CN112870439A - 核壳-串晶结构的纳米纤维骨组织工程支架及其制备方法 - Google Patents
核壳-串晶结构的纳米纤维骨组织工程支架及其制备方法 Download PDFInfo
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Abstract
核壳‑串晶结构的纳米纤维骨组织工程支架及制备方法，核壳结构实现药物装载、缓释功能，纳米纤维表面原位生长的纳米晶片构成的串晶结构改善核壳结构纳米纤维膜的亲水性和细胞相容性。其步骤：（1）氨糖、透明质酸钠水溶胶作为水相；（2）二氯甲烷、Span80与上述溶胶经高速搅拌混合，获得油包水型乳化液；（3）聚己内酯和N,N‑二甲基甲酰胺溶解于乳化液，通过静电纺丝得到核壳结构的纳米纤维膜；（4）核壳结构的纳米纤维膜在聚己内酯稀溶液中浸泡，得到具有核壳‑串晶结构的纳米纤维骨组织工程支架。本发明所得的核壳‑串晶结构的纳米纤维骨组织工程支架在药物装载、缓释及骨修复等生物医学领域具有一定的应用价值。
Description
技术领域
本发明涉及一种核壳-串晶结构的纳米纤维骨组织工程支架及其制备方法，属于生物医学工程骨修复支架领域，在有效控制药物缓释和骨修复方面具有广泛的应用价值。
背景技术
骨是一种复杂的器官，具有造血、储存重要矿物质、保存重要器官和促进运动的功能。天然骨由大约70wt%的无机纳米晶体(如羟基磷灰石)和30wt%的有机基质（如胶原纳米纤维）组成。由于骨组织血管数量不足，具有较高的矿物含量，在大量组织丢失的情况下，骨的愈合是非常困难的。虽然人的骨骼具有愈合和再生的能力，但是这种能力对大型骨缺损、骨折、交通事故和骨肿瘤切除等引起的损伤是无效的。临床上主要采用自体骨移植、异种骨移植手段进行治疗，但是供体来源有限、手术复杂和免疫反应等问题限制了这些技术的应用，组织工程学为解决这一难题提供了新思路。所以构建一种能够快速诱导成骨且高度匹配缺损形状的骨修复支架受到广泛关注。
骨组织工程支架的设计应该具有适当的孔隙率、生物降解性和与组织再生相关的特定功能，如特定的形状和尺寸等。静电纺丝技术是常用的制备组织工程支架的技术，且生产的纤维能够有效模仿骨组织天然细胞外基质的形态。静电纺丝产生的纤维具有很高的比表面积，经过改性后，孔径可以从几微米调节到几十微米。虽然静电纺丝技术在仿生重建中具有广阔的应用前景，但用于制备静电纺丝的材料仍需慎重选择。材料的组成能够影响支架的力学性能、可塑性、生物相容性和降解性，从而进一步影响修复效率。此外，支架的形貌、亲水性、表面活性对细胞的粘附、迁移和增殖有一定影响。
聚己内酯是一种半结晶型聚合物，具有良好的生物相容性和降解性, 在完成降解后产生的产物无毒。然而，聚己内酯疏水性强，细胞附着性差，缺乏生物活性限制了其进一步的应用。氨基葡萄糖能够诱导成骨细胞分化，抑制破骨细胞分化，从而增加骨基质沉积，减少骨吸收，最终促进骨形成。
发明内容
本发明提供力学性能好且具有良好的生物相容性，可以应用于组织工程骨修复且具有药物缓释行为的一种核壳-串晶结构的纳米纤维骨组织工程支架及其制备方法。
为实现上述目的，本发明提供如下技术方案：
核壳-串晶结构的纳米纤维骨组织工程支架，其特征在于：纤维内核为载有氨糖的透明质酸钠，外壳为可生物降解的聚己内酯。
核壳-串晶结构的纳米纤维骨组织工程支架的制备方法，具体为：透明质酸钠（氨糖）水溶胶与二氯甲烷在高速搅拌下得到油包水型乳化液，随后加入聚己内酯配制成一定浓度的纺丝溶液，进行静电纺丝得到核壳结构的纳米纤维膜。将所得的核壳结构的纳米纤维膜在聚己内酯稀溶液中浸泡，真空干燥后得到核壳-串晶结构的纳米纤维骨组织工程支架。
