双因子控制释放纳米纤维支架的仿生构建及骨再生机制研究

Bone regeneration requires the coordinated process of angiogenesis and osteogenesis. During this process, the endogenous angiogenic and osteogenic growth factors are sequentially expressed and coupled together to enhance the bone repair. In this case, constructing the dual-factors release system with controlled release pattern has become a hot spot in the bone tissue engineering. However, how to develop the bone repair materials with superior properties remains a significant challenge, such as safe, efficient and controlled release of biological factors. Dimethyloxaloylglycine (DMOG), a small molecular drug, has been regarded as a pro-angiogenic factor. We hypothesized that sequential and sustained release of DMOG and bone morphogenic protein-2 (BMP-2) derived peptides from the scaffold will result in a synergistic effect on bone regeneration. To demonstrate this hypothesis, a gelatin-based composite nanofibrous scaffold containing DMOG and BMP-2 peptides was developed, in which the two factors were initially loaded using mesoporous silica nanoparticles (MSNs) with different pore sizes. Such dual-factors loaded composite scaffold will allow the sequential release of DMOG and BMP-2 peptides. In this project, the biological properties and osteogenic activity of the composite scaffolds will be systematically investigated by in vitro and in vivo experiments. Additionally, we will explore the probable mechanism of the synergistic effect by sequential release of the two factors for bone regeneration. The implementation of this project will provide the experiment evidence for constructing novel bone scaffolds in bone defect treatment.

在骨再生及修复过程中，血管形成与骨生成密不可分，内源性血管诱导因子和成骨诱导因子顺次表达并相互协同作用促进组织修复。针对临床上大段骨缺损的修复难题，建立模拟骨损伤自我修复过程中多因子释放规律的释放体系已成为当前的研究热点，但如何构建安全、高效且生物因子可控释放的骨修复材料仍需探索。本项目拟从仿生天然骨组织结构、组成和功能角度出发，利用两种不同孔径介孔硅纳米粒子（MSNs）分别作为成骨因子BMP-2活性多肽和促血管化因子二甲基乙二酰甘氨酸（DMOG）的微载体，再分别依次复合到明胶纳米纤维支架上，从而构建DMOG和BMP-2多肽续贯释放的骨修复体系。通过系统性研究该复合支架的体内外生物学性能及骨缺损修复效果，探明这两种因子的释放规律在骨修复过程中的促进作用及可能的协同作用机制，为构建新型骨修复材料提供实验依据。

骨缺损存在治疗过程漫长、疗效不确定等问题，严重影响患者的身心健康和生活质量。随着全球人口老龄化进程加快，各种因素造成的骨缺损患者日益增多，对植骨材料的需求也日益增加。自体骨移植是临床上手术治疗骨缺损的金标准，但是来源有限，而同种异体骨移植存在免疫排斥反应问题，限制了它们的广泛应用。人工骨移植材料主要为金属材料、生物陶瓷、生物医用高分子材料等，这些材料仍然存在生物活性不足等问题，组织工程的发展为生物活性骨移植物的构建提供了新的解决思路。本项目根据骨再生过程中血管生成与骨形成的偶联作用，仿生天然骨组织结构和功能，构建促血管化因子和成骨因子控释的骨修复体系。本项目采用3D打印技术和热致相分离技术构建了以中空结构聚己内酯（PCL）支架为框架、明胶基纳米纤维为填充物的复合支架，并在支架内部和表面分别负载成骨多肽BFP和促血管化药物DMOG，对制备的复合支架进行了理化性能评价，研究了两种因子的释放模式，并研究了复合支架的体外促血管化和促成骨分化能力以及体内骨缺损修复潜能。本项目为功能化骨修复材料的构建以及改善骨再生过程中的血管化难题提供了新的方法和思路。