多功能化可控拓扑表面微球支架构建及其细胞介导机制研究

The clinical repair of bone demands that the structure, composition and drug release of the therapeutic implant are suitable for the bone regeneration. Moreover, the implant should be able to positively direct the cell behaviors related to bone regeneration. However, current implants are not qualified for this multifunction requirement since they somehow have their own defects. To solve this problem, this project proposed to prepare a composite microsphere scaffold which can direct the cell behaviors. We used inorganic component as pore forming agent to obtain a porous composite microsphere in which the pores exhibited a regional distribution. On the whole, this microsphere incorporated the advantages of composition, structure and drug release. Microspheres with different structures could be obtained and assembled into scaffolds with different surface topographies and 3-D shapes via a novel technique and 3-D printing technique. The features of drug release from these different scaffolds were explored. Moreover, the interaction between topography of scaffold and cell was studied in detail, aiming to construct the model of cell direction on the scaffold. In the end, combining properties of drug release and cell direction of this composite microsphere, we supposed to design the optimized multifunctional artificial bone. This project was proposed according to the need in theoretical exploring and clinical application, which had both high academic value and social economic value.

骨的临床修复要求修复体不仅在结构、组成、药物释放等方面有利于新骨形成，还能积极介导成骨相关细胞功能的发挥，最终实现新骨再生。然而传统的修复体都存在各自不足，难以同时满足上述多功能化要求。针对这一问题，本项目拟构建一种能够介导细胞行为的多功能复合微球支架：通过促骨修复无机矿物组分原位成孔技术构建特殊结构的复合多孔微球，保证微球组分、结构和释药的综合性能；进一步精确调控微球表面形貌，利用无损方法和快速原型技术构建具有不同表面特征形貌的个性化微球支架，探讨不同微球支架的药物控释功能；着重研究支架拓扑形貌与细胞之间相互作用规律，建立多功能化支架介导细胞行为的理论模型；最后，协同复合微球支架的释药能力和细胞介导能力，探索满足临床需求的最优化修复体。本项目从理论探索和实际需求出发，不仅具有很高的理论意义和学术价值，也具有很好的临床应用前景和社会经济价值。

骨缺损是临床常见的骨科疾病，骨组织工程的发展为骨缺损治疗提供了新的思路和选择。骨修复植入体表面直接作用于细胞，其表面性质（如亲疏水性、表面成分、表面形貌等）是调控细胞功能活动的重要途径之一。.在本项目的研究过程中，我们通过相分离原理、无机组分原位成孔技术、微流控辅助乳液法等方法，制备得到具有海岛形貌、表面多孔结构等特殊形貌的微球；通过湿态微球低温融合技术成功构建具有精细结构的骨修复支架，支架孔隙率在50%左右，且压缩强度可达到与骨小梁相当的8MPa，同时在保持蛋白类药物生理活性方面具有独到的优势；另外，通过氧气等离子体处理辅助体外矿化改性或Pickering乳液法对骨修复微球表面进行矿化层或Fe元素修饰，赋予微球生物活性。.我们的研究结果表明，通过对骨修复微球的可控形貌构建，可实现药物的程序性释放，以及调控干细胞在微球上的粘附、增殖和成骨分化；在骨修复微球表面进行羟基磷灰石矿化涂层修饰，可实现对生长因子的控释及促进干细胞成骨分化；在骨修复微球表面进行Fe元素修饰，对干细胞的迁移、增殖和成骨分化行为具有积极意义；同时动物实验结果证明，Fe3+具有促进宿主细胞向骨缺损部位迁移和归巢的作用，进而加快新生骨组织在缺损部位生长。.通过本项目的研究，建立了多种构建可控形貌材料方法并提出了相应的机制，阐明了不同形貌的材料以及多种生物活性因子对体内外细胞增殖及向成骨方向分化的影响机制。以上研究成果为多功能微球支架进一步的研究和临床应用奠定了坚实的理论基础。.本项目已资助发表SCI论文26篇，相关内容已获得授权发明专利3件，申请发明专利2件，培养博士生1名和硕士生5名。