活性氧响应性双硒微球介导的老龄骨质疏松微环境调控和骨再生

老龄骨质疏松性骨折的修复治疗是临床亟待解决的难题。老龄化进程中活性氧（ROS）过度积累和细胞衰老是导致骨质流失和抑制再生的重要因素。为此，本项目将紧扣“老龄微环境调控和高效成骨”，提出以活性氧响应性双硒聚己内酯微球负载靶向衰老细胞药物干预微环境进而促进骨再生的新思路。研究拟以高效、温和的点击化反应快速交联形成具有成骨活性的可注射聚乙二醇聚癸二酸甘油酯水凝胶，并巧妙地借助双硒聚己内酯微球的ROS响应性消耗ROS、释放药物清除衰老细胞、原位成孔，为细胞生长和组织再生提供适宜空间和环境，促进骨组织的再生。研究将采用体内外细胞和动物实验，从细胞和分子水平全面诠释ROS和衰老细胞的清除对成骨相关细胞粘附和分化、细胞内基因级联激活，以及骨再生过程的调控规律，提出老龄骨质疏松微环境调控与骨再生的理论框架，丰富引导组织再生的基本理论，并研制新型老龄化骨折修复用材料。

Bone fracture repair of age-related osteoporosis is one of the most challenging clinical problems. Reactive oxygen species (ROS) overaccumulation and cellular senescence are the main factors for bone loss and poor regeneration capacity. To this end, this project aims at "regulation of the aging bone microenvironment for efficient regeneration” and proposes that the utilization of drug-loaded ROS-responsive diselenide-containing poly(ε-caprolactone)-based microspheres mediates ROS- and senescent cells-rich aging microenvironment and thus rejuvenates bone regeneration in situ. Based on efficient and mild click reaction, injectable PEGylated poly(glycerol sebacate) (PEGS) hydrogel can crosslink rapidly at body temperature. And by the ROS activation, diselenide-containing poly(ε-caprolactone)-based microspheres will eliminate ROS, release drugs targeting senescent cells, and collapse leaving micropores in situ, which provide suitable space and environment for cell growth and tissue formation and thereby promote bone regeneration. With both in vitro and in vivo experiments, this project will clarify the effect of ROS scavenging and senescent cell elimination on bone-related cell behaviors, including adhesion, proliferation, differentiation, etc., the gene cascade activation, and thus bone regeneration. The study will summarize the mechanism of the regulation of the age-related osteoporosis microenvironment and bone regeneration, enrich and guide the development of tissue regeneration, and develop new material to overcome clinical challenges in age-related fracture.