CN115352164A - 一种基于压电纳米发电机的心脏再生补片材料的制备方法 - Google Patents

一种基于压电纳米发电机的心脏再生补片材料的制备方法 Download PDF

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CN115352164A
CN115352164A CN202211119531.3A CN202211119531A CN115352164A CN 115352164 A CN115352164 A CN 115352164A CN 202211119531 A CN202211119531 A CN 202211119531A CN 115352164 A CN115352164 A CN 115352164A
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CN115352164B (zh
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王学川
郑漫辉
刘新华
陈星�
岳欧阳
白忠薛
崔博强
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Shaanxi University of Science and Technology
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Abstract

本发明公开了一种基于压电纳米发电机的心脏再生补片材料的制备方法，首先，将壳聚糖溶解于三氯化铁溶液中，再加入丙烯酰胺，得到混合液A；将盐酸多巴胺、聚(3,4‑乙烯二氧噻吩)‑聚苯乙烯磺酸盐溶于超纯水中，加入明胶、N,N’‑亚甲基双丙烯酰胺、过硫酸钾，得到混合液B；将混合液A和混合液B混合，真空干燥，得到粘合层；之后将左旋聚乳酸溶解于二氯甲烷和N,N‑二甲基甲酰胺的混合液中，进行静电纺丝，将得到纺丝薄膜进行退和热处理，得到发电层；将粘合层、发电层、支撑层通过胶原溶液进行粘连，即可。本发明的心脏再生补片材料具有自发电性能的发电层，由纳米发电机提供的微电流电刺激可有效促进受损心肌细胞再生。

Description

一种基于压电纳米发电机的心脏再生补片材料的制备方法
技术领域
本发明属于生物医用材料制备技术领域，具体涉及一种基于压电纳米发电机的心脏再生补片材料的制备方法。
背景技术
心肌梗死是冠状动脉急性、持续性缺血缺氧所引起的心肌坏死。心梗后的心肌再生能力有限，缺损的心肌会被细胞外基质取代，由此引发梗区域及周围的瘢痕形成，从而导致异常的电信号传导，以及不同步的心脏活动和收缩，正常心肌和瘢痕之间缺失的电信号连接导致心脏功能失调。心肌梗死主要治疗方法有药物治疗、冠状动脉支架手术以及外科开胸冠脉搭桥等方法。临床研究表明，血管在介入治疗过程中或先前的损伤都会引发新生内膜增生，这种增生过度就会造成血管官腔的再狭窄。且在搭桥手术后化验发现肌钙蛋白升高至超过正常最大值的10倍，易在别处的心肌又发生梗死，这有可能与心梗手术操作和血液灌注引起的损伤有关。目前，现有的治疗手段都无法使梗死后的受损心肌再生。因此，生物医用材料领域的研究目标是寻找减少导致组织恶化进程的途径，同时有效诱导心肌再生。
明胶作为一种生物大分子，因其独特的生物学特性被广泛应用于组织工程领域的生物材料基质，其作为心脏补片基材具有以下优势：①具备高孔隙率：从而为细胞粘附、细胞外基质的再生及细胞扩散提供足够的空间，满足细胞的生长条件；②生物相容性好：适应细胞黏附、增殖、生长、分化的物理结构，避免免疫排斥反应；③生物降解性：无毒无害，且分解的小分子物质可被人体代谢或吸收，不影响人体正常的生理活动；④形状易控制：形状易于心梗部位相匹配。
