the occurrence of agglomeration.
  • the coating is more uniform; 4)
  • the method for preparing the anticoagulant biological material of the invention can control the flow speed of the polyelectrolyte solution under the vacuum condition, and the shape and structure of the material is not special. Requires that it can be realized on the surface of a plurality of complex shape structural materials; 5)
  • the anticoagulant biomaterial provided by the present invention has a significantly lower water contact angle and a significantly longer rehydration time than the biomaterial in the prior art; 6) the present invention
  • the method for manufacturing an anticoagulant medical device has no special requirements on the shape and structure of the medical device, and can be used in various complicated shape structures. Opposing surface to achieve; 7)
  • the medical apparatus according to the present invention provides an anticoagulant than the prior art medical devices, the water contact angle decreased, recalcification time was significantly prolonged.
  • the anticoagulant coating of the present invention can be coated on the surface of a biological material such as polyethylene, polypropylene, polyurethane, cellulose acetate, polyether sulfone or polyvinyl chloride to form an anticoagulant biomaterial according to different uses, or
  • a biological material such as polyethylene, polypropylene, polyurethane, cellulose acetate, polyether sulfone or polyvinyl chloride
  • the surface of the medical device such as an extracorporeal circulation device, an interventional treatment system, or an artificial organ is coated to form an anticoagulation medical device.
  • Methods of preparing a first anticoagulant biomaterial using the anticoagulant coating of the present invention include:
  • the positively charged polyelectrolyte solution preferably has a pH of 3.5-4.5, and the concentration of the polyelectrolyte-containing electrolyte is preferably 0.015 mg/mL to 0.15 mg/ml; a negatively charged polyelectrolyte citrate solution, the pH of the negatively charged polyelectrolyte solution is preferably 2.5-4.5, and the concentration of the polyelectrolyte-containing electrolyte is preferably 0.10 mg/mL-1.00 mg/mL, which will be positive and negative.
  • the charged polyelectrolyte solution is separately subjected to sonication; the ultrasonic treatment preferably has an operating frequency of 25 kHz, and the ultrasonication time is preferably 2 to 5 minutes.
  • the vacuum degree of the vacuum is preferably in the range of -0.02 MPa to -0.08 MPa; and the material body of the biological material is placed in the positively charged polyelectrolyte citrate solution for 15-30 minutes. Rinse with purified water having a pH of 4.5 for 2 minutes.
  • the material body is placed in a negatively charged polyelectrolyte citrate solution for 15-30 minutes, and then rinsed with purified water having a pH of 4.5 to obtain a bilayer on the surface.
  • purified water having a pH of 4.5
  • a crosslinking agent solution is prepared; the pH of the crosslinking agent solution is preferably 4.6-5.0; the concentration is preferably 0.10 mg/ml-0.50 mg/mL; then the coated biomaterial is formed.
  • the mixture was placed in a cross-linking agent solution for 2-18 hours, and finally rinsed with purified water for 5 minutes to obtain a cross-linked anticoagulant biomaterial.
  • a method of immersing the material body in the polyelectrolytic solution is adopted, so that the belt is positive
  • the negatively charged polyelectrolyte is alternately adsorbed a plurality of times on the surface of the material body.
  • the method of flowing the polyelectrolytic solution through the surface of the material body may also be used, which is not limited in the present invention.
  • a method of preparing a first anticoagulation medical device using the anticoagulant coating of the present invention comprises:
  • the positively charged polyelectrolyte solution preferably has a pH of 3.5-4.5, and the concentration of the polyelectrolyte-containing electrolyte is preferably 0.015 mg/mL to 0.15 mg/ml; a negatively charged polyelectrolyte citrate solution, the pH of the negatively charged polyelectrolyte solution is preferably 2.5-4.5, and the concentration of the polyelectrolyte-containing electrolyte is preferably 0.10 mg/mL-1.00 mg/mL, which will be positive and negative.
  • the charged polyelectrolyte solution is separately subjected to sonication; the ultrasonic treatment preferably has an operating frequency of 25 kHz, and the ultrasonication time is preferably 2 to 5 minutes.
  • the alternately adsorbed positively and negatively charged polyelectrolyte is subjected to a crosslinking reaction by a crosslinking agent.
  • the specific crosslinking process is as follows: First, a crosslinking agent solution is prepared; the pH of the crosslinking agent solution is preferably 4.6-5.0; the concentration is preferably 0.10 mg/ml-0.50 mg/mL; and then the crosslinking agent solution is circulated. The surface of the medical device forming the coating was applied for 2-18 hours, and finally rinsed with purified water for 5 minutes to obtain a coated cross-linked anticoagulant medical device.
  • the dynamic contact angle tester (DCA) and the toluidine blue solution were used to respectively biomaterial before and after the coating. Characterization with medical devices. The obtained structures were all: the water contact angle was reduced from 92.7 ⁇ 1 degrees before modification to 78.8 ⁇ 1 degrees; the modified biomaterial and medical device were stained with toluidine blue and turned purple.
  • the beneficial effects of the present invention will be expressed in combination with the recalcification time, the recalcification time
  • the experiment was carried out by reference to the literature (Journal of Chemical Engineering of Higher Education, 2002, 12, 2369-2374).