本发明为解决核壳结构纳米纤维膜亲水性差的问题，采用溶液结晶的方法，使得核壳结构的纳米纤维诱导同质的聚己内酯形成界面结晶结构以改善核壳结构纳米纤维膜的亲水性。
优选地，所述透明质酸钠来源于马链球菌。
优选地，所述聚己内酯的分子量为80000。
优选地，所述氨糖为D（+）-氨基葡萄糖盐酸盐。
优选地，所述的高速搅拌时间为3min，转速为30000r/min。
优选地，所述聚己内酯稀溶液是用冰乙酸和去离子水进行稀释的。
优选地，所述的浸泡时间为5 min,10 min,15 min或20 min。
最优选的浸泡时间为15 min。
优选地，所述的真空干燥时间为24 h。
优选地，通过调控核壳结构纳米纤维膜的浸泡时间来调节核壳-串晶结构纳米纤维骨组织工程支架的力学性能、亲疏水性和细胞粘附性。
与现有技术相比，本发明的有益效果是：本发明所制备的核壳-串晶结构的纳米纤维骨组织工程支架具有良好的纤维形貌，良好的生物相容性和可降解性，能够缓释氨基葡萄糖。串晶结构可以改善核壳结构纳米纤维膜的亲水性，能够更好地模仿细胞外基质中胶原纤维的微结构，具有引导骨再生的能力，效果显著，可以用于骨组织缺损修复。
附图说明
图1是实施例1中核壳结构纳米纤维膜的SEM图。
图2是实施例1中核壳结构纳米纤维膜的直径分布图。
图3是实施例2中浸泡5min的核壳-串晶结构纳米纤维骨组织工程支架的SEM图。
图4是实施例2中浸泡10min的核壳-串晶结构纳米纤维骨组织工程支架的SEM图。
图5是实施例2中浸泡15min的核壳-串晶结构纳米纤维骨组织工程支架的SEM图。
图6是实施例2中浸泡20min的核壳-串晶结构纳米纤维骨组织工程支架的SEM图。
图7是实施例2中不同浸泡时间核壳-串晶结构纳米纤维骨组织工程支架的亲疏水性能。
图8是实施例3中载有氨糖的核壳结构纳米纤维膜的SEM图。
图9是实施例3中载有氨糖的核壳结构纳米纤维膜的直径分布图。
图10是细胞在不同纳米纤维支架材料上的增殖情况。
具体实施方式
为使本发明的技术方案和优点更加清楚，下面将结合具体实施例进一步阐述本发明。显然。所述的实施例仅仅是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域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，都属于本发明保护的范围。
实施例1
将12mg透明质酸钠溶于988微升去离子水中，混合均匀，制得1.2wt%透明质酸钠水溶胶。将含有3.03ml二氯甲烷和0.01gSpan-80的混合物与透明质酸钠溶胶混合并高速搅拌获得均匀油包水型（W / O）乳化液。将0.5g聚己内酯和2.11mlN,N-二甲基甲酰胺溶解在上述乳液中，得到静电纺丝溶液，将纺丝液吸入在注射器中进行静电纺丝，纺丝电压为18kv，喷丝头和接收板之间的距离为15cm，推进泵的推进速度为0.001mm/s，制备成核壳结构的纳米纤维膜MS。
图1、图2为该支架的扫描电镜图片，可以看到光滑连续的纳米纤维结构，用ImageJ软件分析纳米纤维直径为127±33nm.
实施例2
将0.2g聚己内酯溶于20ml冰乙酸和去离子水的混合溶剂中，60℃下磁力搅拌，其中冰乙酸和去离子水体积比为3:1。充分溶解后将溶液冷却至室温，将实施例1得到的核壳结构的纳米纤维膜浸泡在聚己内酯稀溶液中，浸泡时间分别为5 min,10 min,15 min,20min。之后真空干燥24h，去除残留溶剂，得到核壳-串晶结构的纳米纤维骨组织工程支架SK5, SK10, SK15, SK20.
