自组装生物功能化复合水凝胶用于牙槽骨再生修复的研究

The reconstruction of alveolar bone defect is still a major clinical challenge. The lack of osteogenic activity of grafting materials is a key factor that limits its effect on repair of bone defect. Based on our previously synthetic PCLA-PEG-PCLA triblock copolymers that could be rapidly self-assembled to gels at body temperature, this project intends to develop a thermoreversible biofunctional composite PCLA-PEG-PCLA hydrogel modified with stromal cell-derived factor-1 (SDF-1) and nano-attapulgite (ATT). This biofunctional hydrogel can continuously regulate the behavior of cells through SDF-1 enhanced cell recruitment and then ATT clay-enhanced cell adhesion and osteogenic differentiation, thus improving its osteogenesis activity. Further 15-deoxy-Δ12, 14-prostaglandinJ2 (15d-PGJ2) as an anti-inflammatory drug was incorporated into biofunctional hydrogel for sustained and controlled release to achieve the anti-inflammatory effect. Moreover, this composite hydrogel will be applied to repair the alveolar bone defect and promote bone regeneration in beagles. Through in vitro or in vivo studies at the tissue, cell and molecular levels, this project will elucidate the effect of composite hydrogels on the rapid repair of alveolar bone defect and related regulatory mechanisms. The research results will provide the feasible and theoretical guidance for its clinical application in the future.

牙槽骨缺损治疗仍是目前临床面临的一大挑战。植入材料成骨活性不足是制约牙槽骨缺损修复效果的关键因素。基于前期制备的可在体温条件下快速自组装形成凝胶的PCLA-PEG-PCLA三嵌段共聚物，本项目拟利用促进细胞募集的基质细胞衍生因子-1（SDF-1）和促进细胞粘附及成骨分化的纳米凹凸棒石（ATT）对共聚物分子进行改性，构建可对细胞行为进行连续调控的温敏自组装生物功能化复合水凝胶，从而有效提高植入材料的成骨活性；并利用该复合水凝胶作为抗炎药物15d-PGJ2的缓释载体，赋予材料抗炎性能。进一步应用该材料修复犬牙槽骨缺损，促进骨再生。通过大体、组织、细胞和分子生物学水平的体内外研究，本项目试图阐明构建的复合水凝胶对骨组织快速修复的作用及相关调控机制，为其进入牙槽骨缺损临床应用、缩短骨修复疗程提供实验依据和理论支持。

牙槽骨缺损修复是临床上棘手的问题，组织工程技术是一种新兴、具有前景的治疗方法。本项目制备了一种在体温范围内性质稳定三嵌段共聚物PCLA-PEG-PCLA，结合基质细胞衍生因子-1（SDF-1）与纳米凹凸棒石（ATT），形成一种负载ATT的自组装生物功能化材料，并证实其在体外及体内能有效促进间充质干细胞成骨向分化。在本研究中，我们利用计算机模拟分子对接，明确SDF-1趋化因子与CXCR4之间有特异性结合，并通过碱性磷酸酶染色、茜素红染色、qPCR等实验，从表型及基因层面证实本材料负载ATT后可显著增加大鼠骨髓间充质干细胞BMSCs成骨分化能力。最后，成功建立比格犬下颌骨缺损和骨开窗模型，通过Mirco-CT、HE染色、免疫组化染色等证实负载ATT的自组装生物功能化材料具有原位成骨修复的功能。本项目从解决临床问题的角度出发，通过组织工程技术，构建了一种能促进成骨分化的的生物功能化材料，为牙槽骨缺损修复的治疗提供新的思路。