WO2018196088A1 - 一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法 - Google Patents
一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法 Download PDFInfo
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Definitions
- the invention relates to the technical field of biological materials and medical instruments, in particular to a method for preparing a chitosan/heparinized graphene oxide composite multilayer film on a surface of a medical magnesium alloy.
- Cardiovascular and cerebrovascular lesion stenosis is one of the most common causes of complications of many fatal cardiovascular and cerebrovascular diseases.
- Metal stent implantation is one of the main methods for the treatment of stenotic cardiovascular and cerebrovascular diseases.
- magnesium alloy biomaterials have become a research hotspot of cardiovascular scaffold biomaterials due to their excellent mechanical properties, biodegradability and non-toxicity of degradation products.
- magnesium alloys are chemically active and degrade rapidly under physiological conditions, easily generating excess hydrogen around the implanted tissue and causing local alkalinity in surrounding tissues and secondary corrosion product enrichment, leading to premature loss of mechanical properties of the material. Poor blood compatibility and cytocompatibility, as well as toxicity to surrounding tissues, ultimately lead to delayed healing of materials and tissues, and even implantation failure. Since the corrosion behavior and biocompatibility of the material are closely related to the surface properties of the material, as a vascular scaffold material, surface modification is used to regulate the electrochemical degradation behavior of magnesium alloy, improve blood compatibility and promote endothelial tissue healing. It is of great significance for its clinical application.
- the current research mainly improves the corrosion resistance of magnesium alloy from both alloying and surface modification. Alloying can significantly improve the mechanical properties of magnesium alloys, but the corrosion resistance of prepared magnesium alloy materials in complex physiological environments still needs to be improved, and most alloying elements can not effectively improve the biocompatibility of materials, therefore, alloying
- the surface of the prepared magnesium alloy generally lacks biological activity.
- the surface layer is thinner, less biomolecules, limited improvement in corrosion resistance and biocompatibility of magnesium alloys, and in materials During the degradation process, the surface biomolecules are first degraded and lost, and the magnesium alloy will soon lose its biological activity; various polymer or ceramic coatings have significant effects in improving the corrosion resistance of magnesium alloys, but when used for intravascular implantation of materials. It may still cause coagulation and delayed healing of the endothelium.
- the object of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing a chitosan/heparinized graphene oxide composite multilayer film on the surface of a medical magnesium alloy, by which a multi-functional property can be constructed.
- Magnesium alloy surface and significantly improve the corrosion resistance and biocompatibility of magnesium alloy under physiological conditions, and improve the implantation success rate of materials and their instruments.
- a method for preparing a chitosan/heparinized graphene oxide composite multilayer film on a surface of a medical magnesium alloy comprising the following steps:
- HGO heparinized graphene oxide
- the preparation method of the heparinized graphene oxide is:
- the graphene oxide is ultrasonically dispersed in a NaOH solution having a concentration in the range of 0.1 to 0.5 mol/L for 2 hours;
- the N,N'-dicyclohexyl carbon two In a mixed solution of an imine and 4-(dimethylamino)pyridine the molar ratio of N,N'-dicyclohexylcarbodiimide to 4-(dimethylamino)pyridine was 3:1.
- the surface chemical treatment of the magnesium alloy is:
- the magnesium alloy is first washed and immersed in a NaOH solution having a concentration of 1 to 5 mol/L, and treated at 60 to 85 ° C for 8 to 24 hours.
- the self-assembly method is:
- the NaOH-treated magnesium alloy was immersed in a 16-phosphonylhexadecanoic acid solution having a concentration of 1 to 10 mmol/L for 12 to 24 hours, and the sample was taken out and vacuum-treated at 110 ° C for 12 to 24 hours.
- the method for covalently fixing chitosan is:
- the mole of the carbodiimide/N-hydroxysuccinimide in the step 3.1), in the mixed solution of the carbodiimide/N-hydroxysuccinimide, the mole of the carbodiimide/N-hydroxysuccinimide The ratio is 4:1.