  • the blood collected from the anticoagulant test was placed in a test tube containing 1/10 volume of 0.109 mol/L sodium citrate anticoagulant, centrifuged at 3000 r/min for 10 min, and the supernatant (plasma, yellow) was taken.
  • 0.4 mL of anticoagulated plasma (decalcified) preheated to 37 ° C was added to the coated and closed PVC tube at one end, and after standing at 37 ° C for 1 min in water, the preheated 0.025 mol / was added.
  • a method for preparing a second anticoagulant biomaterial using the anticoagulant coating of the present invention comprises circulating a solution of albumin citrate (pH 4.5) at a concentration of 0.08 mg/ml under vacuum.
  • the PVC tube was chilled for 20 min, then purified water (pH 4.5) for 2 min to obtain a surface for physical adsorption of albumin; a heparin sodium citrate solution (pH 4.5) having a concentration of 0.15 mg/ml was circulated through the surface to be positively charged white.
  • the PVC tube of protein was chilled for 15 min in purified water (pH 4.5) to obtain a surface with negatively charged anticoagulant heparin; an albumin solution (pH 4.5) with a concentration of 0.08 mg/ml was circulated through the surface with a negative charge.
  • the PVC tube of heparin sodium was rinsed for 15 min in purified water (pH 4.5) to obtain a PVC tube with positively charged albumin on the surface, thereby obtaining a three-layer alternating coating surface of positively charged albumin and negatively charged heparin sodium; -ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride solution (pH 5.0) was circulated through the surface of 3 alternating coatings for 6 h to obtain crosslinked positively charged albumin and negative charge Heparin sodium 3 layers alternately coated the surface.
  • a method for preparing a second anticoagulant medical device using the anticoagulant coating of the present invention comprises: circulating a solution of albumin citrate (pH 3.5) at a concentration of 0.15 mg/ml through a bipolar stock using a peristaltic pump The tube was intubated for 15 min, then rinsed with purified water (pH 4.5) for 2 min to obtain a surface for physical adsorption of albumin; a solution of heparin sodium citrate (pH 4.5) at a concentration of 0.10 mg/ml was flowed through the surface to form a positive charge.
  • the bipolar femoral vein of albumin was intubated for 30 min, purified water (pH 4.5) for 2 min to obtain a surface with negatively charged anticoagulant heparin; albumin citrate solution (pH 3.5 with a concentration of 0.15 mg/ml) ) Circulatingly flowing through the bipolar femoral vein cannula with negatively charged sodium heparin on the surface for 15 min, and purifying water (pH 4.5) for 2 min to obtain a bipolar femoral vein cannula with positively charged albumin on the surface, thereby obtaining a positive charge white 3 layers of protein and negatively charged heparin sodium alternately coated on the surface; 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride solution (pH 5.0) was circulated through 3 layers of alternating coating At the surface of the layer for 6 h, a cross-linked positively charged albumin and a negatively charged heparin sodium were alternately coated on the surface.
  • Example 3 and Example 4 After the anticoagulant biomaterial and the anticoagulant medical device respectively obtained by the methods of Example 3 and Example 4, respectively, stained with toluidine blue solution, the surface of the PVC tube and the inner surface of the bipolar femoral vein cannula were found. Both turned purple, indicating the surface of heparin sodium in the PVC tube and bipolar femoral vein cannula. After modification, the water contact angle of the PVC tube and the bipolar femoral vein cannula was significantly reduced.
  • the recalcification time showed that the recalcification time of heparin-coated PVC tube and bipolar femoral vein cannula was longer than that of unheparin-coated PVC tube and bipolar femoral vein cannula for more than 40 min.
  • a method for preparing a third anticoagulant biomaterial using the anticoagulant coating of the present invention comprises circulating a solution of albumin citrate (pH 4.5) at a concentration of 0.10 mg/ml under vacuum. PP hollow fiber for 20 min, then rinsed with purified water (pH 4.5) for 2 min to obtain a surface of physical adsorption of positively charged albumin; a solution of 0.11 mg/ml of heparin sodium citrate solution (pH 4.0) was circulated through the surface.
  • a method for preparing a third anticoagulant medical device using the anticoagulant coating of the present invention comprises: circulating a solution of albumin citrate (pH 4.5) at a concentration of 0.10 mg/ml through a membrane oxygen using a peristaltic pump The oxygenation chamber was closed for 15 min, then rinsed with purified water (pH 4.5) for 2 min to obtain a surface for the physical adsorption of positively charged albumin; a solution of heparin sodium citrate (pH 4.5) at a concentration of 0.15 mg/ml was circulated.
  • the acid salt solution (pH 4.5) was circulated through the membrane oxygenator oxygenation chamber of the surface of the negatively charged polyanionic sodium heparin for 15 min, and purified water (pH 4.5) was washed for 2 min to obtain a membrane with positively charged albumin on the surface.
  • Oxygenator oxygenation chamber thereby obtaining a three-layer alternating coating surface of albumin and heparin sodium; a solution of 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride ( pH 5.0) was circulated through 3 layers of alternating coating surfaces for 3 h to obtain a cross-linked albumin and heparin sodium 3-layer alternating coating surface.