另一方面作为人体基本结构和功能的细胞生活在人体体液环境下，细胞膜内外以及体液所组成的环境相当于一个电容器。当细胞膜处于静息状态时K+极易通过细胞膜，而细胞膜对其他离子通透性极低，此时膜内外会存在一定的离子浓度差；当对细胞给予一定刺激时，细胞膜内外的通透性发生变化，本来难以通过的钾离子大量涌入膜内，使得膜内电位由负转正，即所谓的生物电。生物电广泛存在于人体当中，在胚胎发育、伤口愈合、组织再生以及生物的正常生长等方面具有重要的作用。传统的敷料和补片材料没有完全关闭伤口的希望且具有感染的风险，随着组织工程和再生医学技术的兴起，将导电生物材料整合到现代微型补片材料具有广泛的应用前景。
压电纳米发电机(PENG)是一种利用压电效应将机械能转换为电能的器件，即在外界机械作用下，压电材料产生的极化电荷和随时间变化的电场可驱动电子在外电路发生流动，进而产生电能。以压电纳米发电机为基础的心脏再生材料可以在不需要外加电源的条件下，通过电刺激可促进维持长期循环搏动的血管系统的高度成熟和有组织的心肌细胞的分化，从而进一步完善心脏的功能。
发明内容
本发明的目的在于提供一种基于压电纳米发电机的心脏再生补片材料的制备方法，该材料能够促进心肌细胞的粘附和生长并诱导心肌细胞的再生。
本发明所采用的技术方案是，一种基于压电纳米发电机的心脏再生补片材料的制备方法，具体按照以下步骤实施：
步骤1，制备心脏补片的粘合层；具体为：
步骤1.1，将壳聚糖溶解于三氯化铁溶液中，待完全溶解后在持续搅拌下加入丙烯酰胺，得到混合液A；
步骤1.2，将盐酸多巴胺、聚(3,4-乙烯二氧噻吩)-聚苯乙烯磺酸盐溶于超纯水中，加入明胶，搅拌至完全溶解后加入N,N’-亚甲基双丙烯酰胺、过硫酸钾，得到混合液B；
步骤1.3，将混合液A和混合液B均匀混合后，置于真空干燥箱中，即可得到心脏再生补片的粘合层；
步骤2，制备心脏补片的发电层：将左旋聚乳酸溶解于二氯甲烷和N,N-二甲基甲酰胺的混合液中，进行静电纺丝，将得到的PLLA静电纺丝薄膜进行退火，冷却至室温，然后再次进行热处理，冷却，得到发电层；
步骤3，将心脏补片的粘合层、发电层、支撑层依次通过胶原溶液进行粘连，其中，发电层位于中间，粘合层位于最下层，支撑层位于最上层，即可得到心脏再生补片材料。
本发明的特点还在于，
步骤1.1中，壳聚糖、三氯化铁溶液、丙烯酰胺的质量比为0.1-1：25-250：4-40；三氯化铁溶液的浓度为0.02mol/L。
步骤1.2中，盐酸多巴胺、聚(3,4-乙烯二氧噻吩)-聚苯乙烯磺酸盐、明胶、N,N’-亚甲基双丙烯酰胺、过硫酸钾的质量比为0.05-0.5：1-10：5-50：0.003-0.03：0.05-0.5。
步骤1.3中，超声处理温度为60℃，时间为30min；真空干燥温度为70℃，时间为5-6h。
步骤2中，退火温度为105℃，退火时间为10h；热处理温度为160℃，热处理时间为10h。
步骤2中，静电纺丝条件是：电压为14.0±0.1kV，注射器推送速度为2.0mL/h，滚筒转速为4000rpm。
步骤3中，支撑层为脱细胞猪真皮基质。
本发明的有益效果在于：
(1)明胶分子含有大量RGD序列，能够促进心肌细胞的粘附和生长并诱导心肌细胞的再生，是优异的心脏补片基材；
(2)心脏再生补片材料的粘合层为高孔隙率的三维立体结构，从而为细胞的粘附、细胞外基质的再生和细胞扩散提供足够的空间，且具有一定的机械强度和黏性，能够抵抗一定的组织应力；
(3)本发明制备的心脏再生补片材料的支撑层，不仅增加了补片的机械性能，还可有效防止补片与其他组织发生黏连；
(4)本发明制备的心脏再生补片材料含有大量的活性官能团，可接枝负载不同类型的生长因子及药物，得到缓释、温敏的多功能心脏补片材料，能应用于术心肌梗死后的受损心肌再生的医用材料。与传统的心脏补片材料相比，本发明的心脏再生补片材料具有自发电性能的发电层，由纳米发电机提供的微电流电刺激可有效促进受损心肌细胞再生，增加其作为心脏补片材料的优势。
附图说明
图1为本发明实施例1制备的心脏再生补片粘合层的形貌图；
图2为图1的内部横截面图；
