CN112426564A - 一种类蜂巢结构纳米纤维支架的制备方法 - Google Patents
一种类蜂巢结构纳米纤维支架的制备方法 Download PDFInfo
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Abstract
本发明公开了一种类蜂巢结构纳米纤维支架的制备方法，包括：高聚物溶解于溶剂中，经磁力搅拌形成均匀的高聚物溶液作为纺丝液；设定包括电压、纺丝距离和流速的纺丝参数，同轴静电纺丝或共混静电纺丝制备串珠纳米纤维，在铝箔上收集后于通风橱内通风去除多余溶剂，得到类蜂巢结构纳米纤维支架，其具有致密纤维区和由蜂巢壁层形成的大孔隙三维蜂巢结构，所述蜂巢壁层由串珠纳米纤维纵向生长组装形成且具有纳米级孔径。本发明不需要其他模具辅助，改善传统纳米纤维膜致密的孔隙结构，通过串珠纳米纤维担载药物可有效保护其活性并实现药物在一定时间内长效缓释。
Description
技术领域
本发明涉及静电纺丝领域，特别是一种类蜂巢结构纳米纤维支架的制备方法。
背景技术
组织工程是研究、开发生物材料支架用于修复/重建受损或病变的器官/组织的结构和功能的新兴技术，其核心内容是构建理想的组织工程支架，模拟细胞外基质(ECMs)的天然结构和功能。理想的组织工程支架应能够充分模拟天然细胞外基质的三维结构和功能，并与天然器官/组织的力学强度相似，为细胞组织提供合适的生存环境，如何根据复杂的结构和力学特点构建“仿生化”生物支架是组织工程研究领域的难点。
静电纺丝技术是制备纳米纤维支架最为主要的方法之一，但仍面临一大问题，即二维纳米纤维支架纤维排列紧密、纤维之间的孔隙过小(亚微米级)，缺乏细胞生长和组织形成的大孔隙(几十微米到几百微米)，细胞只能在支架表面粘附、生长形成连续的细胞粘膜层，却无法向支架内部渗透、生长形成具有一定厚度的组织结构，不利于三维组织的修复或形成。由于传统二维细胞培养的局限性，开发大孔隙三维支架结构，受到了更多的关注。
蜂巢结构是覆盖二维平面的最佳拓扑结构，由一个个正六边形组成，具有力学性能优异，空间大等优点，在建筑、航空航天、能源转化等领域应用广泛，但在组织工程上的应用还缺乏系统的研究。静电纺聚合物纳米纤维可以自组装形成类似蜂巢结构的纳米纤维(Nedjari S,Schlatter G,Hébraud,Anne.Thick electrospun honeycomb scaffoldswith controlled pore size[J].Materials Letters,2015,142:180-183.)，但是需要蜂巢状的微结构收集底板来控制蜂巢结构的形成。利用静电纺串珠纳米纤维自组装形成蜂巢结构的纳米纤维支架，其致密纤维区(纳米级)为支架提供力学支撑，相对疏松的蜂巢区(微米级)为细胞向支架内部生长提供可能性。
发明内容
为改善传统二维纳米纤维膜孔径致密的不足，本发明的目的在于提供一种类蜂巢结构纳米纤维支架的制备方法，具有大孔隙三维结构，不需要任何模具即可制得，可用于担载药物和功能性微纳米颗粒。
本发明的上述目的通过以下技术方案实现：
本发明的第一方面，上述类蜂巢结构纳米纤维支架的制备方法包括以下步骤：
(1)高聚物溶解于溶剂中，经磁力搅拌形成均匀的高聚物溶液作为纺丝液；
(2)设定包括电压、纺丝距离和流速的纺丝参数，同轴静电纺丝或共混静电纺丝制备串珠纳米纤维，在铝箔上收集后于通风橱内通风去除多余溶剂，得到类蜂巢结构纳米纤维支架；
其中，所述类蜂巢结构纳米纤维支架具有致密纤维区和由蜂巢壁层形成的大孔隙三维蜂巢结构，所述蜂巢壁层由串珠纳米纤维纵向生长组装形成且具有纳米级孔径。
