BaTiO3/P(VDF-TrFE)/Ni电-磁-力耦合效应及其成骨性能研究

The electrical, magnetic and mechanical properties of bone tissue microenvironment play a key role in bone repair. At present, the electrical or magnetic bioactive materials used in bone regeneration are simple in structure and single in function, and still can't meet the complicated clinical repair requirements of bone defects. How to make the bone repair materials with electric, magnetic and mechanical properties coupling is the key to improve bone repair effect, in which the coordination of various physical properties and the regulation on osteogenic performance are the core scientific problems. Based on the preliminary work, the effects of the composition and structure of BaTiO3/P(VDF-TrFE)/Ni magnetoelectric composite material on the electrical, magnetic and mechanical properties of the material are studied in this study. The synergies relationship among electrical, magnetic and mechanical properties of the composite materials is explored to achieve the biomimetic coupling of multi-phase physical properties. The effects of multiphase physical properties on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) were studied by genome-wide technique and transcriptomics techniques, to clarify the mechanism of multi-physical coupling on the process“transmembrane receptor activation-signal transduction- expression of osteogenic genes in nucleus” of stem cells and to realize the synergistic controllability of bone regeneration based on artificial bone repair material with multi-phase physical properties. This study will provide new approach to design and optimize novel bio-responsive bone repair materials, and also may help to resolve problem of adaptability between materials and cells/tissue.

骨组织微环境的电、磁、力学特性对骨修复起到关键作用。现有生物电/磁活性材料结构简单、功能单一，不能满足复杂的骨缺损临床修复需求。如何使骨修复材料兼具电、磁、力学特性仿生耦合是改善骨修复效果的关键，其中材料多种物理性能协同及其成骨性能调控是核心科学问题。本项目结合前期研究基础，拟进一步系统研究BaTiO3/P(VDF-TrFE)/Ni磁电复合材料组分、结构对材料电、磁、力学性能的影响，明确材料电、磁及力学性能间的协同关系，实现材料多相物理性能的仿生耦合。采用全基因组和转录组学技术研究材料多相物性对骨髓间充质干细胞（BMSCs）成骨分化的影响，阐明多相物性耦合效应对BMSCs“跨膜受体激活-信号转导-核内基因表达”过程的调控机制，实现基于骨修复材料“原位多相物性刺激骨再生”的协同可控，为新型生物反应性骨修复材料的设计优化提供新思路，也有助于解决植入材料与细胞/组织间的适配性问题。

针对材料的电、磁、力学特性仿生耦合调控干细胞行为和骨组织再生修复这一重要科学问题，本项目结合前期研究基础，基于仿生电、磁、力学微环境促进骨修复的重要作用，成功制备出力电耦合材料钛增强电活性复合膜（Ti/P(VDF-TrFE)）、可调表面电学拓扑结构的钛酸钡纤维纳米复合膜材料（BaTiO3/P(VDF-TrFE)）以及磁电耦合材料CFO/P(VDF-TrFE)复合膜，重点研究上述材料电、磁、力学特性调控成骨作用的分子机制，包括干细胞成骨力学转导机制和成骨过程中的免疫调控机制。本项目初步证实了植入材料仿生电、磁、力学特性促进骨髓间充质干细胞（BMSCs）粘附、铺展及成骨分化的有效性，并可实现骨缺损的快速有效修复。进一步发现了仿生电学微环境可能通过激活Itg-FAK-ERK机械信号传导途径来促进BMSCs成骨分化和骨再生。此外，通过构建仿生电学微环境调控骨修复早期的免疫细胞图谱，发现中性粒细胞群体数量在仿生电学微环境作用下的骨缺损修复早期显著增加，而巨噬细胞在仿生电学微环境作用下发生M2极化，由此推测中性粒细胞和M2型巨噬细胞可能在仿生电学微环境介导的骨修复早期发挥重要作用。同时，仿生磁电微环境可通过补体蛋白等免疫相关通路激活骨修复早期免疫反应过程中的巨噬细胞M2极化表型，进而促进骨修复。进一步研究发现在糖尿病条件下，仿生电学微环境对骨缺损修复仍有明显的促进作用，初步证实其可能与调控巨噬细胞免疫反应及其AKT2-IRF5信号通路的激活有关。以上研究成果实现了基于材料的电、磁、力学多种物理性能仿生耦合对促进骨组织再生修复的可调控，并初步解析其作用机制，为今后新型生物响应性骨修复材料的性能优化和满足复杂条件下骨缺损临床修复需求提供设计依据和理论支撑。以上研究成果共发表SCI论文9篇（IF>10有3篇），授权美国发明专利1项，授权国家发明专利1项，申请国家发明专利2项，国际会议邀请报告2次，指导博士、硕士研究生共6名。