图3为图2的横截面放大图；
图4为本发明实施例1制备的心脏再生补片发电层的电镜扫描图；
图5为本发明实施例1制备的心脏再生补片支撑层的原子力显微镜图；
图6为本发明实施例1制备的心脏再生补片粘合层的黏附性能表征图；
图7为本发明实施例1制备的心脏再生补片体外模拟心脏心跳监测结果图；
图8为本发明实施例1制备的心脏再生补片相容性(CCK-8)测试结果图。
具体实施方式
下面结合附图和具体实施方式对本发明进行详细说明。
本发明一种基于压电纳米发电机的心脏再生补片材料的制备方法，具体按照以下步骤实施：
步骤1，制备心脏补片的粘合层；具体为：
步骤1.1，将壳聚糖(CS)溶解于三氯化铁(FeCl3)溶液中，完全溶解后在50℃的条件下持续搅拌并加入丙烯酰胺(AAM)，得到混合液A；
壳聚糖、三氯化铁溶液、丙烯酰胺的质量比为0.1-1：25-250：4-40；
三氯化铁溶液的浓度为0.02mol/L；
步骤1.2，将盐酸多巴胺(DA)、聚(3,4-乙烯二氧噻吩)-聚苯乙烯磺酸盐(PEDOT:PSS)溶于超纯水中，加入明胶，置于45℃恒温水浴锅中搅拌至完全溶解后加入N,N’-亚甲基双丙烯酰胺(MBA)、过硫酸钾(KPS)搅拌均匀，得到混合液B；
盐酸多巴胺、聚(3,4-乙烯二氧噻吩)-聚苯乙烯磺酸盐、明胶、N,N’-亚甲基双丙烯酰胺、过硫酸钾的质量比为0.05-0.5：1-10：5-50：0.003-0.03：0.05-0.5；
本发明的明胶来源于脱细胞胎牛皮真皮基质，具有高生物相容性以及大量RGD序列，并且具有诱导细胞粘附、生长，是优良的心脏再生补片基材。
步骤1.3，将混合液A和混合液B均匀混合后，在60℃的条件下超声处理30分钟，随后置于70℃的真空干燥箱中反应5-6h，即可得到厚度为5～10mm的心脏再生补片粘合层；
粘合层具有粘附性和导电性能，可实现心脏的同步收缩以及心脏电信号的传导；
步骤2，制备心脏补片的发电层；
将左旋聚乳酸(PLLA)溶解于二氯甲烷(DMF)和N,N-二甲基甲酰胺(DCM)的混合液中，得到静电纺丝溶液，进行静电纺丝，纺丝结束后，将得到的PLLA静电纺丝薄膜在105℃下退火10h，冷却至室温，然后在160℃下再次热处理10h并冷却，得到发电层；
PLLA静电纺丝薄膜的厚度为1μm～100μm；
DMF和DCM的体积比为1：4；
静电纺丝条件是：电压为14.0±0.1kV，注射器推送速度为2.0mL/h，滚筒转速为4000rpm；
PLLA静电纺丝薄膜具有压电性，可作为补片的电源，通过收集并将心脏跳动的机械能转化为电能，为心脏再生补片供电，产生的电刺激可有效促进心脏梗死区域受损心肌的再生。
步骤3，将心脏补片的粘合层、发电层、支撑层依次通过胶原溶液进行粘连，发电层位于中间，粘合层位于最下层，支撑层位于最上层，得到基于纳米发电机的心脏再生补片材料。
支撑层为脱细胞猪真皮基质(pADM)，pADM具有与组织相似的结构和机械性能，并且可以防止补片外部与其他组织发生黏连；支撑层厚度为500μm～1mm；
本发明所制备的心脏再生补片材料具有自发电性能，结合生物微电流，自发电产生的微电流电刺激，有效促进心脏梗死区域受损心肌细胞的再生。
本发明以从生物安全性较好的脱细胞胎牛皮真皮基质提取的明胶为基材，复合无细胞毒性的压电材料左旋聚乳酸(PLLA)、导电高分子聚3，4-乙烯二氧噻吩：聚苯乙烯磺酸盐溶液(PEDOT:PSS)、具有粘附性的壳聚糖和盐酸多巴胺(DA)，制备具有不同功能的补片粘合层、发电层和支撑层，并将其组装在一起，得到心脏再生补片；明胶含有大量RDG序列及官能团，可促进细胞的粘附和生长；PLLA具有压电性能，可以为心脏补片供电；PEDOT:PSS溶液具有高导电性，可提高材料的导电率，实现心脏电信号的传导；壳聚糖和多巴胺不仅可以进一步提高材料的黏附性能，还可作为粘合层的增强填料，提高补片粘合层的力学性能。该心脏补片生物相容性好，可实现心脏的同步收缩和电信号的传导，能广泛应用于心脏梗死后心肌再生治疗。