优选地，所述大孔隙三维蜂巢结构的孔径从纳米到微米级梯度分布。
步骤(1)中，还包括将芯层与高聚物溶液混合后形成均匀的悬浮液/溶液/乳液作为纺丝液，所述芯层包括由功能性微纳米颗粒、水溶性药物或挥发性油剂形成的悬浮液/溶液/乳液。
优选地，所述功能性微纳米颗粒为牛乳血清蛋白-葡聚糖的微球、微胶囊或脂质体；和/或所述水溶性药物选自牛乳血清蛋白、盐酸四环素、胰岛素、转化生长因子、血管内皮生长因子、骨形成蛋白中的一种或两种以上组合。
步骤(1)中，所述高聚物为天然高聚物和/或合成高聚物；其中：
所述天然聚物选自纤维素、胶原蛋白、明胶、蚕丝蛋白、壳聚糖、海藻酸钠中的一种或两种以上混合；
所述合成高聚物选自聚乳酸、聚乙二醇、聚丙烯酸、聚环氧乙烷、聚丙烯腈、聚苯胺中的一种或两种以上混合；
或上述任选所述合成高聚物的共聚物。
优选地，步骤(1)中，所述高聚物为聚乳酸-羟基乙酸共聚物(50:50)，重均分子量为93000g/mol，浓度为75～100mg/mL。
步骤(1)中，所述溶剂为有机溶剂或超纯水；其中：
所述有机溶剂选自三氯甲烷、四氢呋喃、丙酮、异丙醇、二氯甲烷、N,N-二甲基甲酰胺、乙醇、甲酸、六异氟丙醇中的一种或两种以上混合。
优选地，步骤(1)中，所述有机溶剂为六异氟丙醇。
步骤(2)中，纺丝参数的调节范围为：电压为5～30kV，纺丝距离为8～30cm，流速为0.5～2mL/h。
步骤(2)中，纺丝环境参数为：温度为室温，相对湿度为40～60％。
本发明的第三方面，所述类蜂巢结构纳米纤维支架在过滤、药物缓释和组织工程中的应用。
与现有技术相比，本发明的有益效果在于：
(1)本发明不需要其他模具辅助，利用静电纺丝串珠纳米纤维自组装形成类蜂巢结构的纳米纤维支架，可降解的生物相容性高聚物赋予支架良好的生物相容性，类蜂巢结构使支架拥有微米级的大孔隙，能够实现对多种药物的包埋，并实现药物长效释放行为，有望应用于药物缓释和组织工程领域的支架结构。
(2)本发明方法简单，成本低，制备所得的蜂巢结构纳米纤维支架具有致密的纤维区和大孔隙的蜂巢结构以及纳米级到微米级的多级孔径分布，致密的蜂巢壁层为支架提供足够的力学支撑，同时能够包埋并释放药物/蛋白质/刺激性因子，引导细胞活动提供可能性，蜂巢结构有效改善传统纳米纤维膜结构致密的不足，有利于细胞向支架内部转移、渗透，促进三维组织的修复或形成。
(3)本发明通过串珠纳米纤维担载药物(功能性微纳米颗粒、水溶性药物、挥发性油剂等)，可有效保护其活性并实现药物在一定时间内长效缓释。
附图说明
图1为本发明中类蜂巢结构纳米纤维支架的结构示意图。
图2为类蜂巢结构纳米纤维支架的蜂巢壁层结构示意图(a)；其中，(b)担载功能性颗粒的串珠纳米纤维示意图；(c)担载水溶性药物或挥发性油剂的同轴纳米纤维示意图；(d)担载功能性颗粒的同轴串珠纳米纤维示意图。
图3为实施例1中类蜂巢结构纳米纤维支架。
图4为实施例2中包埋BSA葡聚糖微球的类蜂巢结构纳米纤维支架。
图5为实施例3中包埋BSA葡聚糖微球的类蜂巢结构纳米纤维支架。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
将100mg聚乳酸-羟基乙酸共聚物溶于1mL的六氟异丙醇中，得到浓度100mg/mL的混合溶液。将以上制得的溶液静电纺丝，纺丝电压为12kV，纺丝距离为10cm，流速为1mL/h，针头规格为22G，相对湿度控制在40％～60％，在铝箔上得到纳米纤维膜，放置于通风橱中24h去除多余的有机溶剂，得到如图3所示的类蜂巢结构纳米纤维支架。