  • Example 5 and Example 6 After the anticoagulant biomaterial and the anticoagulant medical device respectively obtained by the methods of Example 5 and Example 6, respectively, dyeing with toluidine blue solution, the surface of the PP hollow fiber and the surface of the membrane oxygenator oxygenation chamber were found. Both turned from white to purple, indicating the surface of heparin sodium on the PP hollow fiber and membrane oxygenator oxygenation chamber.
  • the recalcification time showed that the recalcification time of the heparin-coated PP hollow fiber and the membrane oxygenator oxygenation chamber was longer than that of the unheparin-coated PP hollow fiber and the membrane oxygenator oxygenation chamber by more than 20 min.
  • the method for preparing a fourth anticoagulant biomaterial by using the anticoagulant coating of the invention comprises: first immersing the PVC tube in an albumin citrate solution (pH 4.5) at a concentration of 0.15 mg/ml for 25 min, and then purifying Water (pH 4.5) was washed for 2 min to obtain the surface of the positively charged albumin physic adsorption; the PVC tube with positive surface charge was immersed in a heparin sodium citrate solution (pH 3.5) at a concentration of 0.15 mg/ml for 15 min, and purified.
  • an albumin citrate solution pH 4.5
  • purifying Water pH 4.5
  • Purified water (pH 4.5) was rinsed for 2 min to obtain a PVC tube with a positively charged albumin surface, thereby obtaining a three-layer alternating coating surface of positively charged albumin and negatively charged heparin sodium;
  • the PVC pipe was immersed in 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride solution (pH 5.0) for 2 h to obtain 3 layers of crosslinked albumin and heparin sodium. surface.
  • Dyeing with toluidine blue solution revealed that the surface of the PVC tube turned purple, indicating that heparin sodium was on the surface of the PVC tube. After modification, the water contact angle of the PVC pipe is significantly reduced. The recalcification time showed that the recalcification time of the heparin-coated PVC tube was significantly prolonged.
  • the anticoagulant biomaterial and the preparation method of the medical device have the same as The following advantages: 1)
