CN106267334B - 一种促神经修复的植入式电极及其制备方法 - Google Patents

一种促神经修复的植入式电极及其制备方法 Download PDF

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CN106267334B
CN106267334B CN201610678205.4A CN201610678205A CN106267334B CN 106267334 B CN106267334 B CN 106267334B CN 201610678205 A CN201610678205 A CN 201610678205A CN 106267334 B CN106267334 B CN 106267334B
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陈岑
罗丹丹
孔祥东
姚晨雪
阮世超
李麟涉
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Jiaxing Yanzhi Network Technology Co ltd
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Abstract

本发明公开了一种促神经修复的植入式电极及其制备方法，属于医疗器械领域。其制备步骤包括：（1）采用射频磁控溅射法在导电玻璃（ITO）基底材料上制备铱薄膜。（2）对于步骤（1）所制备的铱薄膜，利用循环伏安扫描活化得到结合力强、电荷密度高、多孔的氧化铱涂层。（3）通过多巴胺的氧化自聚合在步骤（2）所制备的氧化铱涂层表面形成均匀的纳米级聚多巴胺包覆层。（4）连接细胞粘附蛋白于步骤（3）所制备的纳米级聚多巴胺包覆层。本发明制备出的神经电极导电性能好、稳定性高、生物相容性好，能够促进细胞贴附，是一种很有应用价值的新型生物医用材料，可应用于利用外源电刺激调控神经干细胞（NSCs）的定向分化。

