导电传感心肌支架多材料微纳3D打印研究

Myocardial infarction is a huge threat to the health of human beings. Due to the lack of electrophysiological characteristics, the existing engineered cardiac patches can not integrate with host myocardium for electrical signal transform to realize synchronous contraction, which extremely affect the functional recovery of infarcted myocardium. Here we propose to incorporate conductive and sensing functions into conventional cardiac scaffolds based on micro/nanoscale multi-material 3D printing techniques. This might provide a new tool to explore the pathogenic mechanism and therapy of myocardial infarction. This project will mainly focus on: (1) 3D modeling and optimal design of cardiac scaffolds with multi-scale structures, conductive and sensing functions; (2) the innovation of multi-modal, multi-material and multi-scale 3D printing platform as well as the fabrication processes to meet the requirements of controllable fabrication for scaffold fibers, conductive fibers and nanoscale sensing fibers; (3) the development of novel electrical stimulation approach to promote the growth and synchronous contraction of myocardial cells and the realization of zonal sensing function for the electrophysiological signals of the engineered cardiac patches, based on which to explore the fusion mechanism between engineered patches with host myocardium in vivo. It is envisioned that the results might advance the rapid development of biofabrication techniques from conventional structure fabrication to the fabrication of smart scaffolds with conductive and sensing functions.

心肌梗死是严重威胁人类生命健康的重大疾病，现有的工程化心肌补片由于缺乏电生理特性，从而无法与宿主心肌形成电信号导通而实现收缩同步，严重影响梗死心肌的功能恢复。本项目提出将导电传感功能融入传统心肌支架，通过多材料微纳3D打印技术实现导电传感心肌支架的一体化可控制造，为探索心肌梗死的发病机理与治疗提供新手段。重点研究导电传感心肌支架多尺度结构设计与优化分析方法，建立结构支撑、电刺激与生物传感多功能耦合的三维支架模型；探索导电传感心肌支架多模式、多材料、多尺度3D打印集成创新平台与工艺实现方法，满足支架纤维、导电纤维与纳米传感纤维的三维可控制造需求；研究导电传感支架促进心肌细胞定向生长与同步收缩的电刺激活化方法，探索工程化心肌补片电生理信号的分区传感技术以及与宿主心肌电信号的体内融合机制。研究结果将推动生物制造研究从传统支架结构制造向智能导电传感支架制造方向发展。

本项目提出了多材料生物微纳静电3D打印新方法，发明了大高度微纳纤维结构、近单细胞尺度活性水凝胶结构以及多尺度三维导电心肌支架的可控制造新技术；建立了微米纤维结构引导/约束心肌细胞定向排布生长与同步跳动新方法；研究了支架结构与电刺激对体外心肌组织功能的影响；开展了柔性导电微纳纤维支架修复心肌梗死的动物实验。在以下方面取得了研究进展：.（1）搭建了多材料、多尺度生物静电3D打印系统，发明了恒定电场强度、无静电排斥的大高度微米纤维结构精确沉积打印新技术；研发了海藻酸钠/牛纤维蛋白生物活性墨水，实现了最小水凝胶纤维尺寸<30微米、支持细胞铺展与定向生长的活性结构静电打印；.（2）提出了直线/曲线微米生物纤维与亚微米导电纤维复合的心肌支架静电打印方法，建立了微米纤维结构引导心肌细胞分层定向排布方法，验证了导电纤维、曲线柔性纤维对促进体外心肌细胞功能表达与同步跳动的积极作用； .（3）建立了静电打印微米纤维约束/诱导胶原水凝胶与心肌细胞定向排布新技术，实现了体外活性心肌组织的长时间高频同步跳动（120次/分钟）；.（4）搭建了具有电刺激与电信号监测功能的体外心肌组织培养平台，研究了不同纤维形态与电刺激对体外活性心肌组织功能表达与同步跳动能力的影响规律；.（5） 建立心肌梗死模型，验证了柔性导电微纳纤维心肌支架对修复心肌梗死的有效性。.项目研究在国际权威期刊Small (IF=11.459,2篇), ACS Applied Materials and Interfaces (IF=8.758), Biofabrication (IF=8.213,4篇), Virtual and Physical Prototyping (IF=7.31,2篇), Acta Biomaterialia (IF=7.242)，Nanoscale (IF=6.895)等国际期刊发表论文22篇，其中中科院一区论文14篇；授权中国发明专利9项；做大会或特邀报告5次；受邀担任国际SCI期刊Bio-Design and Manufacturing（IF: 4.05）和International Journal of Bioprinting副编辑，以第1完成人获教育部高等学校自然科学一等奖。本项目研究为推动生物3D打印技术从结构类组织制造向电传导类功能组织制造方向发展提供了技术方法基础。