  • the preparation method of the invention has simple process, can be realized by a simple solution circulation device, and can obtain a relatively stable coating structure by cross-linking; 2) the manufacturing method of the invention is carried out in a mild aqueous environment, Solvent-free toxicity, is an environmentally friendly preparation method; 3)
  • the preparation method of the present invention after the ultrasonic treatment of the polyelectrolyte solution, the polyelectrolyte solute has good dispersibility, avoids the occurrence of agglomeration and the coating is more uniform; 4) the invention
  • the method for preparing the anticoagulant biological material can control the flow speed of the polyelectrolyte solution under the condition of vacuuming, and has no special requirements on the shape and structure of the material, and can be in various complicated shape structures.
  • the surface of the material is realized; 5)
  • the anticoagulant biomaterial provided by the invention has a significantly lower water contact angle than the biomaterial in the prior art, and the recalcification time is obviously prolonged; 6)
  • the method for manufacturing an anticoagulation medical device according to the present invention There is no special requirement for the shape and structure of the medical device, which can be realized on the surface of a medical device of various complicated shape structures; 7) Provided by the present invention Anticoagulant medical device than the prior art medical devices, the water contact angle decreased, recalcification time was significantly prolonged.

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Abstract

一种抗凝血涂层，用于形成于一载体表面，所述涂层由带正电荷的聚电解质和带负电荷的聚电解质交替吸附形成。本发明的工艺简单，可通过简单的溶液循环装置实现，以及通过交联作用，可得到较稳定的涂层结构；本发明制造方法在温和的水溶液环境下进行，无溶剂毒性，是一种环境友好的制备方法，并且聚电解质溶液经过超声处理后，聚电解质溶质分散性好，避免了团聚现象的发生，涂层更均匀。

Description

一种抗凝血涂层及其涂覆方法 技术领域
本发明涉及生物材料及其制备方法，尤其涉及一种抗凝血涂层及其涂覆方法。
背景技术
生物材料是一类具有特殊性能、特殊功能，用于人工器官、外科修复、诊断、检查、治疗疾病等医疗、保健领域而对人体组织、血液不会产生不良影响的材料。作为生物材料，必须具有良好的生物相容性，它包括血液相容性和组织相容性。其中，血液相容性对生物材料的要求较组织相容性更为苛刻。
对于与血液接触的器件，例如体外循环装置、介入治疗系统、人工血管和人工心脏等人造脏器等，血液相容性尤为重要。这些器件和相关材料与血液接触时会诱导蛋白质的吸附或凝血因子在材料表面的活化，导致纤维蛋白凝胶的生成和血小板血栓的形成，最终导致血液凝固。
目前，人们主要通过合成新型抗凝血材料和对现有材料的表面进行改性制备具有良好抗凝血性的生物材料。由于现有的各种生物材料通常具有良好的物理机械性能和较低的价格，并已被广泛地应用在各类生物医用装置中，因此通过对现有材料进行表面改性，在维持材料良好物理机械性能的基础上，改善材料的抗凝血性，是一种经济有效的方式。人们主要通过表面化学接枝、表面光化学接枝、等离子体处理等技术方法，调节材料表面的电荷、亲疏水性或在材料表面接枝生物活性大分子，来改善材料的抗凝血性，并取得了较好的成果。然而，这些表面改性手段普遍存在着溶剂毒性、制备过程复杂、可调控能力差等弱点，不仅大大限制了材料表面的可设计性，而且无法实现对具有复杂几何外形的医用装置的修饰，不能满足医用装置飞速发展的需要。
