CN109316623A - 一种包覆有活性分子的双层多孔生物可降解材料及其制备方法和应用 - Google Patents
一种包覆有活性分子的双层多孔生物可降解材料及其制备方法和应用 Download PDFInfo
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- CN109316623A CN109316623A CN201811093360.5A CN201811093360A CN109316623A CN 109316623 A CN109316623 A CN 109316623A CN 201811093360 A CN201811093360 A CN 201811093360A CN 109316623 A CN109316623 A CN 109316623A
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- hyaluronic acid
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Abstract
本发明公开了一种包覆有活性分子的双层多孔生物可降解材料，该材料通过以下步骤制备：（1）透明质酸与天然多糖进行交联；（2）交联溶液中加入致孔剂，恒温干燥；（3）多次纯化洗去致孔剂；（4）浸没于具有特定功效活性分子的透明质酸溶液中;(5)真空冷冻干燥。本发明具有双层结构，内层结构致密，机械性能和稳定性好，外层遇水产生粘附性，内外层均携带特定活性因子，有缓释效果。且成本低，工艺周期短，污染小，耗能低。能广泛应用于医药、化妆品等多个领域。
Description
技术领域
本发明涉及可生物降解的新材料技术领域，特别涉及一种包覆活性分子的多孔生物可降解材料及其制备方法，并涉及该材料在医用材料及细胞支架中的应用。
背景技术
多孔材料具有相互连通的多孔结构，可制备成薄膜、凝胶、微球等多种形式，为材料外部和内部同时提供可控通路，创造营养物质等可交换流通的环境，被认为是最具有发展前景的组织工程支架材料。
透明质酸(Hyaluronic Acid，简称HA，又称玻璃酸)是广泛存在于人和动物体内的一种天然物质，由葡萄糖醛酸和乙酰氨基己糖组成双糖单位聚合而成的一种高分子黏多糖，无种属差异性，在医学领域，被广泛应用于外科手术领域用于防粘连及血管组织工程中作为内层支架材料，同时，由于透明质酸良好的生物相容性，其作为一种药物传递***的媒介和载体被人们所熟知。将透明质酸进行适当程度的交联，能够使其分子结构更加稳定，水溶性相对减弱，粘弹性和力学强度增强，不改变生物相容性，可生物降解，安全，无免疫原性，对酸、碱、热、自由基和透明质酸酶的降解作用有更强的抵抗力，其中，添加纤维素等天然多糖的交联透明质酸材料不仅保留有可生物降解、良好生物相容性等优点，而且更具有了消炎、止血、柔韧性更高等优势。
基于交联透明质酸或者其他多糖类的产品，包括防粘连类和烧伤止血类等产品，大多不具有可控的孔隙结构，这些产品在保护创伤面的同时，也阻碍了一些具有消炎、促进愈合等功效的物质的流通，不利于创伤面的营养愈合。而具有可控多孔结构的交联透明质酸及其他天然多糖材料则可以弥补这一不足，具有很大研究价值。另外，透明质酸作为一种可降解的高分子材料，在缓控释与靶向给药***中的应用研究已经比较深入，而在生物材料中加入特定药物分子更可以大大增加其功能性。
致孔剂滤沥法是最常用的多孔材料制备方法，包括溶液浇铸-致孔剂滤沥法，挤出成型-致孔剂滤沥法等。