实施例2
双乳液冷冻相分离法制备牛乳血清蛋白微球：将5％牛乳血清蛋白水溶液和5％葡聚糖水溶液以1:1体积比共混，形成均匀的溶液1；将溶液1加入到50％聚乙二醇水溶液中(体积比1：5)，利用均质仪混合均匀，在-80℃下冷冻24h后，在冷冻干燥机中干燥48h并用二氯甲烷去除分散相聚乙二醇，得到的牛乳血清蛋白-葡聚糖微球在通风处中干燥24h去除掉多余的有机溶剂，制得的牛乳血清蛋白微球直径在400nm左右。
含牛乳血清蛋白微球的类蜂巢结构纳米纤维的制备：将75mg聚乳酸-羟基乙酸共聚物溶于1mL的六氟异丙醇中，得到浓度75mg/mL的混合溶液；一点一点加入载药量为2.5％的牛乳血清蛋白微球混合得到均匀的悬浮液，将悬浮液加入注射器中静电纺丝，纺丝电压为12kV，纺丝距离为10cm，流速为1mL/h，针头规格为22G，相对湿度40％～60％，在铝箔上得到纳米纤维膜，放置于通风橱中24h去除多余的有机溶剂，得到如图4所示的类似于蜂巢结构的纳米纤维支架。
实施例3
双乳液冷冻相分离法制备牛乳血清蛋白微球：将5％牛乳血清蛋白水溶液和5％葡聚糖水溶液以1:1体积比共混，形成均匀的溶液1；将溶液1加入到50％聚乙二醇水溶液中(体积比1：5)，利用均质仪混合均匀，在-80℃下冷冻24h后，在冷冻干燥机中干燥48h并用二氯甲烷去除分散相聚乙二醇，得到的牛乳血清蛋白-葡聚糖微球在通风处中干燥24h去除掉多余的有机溶剂，制得的牛乳血清蛋白微球直径在400nm左右。
含牛乳血清蛋白微球的类蜂巢结构纳米纤维的制备：将100mg聚乳酸-羟基乙酸共聚物溶于1mL的六氟异丙醇中，得到浓度100mg/mL的混合溶液；一点一点加入载药量为2.5％的牛乳血清蛋白微球混合得到均匀的悬浮液，将悬浮液加入注射器中静电纺丝。纺丝电压为12kV，纺丝距离为10cm，流速为1mL/h，针头规格为22G，相对湿度40％～60％，在铝箔上得到纳米纤维膜，放置于通风橱中24h去除多余的有机溶剂，得到如图5所示的类蜂巢结构纳米纤维支架。
实施例4
将75mg PLCL溶于1mL的六氟异丙醇中，得到浓度75mg/mL的混合溶液，作为壳层溶液；将5mg牛乳血清蛋白溶于1mL超纯水，搅拌30min，得到均匀的牛乳血清蛋白水溶液，作为芯层溶液。将以上制得的溶液进行同轴静电纺丝，纺丝电压为12kV，纺丝距离为10cm，外层流速为1mL/h，内层流速为0.1mL/h，外层针头规格为22G，内层针头规格为18G，相对湿度40％～60％，将铝箔上接收到的纳米纤维置于通风橱中24h去除多余的有机溶剂，即可得到类蜂巢结构纳米纤维膜。
上述对实施例的描述是为了便于该技术领域的普通技术人员能理解和使用本发明。熟悉本领域技术人员显然可以容易的对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中，而不必经过创造性的劳动。因此，本发明不限于上述实施例。本领域技术人员根据本发明的原理，不脱离本发明的范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (10)
1.一种类蜂巢结构纳米纤维支架的制备方法，其特征在于，包括以下步骤：
(1)高聚物溶解于溶剂中，经磁力搅拌形成均匀的高聚物溶液作为纺丝液；
(2)设定包括电压、纺丝距离和流速的纺丝参数，同轴静电纺丝或共混静电纺丝制备串珠纳米纤维，在铝箔上收集后于通风橱内通风去除多余溶剂，得到类蜂巢结构纳米纤维支架；