发明内容
本发明所要解决的技术问题是提供一种抗凝血涂层及将抗凝血涂层涂覆于载体表面的方法，涂覆方法简单，无溶剂毒性，具有环境友好性，分别制备得到的抗凝血生物材料和医用装置具有良好的抗凝血性。
本发明为解决上述技术问题而采用的技术方案是提供一种抗凝血涂层，用于形成于一载体表面，所述涂层由带正电荷的聚电解质和带负电荷的聚电解质交替吸附形成。
优选地，所述带正电荷的聚电解质和带负电荷的聚电解质通过交联剂交联结合在一起。
优选地，所述交联剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、戊二醛或高碘酸。
优选地，所述载体为生物材料。
优选地，所述载体为聚乙烯、聚丙烯、聚氨酯、醋酸纤维素、聚醚砜或聚氯乙烯。
优选地，所述载体为医用装置。
优选地，所述载体为体外循环装置、介入治疗系统或人造脏器。
优选地，所述带正电荷的聚电解质为血清蛋白、人纤维蛋白原、抗人绒毛膜促性腺激素、胶原蛋白、卵清蛋白、豆清蛋白或乳清蛋白。
优选地，所述带负电荷的聚电解质为肝素钠、水蛭素、海藻酸钠或葡聚糖硫酸酯。
本发明为解决上述技术问题而采用的另一技术方案是提供一种将抗凝血涂层涂覆于载体的表面的方法，包括如下步骤：a)提供一载体；以及b)在所述载体的表面交替吸附带正电荷的聚电解质和带负电荷的聚电解质，以形成抗凝血涂层。
优选地，涂覆方法还包括通过交联剂使所述交替吸附的带正负电荷的聚电解质发生交联反应。
优选地，所述交联剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、戊二醛或高碘酸。
优选地，涂覆方法还包括在所述交联反应后，使用纯化水冲洗涂覆有所 述抗凝血涂层的所述载体。
优选地，所述交联剂的pH值为4.6-5.0。
优选地，所述载体为生物材料，所述步骤b)包括：b1)配制所述带正电荷的聚电解质溶液和所述带负电荷的聚电解质溶液，对所述带正电荷的聚电解质溶液和所述带负电荷的聚电解质溶液分别进行超声处理；以及，b2)在抽真空的条件下，将所述生物材料交替置于所述带正电荷的聚电解质溶液和所述带负电荷的聚电解溶液，从而在所述生物材料的表面形成所述抗凝血涂层。
优选地，所述步骤b2)进一步包括如下步骤：
b21)在抽真空的条件下，将所述生物材料置于所述带正电荷的聚电解质溶液中一段预定时间，再用纯化水冲洗；
b22)在抽真空的条件下，将所述生物材料置于所述带负电荷的聚电解质溶液中一段预定时间，再用纯化水冲洗；以及
b23)重复所述步骤b21)和b22)，使得所述带正电荷的聚电解质和所述带负电荷的聚电解质在所述生物材料的表面交替吸附多次，从而在所述生物材料的表面形成所述抗凝血涂层。
优选地，所述步骤b2)包括：使所述带正电荷的聚电解质溶液和所述带负电荷的聚电解溶液交替流过所述生物材料的表面。
优选地，所述抽真空的条件为真空度范围在-0.02MPa到-0.08MPa内。
优选地，所述生物材料为聚乙烯、聚丙烯、聚氨酯、醋酸纤维素、聚醚砜或聚氯乙烯。
优选地，所述载体为医用装置，所述步骤b)包括：b1)配制带正电荷的聚电解质溶液和带负电荷的聚电解质溶液，对所述带正电荷的聚电解质溶液和所述带负电荷的聚电解质溶液分别进行超声处理；以及，b2)使所述带正电荷的聚电解质溶液和所述带负电荷的聚电解溶液交替流过所述医用装置的表面，从而在所述医用装置的表面形成所述抗凝血涂层。
优选地，所述步骤b2)还包括：
b21)使所述带正电荷的聚电解质溶液循环流过所述医用装置的表面一段预定时间，再用纯化水冲洗；
b22)使所述带负电荷的聚电解质溶液循环流过所述医用装置的表面一段预定时间，再用纯化水冲洗；以及
b23)重复上述步骤b21)和b22)，使得所述带正电荷的聚电解质和所述带负电荷的聚电解质在所述医用装置的表面交替吸附多次，从而在所述医用装置的表面形成所述抗凝血涂层。
优选地，所述医用装置为体外循环装置、介入治疗系统或人造脏器。
优选地，所述带正电荷的聚电解质溶液的pH值为3.5-4.5，所述带负电荷的聚电解质溶液的pH值为2.5-4.5。
优选地，所述超声处理的工作频率为25kHz，超声时间为2-5分钟。
优选地，所述带正电荷的聚电解质为血清蛋白、人纤维蛋白原、抗人绒毛膜促性腺激素、胶原蛋白、卵清蛋白、豆清蛋白或乳清蛋白。
优选地，所述带负电荷的聚电解质为肝素钠、水蛭素、海藻酸钠或葡聚糖硫酸酯。
本发明对比现有技术有如下的有益效果：1)本发明制备方法工艺简单，可通过简单的溶液循环装置实现，以及通过交联作用，可得到较稳定的涂层结构；2)本发明制造方法在温和的水溶液环境下进行，无溶剂毒性，是一种环境友好的制备方法；3)本发明制备方法聚电解质溶液经过超声处理后，聚电解质溶质分散性好，避免了团聚现象的发生，涂层更均匀；4)本发明制备抗凝血生物材料的方法在抽真空条件下，通过真空度的调控，可以较好的控制聚电解质溶液流动的速度，且对材料的形状结构没有特殊的要求，可在多种复杂形状结构材料表面实现；5)本发明所提供的抗凝血生物材料较现有技术中的生物材料，水接触角明显降低，复钙时间明显延长；6)本发明制造抗凝血医用装置的方法对医用装置的形状结构没有特殊的要求，可在多种复杂形状结构的医用装置表面实现；7)本发明所提供的抗凝血医用装置较现有技术中的医用装置，水接触角明显降低，复钙时间明显延长。
具体实施方式
本发明的抗凝血涂层根据不同的用途，可以涂覆在聚乙烯、聚丙烯、聚氨酯、醋酸纤维素、聚醚砜或聚氯乙烯等生物材料表面以形成抗凝血生物材料，也可以涂覆在体外循环装置、介入治疗系统或人造脏器等医用装置表面以形成抗凝血医用装置。下面结合实施例对本发明的各种用途作进一步的描述。
实施例1