Description

一种促神经修复的植入式电极及其制备方法
技术领域
本申请涉及一种促进神经修复的植入式电极材料，特别涉及一种能利用外源电刺激促进神经干细胞定向分化的高效神经修复材料。
背景技术
随着生物材料学的发展，神经电极的各种性能在不断提高，但是其生物相容性问题严重地阻碍了植入式神经电极的发展。为了增强植入式电极的组织相容性，减轻炎症反应，研究者研究了很多新的电极材料和电极界面的修饰技术。目前，尚未见报道采用氧化铱作为导电涂层，利用聚多巴胺作为黏性因子，将细胞粘附蛋白（laminin）固定到氧化铱表面制备神经电极的方法。
氧化铱具有良好的抗腐蚀性能和生物相容性，它的可逆电化学反应特性可提供高安全注入电荷量和低电极阻抗。多巴胺在碱性水溶液条件下能发生氧化自聚合反应，在聚合物、金属、陶瓷、玻璃等一系列固体材料表面能形成一层薄的、强黏性的聚多巴胺包覆层。聚多巴胺层富含的官能团还能与含有氨基（-NH2）、巯基（-SH）等基团的生物活性分子发生迈克尔加成反应或希夫碱反应，有利于生物活性分子的固定，使材料表面进一步功能化。尤其是将生物活性分子细胞粘附蛋白（laminin）连接在聚多巴胺层后，可使材料表面获得促细胞粘附的能力，并且能诱导促进神经细胞的繁殖及神经细胞轴突的生长，可用于神经组织修复。
发明内容
本发明的目的是提供一种用于促神经修复的植入式神经电极的制备方法。 本发明的制备方法包括如下步骤：
（1）采用射频磁控溅射在导电玻璃（ITO）基底材料上制备铱薄膜：将经过丙酮，无水乙醇，去离子水分别超声清洗8 ~ 20 min之后的导电玻璃放于射频磁控溅射镀膜仪的溅射腔室，将溅射腔室抽真空。通入氩气，输入功率使氩气电离、起辉，调节适当的压力，开始铱薄膜的溅射。制备所得铱电极。
（2） 利用循环伏安扫描活化得到氧化铱涂层：将步骤（1）中所得的铱电极清洗干燥后，放于电解槽的活化溶液中。通过参比电极与辅助电极以及待活化铱电极构成的回路，施加极化¬时间三角波形进行活化处理。活化所得即为氧化铱电极。
（3）通过多巴胺的氧化自聚合在氧化铱表面形成纳米级聚多巴胺包覆层：将步骤（2）中所得的氧化铱电极清洗干燥后，浸泡于新鲜配制的多巴胺溶液中（pH = 8 ~ 9），室温放置，经过特定时间的氧化聚合反应，得到的即为表面包覆聚多巴胺的氧化铱复合电极。
（4）配制1-(3-二甲氨基丙基)-3-乙基碳二亚胺（EDC）和N-羟基琥珀酰亚胺（NHS）混合溶液：分别将EDC和NHS溶于pH为7 ~ 8的磷酸盐缓冲溶液，室温下混合均匀，得到10 mM的EDC和25 mM的NHS混合溶液。
（5）配制细胞粘附蛋白（laminin）溶液：将laminin溶于上述步骤（5）中所配制的10mM的EDC和25 mM的NHS混合溶液，室温下混合均匀，得到一定浓度的laminin溶液。
（6）连接细胞粘附蛋白于表面包覆聚多巴胺的氧化铱复合电极上：将所制备的氧化铱复合电极清洗干燥后，室温浸泡于上述步骤（5）中所配制的细胞粘附蛋白（laminin）溶液中，经过特定时间的二次功能化反应，得到的即为具有生物活性的氧化铱复合电极。
本发明使具有良好的抗腐蚀性能和生物相容性的氧化铱材料和具有超强黏附性能的多巴胺，以及细胞粘附蛋白laminin复合在一起，形成了表面均匀且具有良好生物活性的复合电极，极大程度上实现了性能互补，成为了一种很有应用价值的新型生物医用材料，尤其可应用于利用外源电刺激调控神经干细胞（NSCs）的定向分化。
附图说明
图1为实施例二的以导电玻璃为基底，以氧化铱为导电涂层，以聚多巴胺为介质连接有浓度为20 μg/mL 的细胞粘附蛋白（laminin）的电极的场发射扫描电镜图。
图2分别为实施例一、例二、例三的以导电玻璃为基底，以氧化铱为导电涂层，以聚多巴胺为介质连接有浓度分别为10 μg/mL、20 μg/mL、40 μg/mL的细胞粘附蛋白（laminin）的氧化铱复合电极上神经元细胞贴附图片。由图可见，随着细胞粘附蛋白（laminin）的浓度的增大，细胞贴附的数目逐渐增多，且细胞状态逐渐舒展。说明所制备的电极材料的促细胞贴附性能较好。
图3为实施例二的以导电玻璃为基底，以氧化铱为导电涂层，以聚多巴胺为介质连接有浓度为20 μg/mL的细胞粘附蛋白（laminin）的氧化铱复合电极上神经元细胞活死染色图片。通过阴性对照、阳性对照以及实验组材料的细胞毒性结果的对比，由图可见，种植在所制备的电极材料的表面的细胞在分别增殖至24 h，48 h时，生长状态良好。说明所制备的电极材料具有相当好的生物相容性。
