CN114438782B - 一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法 - Google Patents

一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法 Download PDF

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CN114438782B
CN114438782B CN202210296705.7A CN202210296705A CN114438782B CN 114438782 B CN114438782 B CN 114438782B CN 202210296705 A CN202210296705 A CN 202210296705A CN 114438782 B CN114438782 B CN 114438782B
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fiber membrane
polylactic acid
iron
cysteine
composite fiber
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CN114438782A (zh
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王英波
仇亚妮
高雅
刘永钢
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Xinjiang Normal University
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Abstract

本发明公开了一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法，该方法首先采用静电纺丝技术制备了聚乳酸纤维基底，采用自组装法，将单宁酸三价铁离子鳌合，并将半胱氨酸通过迈克尔加成反应接枝在其表面，该方法综合了聚乳酸良好的生物相容性，单宁酸良好的抗氧化活性和对铁离子的螯合作用，铁具有广谱抗菌性及单宁酸‑铁配合物强化其对近红外光的响应等特性，该配合物在光热强效抗菌的同时，又可清除局部过量累积的活性氧，表现出抗氧化能力并刺激细胞增殖和促进成骨，作为骨修复材料具有良好的应用前景。

Description

一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法
技术领域
本发明属于医用高分子复合材料技术领域，特别是涉及一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法。
背景技术
全世界数百万患者患有骨疾病或骨缺损，骨修复材料的研发是亟需解决的难题，理想的人工骨合成生物材料应该具有良好的生物相容性、生物活性、骨诱导性和抗菌性。
聚乳酸（Polylactic acid，PLLA）由于其良好的生物相容性、可生物降解、无毒等优点，已经被美国食品药品监督管理局（FDA）批准用于临床应用，在临床上主要应用于引导骨组织再生、药物输送、软组织修复等，是目前人工骨生物医用材料的研究热点之一，但缺乏骨诱导和抗菌性能，这限制了它在骨组织工程中的应用。
单宁酸(Tannic acid，TA)是一种天然的抗氧化剂，具有一定的还原能力和抗菌性，而且能够响应近红外光。由于具有邻苯二酚的结构特点，TA被广泛用于基底表面修饰，用以改善材料与基底间的粘附性；此外TA具有抗氧化功能，当活性氧(ROS)的平衡因缺乏抗氧化剂或ROS产生系统的突变而被打破时，异常过量的ROS会通过损害蛋白质、脂质和DNA对人类造成病理上的有害影响。因此，清除过量ROS是十分必要的。据报道，氧化锰纳米颗粒、二氧化铈纳米颗粒、TA、没食子酸等都能有效地消除ROS，虽然几种金属氧化物表现出很强的ROS清除能力，但存在生物相容性差和潜在毒性等问题，TA这种天然的抗氧化剂就避免了这个问题，同时TA比其他天然抗氧化剂更稳定。因此，TA引入骨修复复合材料能赋予材料抗氧化性能。