采用本发明的抗凝血涂层制备第一种抗凝血生物材料的方法包括：
1)配制带正电荷的聚电解质柠檬酸盐溶液，所述带正电荷的聚电解质溶液pH值优选为3.5-4.5，含聚电解质的浓度优选为0.015mg/mL-0.15mg/ml；配置带负电荷的聚电解质柠檬酸盐溶液，所述带负电荷的聚电解质溶液的pH值优选为2.5-4.5，含聚电解质的浓度优选为0.10mg/mL-1.00mg/mL，将带正、负电荷的聚电解质溶液分别进行超声处理；所述超声处理的工作频率优选为25kHz，超声时间优选为2-5分钟。
2)在抽真空的条件下，所述抽真空的真空度范围优选为-0.02MPa到-0.08MPa；将生物材料的材料本体置于带正电荷的聚电解质柠檬酸盐溶液中15-30分钟，再用pH值为4.5的纯化水冲洗2分钟。
3)仍然在上述抽真空的条件下,将材料本体置于带负电荷的聚电解质柠檬酸盐溶液中15-30分钟，再用pH值为4.5的纯化水冲洗，得到表面含一个双分子层的生物材料。
4)交替重复上述步骤2)和3)，使得带正负电荷的聚电解质在材料本体表面交替吸附多次，得到带正负电荷的聚电解质交替吸附的抗凝血生物材料。交替重复的次数优选为2～5次。
5)最后，通过交联剂将所述交替吸附的带正负电荷的聚电解质进行交联反应。具体交联过程如下：首先，配制交联剂溶液；所述交联剂溶液的pH值优选为4.6-5.0；浓度优选为0.10mg/ml-0.50mg/mL；然后将形成涂层的生物材料置于交联剂溶液中2-18小时，最后用纯化水冲洗5分钟，得到涂层交联的抗凝血生物材料。
在本实施例中，采用了将材料本体浸入聚电解溶液中的方法，使得带正 负电荷的聚电解质在材料本体的表面，交替吸附多次，而在其它实施例中，也可以用使聚电解溶液流过材料本体表面的方法，本发明对此不作限制。
实施例2
采用本发明的抗凝血涂层制备第一种抗凝血医用装置的方法包括：
1)配制带正电荷的聚电解质柠檬酸盐溶液，所述带正电荷的聚电解质溶液pH值优选为3.5-4.5，含聚电解质的浓度优选为0.015mg/mL-0.15mg/ml；配置带负电荷的聚电解质柠檬酸盐溶液，所述带负电荷的聚电解质溶液的pH值优选为2.5-4.5，含聚电解质的浓度优选为0.10mg/mL-1.00mg/mL，将带正、负电荷的聚电解质溶液分别进行超声处理；所述超声处理的工作频率优选为25kHz，超声时间优选为2-5分钟。
2)将带正电荷的聚电解质柠檬酸盐溶液循环流过装置本体表面15-30分钟，再用pH值为4.5的纯化水冲洗2分钟。
3)将带负电荷的聚电解质柠檬酸盐溶液循环流过装置本体表面15-30分钟，再用pH值为4.5的纯化水冲洗，得到表面含一个双分子层的医用装置。
4)交替重复上述步骤2)和3)，带正负电荷的聚电解质在装置本体表面交替吸附多次，得到带正负电荷的聚电解质交替吸附的抗凝血医用装置。交替重复的次数优选为2～5次。
5)通过交联剂将所述交替吸附的带正负电荷的聚电解质进行交联反应。具体交联过程如下：首先，配制交联剂溶液；所述交联剂溶液的pH值优选为4.6-5.0；浓度优选为0.10mg/ml-0.50mg/mL；然后将交联剂溶液循环流过形成涂层的医用装置表面2-18小时，最后用纯化水冲洗5分钟，得到涂层交联的抗凝血医用装置。
在分别经实施例1和实施例2的方法分别得到的抗凝血生物材料和抗凝血医用装置后，利用动态接触角测试仪(DCA)、甲苯胺蓝溶液分别对涂层前后的生物材料和医用装置进行表征。得到的结构皆为：水接触角从改性前的92.7±1度降低到78.8±1度；改性后的生物材料和医用装置用甲苯胺蓝染色后变成紫色。
在以下实施例中，将结合复钙时间来表现本发明的有益效果，复钙时间 实验参照文献(高等学校化学学报，2002，12，2369-2374)方法进行。从抗凝血液试验中采得的血置于含有1/10体积为0.109mol/L枸橼酸钠抗凝液的试管中，3000r/min离心10min，取上层液(血浆，黄色)。将预热至37℃的抗凝血浆(去钙)0.4mL加入经过涂层处理且一端封闭的聚氯乙烯管中，在37℃水沿中静置1min后，加入已预热的0.025mol/L氯化钙溶液0.4mL，将一根不锈钢探针伸入溶液中均匀缓慢的搅动，记录探针上刚开始出现白色丝状物的时间，此即是复钙时间，复钙时间越长，则表明抗凝血性越好。另外，在以下实施例中，带正、负电荷的聚电解质溶液已分别进行超声处理，在此不再赘述。
实施例3
采用本发明的抗凝血涂层制备第二种抗凝血生物材料的方法包括：在抽真空条件下，将浓度为0.08mg/ml的白蛋白柠檬酸盐溶液(pH4.5)循环流过PVC管20min，然后纯化水(pH4.5)冲洗2min，获得白蛋白物理吸附的表面；将浓度为0.15mg/ml的肝素钠柠檬酸盐溶液(pH4.5)循环流过表面为正电荷白蛋白的PVC管15min，纯化水(pH4.5)冲洗2min，获得带负电荷抗凝血肝素的表面；将浓度为0.08mg/ml的白蛋白溶液(pH4.5)循环流过表面带负电荷肝素钠的PVC管15min，纯化水(pH4.5)冲洗2min，获得表面带正电荷白蛋白的PVC管，由此，获得正电荷白蛋白和负电荷肝素钠3层交替涂层表面；将1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐溶液(pH5.0)循环流过3层交替涂层表面6h，获得交联的正电荷白蛋白和负电荷肝素钠3层交替涂层表面。
实施例4