- the preparation method of the chitosan/heparinized graphene oxide composite multilayer film is:
- the material obtained in the step 3) is alternately immersed in a heparinized graphene oxide having a concentration in the range of 0.1 to 1 mg/ml and a chitosan solution having a concentration in the range of 1 to 5 g/L, each adsorbing for 20 to 60 minutes. It is sufficiently dried after each adsorption to obtain a Chi/HGO composite multilayer film.
- the more times the alternating immersion is performed the thicker the thickness of the Chi/HGO composite multilayer film.
- the present invention proposes to comprehensively adopt various surface treatment techniques to construct chitosan/heparinized graphite oxide.
- a multilayer coating designed to solve the key technical problems of magnesium alloy biomaterial degradation rate and poor biocompatibility.
- the surface modification technology of the magnesium alloy used in the invention can not only improve the corrosion resistance of the magnesium alloy, It can also significantly improve the biocompatibility of magnesium alloys. Different coating thicknesses can be used to control and optimize the electrochemical behavior and biocompatibility of magnesium alloys, so as to achieve perfect electrochemical behavior and biocompatibility. Match.
- the Chi/HGO multilayer film coating constructed by the invention is gradually degraded under physiological environment,
- the chitosan and HGO are gradually released during the degradation process, which not only can exert the biological activity of different substances, but also the coating can maintain high biological activity and biocompatibility for a long time due to the gradual degradation of the coating, and significantly improve the magnesium alloy material. Implantation success rate.
- a method for preparing a chitosan/heparinized graphene oxide composite multilayer film on a surface of a medical magnesium alloy which has good corrosion resistance, heparinized graphene oxide and shell aggregation due to alkali heat treatment chemical conversion layer
- the multi-layer film coating constructed by the present invention will be fundamentally solved by the coating effect of sugar on the surface of magnesium alloy, the growth promoting effect of chitosan on endothelial cells, the excellent anticoagulant performance of heparin and the selective promotion of endothelial cell growth.
- Magnesium alloy corrosion degradation is too fast and poor biocompatibility, can be used for vascular stents Such as the surface modification of medical devices.
- FIG. 1 is a schematic flow chart of a method for preparing a chitosan/heparinized graphene oxide composite multilayer film on a medical magnesium alloy surface.
- the figure includes the following steps:
- the present invention includes the following steps:
- HGO heparinized graphene oxide
- the preparation method of the heparinized graphene oxide is:
- the graphene oxide is ultrasonically dispersed in a NaOH solution having a concentration of 0.3 mol/L for 2 hours;
- N,N'-dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine N,N'-dicyclohexylcarbodiimide and 4- The molar ratio of (dimethylamino)pyridine was 3:1.
- the surface chemical treatment of the magnesium alloy is:
- the magnesium alloy was first washed, immersed in a NaOH solution having a concentration of 3 mol/L, and treated at 60 to 85 ° C for 15 hours.
- the self-assembly method is:
- the NaOH-treated magnesium alloy was immersed in a 16-phosphonylhexadecanoic acid solution having a concentration of 7 mmol/L for 18 hours, and the sample was taken out and vacuum-treated at 110 ° C for 20 hours.
- the method for covalently immobilizing chitosan is:
- the molar ratio of the carbodiimide/N-hydroxysuccinimide is 4:1.
- the preparation method of the chitosan/heparinized graphene oxide composite multilayer film is:
- the material obtained in the step 3) was alternately immersed in a heparinized graphene oxide having a concentration of 0.4 mg/ml and a chitosan solution having a concentration of 3 g/L, each adsorbed for 30 minutes, and sufficiently dried after each adsorption.
- a Chi/HGO composite multilayer film was obtained; the more times the alternating immersion was performed, the thicker the thickness of the Chi/HGO composite multilayer film.