专利CN 102178980 A发明了一种天然高分子复合多孔纤维支架的制备方法：采用明胶、丝素蛋白、透明质酸中的一种或多种物质的混合物，以不同直径分布范围的石蜡微球为致孔剂，将天然高分子溶液倒入模具中浸没石蜡微球并冷冻，然后于不同溶剂中发生相分离洗去致孔剂，真空干燥后即可得到多孔纤维支架材料。该支架为块状结构，具有很高孔隙率、良好力学性能和孔隙连通结构，适用于细胞生长及组织修复再生的生物医用材料。该支架中所采用的蛋白、多糖等材料未经过交联，稳定性差，相分离过程中易发生溶解，真空冷冻干燥后即使不添加致孔剂，材料也具有多孔结构，以不同直径分布范围的石蜡微球为致孔剂意义不大，且成分之一的丝素蛋白为过敏原，可能会引起严重的过敏反应。
专利CN 1562389阐述了一种矿化丝蛋白/高分子复合多孔材料及其制备方法：该材料主要含有矿化丝蛋白和聚乳酸、透明质酸、壳聚糖等高分子材料中的任何一种，包含骨生长因子，首先制备水溶性脱胶丝蛋白，经过调节体系pH值、静置、离心、洗涤至中性，将沉淀真空干燥，研磨后和生物相容性较好的高分子复合得到多孔框架材料。该材料结构单一且加入的生长因子只能随材料降解而缓慢释放。
专利CN 1621097 A发明的多孔骨修复材料，由壳聚糖或其衍生物形成的纤维集合体构成，其间承载有磷酸钙颗粒。该材料所采用的壳聚糖为动物源性材料，相较于人体内源物质透明质酸，可能会引起严重过敏反应，且该材料作为细胞分化的诱导材料，未有促生长等其他作用，功能较为单一。
专利CN 102380129 A发明了一种透明质酸和魔芋葡甘聚糖多孔支架材料及其制备方法：采用透明质酸、魔芋葡甘聚糖两种材料，以不同配比以及魔芋葡甘聚糖的交联，通过冷冻干燥法制得一种透明质酸和魔芋葡甘聚糖多孔支架材料，用于软骨修复领域。此发明材料目的在于为干细胞提供生存空间，使细胞获得足够的营养物质，进行气体交换，但是该材料只具备单一的多孔结构，未添加一些特定的药物分子，功能较为单一。
专利CN 1200951C中提到多重交联HA技术，利用两种或多种选自羟基、羧基和氨基的官能团与透明质酸交联，采用戊二醛、碳化二亚胺、丁二醇二缩水甘油基醚等为交联剂，专利中提到的多重交联透明质酸技术既可以用于制备凝胶状态，也可以制备多重交联的透明质酸薄膜，不具备多孔结构，无法提供创伤面愈合所需的生长因子，且仅采用透明质酸，由于材料本身特性，往往会在伤口未愈合之前而降解掉。
专利CN 101027344发明了一种多孔可生物降解的薄膜，包含至少一种多糖衍生物以及至少一种由二元羧酸或羟基酸和二元醇获得的脂族或脂族-芳族可生物降解的聚酯，该材料主要应用于卫生用品领域，含有高分子聚酯，生物相容性差。专利CN 102580166阐述的一种医用仿生透明薄膜植入材料及其制备方法和应用，其中公开的材料是通过静电纺丝和交联得到的透明多孔薄膜，含有胶原、多糖以及治疗性物质，所载治疗性物质随着薄膜降解而缓释，制备该材料采用的静电纺丝方法成本较高且对环境湿度、温度等要求较苛刻。
发明内容
为了解决目前存在的材料中存在的稳定性差，降解速度及活性分子释放速度单一，无孔结构不利于营养物质或空气流通等问题。本发明提供一种包覆有活性分子的多孔生物可降解材料。
一种制备包覆有活性分子的双层多孔生物可降解材料，采用以下步骤制成：
（1）将透明质酸和天然多糖溶解，加入交联剂，进行交联；所述透明质酸的质量浓度为0.5%~5.0%，所述的天然多糖质量浓度为0.25%~4.0%；透明质酸与天然多糖的质量比为1:0.25~2；
（2）将步骤（1）制得的材料加入致孔剂，混合均匀后，进行恒温干燥；
（3）将步骤（2）干燥后的材料加入溶剂发生相分离洗去致孔剂，制得透明质酸多孔交联多糖材料；
（4）将步骤（3）制得的透明质酸多孔交联多糖材料，浸没于含有具有特定功效活性分子的透明质酸溶液中，使活性分子随透明质酸溶液吸附着于透明质酸多孔交联多糖材料的表面或包埋于多孔结构内；
（5）将步骤（4）的材料进行二次干燥，真空冷冻干燥，制得具有双层结构的多孔生物可降解材料。
