基于药物缓释及仿骨基质的高生物响应性纳米复合GBR膜的制备及成骨机制初探

Guided bone regeneration (GBR) has been one of the most wildly used techniques for bone tissue regeneration. However, most of the present GBR membranes degradated rapidly and do not have the ability of tissue induction. Therefore, in this study, a novel bone formation-inducing GBR membrane with controlled drug-release ability and bone matrix-mimicking structure is to be fabricated for guided bone regeneration. The GBR membrane is first prepared by gradient electrospinning technology and the nanofiber in this GBR membrane is modified by drug delivery system, which consist of metal organic framework and Risedronate (ZIF8-RIS). This membrane consists of two layers: The top layer, which gets into contact with the soft tissue, is dense and antibacterial with consistent degradation rate for bone formation. The bottom layer is loose which imitated the bone matrix structure. With the sustained release of Zinc and Risedronate, the bottom layer can promote osteogenesis and inhibit activity of osteoclast, and finally promote the healing and growth of bone tissue. The composite GBR membrane designed in this proposal has excellent chemical and physical characteristics, which make it a promising biomaterial for guided bone regeneration. We anticipate this novel osteoinductive and antibacterial membrane can diverse applications widely in bone engineering and regenerative medicine.

GBR技术是目前临床最常用,效果最稳定的骨组织增量技术,但目前常用的GBR膜生物降解速度难以控制且缺乏主动诱导骨再生的能力。本课题拟制备一种具有药物缓释功能及仿骨基质结构的高生物响应性纳米复合GBR膜用于引导组织再生。该GBR膜利用静电纺丝技术首先制备仿骨基质结构的胶原/聚己内酯复合双层GBR膜，再以载药系统金属有机骨架-利塞膦酸钠(ZIF8-RIS)对GBR膜的纳米纤维进行表面改性。通过调整参数使该双层GBR膜具有以下特性：上层接触软组织的致密面降解速度与骨形成速度一致，可持续释放锌(Zn)从而具有抗菌活性；下层接触骨组织的疏松面仿骨基质结构，通过负载的ZIF8-RIS控释缓释促进成骨的Zn及抑制破骨的药物RIS，达到主动诱导骨再生的作用。该GBR生物膜不仅具有优良的理化特性,能满足常规生物膜的屏障作用,还具有良好的降解可控性及引导组织再生的能力。

本课题利用静电纺丝技术在优化胶原/PCL纳米复合GBR双层膜的基础上，通过反复试验，成功在胶原/PCL静电纺丝膜表面制备出纳米级ZIF-8涂层，除了可以缓释适宜浓度的锌离子，具有稳定的拉伸强度、可控的降解速率之外，还可以促进体外成骨、成血管以及在大鼠颅骨缺损模型中促进体内成骨，得到了较为理想的结果，完成了本实验预期的内容，有望成为胶原膜的替代品。课题组还利用ZIF-8的载药优势，将抑制破骨的药物利塞膦酸钠(RIS)成功负载于ZIF-8，并研究了ZIF8-RIS载药系统在促成骨和抑破骨的协同作用。除此之外，我们还扩展探索了ZIF-8涂层植体促成骨性能、ZIF8负载DMOG载药系统的合成以及小鼠牙槽骨成骨模型的建立及研究。综上所述，本课题研究不仅顺利完成了既定目标，还对所引入材料的性能进行了更为细致深入的探究。研究结果扩展到了纳米材料促成骨领域，证明了ZIF-8是一种有前途的骨再生材料，为MOFs材料应用于医药平台奠定了更深的基础。