Abstract
一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，包括步骤：制备带负电荷的肝素化氧化石墨烯；对医用镁合金进行表面化学处理后自组装16-膦酰基十六烷酸分子，将壳聚糖共价固定在镁合金表面，构建正电荷的材料表面；将表面改性的镁合金材料交替浸没到肝素化氧化石墨烯和壳聚糖溶液中充分吸附，经干燥后得到壳聚糖/肝素化氧化石墨烯复合多层膜。采用该方法对医用镁合金进行表面改性，可以显著提高镁合金的耐蚀性能和生物相容性，为镁合金在诸如血管支架等植入性医疗器械领域的应用奠定基础。
Description
本发明涉及生物材料与医疗器械的技术领域，具体涉及一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法。
心脑血管病损狭窄是许多致死性心脑血管疾病并发症的一个最主要原因，金属血管支架植入是治疗狭窄心脑血管疾病的主要手段之一。近年来，镁合金生物材料由于具有良好的力学性能、可生物降解性能以及降解产物对人体无毒等优异特点，已经成为心血管支架生物材料的研究热点。
然而，镁合金化学性质活泼，在生理条件下降解较快，容易在植入组织周围产生过量氢气并引发周围组织局部碱性升高和二次腐蚀产物富集，导致材料力学性能的过早丧失、较差的血液相容性与细胞相容性以及对周围组织的毒性反应，最终导致材料与组织的延迟愈合，甚至植入失败。由于材料的腐蚀行为与生物相容性都与材料的表面性能密切相关，因此，作为血管支架材料，通过表面改性来调控镁合金的电化学降解行为、提高血液相容性以及促进内皮组织愈合，对其临床应用具有十分重要的意义。
针对镁合金在生理环境下降解过快的问题，目前的研究主要从合金化和表面改性两方面来提高镁合金的耐蚀性能。合金化可以显著改善镁合金的力学性能，但是制备的镁合金材料在复杂生理环境下的耐蚀性能仍有待改善，并且大多数合金元素并不能有效提升材料的生物相容性，因此，合金化制备的镁合金表面通常缺乏生物活性。
目前国内外在镁合金表面改性提高耐蚀性方面的研究主要集中在三个方
面，一是采用表面化学处理或电化学处理在表面形成化学转化层；二是通过改变表面的组织结构形成表面改性层；三是通过在表面引入有机分子、高分子或者制备无机非金属涂层在镁合金表面形成表面覆盖层。这些方法在表面形成了耐蚀性更好的转化层或者覆盖层，可以将基体与周围环境介质隔离，有效提高了镁合金的耐蚀性并显著减少了快速降解导致的生理副反应，在一定程度上提高了材料的生物相容性。
在表面引入生物活性分子是提高镁合金等生物材料的生物相容性最为有效的方法之一。然而，镁合金化学性质活泼，用于不可降解生物材料的表面改性策略往往需要在电解质溶液中进行，可能会造成镁合金的腐蚀降解，因此，应用这些策略必须首先提高其耐蚀性。尽管目前国内外在镁合金表面改性方面进行了大量卓有成效的工作，但是，作为血管内植入材料，目前的表面改性方法无论是在提高镁合金耐蚀性方面还是增强生物相容性方面都没有达到临床满意的效果。表面化学聚合、自组装表面改性以及表面原位生物分子固定等技术，构建的表面层较薄，生物分子较少，对镁合金的耐蚀性和生物相容性的改善有限，而且在材料的降解过程中，表面生物分子首先降解流失，镁合金将很快失去生物活性；各种高分子或者陶瓷涂层，在提高镁合金耐蚀性方面效果显著，但是用于血管内植入材料时，仍然可能导致凝血发生和内皮延迟愈合。
发明内容
本发明的目的在于：克服现有技术的不足，提供一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，通过该方法可以构建一种具有多功能特性的镁合金表面，并显著提升镁合金在生理条件下的耐蚀性能和生物相容性，提高材料及其器械的植入成功率。
本发明所采取的技术方案是：
一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，包括以下步骤：
1)首先制备带负电荷的肝素化氧化石墨烯(HGO)；
2)然后对医用镁合金进行表面化学处理和自组装表面改性；
3)进一步将壳聚糖(Chi)共价固定在镁合金表面，从而构建正电荷的材料表面；
4)再将表面改性的镁合金材料交替浸没到HGO和Chi溶液中充分吸附；
5)最后经干燥后得到Chi/HGO复合多层膜。
本发明进一步改进方案是，所述步骤1)中，肝素化氧化石墨烯的制备方法为：