骨感染是临床骨修复过程中急需攻克的难题，由于细菌所引起的骨感染会损害骨组织的愈合修复能力，导致植入物植入失败，因此研发具有抗菌性能的植入材料成为目前研究热点之一。骨感染主要由细菌感染引起，及时有效的杀死组织表面的细菌并抑制细菌生物膜的形成是抑制感染、促进骨组织愈合的关键所在。目前常见的治疗骨感染的方法是清创术和全身抗生素治疗，但在长期或过度使用抗生素会增加手术风险和产生耐药。因此，提高生物材料的细菌耐药性、抗骨感染能力成为亟待解决的难题。铁是人体必需的微量元素，三价铁离子(Ferric ion, Fe3+)具有广泛的抗菌性和抗细菌耐药性能，单宁酸与三价铁形成的配合物对近红外光具有响应性，在临床上被应用于杀灭生物材料上的细菌，其杀菌机制首先是Fe3+在细菌的细胞膜中积累和溶解，改变了细菌膜的通透性杀死细菌，其次水在TA-Fe配合物在近红外光的催化作用下产生了活性氧导致蛋白质功能障碍，从而杀死细菌，TA-Fe配合物对近红外光有响应，使得近红外光被吸收转化为热，进一步加强杀菌效果。因此将Fe3+纳米粒子引入骨修复复合材料能赋予材料快速、持久抗菌性能。
L-半胱氨酸(L-Cysteine，Cys)，一种生物体内常见的氨基酸。Cys增加了 IGF-I的 mRNA 表达，生长板中的软骨内细胞增殖导致骨骼生长。Cys增加了生长板厚度(生长板厚度是线性骨生长的直接指标)。Cys通过 JAK2-STAT5 的磷酸化促进线性骨生长。Cys提高了胫骨骨密度(BMD)。Cys改善了骨骼参数（它增加了骨体积分数、骨小梁厚度、骨小梁数量、连接密度，并降低了总孔隙率）。同时，Cys中的巯基中含有的硫元素，对骨骼生长也具有促进作用。因此将Cys引入骨修复复合材料能赋予材料成骨性能。
静电纺丝技术可构建形貌可控、有类似于天然细胞外基质(Extracellularmatrix, ECM)的纤维结构，设计理想的仿生环境用于细胞粘附和增殖，促进新组织生长在骨组织工程中具有重要的应用价值。
基于此，综合PLLA良好的生物相容性和可降解性，TA对金属离子的高亲和力、还原能力和抗氧化性，三价铁离子的广谱抗菌性、抗细菌耐药性；TA-Fe配合物的光热效应；Cys的骨诱导性等各自特点，以及静电纺丝技术在构建形貌可控的仿生纤维结构方面的独特优势，本发明提供一种快速抗菌/抗氧化活性的PLLA/TA/Fe/Cys骨诱导复合纤维膜的制备方法。
发明内容
本发明的目的在于提供一种快速抗菌/抗氧化活性的PLLA/TA/Fe/Cys骨诱导复合纤维膜的制备方法，基于自组装技术将TA-Fe、Cys负载到生物相容性和可降解性优越的聚乳酸基纤维膜上，该骨修复材料能广泛应用于骨损伤修复和骨缺损治疗领域。
本发明通过下述的技术方案来实现：
一种快速抗菌/抗氧化活性的PLLA/TA/Fe/Cys骨诱导复合纤维膜的制备方法，包括如下步骤：
（1）将PLLA溶于有机溶剂中，机械搅拌使其完全溶解，得到均匀的聚乳酸静电纺丝溶液；
（2）以步骤（1）所得PLLA静电纺丝溶液为原料进行静电纺丝，得到PLLA纤维膜；
（3）将步骤（2）所得的PLLA纤维膜在真空条件下干燥完全后，将所得的纤维膜剪成一定尺寸的块状，保存在37℃的恒温箱中备用；
（4）将氯化钠溶于去离子水中，机械搅拌使其完全溶解；再加入TA，机械搅拌使其完全溶解；再加入三氯化铁(Ⅲ)六水合物，继续搅拌使溶解，并形成均一稳定的混合溶液。
（5）将步骤（3）所得的块状PLLA纤维膜浸泡于步骤（4）所得的混合溶液中，在常温下浸泡6h至反应完全，得到PLLA/TA/Fe复合纤维膜；
（6）将Cys溶于去离子水中，机械搅拌使其完全溶解；
（7）将步骤（5）所得的复合纤维膜浸泡于步骤（6）所得的Cys溶液中，在常温下浸泡12h至反应完全，得到PLLA/TA/Fe/Cys复合纤维膜；
（8）将步骤（7）所得的复合纤维膜在真空条件下干燥完全后，保存在37℃的恒温箱中备用。
作为本发明技术方案的进一步优化，步骤（1）中所述PLLA的加入浓度范围为100-220 g/L，步骤（4）中所述氯化钠的加入浓度范围为70 mM/L -80 Mm/L，单宁酸的加入浓度范围为0.5-2.0 g/L，三氯化铁(Ⅲ)六水合物的加入浓度范围为0-0.5 g/L，步骤（6）中所述半胱氨酸的加入浓度范围为0.5-1.0 g/L。
作为本发明技术方案的进一步优化，步骤（1）中所述的有机溶剂为三氟乙醇、六氟异丙醇、二氯甲烷、三氯甲烷、N, N-二甲基甲酰胺或二甲基亚砜中的至少一种。
作为本发明技术方案的进一步优化，步骤（1）、步骤（4）和步骤（6）中所述的机械搅拌转速范围为600-1600 r/min，其中步骤（1）的搅拌时间为10-24 h，步骤（4）和步骤（6）的搅拌时间为10-30min。