具体实施方式下面结合实例和附图对本发明作进一步的描述。
实施例一
将经过丙酮，无水乙醇，去离子水分别超声清洗15 min之后的导电玻璃放于射频磁控溅射镀膜仪的溅射腔室，将溅射腔室抽真空至3×10-5 torr。通入氩气，流量大小控制在50 sccm，调节压力至3.2×10-3 torr，开始溅射铱薄膜，溅射15 min。制备所得铱电极。将清洗干燥后的待活化的铱电极放于电解槽中0.1 M H2SO4活化溶液中。利用循环伏安扫描活化得到氧化铱涂层。称取盐酸多巴胺粉末20 mg于10 mL 10 mM的Tris溶液中配制，配制所得的浓度为2 mg/mL （pH = 8.5）。将所制备的氧化铱清洗干燥后，浸泡于新鲜配制的多巴胺溶液中，室温放置18 h，得到的氧化铱电极所包覆的聚多巴胺膜厚度为30 nm。
将EDC和NHS溶于pH为7.2的磷酸盐缓冲溶液，室温下摇晃后，得到10 mM的EDC和25mM的NHS混合溶液。将laminin溶于所配制的10 mM的EDC和25 mM的NHS混合溶液，室温下摇晃后，得到10 μg/mL laminin溶液。将所制备的包覆有聚多巴胺薄膜的氧化铱复合电极清洗干燥后，室温浸泡于新鲜配制的laminin溶液中18 h。用去离子水轻轻冲洗样品1 min，随后用氮气吹干。得到具有生物活性的复合电极材料。
将神经元细胞种植在所制备的复合电极材料表面，培养后观察细胞贴附情况。
实施例二
将经过丙酮，无水乙醇，去离子水分别超声清洗10 min之后的导电玻璃放于射频磁控溅射镀膜仪的溅射腔室，将溅射腔室抽真空至3×10-5 torr。通入氩气，流量大小控制在40 sccm，调节压力至3×10-3 torr，开始溅射铱薄膜，溅射10 min。制备所得铱电极。将清洗干燥后的待活化的铱电极放于电解槽中0.1 M H2SO4活化溶液中。利用循环伏安扫描活化得到氧化铱涂层。称取盐酸多巴胺粉末20 mg于10 mL 10 mM的Tris溶液中配制，配制所得的浓度为2 mg/mL （pH = 8.5）。将所制备的氧化铱清洗干燥后，浸泡于新鲜配制的多巴胺溶液中，室温放置24 h，得到的氧化铱电极所包覆的聚多巴胺膜厚度为37 nm。
将EDC和NHS溶于pH为7.2的磷酸盐缓冲溶液，室温下摇晃后，得到10 mM的EDC和25mM的NHS混合溶液。将laminin溶于所配制的10 mM的EDC和25 mM的NHS混合溶液，室温下摇晃后，得到20 μg/mL laminin溶液。将所制备的包覆有聚多巴胺薄膜的氧化铱复合电极清洗干燥后，室温浸泡于新鲜配制的laminin溶液中24 h。用去离子水轻轻冲洗样品2 min，随后用氮气吹干。得到具有生物活性的复合电极材料。
将神经元细胞种植在所制备的复合电极材料表面，培养后观察细胞贴附情况以及细胞毒性检测。
实施例三
将经过丙酮，无水乙醇，去离子水分别超声清洗20 min之后的导电玻璃放于射频磁控溅射镀膜仪的溅射腔室，将溅射腔室抽真空至3×10-5 torr。通入氩气，流量大小控制在50 sccm，调节压力至3.2×10-3 torr，开始溅射铱薄膜，溅射20 min。制备所得铱电极。将清洗干燥后的待活化的铱电极放于电解槽中0.1 M H2SO4活化溶液中。利用循环伏安扫描活化得到氧化铱涂层。称取盐酸多巴胺粉末20 mg于10 mL 10 mM的Tris溶液中配制，配制所得的浓度为2 mg/mL （pH = 8.5）。将所制备的氧化铱清洗干燥后，浸泡于新鲜配制的多巴胺溶液中，室温放置24 h，得到的氧化铱电极所包覆的聚多巴胺膜厚度为37 nm。
将EDC和NHS溶于pH为7.2的磷酸盐缓冲溶液，室温下摇晃后，得到10 mM的EDC和25mM的NHS混合溶液。将laminin溶于所配制的10 mM的EDC和25 mM的NHS混合溶液，室温下摇晃后，得到40 μg/mL laminin溶液。将所制备的包覆有聚多巴胺薄膜的氧化铱复合电极清洗干燥后，室温浸泡于新鲜配制的laminin溶液中24 h。用去离子水轻轻冲洗样品3 min，随后用氮气吹干。得到具有生物活性的复合电极材料。
将神经元细胞种植在所制备的复合电极材料表面，培养后观察细胞贴附情况。