实施例1
(1)心脏补片粘合层的制备：
混合液A的制备：称取0.1g壳聚糖(CS)溶解于25mL 0.02mol/L三氯化铁(FeCl3)溶液中，完全溶解后在50℃的持续搅拌下加入4g丙烯酰胺(AAM)，得到混合液A；
混合液B的制备：称取0.05g盐酸多巴胺(DA)以及1mL聚(3,4-乙烯二氧噻吩)-聚苯乙烯磺酸盐(PEDOT:PSS)溶于12mL超纯水中，加入5g明胶，置于45℃恒温水浴锅中搅拌至完全溶解后加入0.003g N,N’-亚甲基双丙烯酰胺(MBA)、0.05g过硫酸钾(KPS)搅拌均匀后，得到混合液B；
将混合液A和混合液B均匀混合后，在60℃的条件下超声处理30分钟，随后置于70℃的真空干燥箱中反应5h，即可得到心脏再生补片的粘合层。
(2)心脏补片发电层的制备：称取0.05g左旋聚乳酸(PLLA)溶解于10mL二氯甲烷(DMF)和N,N-二甲基甲酰胺(DCM)的混合液中得到静电纺丝溶液，其中，DMF和DCM的体积比为1:4，静电纺丝条件如下：电压14.0±0.1kV，注射器推送速度为2.0mL/h，滚筒转速为4000rpm。纺丝结束后，将得到的压电PLLA薄膜在105℃下退火10h，冷却至室温，然后在160℃下再次热处理10h并冷却；
(3)将心脏补片的粘合层、发电层、支撑层通过具有黏合性能的胶原溶液组装在一起，得到基于纳米发电机的心脏再生补片。
图1-3为心脏再生补片粘合层的扫描电镜图，依次为表面形貌图、内部横截面图以及横截面放大图，从放大图可以看出PEDOT:PSS沉积并包裹在纤维表面，从而保证了粘合层的导电性；图4为心脏再生补片发电层的电镜扫描图；从图中可以看出静电纺丝的PLLA纤维直径在100nm，呈蜘蛛网状；图5为心脏再生补片支撑层的原子力显微镜图片，由图可知，pADM保留了胶原纤维特有的D周期横纹结构，该特殊结构保证了pADM具有较强的韧性和抗拉力，可作为材料的支撑层；图6为心脏再生补片粘合层的黏附性能表征：该粘合层具有良好的黏附性能，可以粘附在塑料、玻璃、不锈钢等基材表面，为补片体内黏附在心脏表面提供基础；图7为制备的心脏再生补片体外模拟心脏心跳监测：该补片可实现心跳同步收缩和电信号的传导；图8为制备的心脏再生补片相容性(CCK-8)测试结果：可以看出该心脏补片材料具有较高的生物相容性。
实施例2
(1)心脏补片粘合层的制备：
混合液A的制备：称取0.5g壳聚糖(CS)溶解于25mL 0.02mol/L三氯化铁(FeCl3)溶液中，完全溶解后在50℃的持续搅拌下加入4.5g丙烯酰胺(AAM)，得到混合液A；
混合液B的制备：称取0.1g盐酸多巴胺(DA)以及1mL聚(3,4-乙烯二氧噻吩)-聚苯乙烯磺酸盐(PEDOT:PSS)溶于13.5mL超纯水中，加入5g明胶，置于45℃恒温水浴锅中搅拌至完全溶解后加入0.003g N,N’-亚甲基双丙烯酰胺(MBA)、0.05g过硫酸钾(KPS)搅拌均匀后得到混合液B；
将混合液A和混合液B均匀混合后，在60℃的条件下超声处理30分钟，随后置于70℃的真空干燥箱中反应6h，即可得到该心脏再生补片的粘合层。
(2)心脏补片发电层的制备：称取0.1g左旋聚乳酸(PLLA)溶解于10mL二氯甲烷(DMF)和N,N-二甲基甲酰胺(DCM)的混合液中得到静电纺丝溶液，其中，DMF和DCM的体积比为1:4。静电纺丝条件如下：电压14.0±0.1kV，注射器推送速度为2.0mL/h，滚筒转速为4000rpm。纺丝结束后，将得到的压电PLLA薄膜在105℃下退火10h，冷却至室温，然后在160℃下再次热处理10h并冷却。
(3)将心脏补片的粘合层、发电层、支撑层通过具有黏合性能的胶原溶液组装在一起，最终得到基于纳米发电机的心脏再生补片。
实施例3
(1)心脏补片粘合层的制备：
混合液A的制备：称取1.0g壳聚糖(CS)溶解于25mL 0.02mol/L三氯化铁(FeCl3)溶液中，完全溶解后在50℃的持续搅拌下加入5g丙烯酰胺(AAM)，得到混合液A；