采用本发明的抗凝血涂层制备第二种抗凝血医用装置的方法包括：采用蠕动泵将浓度为0.15mg/ml的白蛋白柠檬酸盐溶液(pH3.5)循环流过双极股静脉插管15min，然后纯化水(pH4.5)冲洗2min，获得白蛋白物理吸附的表面；将浓度为0.10mg/ml的肝素钠柠檬酸盐溶液(pH4.5)循环流过表面为正电荷白蛋白的双极股静脉插管30min，纯化水(pH4.5)冲洗2min，获得带负电荷抗凝血肝素的表面；将浓度为0.15mg/ml的白蛋白柠檬酸盐溶液(pH3.5) 循环流过表面带负电荷肝素钠的双极股静脉插管15min，纯化水(pH4.5)冲洗2min，获得表面带正电荷白蛋白的双极股静脉插管，由此，获得正电荷白蛋白和负电荷肝素钠3层交替涂层表面；将1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐溶液(pH5.0)循环流过3层交替涂层表面6h，获得交联的正电荷白蛋白和负电荷肝素钠3层交替涂层表面。
在分别经实施例3和实施例4的方法分别得到的抗凝血生物材料和抗凝血医用装置后，用甲苯胺蓝溶液染色发现，PVC管的表面和双极股静脉插管的内表面都变成紫色，说明了肝素钠在PVC管和双极股静脉插管的表面。改性后，PVC管和双极股静脉插管的水接触角明显降低。复钙时间显示肝素涂层的PVC管和双极股静脉插管的复钙时间比未肝素涂层PVC管和双极股静脉插管的复钙时间延长了40min以上。
实施例5
采用本发明的抗凝血涂层制备第三种抗凝血生物材料的方法包括：在抽真空条件下，将浓度为0.10mg/ml的白蛋白柠檬酸盐溶液(pH4.5)循环流过PP中空纤维20min，然后纯化水(pH4.5)冲洗2min，获得正电荷白蛋白物理吸附的表面；将浓度为0.11mg/ml的肝素钠柠檬酸盐溶液(pH4.0)循环流过表面为正电荷白蛋白的PP中空纤维15min，纯化水(pH4.5)冲洗2min，获得负电荷聚阴离子抗凝血肝素的表面；将浓度为0.10mg/ml的白蛋白溶液(pH4.5)循环流过表面带负电荷的聚阴离子肝素钠的PP中空纤维15min，纯化水(pH4.5)冲洗2min，获得表面为正电荷白蛋白的PP中空纤维，由此，获得白蛋白和肝素钠3层交替涂层表面；将1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐溶液(pH4.6)循环流过3层交替涂层表面3h，获得交联的白蛋白和肝素钠3层交替涂层表面。
实施例6
采用本发明的抗凝血涂层制备第三种抗凝血医用装置的方法包括：采用蠕动泵将浓度为0.10mg/ml的白蛋白柠檬酸盐溶液(pH4.5)循环流过膜式氧合器氧合室15min，然后纯化水(pH4.5)冲洗2min，获得正电荷白蛋白物理吸附的表面；将浓度为0.15mg/ml的肝素钠柠檬酸盐溶液(pH4.5)循环流过 表面为正电荷白蛋白的膜式氧合器氧合室20min，纯化水(pH4.5)冲洗2min，获得负电荷聚阴离子抗凝血肝素的表面；将浓度为0.10mg/ml的白蛋白柠檬酸盐溶液(pH4.5)循环流过表面带负电荷的聚阴离子肝素钠的膜式氧合器氧合室15min，纯化水(pH4.5)冲洗2min，获得表面为正电荷白蛋白的膜式氧合器氧合室，由此，获得白蛋白和肝素钠3层交替涂层表面；将1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐溶液(pH5.0)循环流过3层交替涂层表面3h，获得交联的白蛋白和肝素钠3层交替涂层表面。
在分别经实施例5和实施例6的方法分别得到的抗凝血生物材料和抗凝血医用装置后，用甲苯胺蓝溶液染色发现，PP中空纤维表面和膜式氧合器氧合室表面均由白色变成紫色，说明了肝素钠在PP中空纤维和膜式氧合器氧合室的表面。复钙时间显示肝素涂层的PP中空纤维和膜式氧合器氧合室的复钙时间比未肝素涂层PP中空纤维和膜式氧合器氧合室的复钙时间延长了20min以上。
实施例7
采用本发明的抗凝血涂层制备第四种抗凝血生物材料的方法包括：将PVC管首先浸到浓度为0.15mg/ml的白蛋白柠檬酸盐溶液(pH4.5)25min，然后纯化水(pH4.5)清洗2min，获得正电荷白蛋白物理吸附的表面；将表面为正电荷的PVC管浸到浓度为0.15mg/ml的肝素钠柠檬酸盐溶液(pH3.5)15min，纯化水(pH4.5)冲洗2min，获得负电荷抗凝血肝素的表面；将表面为负电荷肝素钠的PVC管浸到浓度为0.15mg/ml的白蛋白柠檬酸盐溶液(pH4.5)15min，纯化水(pH4.5)冲洗2min，获得表面为正电荷白蛋白的PVC管，由此，获得正电荷白蛋白和负电荷肝素钠3层交替涂层表面；将表面为3层交替涂层的PVC管浸到1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐溶液(pH5.0)2h，获得交联的白蛋白和肝素钠3层交替涂层表面。
用甲苯胺蓝溶液染色发现，PVC管表面变成紫色，说明了肝素钠在PVC管的表面。改性后，PVC管的水接触角明显降低。复钙时间显示肝素涂层的PVC管的复钙时间发生了明显的延长。
综上，本发明的提供的抗凝血生物材料和医用装置的制备方法，具有如 下优点：1)本发明制备方法工艺简单，可通过简单的溶液循环装置实现，以及通过交联作用，可得到较稳定的涂层结构；2)本发明制造方法在温和的水溶液环境下进行，无溶剂毒性，是一种环境友好的制备方法；3)本发明制备方法聚电解质溶液经过超声处理后，聚电解质溶质分散性好，避免了团聚现象的发生，涂层更均匀；4)本发明制备抗凝血生物材料的方法在抽真空条件下，通过真空度的调控，可以较好的控制聚电解质溶液流动的速度，且对材料的形状结构没有特殊的要求，可在多种复杂形状结构材料表面实现；5)本发明所提供的抗凝血生物材料较现有技术中的生物材料，水接触角明显降低，复钙时间明显延长；6)本发明制造抗凝血医用装置的方法对医用装置的形状结构没有特殊的要求，可在多种复杂形状结构的医用装置表面实现；7)本发明所提供的抗凝血医用装置较现有技术中的医用装置，水接触角明显降低，复钙时间明显延长。