其中，所述步骤（1）中，透明质酸分子量为500 kD~3000 kD；天然多糖为羧甲基纤维素、羟乙基纤维素或羟丙基纤维素，黏度范围为600 ~1200 mPa.s。
其中，所述步骤（2）中，所述的致孔剂为纳米碳酸钙或石蜡，致孔剂直径为0.08 µm~150 µm，致孔剂加入后的质量浓度为0.1%~2%；恒温干燥的温度25~45℃。
其中，所述步骤（4）中，所述的特定功效活性分子为生长因子、非甾体类抗炎药、抗凝药物、纤溶药物或抗生素；所述透明质酸溶液中透明质酸的质量浓度为0.5%~2.5%，特定功效活性分子为的质量浓度为0.01%~3%。
其中，所述步骤（1）中，所述的交联为下述任一种方式：
①单交联：所述的交联剂为碳化二亚胺，在pH 5.0的磷酸盐缓冲液环境中进行单交联，碳化二亚胺的浓度为0.1M；
②双重交联：所述的交联为丁二醇二缩水甘油醚和碳化二亚胺；先采用丁二醇二缩水甘油醚，在碱性条件（pH为10~12）下形成醚键，酸性条件（pH为3~5）下形成酯键；再采用碳化二亚胺在偏酸性环境（pH为3~6）中交联氨基和羧基形成酰胺键；所述丁二醇二缩水甘油醚的浓度为0.2%~1%，所述碳化二亚胺的浓度为0.04%~4%；
③多重交联：所述的交联剂丁二醇二缩水甘油醚，用1% NaOH调节pH为10~12进行碱性反应，40℃~50℃下反应2~5 h；随后采用醋酸调节pH 3~5进行酸性反应，40℃~50℃下交联2~5 h，丁二醇二缩水甘油醚的浓度为0.2%~4%。
本发明还提供上述包覆有活性分子的双层多孔生物可降解材料在制备药物、医药或化妆品上应用。
其中，所述的应用具体为制备防粘连的外科敷料产品、美容产品。
其中，所述的美容产品为面膜。
本发明的有益效果：
（1）两次干燥获得双层结构，外层结构疏松，遇水产生特殊黏附性，内层结构致密，机械性能和稳定性好；
（2）内外层都吸附了活性因子，外层易降解，可快速释放活性因子，并逐渐露出内层稳定的交联多孔结构，内层多孔结构中负载的活性分子释放较慢，提高了活性因子的有效持续时间；
（3）通过外敷，活性因子可在固定部位快速释放，材料可生物降解，同时允许一定大小的分子通过。孔径大小、数量可控，交错纵横的孔结构为材料外部和内部提供了营养物质的交换环境，可保留更长时间。作为材料主要成分和骨架的透明质酸等天然多糖安全无免疫原性；
（4）一次干燥后采用乙醇-去离子水相分离法多次洗脱纯化，充足的去离子水洗脱，在除去致孔剂同时，除去未反应的透明质酸、纤维素和交联剂等物质，提高产品的纯度；
（5）本发明制备的多孔材料成本低，工艺周期短，污染小，耗能低。
具体实施方式
结合实施例对本发明所涉及的制备方法做进一步地说明，应该说明的是，下述说明仅是为了解释本发明，并不对其内容进行限定。
实施例1：
制备包覆抗生素的多孔可降解材料
（1）将分子量为500 kD的透明质酸和1300 kD羟乙基纤维素溶于纯化水中充分溶解，配制成透明质酸和羟乙基纤维素质量浓度均为1.0 %的混合铸膜液，使用氢氧化钠溶液调节pH值为12，得碱性溶液；
（2）向碱性溶液中加入环氧化合物交联剂1,4-丁二醇二缩水甘油醚0.2 µl/ml，搅拌均匀，40℃环境中进行交联，反应时间为6h；
（3）交联多糖溶液中加入直径0.08 µm纳米碳酸钙溶液，分散均匀，其中致孔剂质量浓度为0.1%~0.9%（w/v），倒入干燥模具中，25℃恒温干燥成型；
（4）将干燥成型薄膜置于乙醇中纯化48h，每12h更换一次乙醇，随后将薄膜置于纯化中纯化8h，每2 h更换一次纯化水，洗去致孔剂；
（5）将洗去致孔剂的多孔薄膜分别浸没于均含有0.05%抗生素的透明质酸溶液中，抗生素采用A组左氧氟沙星，B组环丙沙星，C组米诺环素，D组庆大霉素，透明质酸溶液浓度均为2%，采用的透明质酸分子量为2040 kD，37℃下浸没2 h；