图3~图6为不同浸泡时间核壳-串晶结构纳米纤维骨组织工程支架的扫面电镜图，经测定，核壳结构纳米纤维表面的串晶结构能够提高核壳结构纳米纤维膜的亲水性，且核壳-串晶结构纳米纤维骨组织工程支架SK15的效果最显著（图7所示）。
实施例3
将12mg透明质酸钠溶于988微升去离子水中，混合均匀，制得1.2wt%透明质酸钠水溶胶。然后，将10µl 氨糖(100µg/ml)混合到50µl透明质酸水溶胶中。将含有3.03ml二氯甲烷和0.01gSpan-80的混合物与上述溶胶混合并高速搅拌获得均匀油包水（W / O）型乳化液。将0.5g聚己内酯和2.11mlN,N-二甲基甲酰胺溶解在上述乳化液中，得到静电纺丝溶液，将纺丝液吸入在注射器中进行静电纺丝，纺丝电压为18kv，喷丝头和接收板之间的距离为15cm，推进泵的推进速度为0.001mm/s，制备成载有氨糖的核壳结构的纳米纤维膜MS-GLU（图8、图9所示）。
实施例4
将0.2g聚己内酯溶于20ml冰乙酸和去离子水的混合溶剂中，60℃下磁力搅拌，其中冰乙酸和去离子水体积比为3:1。充分溶解后将溶液冷却至室温，将实施例3得到的载有氨糖的核壳结构的纳米纤维膜浸泡在聚己内酯稀溶液中，浸泡时间为15 min。之后真空干燥24h，去除残留溶剂，得到载有氨糖的串晶-核壳结构的纳米纤维骨组织工程支架SKMS-GLU。
实施例5
取上述实施例中的纳米纤维支架制成直径为1cm的圆片状并置于24孔板中，与细胞共培养1、4、7天后，每孔加入50微升CCK-8溶液，不含纳米纤维支架为空白对照组。在细胞培养箱内孵育0.5小时后，450nm测定吸光度。其中，样品SK15记为SKMS。
检测结果如图10所示，实施例2、3、4样品有利于细胞增殖，且实施例4所述样品增值效果更显著。
Claims (6)
1.核壳-串晶结构的纳米纤维骨组织工程支架，其特征在于：纤维内核为载有氨糖的透明质酸钠，外壳为可生物降解的聚己内酯。
2.根据权利要求1所述核壳-串晶结构的纳米纤维骨组织工程支架，其特征在于：采用溶液结晶的方法，使得核壳结构的纳米纤维诱导同质的聚己内酯形成界面结晶结构。
3.根据权利要求2所述核壳-串晶结构的纳米纤维骨组织工程支架，其特征在于，通过调控核壳结构纳米纤维膜的浸泡时间来调节核壳-串晶结构纳米纤维骨组织工程支架的力学性能、亲疏水性和细胞粘附性。
4.根据权利要求1或2所述核壳-串晶结构的纳米纤维骨组织工程支架，其特征在于：它的制备方法包括如下步骤：
（1）将透明质酸钠溶于去离子水中，混合均匀，制得1.2wt%透明质酸钠水溶胶，将10µl浓度是100µg/ml的氨糖混合到50µl透明质酸钠水溶胶中；
（2）将含有3.03ml二氯甲烷和0.01gSpan-80的混合液与透明质酸钠溶胶混合并高速搅拌获得均匀油包水型乳化液；
（3）将0.5g聚己内酯和2.11mlN,N-二甲基甲酰胺溶解在上述乳化液中，得到静电纺丝溶液，利用静电纺丝技术得到具有核壳结构的纳米纤维膜；
（4）将聚己内酯溶于冰乙酸和去离子水的混合溶剂中，60℃下磁力搅拌；充分溶解后将溶液冷却至室温，将上述具有核壳结构的纳米纤维膜浸泡在聚己内酯稀溶液中，真空干燥24h，去除残留溶剂，得到核壳-串晶结构的纳米纤维骨组织工程支架。
5.根据权利要求4所述核壳-串晶结构的纳米纤维骨组织工程支架， 其特征在于所述静电纺丝的工艺参数为：电压为18kv，喷丝头和接收板之间的距离为15cm，推进泵的推进速度为0.001mm/s。
6.根据权利要求4所述核壳-串晶结构的纳米纤维骨组织工程支架，其特征在于所述聚己内酯稀溶液中聚己内酯的质量分数为1%，冰乙酸和去离子水的体积比为3:1，聚己内酯的分子量为80000。
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