虽然本发明已以较佳实施例揭示如上，然其并非用以限定本发明，任何本领域技术人员，在不脱离本发明的精神和范围内，当可作些许的修改和完善，因此本发明的保护范围当以权利要求书所界定的为准。

Claims (25)

  1. 一种抗凝血涂层，用于形成于一载体表面，其特征在于，所述涂层由带正电荷的聚电解质和带负电荷的聚电解质交替吸附形成。
  2. 如权利要求1所述的抗凝血涂层，其特征在于，所述带正电荷的聚电解质和所述带负电荷的聚电解质通过交联剂交联结合在一起。
  3. 如权利要求2所述的抗凝血涂层，其特征在于，所述交联剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、戊二醛或高碘酸。
  4. 如权利要求1所述的抗凝血涂层，其特征在于，所述载体为生物材料。
  5. 如权利要求4所述的抗凝血涂层，其特征在于，所述载体为聚乙烯、聚丙烯、聚氨酯、醋酸纤维素、聚醚砜或聚氯乙烯。
  6. 如权利要求1所述的抗凝血涂层，其特征在于，所述载体为医用装置。
  7. 如权利要求6所述的抗凝血涂层，其特征在于，所述载体为体外循环装置、介入治疗系统或人造脏器。
  8. 如权利要求1所述的抗凝血涂层，其特征在于，所述带正电荷的聚电解质为血清蛋白、人纤维蛋白原、抗人绒毛膜促性腺激素、胶原蛋白、卵清蛋白、豆清蛋白或乳清蛋白。
  9. 如权利要求1所述的抗凝血涂层，其特征在于，所述带负电荷的聚电解质为肝素钠、水蛭素、海藻酸钠或葡聚糖硫酸酯。
  10. 一种将抗凝血涂层涂覆于载体的表面的方法，其特征在于，包括如下步骤：
    a)提供一载体；以及
    b)在所述载体的表面交替吸附带正电荷的聚电解质和带负电荷的聚电解质，以形成抗凝血涂层。
  11. 如权利要求10所述的方法，其特征在于，还包括通过交联剂使所述带正电荷的聚电解质和所述带负电荷的聚电解质发生交联反应。
  12. 如权利要求11所述的方法，其特征在于，所述交联剂为1-乙基-(3- 二甲基氨基丙基)碳酰二亚胺盐酸盐、戊二醛或高碘酸。
  13. 如权利要求11所述的方法，其特征在于，还包括在所述交联反应后，使用纯化水冲洗涂覆有所述抗凝血涂层的所述载体。
  14. 如权利要求11所述的方法，其特征在于，所述交联剂的pH值为4.6-5.0。
  15. 如权利要求10所述的方法，其特征在于，所述载体为生物材料，所述步骤b)包括：b1)配制所述带正电荷的聚电解质溶液和所述带负电荷的聚电解质溶液，对所述带正电荷的聚电解质溶液和所述带负电荷的聚电解质溶液分别进行超声处理；以及，b2)在抽真空的条件下，将所述生物材料交替置于所述带正电荷的聚电解质溶液和所述带负电荷的聚电解溶液，从而在所述生物材料的表面形成所述抗凝血涂层。
  16. 如权利要求15所述的方法，其特征在于，所述步骤b2)进一步包括如下步骤：
    b21)在抽真空的条件下，将所述生物材料置于所述带正电荷的聚电解质溶液中一段预定时间，再用纯化水冲洗；
    b22)在抽真空的条件下，将所述生物材料置于所述带负电荷的聚电解质溶液中一段预定时间，再用纯化水冲洗；以及
    b23)重复所述步骤b21)和b22)，使得所述带正电荷的聚电解质和所述带负电荷的聚电解质在所述生物材料的表面交替吸附多次，从而在所述生物材料的表面形成所述抗凝血涂层。
  17. 如权利要求15所述的抗凝血涂层的涂覆方法，其特征在于，所述抽真空的条件为真空度范围在-0.02MPa到-0.08MPa内。
  18. 如权利要求15所述的方法，其特征在于，所述生物材料为聚乙烯、聚丙烯、聚氨酯、醋酸纤维素、聚醚砜或聚氯乙烯。
  19. 如权利要求10所述的方法，其特征在于，所述载体为医用装置，所述步骤b)包括：b1)配制带正电荷的聚电解质溶液和带负电荷的聚电解质溶液，对所述带正电荷的聚电解质溶液和所述带负电荷的聚电解质溶液分别进行超声处理；以及，b2)使所述带正电荷的聚电解质溶液和所述带负电荷的聚 电解溶液交替流过所述医用装置的表面，从而在所述医用装置的表面形成所述抗凝血涂层。
  20. 如权利要求19所述的方法，其特征在于，所述步骤b2)还包括：
    b21)使所述带正电荷的聚电解质溶液循环流过所述医用装置的表面一段预定时间，再用纯化水冲洗；
    b22)使所述带负电荷的聚电解质溶液循环流过所述医用装置的表面一段预定时间，再用纯化水冲洗；以及
    b23)重复上述步骤b21)和b22)，使得所述带正电荷的聚电解质和所述带负电荷的聚电解质在所述医用装置的表面交替吸附多次，从而在所述医用装置的表面形成所述抗凝血涂层。
  21. 如权利要求19所述的方法，其特征在于，所述医用装置为体外循环装置、介入治疗系统或人造脏器。
  22. 如权利要求15或19所述的方法，其特征在于，所述带正电荷的聚电解质溶液的pH值为3.5-4.5，所述带负电荷的聚电解质溶液的pH值为2.5-4.5。
  23. 如权利要求15或19所述的方法，其特征在于，所述超声处理的工作频率为25kHz，超声时间为2-5分钟。
  24. 如权利要求15或19所述的方法，其特征在于，所述带正电荷的聚电解质为血清蛋白、人纤维蛋白原、抗人绒毛膜促性腺激素、胶原蛋白、卵清蛋白、豆清蛋白或乳清蛋白。
  25. 如权利要求15或19所述的方法，其特征在于，所述带负电荷的聚电解质为肝素钠、水蛭素、海藻酸钠或葡聚糖硫酸酯。
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