表面纳米形貌通过整合素β1/Ras/ERK信号调控H型骨血管新生促进成骨

The loosening of titanium bone implants is a frequent clinical problem, mainly caused by the poor bone regeneration and insufficient osteointegration at the “material-bone” interface. In order to solve this problem by developing better implant materials, insights into the effects of the physical and chemical properties of biomaterials on “material-tissue” interaction and bone regeneration are urgently needed. Angiogenesis is a critical process in tissue regeneration. Research breakthroughs published on “Nature” in 2014 indicated that type H blood vessels, an organ-specific vascular subtype in bone, serves as a key regulator of bone formation by secreting crucial cytokines for osteogenesis, mediating the coupling of angiogenesis and osteogenesis. Factors influencing type H vessels will make a great difference to bone formation. However, the influences of biomaterials on type H vessels remain unknown. The topographies of material surfaces could modulate cell behaviors and tissue regeneration, and their effects greatly depend on their size features. The impact of surface topographies on the angiogenesis of type H vessels, however, are still unclear. Our recent work suggested that 1) titania surface nanotubes, a representative nanoscale surface topography, could regulate integrin β1, a key molecule for the specification of vascular endothelial cells (VEC) in bone, and affect the angiogenesis of type H vessels, and 2) different diameters of surface nanotubes led to significantly different effects. In this project, we aim to investigate the effects of surface topography on the angiogenesis of type H vessels and the underlying mechanisms, with the experimental model of titania nanotubes. We will 1) make clear the specific effects of nanoscale surface topographies and their size feature on the angiogenesis of type H vessels, finding the best size, and 2) investigate the integrin β1-related molecular mechanisms underlying these effects. These research will give us totally new understanding of how material structures affect organ-specific special vascular subtypes and bone regeneration, providing basis for modifying the microstructures of implant surfaces to promote the osteointegration of implants and reduce the pain of patients caused by implant loosening.

钛金属骨植入材料临床松动率高，危害巨大，而新材料研发以明确材料特性对组织细胞行为的影响为关键前提。H型骨血管是调控骨新生的关键血管亚型，但生物材料对H型骨血管的影响未知。我们发现：钛表面纳米管不同管径对H型骨血管新生及调控骨血管内皮细胞（VEC）分化的关键分子整合素β1（integrin β1）产生不同影响，提示材料微观结构可能通过integrin β1信号调节H型骨血管新生。本课题拟从钛纳米管入手①建立“钛-骨”界面“血管新生-骨新生”偶联模型，明确表面纳米形貌及其尺寸因素对H型骨血管新生的调节作用；②以integrin β1/Ras/ERK信号通路为重点，阐明表面纳米形貌调控H型骨血管的关键分子机制；③揭示表面纳米形貌调控H型骨血管新生对骨再生和材料骨整合的意义。为认识材料结构调控特定细胞行为和骨再生的作用和机制提供全新认知，为精确改造钛表面形貌以降低骨内植物的临床松动率奠定基础。

骨植入固定材料临床松动率高，危害巨大，而新材料的研发需要首先明确材料特性对组织细胞行为的影响。H型骨血管是调控骨新生的关键血管亚型，但生物材料对H型骨血管的影响未知。本项目重点研究材料纳米结构及其尺寸影响H型骨血管的作用和机制。新发现：①材料纳米形貌调节H型骨血管内皮的多种行为，尺寸不同效应不同。管径在20-100nm范围内的钛表面纳米管不同程度地促进H型血管新生，约70nm管径的作用最佳,而>100nm的管径可能造成负面效应。②机制：纳米形貌通过细胞膜上的integrin分子直接调节内皮细胞，也通过调节成骨祖细胞等其他细胞及细胞间对话，间接调节血管内皮，而在体内以间接调节机制为主。③不同组织来源的同类细胞可能对相同材料产生不同反应。④将某种细胞单独与材料接触进行体外实验，产生的结论可能与体内真实情况不同，在“材料-组织”交互作用研究中，应重视体内实验分析，体外实验应通过细胞共培养等模拟体内的多细胞微环境，以获取更加准确的信息。这些为认识材料物理特性调控特定细胞行为和骨再生的作用和机制提供了全新认知，为精确改造材料表面形貌以降低骨内固定物的临床松动率奠定了基础，也为生物材料相关研究提出了新理念。