作为本发明技术方案的进一步优化，步骤（2）中所述的静电纺丝参数包括，高压静电场电压范围12-20 kV，纺丝接收间距10-20 cm，注射器推进速度2-4 mL/h，收集器的材质为钛、钛合金(Ti6Al4V)、铝或不锈钢。
作为本发明技术方案的进一步优化，步骤（4）中所述的三氯化铁(Ⅲ)六水合物为可溶于水铁盐的至少一种。
作为本发明技术方案的进一步优化，步骤（5）中所述的浸泡温度范围为室温，浸泡时间为6h；步骤（7）中所述的浸泡温度范围为室温，浸泡时间为12h。
作为本发明技术方案的进一步优化，步骤（3）和步骤（8）中所述的真空干燥温度为60-80℃，干燥时间为48-96 h。
作为本发明技术方案的进一步优化，所述铁为三价铁离子。
综上所述，本发明复合纤维膜的制备方法的优点在于：基于静电纺丝技术制备了一种快速抗菌/抗氧化活性的PLLA/TA/Fe/Cys骨诱导复合纤维膜，该复合纤维膜能模拟体内的天然细胞外基质，促进成骨和血管生成，达到快速并持久抗细菌感染，同时具有抗氧化的效果，从而促进骨组织修复。该制备方法操作简便，成本低廉，制得的复合纤维作为骨修复材料具有良好的应用前景。
附图说明
图1为本发明的实施例一制得的复合纤维膜的扫描电镜（SEM）图片；
图2为本发明的实施例一制得的复合纤维膜的能谱（EDS）图；
图3为本发明的实施例一制得的复合纤维膜接收近红外光照射以后温度随时间变化曲线图。
具体实施方式
下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通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。
实施例一
本发明提供一种快速抗菌/抗氧化活性的PLLA/TA/Fe/Cys骨诱导复合纤维膜的制备方法，包括如下步骤：
（1）将1.44 gPLLA溶于于9 ml三氟乙醇中，使用转速1300 r/min的机械搅拌16 h使其完全溶解，得到均匀的PLLA静电纺丝溶液；
（2）以步骤（1）所得PLLA静电纺丝溶液为原料进行静电纺丝，其参数为高压静电场电压15 kv，纺丝接收间距13 cm，注射器推进速度3 ml/h，得到附着于钛箔收集器表面的PLLA纤维膜；
（3）将步骤（2）所得的PLLA纤维膜在70℃下真空干燥72 h以完全除去残余溶剂，然后将所得的纤维膜剪成2 cm×2 cm的块状，保存在37℃的恒温箱中备用；
（4）将1.7532 g氯化钠溶于400 ml去离子水中，机械搅拌使其完全溶解；再加入0.8 gTA，使用转速1000 r/min的机械搅拌10min使其完全溶解；再加0.12 g入三氯化铁(Ⅲ)六水合物，使用转速1000 r/min的机械搅拌10min使其完全溶解，并形成均一稳定的混合溶液。
（5）将步骤（3）所得的块状PLLA纤维膜浸泡于步骤（4）所得的混合溶液中，在常温下浸泡6 h至反应完全，得到PLLA/TA/Fe复合纤维膜；
（6）将0.4g Cys溶于400 mL去离子水中，使用转速1000 r/min的机械搅拌10min使其完全溶解；
（7）将步骤（5）所得的复合纤维膜浸泡于步骤（6）所得的Cys溶液中，在常温下浸泡12h至反应完全，得到PLLA/TA/Fe/Cys复合纤维膜；
（8）将步骤（7）所得的复合纤维膜在真空条件下干燥完全后，保存在37℃的恒温箱中备用。
如图1-3所示，图1为PLLA/TA/Fe/Cys复合纤维的SEM图，从图中可以看出，复合纤维上的Fe3+分布较为均匀，尺寸较小，其抗菌性会越好；图2为PLLA/TA/Fe/Cys复合纤维的EDS图，从图中可以看出，复合纤维上的铁元素分布较为均匀；图3为接收近红外光照射以后温度随时间变化曲线图，从图中可以看出，当复合纤维接受功率为1.5W、频率为808 nm的近红外光照射10min时，PLLA/TA复合纤维比聚丁二酸丁二醇酯（PBS）和PLLA纤维在相同时间时具有较高的温度，说明TA对近红外光具有一定的响应性，但光产生热的效果不佳，而PLLA/TA/Fe/Cys复合纤维的温度达到了55.3℃，接近杀死细菌的温度且在人体组织可承受的温度范围内，说明TA-Fe吸收了近红外光后将光转化为了热，结合铁的物理杀菌作用，会使得铁在更短的时间内快速杀死细菌。
以上所述，仅用以说明本发明的技术方案而非限制，本领域普通技术人员对本发明的技术方案所做的其它修改或者等同替换，只要不脱离本发明技术方案的精神和范围，均应涵盖在本发明的权利要求范围当中。