Claims (7)

1.一种促神经修复的植入式电极的制备方法，所述植入式电极为厚度为2 mm，长宽分别为10 mm的方形材料；此植入式电极导电性能良好、稳定性高且生物相容性较好，能够促进细胞贴附，其特征在于：包括以下步骤：
（1）采用射频磁控溅射在导电玻璃ITO基底材料上制备铱薄膜：将经过丙酮，无水乙醇，去离子水分别超声清洗8 ~ 20 min之后的导电玻璃放于射频磁控溅射镀膜仪的溅射腔室，将溅射腔室抽真空；通入氩气，输入功率使氩气电离、起辉，调节适当的压力，开始铱薄膜的溅射；制备所得铱电极；
（2）利用循环伏安扫描活化得到氧化铱涂层：将步骤（1）中所得的铱电极清洗干燥后，放于电解槽的活化溶液中；通过参比电极与辅助电极以及待活化铱电极构成的回路，施加极化时间三角波形进行活化处理；活化所得即为氧化铱电极；
（3）通过多巴胺的氧化自聚合在氧化铱表面形成纳米级聚多巴胺包覆层：将步骤（2）中所得的氧化铱电极清洗干燥后，浸泡于新鲜配制的多巴胺溶液中，该多巴胺溶液pH = 8 ~9，室温放置，经过特定时间的氧化聚合反应，得到的即为表面包覆聚多巴胺的氧化铱复合电极；
（4）配制1-(3-二甲氨基丙基)-3-乙基碳二亚胺（EDC）和N-羟基琥珀酰亚胺（NHS）混合溶液：分别将EDC和NHS溶于pH为7 ~ 8的磷酸盐缓冲溶液，室温下混合均匀，得到10 mM的EDC和25 mM的NHS混合溶液；
（5）配制细胞粘附蛋白溶液：将胞粘附蛋白溶于上述步骤（4）中所配制的10 mM的EDC和25 mM的NHS混合溶液，室温下混合均匀，得到一定浓度的胞粘附蛋白溶液；
（6）连接细胞粘附蛋白于表面包覆聚多巴胺的氧化铱复合电极上：将所制备的氧化铱复合电极清洗干燥后，室温浸泡于上述步骤（5）中所配制的细胞粘附蛋白溶液中，经过特定时间的二次功能化反应，得到的即为具有生物活性的氧化铱复合电极。
2.根据权利要求1所述的促神经修复的植入式电极的制备方法，其特征在于：所述步骤（1）中所述的溅射腔室真空抽至3×10-5 torr；
通入氩气的流量大小控制在40 ~ 50 sccm，溅射时压力升至1×10-3 ~ 5×10-3 torr；溅射时间为10 ~ 20 min。
3.根据权利要求1所述的促神经修复的植入式电极的制备方法，其特征在于：所述步骤（2）、（3）、（6）中电极的清洗干燥即为用去离子水轻轻冲洗样品1 ~ 3 min，随后用氮气吹干。
4.根据权利要求1所述的促神经修复的植入式电极的制备方法，其特征在于：所述步骤（2）中所述的活化溶液为0.1 M H2SO4溶液；
所述的参比电极为银—氯化银参比电极，辅助电极为铂电极。
5.根据权利要求1所述的促神经修复的植入式电极的制备方法，其特征在于：所述步骤（3）中的所述pH = 8 ~ 9的多巴胺溶液是称取盐酸多巴胺粉末于10 mM的Tris溶液中配制，配制所得的浓度为1.8 ~ 2.2 mg/mL；所述室温放置的时间为18 ~ 24 h。
6.根据权利要求1所述的促神经修复的植入式电极的制备方法，其特征在于：所述步骤（5）中的所述的配制的细胞粘附蛋白的浓度范围为10 ~ 40 μg/mL。
7.根据权利要求1所述的促神经修复的植入式电极的制备方法，其特征在于：所述步骤（6）中所述的二次功能化反应时间为18 ~ 24 h。
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