1.1)首先将氧化石墨烯在浓度在0.1～0.5mol/L范围内的NaOH溶液中超声分散2小时；
1.2)然后，加入过量的氯乙酸超声反应2～4小时；
1.3)再将溶液反复离心水洗至中性以除去杂质，得到羧基化氧化石墨烯；
1.4)将得到的羧基化氧化石墨烯超声分散；
1.5)接着加入N,N’-二环己基碳二亚胺和4-(二甲氨基)吡啶的混合溶液中振荡反应2～4小时；
1.6)然后将溶液反复离心水洗除去杂质；
1.7)再将活化的氧化石墨烯加入到肝素溶液中充分反应4～12小时；
1.8)最后反复离心水洗后得到HGO。
本发明更进一步改进方案是，所述步骤1.5)中，所述N,N’-二环己基碳二
亚胺和4-(二甲氨基)吡啶的混合溶液中，N,N’-二环己基碳二亚胺和4-(二甲氨基)吡啶的摩尔比为3:1。
本发明更进一步改进方案是，所述步骤2)中，镁合金表面化学处理为：
先将镁合金清洗后浸没到浓度在1～5mol/L范围内的NaOH溶液中，在60～85℃的条件下处理8～24小时。
本发明更进一步改进方案是，所述步骤2)中，自组装方法为：
将NaOH处理的镁合金浸没到浓度在1～10mmol/L范围内的16-膦酰基十六烷酸溶液中反应12～24小时，样品取出后在110℃的条件下真空处理12～24小时。
本发明更进一步改进方案是，所述步骤3)中，壳聚糖共价固定方法为：
3.1)将步骤2)中得到的表面改性样品浸没到碳二亚胺/N-羟基丁二酰亚胺的混合溶液中反应；
3.2)反应2～8小时之后进行干燥；
3.3)干燥后浸没到浓度在1～5g/L范围内的壳聚糖溶液中继续反应；
3.4)继续反应2～8小时后，样品清洗干燥后得到壳聚糖改性的带正电荷的镁合金。
本发明更进一步改进方案是，所述步骤3.1)中，所述碳二亚胺/N-羟基丁二酰亚胺的混合溶液中，碳二亚胺/N-羟基丁二酰亚胺的摩尔比为4:1。
本发明更进一步改进方案是，所述步骤4)中，壳聚糖/肝素化氧化石墨烯复合多层膜的制备方法为：
将步骤3)中得到的材料交替浸没到浓度在0.1～1mg/ml范围内的肝素化氧化石墨烯和浓度在1～5g/L范围内的壳聚糖溶液中，每次吸附20～60分钟，每次吸附后充分干燥，从而获得Chi/HGO复合多层膜。
本发明更进一步改进方案是，交替浸没的次数越多，所述Chi/HGO复合多层膜的厚度越厚。
本发明的有益效果在于：
第一、本发明的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，本发明提出了综合采用多种表面处理技术构建壳聚糖/肝素化氧化石墨烯多层膜涂层，以解决镁合金生物材料降解速率过快以及生物相容性不佳的关键技术问题的创新设计策略。
第二、本发明的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，本发明采用的镁合金表面改性技术不仅可以提高镁合金的耐蚀性能，也可以显著提升镁合金的生物相容性，采用不同的涂层厚度，可以实现对镁合金电化学行为和生物相容性的调控与优化，从而达到电化学行为和生物相容性的完美适配。
第三、本发明的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，本发明构建的Chi/HGO多层膜涂层在生理环境下逐渐降解，在降解的过程中逐渐释放壳聚糖和HGO，不仅可以发挥不同物质的生物活性，并且由于涂层的逐渐降解使得涂层可以长期保持较高的生物活性和生物相容性，显著提升镁合金材料的植入成功率。
第四、本发明的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，由于碱热处理化学转化层的良好耐蚀性能、肝素化氧化石墨烯和壳聚糖对镁合金表面的覆盖作用、壳聚糖的促内皮细胞生长作用、以及肝素优异的抗凝血性能和选择性促内皮细胞生长功能，本发明构建的多层膜涂层将从根本上解决镁合金腐蚀降解过快和生物相容性不佳的问题，可用于血管支架
等医疗器械的表面改性。
图1为医用镁合金表面壳聚糖/肝素化氧化石墨烯复合多层膜制备方法的流程示意图。
图中包括以下步骤：
(1)氧化石墨烯的羧基化改性；
(2)肝素化氧化石墨烯的制备；
(3)镁合金表面碱热处理；
(4)表面自组装；
(5)镁合金表面共价固定壳聚糖；
(6)壳聚糖/肝素化氧化石墨烯复合多层膜的制备。
如图1可知，本发明包括以下步骤：
