类肝素多糖促进成骨过程中血管化的机制研究

Rapid and efficient angiogenesis plays a crucial role in bone regeneration. Synergisms of series of growth factors are involved in the vascularization. However, growth factor is accessible to degradation in vivo which leads to lose of activity; the higher potential hazard would be existed if large doses of various growth factors are applied. Therefore, in this project, the heparin-like sulfated polysaccharide with tunable structure mimicking the in vivo glycosylation process will be synthesized in light of the synergistic effects between sulfated proteoglycans and growth factors, as well as the integrating methods of materials and biological molecules. It is anticipated hypothesis that the heparin-like polysaccharides are capable of binding with vessel endothelial growth factor (VEGF) and enhance its biological activities, which resulting improvement of angiogenesis. Furthermore, both improved osteogenesis and vascularization can be obtained simultaneously attributing to the bone morphogenetic protein-2 (BMP-2) mediated cascade response. The research will systematically investigate the relationship between molecular structures of heparin-like polysaccharide and bioactivity of VEGF and discuss the synergistic effect from cell and molecule levels. Angiogenesis mechanism modulated by heparin-like polysaccharide during the process of bone repairing would be either clarified. The research will raise a novel thought of promoting bone regeneration through regulating biological activity of growth factor and triggering its cascade response via appropriate supplying of specific materials. These hypotheses will be validated though in vivo animal test. The work will explore a breakthrough of facilitating angiogenesis during bone repairing, as well as provide a fresh thought designing of novel bone-regeneration biomaterials. Furthermore, the research will supply experimental basis and theoretic reference to other analogical growth factors.

迅速有效的血供重建是决定修复质量的关键。血管化涉及到多种生长因子的协同作用，但生长因子在体内易失活，大剂量使用存在较高的潜在风险。本项目仿生体内肝素与生长因子的糖基化相互作用，结合材料学和分子生物学的研究方法，设计制备结构可控的类肝素材料，使其与血管内皮生长因子（VEGF）结合后可直接提高因子的成血管活性；并可通过与骨诱导生长因子骨形态发生蛋白-2（BMP-2）的相互作用间接促进血管再生，起到同时促进成骨和血管化的作用。本项目将从细胞和分子水平研究类肝素的分子结构影响VEGF生物活性的构效关系，明确其协同作用规律，阐明类肝素多糖对成骨过程中血管化的促进机制，提出用材料促进生长因子活性、调控其级联反应，进而促进组织修复的学术思想，并通过在动物体内进行实验验证，为促进骨修复中的血管再生寻找一个新的突破口，为构建新型骨修复材料提供新思路，同时也为骨修复中其它生长因子的研究提供实验依据和理论借鉴。

迅速有效的血供重建是决定修复质量的关键。本项目以提高成骨过程的血管化为目标，研究了类肝素磺化壳聚糖对人脐静脉内皮细胞（HUVECs）行为的影响、以及与骨修复中重要的生长因子血管内皮生长因子（VEGF）、骨形态发生蛋白-2（BMP-2）间的相互作用。研究发现，2-N,6-O-磺化壳聚糖（26SCS）具有促血管化作用，对内皮细胞的增殖和粘附、血管化相关因子分泌和相对基因表达等行为产生影响，并且呈浓度依赖性；26SCS与VEGF间存在相互作用，26SCS存在下，VEGF的促细胞血管发生能力显著增强，促进内皮细胞增殖、迁移、芽体发生、血管化基因表达以及相关分子分泌，体内动物实验也验证了其协同VEGF促进损伤区域的血管网络重建；同时，研究发现26SCS还能促进BMP-2诱导成骨中的血管化基因表达和VEGF分泌，表明26SCS还可借助BMP-2进一步促进血管发生。基于26SCS的骨修复材料在临界尺寸骨修复的动物实验中取得良好效果，有效促进缺损部位血管网络修复，进而促进骨组织修复。本研究发现了磺化壳聚糖促血管化效应，阐明了其促血管发生机制，并构建了基于磺化壳聚糖的生物材料，为促进骨修复中的血管再生提供新思路，也为构建新型骨修复材料提供实验依据和理论借鉴。

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