（6）真空冷冻干燥获得包覆有抗生素的四组双层多孔交联透明质酸薄膜；
（7）采用A组作为包覆抗生素的代表性敷料进行功能考察。
Ⅰ采用琼脂覆盖法制作染菌创伤白兔模型，分别采用A组材料以及O组材料（未包覆抗生素）处理包扎，并采用活组织培养法检测两组的菌落数，根据细胞反应分级评价细胞毒性，结果显示：A组菌落数明显低于O组，差异具有统计学意义（P＜0.05）；A组和O组的体外细胞毒性反应均为0级。
Ⅱ包覆了游离透明质酸和抗生素的膜在维持了良好机械强度，随着加入致孔剂浓度的增加，相同大小膜的质量、断裂力、断裂位移逐渐下降，采用过量溶菌酶降解过程中可明显观察到包覆层迅速降解后裸露出多孔骨架结构，如表1：
表1
* O为未包覆抗生素的膜，A为包覆有左氧氟沙星的膜；
1、2、3、4、5对应的致孔剂的加入量分别为0.1、0.3、0.5、0.7、0.9%（w/v）。
实施例2：
制备包覆血管内皮生长因子和重组人表皮生长因子的多孔交联薄膜
（1）在A1、A2、B1、B2四组样品中各将分子量为1500 kD的透明质酸和90 kD羧甲基纤维素溶于20mMpH 5.0的磷酸盐缓冲液中，透明质酸、羧甲基纤维素的质量浓度为2%、1%；
（2）向溶液中加入0.1mol交联剂碳化二亚胺，搅拌均匀， 45℃ 4h进行交联反应；
（3）A1、A2样品中加入分散均匀的0.1 µm纳米碳酸钙颗粒，B1、B2样品中加入分散均匀的150 µm石蜡微球，质量浓度均为1%，25℃恒温干燥成型；
（4）将薄膜置于乙醇中纯化48h，每12h更换一次乙醇，随后将薄膜置于去离子水中纯化8h，每2 h更换一次纯化水，除去致孔剂；
（5）将去除致孔剂的多孔薄膜分别浸没于含有0.1%血管内皮生长因子（A1、B1）以及含有0.1%重组人表皮生长因子（A2、B2）的透明质酸溶液中，透明质酸溶液浓度均为5%，采用的透明质酸分子量为1070 kD，37℃下浸没2 h；
（6）取出后真空冷冻干燥，即得包覆有血管内皮生长因子和重组人表皮生长因子的孔径不同的可降解双层多孔材料。
相较以0.1 µm纳米碳酸钙颗粒为致孔剂所得多孔薄膜，以150 µm石蜡微球为致孔剂的薄膜机械强度明显偏小，酶解速度较快，放入酶解液一段时间，可明显观察到其多孔结构。所得薄膜检测数据如表2：
表2
*A致孔剂为直径0.1 µm纳米碳酸钙颗粒，B致孔剂为直径150 µm的石蜡微球。
实施例3：
制备包覆非甾体类抗炎药的多孔交联透明质酸材料
（1）将分子量为3000 kD的透明质酸和羧甲基纤维素溶于20mM pH 5.0的磷酸盐缓冲液中，透明质酸、羧甲基纤维素质量浓度分别为5%、1.25%；
（2）向溶液中加入1M交联剂碳化二亚胺，搅拌均匀，30℃进行交联反应8h；
（3）溶液中加入质量浓度2%的50 µm纳米碳酸钙颗粒，分散均匀，25℃恒温干燥；
（4）干燥后交联材料置于乙醇中纯化48h，每12h更换一次乙醇，随后将薄膜置于去离子水中纯化8h，放入40目筛中至无液体流下；
（5）将洗去致孔剂的交联多孔材料分别放入含有0.3%对乙酰氨基酚（A）和含有0.08%酮洛酸的透明质酸溶液中，45℃环境下静置6 h，其中，透明质酸溶液的浓度为1.5%，采用透明质酸的分子量为1500 kD；
（6）放入模具中真空冷冻干燥成型。
加入过量溶菌酶42℃降解1 g所得双层多孔材料，4 h可被完全降解。
实施例4：
制备包覆利多卡因的多孔交联材料
（1）制备A、B两组材料，将分子量为2040 kD的透明质酸和1000 kD羟丙基纤维素溶于纯化水中充分溶解，配制成透明质酸和羟丙基纤维素浓度均为5.0 %的混合铸膜液，使用氢氧化钠溶液调节pH值为12，得碱性溶液；