1)首先制备带负电荷的肝素化氧化石墨烯(HGO)；
2)然后对医用镁合金进行表面化学处理和自组装表面改性；
3)进一步将壳聚糖(Chi)共价固定在镁合金表面，从而构建正电荷的材料表面；
4)再将表面改性的镁合金材料交替浸没到HGO和Chi溶液中充分吸附；
5)最后经干燥后得到Chi/HGO复合多层膜。
本发明进一步改进方案是，所述步骤1)中，肝素化氧化石墨烯的制备方法为：
1.1)首先将氧化石墨烯在浓度为0.3mol/L的NaOH溶液中超声分散2小时；
1.2)然后，加入过量的氯乙酸超声反应3小时；
1.3)再将溶液反复离心水洗至中性以除去杂质，得到羧基化氧化石墨烯；
1.4)将得到的羧基化氧化石墨烯超声分散；
1.5)接着加入N,N’-二环己基碳二亚胺和4-(二甲氨基)吡啶的混合溶液中振荡反应3小时；
1.6)然后将溶液反复离心水洗除去杂质；
1.7)再将活化的氧化石墨烯加入到肝素溶液中充分反应10小时；
1.8)最后反复离心水洗后得到HGO。
所述步骤1.5)中，所述N,N’-二环己基碳二亚胺和4-(二甲氨基)吡啶的混合溶液中，N,N’-二环己基碳二亚胺和4-(二甲氨基)吡啶的摩尔比为3:1。
所述步骤2)中，镁合金表面化学处理为：
先将镁合金清洗后浸没到浓度为3mol/L的NaOH溶液中，在60～85℃的条件下处理15小时。
所述步骤2)中，自组装方法为：
将NaOH处理的镁合金浸没到浓度为7mmol/L的16-膦酰基十六烷酸溶液中反应18小时，样品取出后在110℃的条件下真空处理20小时。
所述步骤3)中，壳聚糖共价固定方法为：
3.1)将步骤2)中得到的表面改性样品浸没到碳二亚胺/N-羟基丁二酰亚胺的混合溶液中反应；
3.2)反应5小时之后进行干燥；
3.3)干燥后浸没到浓度为3g/L的壳聚糖溶液中继续反应；
3.4)继续反应6小时后，样品清洗干燥后得到壳聚糖改性的带正电荷的镁
合金。
所述步骤3.1)中，所述碳二亚胺/N-羟基丁二酰亚胺的混合溶液中，碳二亚胺/N-羟基丁二酰亚胺的摩尔比为4:1。
所述步骤4)中，壳聚糖/肝素化氧化石墨烯复合多层膜的制备方法为：
将步骤3)中得到的材料交替浸没到浓度位0.4mg/ml的肝素化氧化石墨烯和浓度为3g/L的壳聚糖溶液中，每次吸附30分钟，每次吸附后充分干燥，从而获得Chi/HGO复合多层膜；交替浸没的次数越多，所述Chi/HGO复合多层膜的厚度越厚。
Claims (9)
- 一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，其特征在于包括以下步骤：1)首先制备带负电荷的肝素化氧化石墨烯；2)然后对医用镁合金进行表面化学处理和自组装表面改性；3)进一步将壳聚糖共价固定在镁合金表面，从而构建正电荷的材料表面；4)再将表面改性的镁合金材料交替浸没到肝素化氧化石墨烯和壳聚糖溶液中充分吸附；5)最后经干燥后得到壳聚糖/肝素化氧化石墨烯复合多层膜。
- 如权利要求1所述的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，其特征在于：所述步骤1)中，肝素化氧化石墨烯的制备方法为：1.1)首先将氧化石墨烯在浓度在0.1～0.5mol/L范围内的NaOH溶液中超声分散2小时；1.2)然后，加入过量的氯乙酸超声反应2～4小时；1.3)再将溶液反复离心水洗至中性以除去杂质，得到羧基化氧化石墨烯；1.4)将得到的羧基化氧化石墨烯超声分散；1.5)接着加入N,N’-二环己基碳二亚胺和4-(二甲氨基)吡啶的混合溶液中振荡反应2～4小时；1.6)然后将溶液反复离心水洗除去杂质；1.7)再将活化的氧化石墨烯加入到肝素溶液中充分反应4～12小时；1.8)最后反复离心水洗后得到肝素化氧化石墨烯。
- 如权利要求2所述的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨 烯复合多层膜的方法，其特征在于：所述步骤1.5)中，所述N,N’-二环己基碳二亚胺和4-(二甲氨基)吡啶的混合溶液中，N,N’-二环己基碳二亚胺和4-(二甲氨基)吡啶的摩尔比为3:1。
- 如权利要求1所述的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，其特征在于：所述步骤2)中，镁合金表面化学处理为：先将镁合金清洗后浸没到浓度在1～5mol/L范围内的NaOH溶液中，在60～85℃的条件下处理8～24小时。