Claims (8)

1.一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法，其特征在于，包括如下步骤：
(1)将聚乳酸溶于有机溶剂中，机械搅拌使其完全溶解，得到均匀的聚乳酸静电纺丝溶液；
(2)以步骤(1)所得聚乳酸静电纺丝溶液为原料进行静电纺丝，得到聚乳酸纤维膜；
(3)将步骤(2)所得的聚乳酸纤维膜在真空条件下干燥完全后，将所得的纤维膜剪成一定尺寸的块状，保存在37℃的恒温箱中备用；
(4)将氯化钠溶于去离子水中，机械搅拌使其完全溶解；再加入TA，机械搅拌使其完全溶解；再加入三氯化铁六水合物，继续搅拌使溶解，并形成均一稳定的混合溶液；
(5)将步骤(3)所得的块状聚乳酸纤维膜浸泡于步骤(4)所得的混合溶液中，在常温下浸泡至反应完全，得到聚乳酸/单宁酸/铁复合纤维膜；
(6)将半胱氨酸溶于去离子水中，机械搅拌使其完全溶解；
(7)将步骤(5)所得的复合纤维膜浸泡于步骤(6)所得的半胱氨酸溶液中，在常温下浸泡至反应完全，得到聚乳酸/单宁酸/铁/半胱氨酸复合纤维膜；
(8)将步骤(7)所得的复合纤维膜在真空条件下干燥完全后，保存在37℃的恒温箱中备用。
2.根据权利要求1所述的一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法，其特征在于：步骤(1)中所述聚乳酸的加入浓度范围为100-220g/L，步骤(4)中所述氯化钠的加入浓度范围为70mM/L-80mM/L，TA的加入浓度范围为0.5-2.0g/L，三氯化铁六水合物的加入浓度范围为0-0.5g/L，浓度不为0，步骤(6)中所述半胱氨酸的加入浓度范围为0.5-1.0g/L。
3.根据权利要求1所述的一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法，其特征在于：步骤(1)中所述的有机溶剂为三氟乙醇、六氟异丙醇、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺或二甲基亚砜中的至少一种。
4.根据权利要求1所述的一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法，其特征在于：步骤(1)、步骤(4)和步骤(6)中所述的机械搅拌转速范围为600-1600r/min，其中步骤(1)的搅拌时间为10-24h，步骤(4)和步骤(6)的搅拌时间为10-30min。
5.根据权利要求1所述的一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法，其特征在于：步骤(2)中所述的静电纺丝参数包括，高压静电场电压范围12-20kV，纺丝接收间距10-20cm，注射器推进速度2-4mL/h，收集器的材质为钛、钛合金Ti6Al4V、铝或不锈钢。
6.根据权利要求1或2所述的一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法，其特征在于：步骤(4)中所述的三氯化铁六水合物为可溶于水铁盐的至少一种。
7.根据权利要求1所述的一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法，其特征在于：步骤(5)中所述的浸泡温度范围为室温，浸泡时间至少为6h；步骤(7)中所述的浸泡温度范围为室温，浸泡时间至少为12h。
8.根据权利要求1所述的一种快速抗菌/抗氧化活性的聚乳酸/单宁酸/铁/半胱氨酸骨诱导复合纤维膜的制备方法，其特征在于：步骤(3)和步骤(8)中所述的真空干燥温度为60-80℃，干燥时间为48-96h。
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