（2）向碱性溶液中加入环氧化合物交联剂1,4-丁二醇二缩水甘油醚3 µl/ml，搅拌均匀，25℃环境中进行交联反应形成醚键，反应时间为8h；
（3）交联溶液中加入直径150 µm纳米碳酸钙致孔剂，质量浓度为2%（w/v），分散均匀，倒入干燥模具中，45℃恒温干燥成型；
（4）将成型多孔材料置于乙醇中纯化48h，每12h更换一次乙醇，随后将薄膜置于去离子水中纯化8h，每2 h更换一次去离子水，去除致孔剂获得样品A；
（5）将去除致孔剂的材料浸没于含有1%利多卡因的透明质酸溶液中，透明质酸溶液浓度为1%，采用的透明质酸分子量为3000 kD，45℃环境下静置6 h。
（6）将复合溶液真空冷冻干燥成型获得样品B，同时，相同重量的含1%利多卡因的透明质酸溶液直接真空冷冻干燥成型，获得样品C。
样品A为一次干燥，结构致密的交联多孔材料；样品B为两次干燥，具有两层结构（内层致密稳定，外层疏松易降解），负载利多卡因的多孔材料；样品C为一次真空冷冻干燥，未交联含有利多卡因的疏松结构，比较三者区别，见表3。
表3
相较样品A、C，两次干燥的多孔材料B具有诸多优势：具有双层结构，机械性能和粘附性良好，且可以包覆活性分子具有更大的应用空间及应用效果。
实施例5
制备包覆特定功效活性分子的多孔交联材料:
（1）将分子量为1500 kD的透明质酸和1000 kD羧甲基纤维素溶于纯化水中充分溶解，配制成透明质酸和羧甲基纤维素浓度均为5.0 %的混合铸膜液，使用氢氧化钠溶液调节pH值为11，得碱性溶液；
（2）向碱性溶液中加入环氧化合物交联剂1,4-丁二醇二缩水甘油醚3 µl/ml，搅拌均匀，25℃环境中进行交联反应形成醚键，反应时间为8h；
（3）交联溶液中加入直径150 µm纳米碳酸钙致孔剂，质量浓度为2%，分散均匀，倒入干燥模具中，45℃恒温干燥成型；
（4）对照样品F制备中，交联溶液中不添加致孔剂，直接倒入干燥模具中，45℃恒温干燥成型后依次按照步骤（6）、（7）进行；
（5）步骤（3）中干燥成型的多孔材料置于乙醇中纯化48h，每12h更换一次乙醇，随后将薄膜置于去离子水中纯化8h，每2 h更换一次去离子水，去除致孔剂；
（6）将去除致孔剂的材料浸没于含有特定功效活性分子的透明质酸溶液中，透明质酸溶液浓度为1g/L，采用的透明质酸分子量为3000 kD，置于4℃摇床过夜吸附，活性分子种类及添加量如下：
（7）将复合特定功效活性分子溶液真空冷冻干燥成型获得样品。
将载有特定功效活性分子的双层结构材料称取0.5mg加入10ml PBS的EP管中混匀，37℃摇床震荡，在5min、30min、2h、4h、8h、16h、48h、72h、96h时间点，以10000r/min离心10分剂盒（ELISA法），取出1ml悬液，加入1ml新鲜PBS，检测上清中释放的特定功效活性分子量。
表4 载特定功效活性分子多孔材料体外缓释的结果（%）
本发明通过二次干燥后得到的双层结构，二段释放，外层快速释放，内层缓释,可作为缓释生物材料广泛应用于医药、化妆品等多个领域，具有广阔的应用空间。
Claims (10)
1.一种包覆有活性分子的双层多孔生物可降解材料，其特征在于，采用以下步骤制成：
（1）将透明质酸和天然多糖溶解，加入交联剂，进行交联；所述透明质酸的质量浓度为0.5%~5.0%，所述的天然多糖质量浓度为0.25%~4.0%；透明质酸与天然多糖的质量比为1:0.25~2；
（2）将步骤（1）制得的材料加入致孔剂，混合均匀后，进行恒温干燥；
（3）将步骤（2）干燥后的材料加入溶剂发生相分离洗去致孔剂，制得透明质酸多孔交联多糖材料；
（4）将步骤（3）制得的透明质酸多孔交联多糖材料，浸没于含有具有特定功效活性分子的透明质酸溶液中，使活性分子随透明质酸溶液吸附着于透明质酸多孔交联多糖材料的表面或包埋于多孔结构内；
