新型成骨诱导性磷酸化聚酯聚氨酯间聚物纳米纤维支架的设计制备及其在无细胞骨组织工程中的应用

Pure synthetic material based cell-free tissue engineering is a very attractive emerging idea in regenerative medicine and has been preliminarily deomonstrated in blood vessel regeneration. Here we would like to apply this principle to bone regeneration. The key is to develop osteoinductive materials, which still represents a significant challenge in organic biomaterials field. Biological studies and clinical practices have revealed that phosphorated organic phase plays a key role in ossification. Thus biomimetic phosphorated polymers are promising for new generation bone tissue engineering scaffolds. In this proposal, we design novel phosphorated polyester-co-polyurethane based nanofiber scaffolds to mimick the microenvironment of native bone. We expect they will recapitulate the essence of phosphorated glycoproteins critical for bone mineralization, and provide an instructive niche for bone regeneration. We will systematically investigate the in vitro and in vivo osteogenetic abilities of these scaffolds. The study will provide an insight on the relationship between phosphorylation of materials and their osteoinductivity, and would lead to a new generation of osteoindutive materials for cell-free bone regeneration. In addition, the title polyester-co-polyurethanes will be synthesized from our newly developed acid-induced epoxide ring-opening polymerization. This study will substantially broaden the appplications of this polymerization technology. Overall, in this proposal, we are going to address a significant clinical challenge via novel biomimetic materials. We expect to foster some original innovations in this multidisciplinary field.

以纯合成材料为核心的无细胞组织工程是再生医学领域初见端倪的前沿方向，其可行性已在血管再生中得到初步证实。本课题拟将该理念应用到骨再生中，其关键是发展具有成骨诱导性的生物材料。而现有的有机骨组织工程材料通常缺乏生物活性，是该领域发展的瓶颈，本课题针对这一难点，对生命科学和临床医学证实的在成骨中起关键作用的磷酸化有机组分进行纳米尺度上仿生，设计合成具有潜在成骨诱导性的磷酸化聚酯聚氨酯间聚物，并研制其对应的纳米纤维支架，系统研究其体内外的成骨能力，试图总结出磷酸化和材料成骨能力的内在联系，发展出适合骨组织特定微环境的成骨诱导性材料,实现无细胞骨修复。同时本课题在材料设计合成上融入了我们最新开发的酸诱导环氧开环聚合反应，将进一步拓宽这一新合成平台在生物材料中的应用。总之本课题面向人类重大需求，紧跟学科发展前沿，着眼于科学问题本源，力求在学科交叉点上取得突破，产生有特色的研究成果。

面向临床上需求巨大的骨修复问题，研制促成骨材料。根据近来发展的酸诱导环氧开环聚合反应，我们设计合成了结构新颖的基于聚（癸二酸甘油酯）的功能化聚酯聚氨酯间聚物，考察了其和成骨细胞的生物相容性。合成了聚（癸二酸甘油酯）骨架系列材料，证实其能促进成骨细胞和间充质干细胞的贴附、增殖、成骨分化和细胞外基质矿化；证实材料磷酸化后能进一步促进间充质干细胞的成骨分化和细胞外基质矿化，并揭示磷酸化程度对成骨分化也有显著的影响；证实了磷酸根这样的小分子功能基来调控材料生物活性的可行性，为磷酸化高分子的设计和应用提供了参考。利用聚（癸二酸甘油酯）骨架材料制备的多孔支架复合干细胞，在大鼠颅骨标准缺损修复上取得了一定的效果。总之本课题研制了一系列有价值的生物材料，提供了新的生物材料设计思路和制备方法，为实现骨修复等生物医学应用提供了潜在的有希望的途径。