磁性纳米复合人工骨的激光增材制备及成骨机理研究

Hydroxyapatite (HA) possesses excellent bioactivity and good compressive strength. Poly (lactic acid) (PLA) has favorable biocompatibility and biodegradability, while magnetic materials can stimulate osteoblast proliferation and differentiation and promote the healing of bone defects. Therefore, the combination of these three materials can not only solve the mechanical and biological issues of artificial bone, but also induce and stimulate the formation of new bone..In this project, magnetic nanocomposite artificial bone will be fabricated with nano-HA and PLA powders as raw materials, magnetic ferroferric oxide (Fe3O4) nanoparticles as magnetic source and selective laser sintering as processing technique. The evolution rules of the composition and structure of artificial bone scaffolds, the dispersion and agglomeration of particles, as well as the size and crystallinity of grains during the preparation process will be studied. The effects of component ratio and preparation process on the mechanical and biological properties will be investigated. Emphases will be put on the mechanisms of the magnetic properties of Fe3O4 including magnetic permeability and magnetic moment, and the intensity and action time of external magnetic field on cell proliferation, viability and morphology, as well as the influence rules on mineralization and osteogenetic capability. Moreover, an optimized and matched multi-parameter process model will be established by identifying the mapping rules between the magnetic, degradation rate, microstructure, etc. and process parameters. These studies will provide the theoretical basis for the developments of manufacturing technology and equipment for high performance magnetic nanocomposite artificial bone with our own independent intellectual property.

羟基磷灰石（HA）生物活性好、抗压强度高，聚乳酸（PLA）具有良好的生物相容性和降解性，而磁性材料能够刺激成骨细胞增殖分化，加速骨缺损的愈合，将三者复合既可解决人工骨的力学和生物学问题，又可诱导和刺激新骨形成。.本申请拟以纳米HA和PLA粉末为原料、以磁性四氧化三铁纳米颗粒为磁源、以选择性激光烧结为工艺，制备磁性纳米复合人工骨。研究制备过程中人工骨支架的组成与结构、颗粒的分散与团聚、晶粒的大小与结晶度等的演变规律，查明组分配比、制备工艺对力学性能和生物学性能的影响；重点研究四氧化三铁的磁学性能如磁导率、磁矩和外加磁场的强度大小、作用时间对细胞增殖、细胞活力及细胞形貌的作用机制，以及对矿化沉积和成骨能力的影响规律；通过查明磁性、降解速率、微观结构等与工艺参数的映射规律，建立多参数优化匹配的工艺模型；为发展具有我国自主知识产权的高性能磁性纳米复合人工骨制造技术与装备提供理论基础。

由创伤、感染和骨肿瘤导致的骨缺损不断增多，人们对人工骨支架的需求日益增大。然而，目前的人工骨支架因缺乏有效的调制细胞生长/组织重建行为的能力，致使骨再生速度缓慢，甚至导致骨移植失败。磁刺激是一种有效刺激细胞和组织生长的手段。四氧化三铁（Fe3O4）磁纳米颗粒具有优异的磁性能和生物相容性，释放的磁信号能刺激细胞响应并做出成骨反应，在增强骨组织再生与功能重建方面展现出巨大的潜力。为此，本项目利用选择性激光烧结（SLS）技术制备仿生骨支架，并利用Fe3O4纳米颗粒作为磁源在骨支架中构建磁性微环境，提高骨支架的细胞响应能力，主要研究内容如下：.研究SLS过程中工艺参数对支架成型质量的影响机制，发现激光能量密度低时，粉层不能完全熔融，导致支架分层现场严重、力学性能较低，而激光能量密度过高时，会导致粉层熔融区过热，激光能量渗透过深，从而出现一系列“深孔”；揭示了Fe3O4磁纳米颗粒在支架中构建的磁性微环境对细胞行为的调控机制，发现磁性骨支架通过磁刺激效应显著提高了细胞活性，促进了细胞粘附、增殖和分化；利用静磁场对磁性骨支架进行曝磁，发现静磁场作用下，磁性骨支架显著促进了干细胞的粘附、增殖和成骨分化，增强了缺损区的新骨组织形成，从而加快了骨修复进程，且药代动力学研究证实磁性骨支架植入体内具有生物安全性；利用油酸对Fe3O4磁纳米颗粒进行表面修饰，发现修饰后的Fe3O4在支架中具有更优的分散性和稳定性，使得Fe3O4在支架中的添加量提高至12 wt%，有效增强了骨支架对细胞的磁刺激效应；利用氧化石墨烯与Fe3O4构建共分散纳米系统，查明骨支架的力学性能与氧化石墨烯、Fe3O4之间的比例及其总含量密切相关，当二者分别为10:1和9 wt%时，骨支架的力学性能达到最优，此时拉伸强度、压缩强度和压缩模量分别提高了67.1%、132%和75.7%。.以上研究成果共发表国内外学术论文64篇，授权国家专利14项，出版英文专著1部，研究成果获2019年湖南医学科技一等奖（排第1）。本项目解决了骨支架制备难及成骨能力弱的关键技术问题，掌握了磁性骨支架对新生组织的刺激机制，开发了兼具成骨能力和力学强度的磁性骨支架，为发展具有自主知识产权的高性能磁性骨支架的仿生制造与性能提供了理论基础。