n-HA/Col复合涂层多孔钛的构建及其抗肿瘤和节段骨缺损修复作用研究

This project is proposed to solve two clinical problems about segmental bone defect and tumor local recurrence after bone tumor resection. Base on the potential application of porous titanium in weight-bearing bone defect repairing, the precise personalized multifunctional n-HA/Col porous titanium which has antitumor and osteoinductive activity is designed and constructed through integration and innovation of the advanced 3D printing technology and surface modification technology, cell adhesion promoting effect of collagen, antitumor activity of n-HA particles and the bone regeneration effect of modified porous titanium. The key points of the technique are the personalized preparation of porous titanium possessing bone like structure and mechanical properties, the n-HA/Col composite coatings assemble by electrophoretic deposition which can controlled release and effective concentration maintain of antitumor n-HA particles, as well as the construction and evaluation of animal orthotopic model of bone tumors. Furthermore, the effect and molecular mechanism of repairing segmental bone defect and antitumor activity by n-HA/Col composite coatings porous titanium are investigated by advanced materials synthesis and characterization, cell and molecular biology and histological analysis. The objective of this study is to provide a new method and material for segmental bone defect reconstruction and tumor local recurrence suppression after bone tumor resection.

本项目针对临床面临的骨肿瘤切除后形成的大段骨缺损修复和局部肿瘤复发两大难题提出。基于多孔钛在承力部位骨缺损修复中的应用潜能，通过先进的3D打印技术和表面改性技术的集成与创新，协同利用胶原的促细胞粘附，n-HA的抗肿瘤活性，以及改性多孔钛的促骨生成效应，设计构建兼具促骨再生、抗肿瘤和个性化精准修复的新型多功能n-HA/Col复合涂层多孔钛。其技术核心是多孔钛仿骨结构和力学性能的个性化制备，电泳沉积层层组装n-HA/Col的制备以满足抗肿瘤n-HA的可控释放和局部有效浓度维持，以及动物原位骨肿瘤模型的构建和评价体系。同时，结合先进的材料制备表征、细胞及分子生物学、组织学分析等考察所制备n-HA/col涂层多孔钛的大段骨缺损修复效果和抗肿瘤活性，并探索其内含的分子机制，为临床骨肿瘤切除术后大段骨缺损个性化精准修复和抑制局部肿瘤复发提供新的治疗思路和材料基础。

本项目针对临床面临的骨肿瘤切除后形成的大段骨缺损修复和局部肿瘤复发两大难题提出。项目成功构建了纳米羟基磷灰石/胶原（n-HA/Col）复合涂层多孔钛修复体，但Col控释效率不高，经优化改进后，采用发泡沉淀法制备了n-HA/3D打印多孔钛修复体。实验结果显示，该修复体携带n-HA能力和缓释效率均明显优于n-HA/Col 复合涂层多孔钛假体。体外体内成骨实验结果显示：n-HA/3D打印多孔钛修复体成骨能力优于单纯3D打印多孔钛。体内外成骨实验结果显示：所构建的n-HA/3D打印多孔钛成骨能力优异，优于单纯3D打印多孔钛；体外体内抗肿瘤实验结果显示：n-HA/3D打印多孔钛具备较强的抗肿瘤能力。实验结果达到实验预期，且具备良好的临床转化潜能，有望成为临床骨肿瘤患者肿瘤切除后骨缺损修复和抑制局部肿瘤复发的优异修复体。另外，虽然本实验结果显示Col控释n-HA效率不高，但该法仍有潜在优势，后期可望通过优化可进一步提高Col控释效率，比如引入酸响应或ROS功能健等方法，以期最终获得携带n-HA量大、可层层释放、效率高、速率易调控的Col控释系统，进一步优化和完善本项目。本项目支持或部分支持下，共发表学术论文12篇，其中SCI论文11篇、中文核心期刊1篇，获授权国家发明专利1项。