其中，所述类蜂巢结构纳米纤维支架具有致密纤维区和由蜂巢壁层形成的大孔隙三维蜂巢结构，所述蜂巢壁层由串珠纳米纤维纵向生长组装形成且具有纳米级孔径。
2.根据权利要求1所述类蜂巢结构纳米纤维支架的制备方法，其特征在于，所述大孔隙三维蜂巢结构的孔径从纳米到微米级梯度分布。
3.根据权利要求1所述类蜂巢结构纳米纤维支架的制备方法，其特征在于，步骤(1)中，还包括将芯层与高聚物溶液混合后形成均匀的悬浮液/溶液/乳液作为纺丝液，所述芯层包括由功能性微纳米颗粒、水溶性药物或挥发性油剂形成的悬浮液/溶液/乳液。
4.根据权利要求3所述类蜂巢结构纳米纤维支架的制备方法，其特征在于，所述功能性微纳米颗粒为牛乳血清蛋白-葡聚糖的微球、微胶囊或脂质体；和/或所述水溶性药物选自牛乳血清蛋白、盐酸四环素、胰岛素、转化生长因子、血管内皮生长因子、骨形成蛋白中的一种或两种以上组合。
5.根据权利要求1所述类蜂巢结构纳米纤维支架的制备方法，其特征在于，步骤(1)中，所述高聚物为天然高聚物和/或合成高聚物；其中，
所述天然聚物选自纤维素、胶原蛋白、明胶、蚕丝蛋白、壳聚糖、海藻酸钠中的一种或两种以上混合；
所述合成高聚物选自聚乳酸、聚乙二醇、聚丙烯酸、聚环氧乙烷、聚丙烯腈、聚苯胺中的一种或两种以上混合，或上述任选所述合成高聚物的共聚物。
6.根据权利要求5所述类蜂巢结构纳米纤维支架的制备方法，其特征在于，所述高聚物为聚乳酸-羟基乙酸共聚物，重均分子量为93000g/mol，浓度为75～100mg/mL。
7.根据权利要求1所述类蜂巢结构纳米纤维支架的制备方法，其特征在于，步骤(1)中，所述溶剂为有机溶剂或超纯水；其中，
所述有机溶剂选自三氯甲烷、四氢呋喃、丙酮、异丙醇、二氯甲烷、N,N-二甲基甲酰胺、乙醇、甲酸、六异氟丙醇中的一种或两种以上混合。
8.根据权利要求7所述类蜂巢结构纳米纤维支架的制备方法，其特征在于，所述有机溶剂为六异氟丙醇。
9.根据权利要求1所述类蜂巢结构纳米纤维支架的制备方法，其特征在于，步骤(2)中，纺丝参数的调节范围为：电压为5～30kV，纺丝距离为8～30cm，流速为0.5～2mL/h；和/或
纺丝环境参数为：温度为室温，相对湿度为40～60％。
10.权利要求1至9中任一项所述类蜂巢结构纳米纤维支架在过滤、药物缓释和组织工程中的应用。
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| CN114874970A (zh) * | 2022-05-10 | 2022-08-09 | 浙江大学医学院附属第一医院 | 一种高分子三维支架及其制备方法 |
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| CN111575917A (zh) * | 2020-05-25 | 2020-08-25 | 东华大学 | 一种高比表面积类蜂巢结构纳米纤维材料及其制备方法 |
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| CN113373543A (zh) * | 2021-07-20 | 2021-09-10 | 广州医科大学附属第五医院 | 一种调控串珠状纳米纤维中串珠形貌的方法 |
| CN114874970A (zh) * | 2022-05-10 | 2022-08-09 | 浙江大学医学院附属第一医院 | 一种高分子三维支架及其制备方法 |
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