混合液B的制备：称取0.2g盐酸多巴胺(DA)以及1mL聚(3,4-乙烯二氧噻吩)-聚苯乙烯磺酸盐(PEDOT:PSS)溶于15mL超纯水中，加入5g明胶，置于45℃恒温水浴锅中搅拌至完全溶解后加入0.003g N,N’-亚甲基双丙烯酰胺(MBA)、0.05g过硫酸钾(KPS)搅拌均匀后得到混合液B；
将混合液A和混合液B均匀混合后，在60℃的条件下超声处理30分钟，随后置于70℃的真空干燥箱中反应7个小时，即可得到该心脏再生补片的粘合层。
(2)心脏补片发电层的制备：称取0.2g左旋聚乳酸(PLLA)溶解于10mL二氯甲烷(DMF)和N,N-二甲基甲酰胺(DCM)的混合液中得到静电纺丝溶液，其中，DMF和DCM的体积比为1:4。静电纺丝条件如下：电压14.0±0.1kV，注射器推送速度为2.0mL/h，滚筒转速为4000rpm。纺丝结束后，将得到的压电PLLA薄膜在105℃下退火10h，冷却至室温，然后在160℃下再次热处理10h并冷却。
(3)将心脏补片的粘合层、发电层、支撑层通过具有黏合性能的胶原溶液组装在一起，最终得到基于纳米发电机的心脏再生补片。

Claims (7)

1.一种基于压电纳米发电机的心脏再生补片材料的制备方法，其特征在于，具体按照以下步骤实施：
步骤1，制备心脏补片的粘合层；具体为：
步骤1.1，将壳聚糖溶解于三氯化铁溶液中，待完全溶解后在持续搅拌下加入丙烯酰胺，得到混合液A；
步骤1.2，将盐酸多巴胺、聚(3,4-乙烯二氧噻吩)-聚苯乙烯磺酸盐溶于超纯水中，加入明胶，搅拌至完全溶解后加入N,N’-亚甲基双丙烯酰胺、过硫酸钾，得到混合液B；
步骤1.3，将混合液A和混合液B均匀混合后，置于真空干燥箱中，即可得到心脏再生补片的粘合层；
步骤2，制备心脏补片的发电层：将左旋聚乳酸溶解于二氯甲烷和N,N-二甲基甲酰胺的混合液中，进行静电纺丝，将得到的PLLA静电纺丝薄膜进行退火，冷却至室温，然后再次进行热处理，冷却，得到发电层；
步骤3，将心脏补片的粘合层、发电层、支撑层依次通过胶原溶液进行粘连，其中，发电层位于中间，粘合层位于最下层，支撑层位于最上层，即可得到心脏再生补片材料。
2.根据权利要求1所述的一种基于压电纳米发电机的心脏再生补片材料的制备方法，其特征在于，所述步骤1.1中，壳聚糖、三氯化铁溶液、丙烯酰胺的质量比为0.1-1：25-250：4-40；三氯化铁溶液的浓度为0.02mol/L。
3.根据权利要求1所述的一种基于压电纳米发电机的心脏再生补片材料的制备方法，其特征在于，所述步骤1.2中，盐酸多巴胺、聚(3,4-乙烯二氧噻吩)-聚苯乙烯磺酸盐、明胶、N,N’-亚甲基双丙烯酰胺、过硫酸钾的质量比为0.05-0.5：1-10：5-50：0.003-0.03：0.05-0.5。
4.根据权利要求1所述的一种基于压电纳米发电机的心脏再生补片材料的制备方法，其特征在于，所述步骤1.3中，超声处理温度为60℃，时间为30min；真空干燥温度为70℃，时间为5-6h。
5.根据权利要求1所述的一种基于压电纳米发电机的心脏再生补片材料的制备方法，其特征在于，所述步骤2中，退火温度为105℃，退火时间为10h；热处理温度为160℃，热处理时间为10h。
6.根据权利要求1所述的一种基于压电纳米发电机的心脏再生补片材料的制备方法，其特征在于，所述步骤2中，静电纺丝条件是：电压为14.0±0.1kV，注射器推送速度为2.0mL/h，滚筒转速为4000rpm。
7.根据权利要求1所述的一种基于压电纳米发电机的心脏再生补片材料的制备方法，其特征在于，所述步骤3中，支撑层为脱细胞猪真皮基质。
CN202211119531.3A 2022-09-14 2022-09-14 一种基于压电纳米发电机的心脏再生补片材料的制备方法 Active CN115352164B (zh)

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