（5）将步骤（4）的材料进行二次干燥，真空冷冻干燥，制得具有双层结构的多孔生物可降解材料。
2.根据权利要求1所述的双层多孔生物可降解材料，其特征在于：所述步骤（1）中，透明质酸分子量为500 kD~3000 kD；天然多糖为羧甲基纤维素、羟乙基纤维素或羟丙基纤维素，黏度范围为600 ~1200 mPa.s。
3.根据权利要求1所述的双层多孔生物可降解材料，其特征在于，所述步骤（2）中，所述的致孔剂为纳米碳酸钙或石蜡，致孔剂直径为0.08 µm~150 µm，致孔剂加入后的质量浓度为0.1%~2%；恒温干燥的温度25~45℃。
4.根据权利要求1所述的双层多孔生物可降解材料，其特征在于，所述步骤（4）中，所述透明质酸溶液中透明质酸的质量浓度为0.5%~2.5%，特定功效活性分子为的质量浓度为0.01%~3%。
5.根据权利要求1所述的双层多孔生物可降解材料，其特征在于，所述步骤（4）中，所述的特定功效活性分子为生长因子、非甾体类抗炎药、麻醉剂、抗生素，其中生长因子为：血管内皮生长因子、重组人表皮生长因子、重组人类血小板源性生长因子、粒细胞集落刺激因子中的一种，非甾体类抗炎药为：对乙酰氨基酚、布洛芬、酮洛酸中的一种，麻醉剂为：利多卡因、丁卡因中的一种，抗生素为左氧氟沙星、环丙沙星、米诺环素、庆大霉素中的一种。
6.根据权利要求1所述的双层多孔生物可降解材料，其特征在于，所述步骤（1）中，所述的交联为下述任一种方式：
单交联：所述的交联剂为碳化二亚胺，在pH 5.0的磷酸盐缓冲液环境中进行单交联，碳化二亚胺的浓度为0.1M；
双重交联：所述的交联为丁二醇二缩水甘油醚和碳化二亚胺；先采用丁二醇二缩水甘油醚，在pH为10~12下形成醚键，pH为3~5下形成酯键；再采用碳化二亚胺在pH为3~6中交联氨基和羧基形成酰胺键；所述丁二醇二缩水甘油醚的浓度为0.2%~1%，所述碳化二亚胺的浓度为0.04%~4%；
多重交联：所述的交联剂丁二醇二缩水甘油醚，用1% NaOH调节pH为10~12进行碱性反应，40℃~50℃下反应2~5 h；随后采用醋酸调节pH 3~5进行酸性反应，40℃~50℃下交联2~5h，丁二醇二缩水甘油醚的浓度为0.2%~4%。
7.一种权利要求1-6任一所述的包覆有活性分子的双层多孔生物可降解材料的制备方法，其特征在于，包括以下步骤：
（1）将透明质酸和天然多糖溶解，加入交联剂，进行交联；所述透明质酸的质量浓度为0.5%~5.0%，所述的天然多糖质量浓度为0.25%~4.0%；透明质酸与天然多糖的质量比为1:0.25~2；
（2）将步骤（1）制得的材料加入致孔剂，混合均匀后，进行恒温干燥；
（3）将步骤（2）干燥后的材料加入溶剂发生相分离洗去致孔剂，制得透明质酸多孔交联多糖材料；
（4）将步骤（3）制得的透明质酸多孔交联多糖材料，浸没于含有具有特定功效活性分子的透明质酸溶液中，使活性分子随透明质酸溶液吸附着于透明质酸多孔交联多糖材料的表面或包埋于多孔结构内；
（5）将步骤（4）的材料进行二次干燥，真空冷冻干燥，制得双层多孔生物可降解材料。
8.一种权利要求1所述双层多孔生物可降解材料，在医药或化妆品上的应用。
9.根据权利要求8所述的应用，其特征在于，所述的应用为外科敷料产品、美容产品。
10.根据权利要求9所述的应用，其特征在于，所述的美容产品为面膜。
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| CN111467582A (zh) * | 2020-03-03 | 2020-07-31 | 昆明医科大学 | 一种血管支架及其制备方法 |
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