- 如权利要求1所述的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，其特征在于：所述步骤2)中，自组装方法为：将NaOH处理的镁合金浸没到浓度在1～10mmol/L范围内的16-膦酰基十六烷酸溶液中反应12～24小时，样品取出后在110℃的条件下真空处理12～24小时。
- 如权利要求1所述的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，其特征在于：所述步骤3)中，壳聚糖共价固定方法为：3.1)将步骤2)中得到的表面改性样品浸没到碳二亚胺/N-羟基丁二酰亚胺的混合溶液中反应；3.2)反应2～8小时之后进行干燥；3.3)干燥后浸没到浓度在1～5g/L范围内的壳聚糖溶液中继续反应；3.4)继续反应2～8小时后，样品清洗干燥后得到壳聚糖改性的带正电荷的镁合金。
- 如权利要求6所述的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，其特征在于：所述步骤3.1)中，所述碳二亚胺/N-羟基丁二酰亚胺的混合溶液中，碳二亚胺/N-羟基丁二酰亚胺的摩尔比为4:1。
- 如权利要求1所述的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，其特征在于：所述步骤4)中，壳聚糖/肝素化氧化石墨烯复合多层膜的制备方法为：将步骤3)中得到的材料交替浸没到浓度在0.1～1mg/ml范围内的肝素化氧化石墨烯和浓度在1～5g/L范围内的壳聚糖溶液中，每次吸附20～60分钟，每次吸附后充分干燥，从而获得壳聚糖/肝素化氧化石墨烯复合多层膜。
- 如权利要求8所述的一种在医用镁合金表面制备壳聚糖/肝素化氧化石墨烯复合多层膜的方法，其特征在于：交替浸没的次数越多，所述壳聚糖/肝素化氧化石墨烯复合多层膜的厚度越厚。
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| CN103764076A (zh) * | 2011-06-30 | 2014-04-30 | 万能医药公司 | 可生物降解的内置假体及其制造方法 |
| CN103100114A (zh) * | 2013-01-23 | 2013-05-15 | 西南交通大学 | 一种医用金属表面缓释生长因子涂层的制备方法 |
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| CN104231703A (zh) * | 2014-08-06 | 2014-12-24 | 中国海洋大学 | 一种石墨烯复合防腐涂层的制备方法 |
| CN105879121A (zh) * | 2014-10-10 | 2016-08-24 | 重庆首键医药包装有限公司 | 植入式医疗器械的生物相容性表面涂层及其涂覆方法 |
| CN105343890A (zh) * | 2015-11-18 | 2016-02-24 | 山东大学 | 一种肝素或其盐修饰的氧化石墨烯及其制备方法与应用 |
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| CN117138131A (zh) * | 2023-10-31 | 2023-12-01 | 北京航天长峰股份有限公司 | 一种抗凝血涂层及其制备方法和应用以及一种ecmo套包中抗凝血涂层的涂敷工艺 |
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Also Published As
| Publication number | Publication date |
|---|---|
| CN107137788B (zh) | 2019-05-24 |
| US20200254151A1 (en) | 2020-08-13 |
| CN107137788A (zh) | 2017-09-08 |
| US10729821B1 (en) | 2020-08-04 |
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