Key Laboratory for Biomechanics and Mechanobiology (Beihang University) of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, P.R. China.
Department of Orthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
ACS Nano. 2024 Mar 26;18(12):8777-8797. doi: 10.1021/acsnano.3c11542. Epub 2024 Mar 15.
Stem cell-derived extracellular vesicles (EVs) show great potential for promoting bone tissue regeneration. However, normal EVs (Nor-EVs) have a limited ability to direct tissue-specific regeneration. Therefore, it is necessary to optimize the osteogenic capacity of EV-based systems for repairing extensive bone defects. Herein, we show that hydrogels loaded with osteoinductive dental pulp stem cell-derived EVs (Ost-EVs) enhanced bone tissue remodeling, resulting in a 2.23 ± 0.25-fold increase in the expression of bone morphogenetic protein 2 (BMP2) compared to the hydrogel control group. Moreover, Ost-EVs led to a higher expression of alkaline phosphatase (ALP) (1.88 ± 0.16 of Ost-EVs relative to Nor-EVs) and the formation of orange-red calcium nodules (1.38 ± 0.10 of Ost-EVs relative to Nor-EVs) . RNA sequencing revealed that Ost-EVs showed significantly high miR-1246 expression. An ideal hydrogel implant should also adhere to surrounding moist tissues. In this study, we were drawn to mussel-inspired adhesive modification, where the hydrogel carrier was crafted from hyaluronic acid (HA) and polyethylene glycol derivatives, showcasing impressive tissue adhesion, self-healing capabilities, and the ability to promote bone growth. The modified HA (mHA) hydrogel was also responsive to environmental stimuli, making it an effective carrier for delivering EVs. In an ectopic osteogenesis animal model, the Ost-EV/hydrogel system effectively alleviated inflammation, accelerated revascularization, and promoted tissue mineralization. We further used a rat femoral condyle defect model to evaluate the osteogenic ability of the Ost-EVs/hydrogel system. Collectively, our results suggest that Ost-EVs combined with biomaterial-based hydrogels hold promising potential for treating bone defects.
干细胞衍生的细胞外囊泡（EVs）在促进骨组织再生方面具有巨大潜力。然而，正常 EVs（Nor-EVs）在指导组织特异性再生方面的能力有限。因此，有必要优化基于 EV 的系统的成骨能力，以修复广泛的骨缺损。在此，我们展示了负载有诱导成骨的牙髓干细胞衍生 EVs（Ost-EVs）的水凝胶增强了骨组织重塑，与水凝胶对照组相比，骨形态发生蛋白 2（BMP2）的表达增加了 2.23±0.25 倍。此外，Ost-EVs 导致碱性磷酸酶（ALP）的表达更高（Ost-EVs 相对 Nor-EVs 为 1.88±0.16），并且形成橙红色钙结节（Ost-EVs 相对 Nor-EVs 为 1.38±0.10）。RNA 测序显示，Ost-EVs 表现出显著高的 miR-1246 表达。理想的水凝胶植入物也应该与周围湿润的组织黏附。在这项研究中，我们被贻贝启发的黏附修饰所吸引，水凝胶载体由透明质酸（HA）和聚乙二醇衍生物制成，具有令人印象深刻的组织黏附性、自修复能力和促进骨生长的能力。修饰后的 HA（mHA）水凝胶还对环境刺激有响应，使其成为递送 EVs 的有效载体。在异位成骨动物模型中，Ost-EV/水凝胶系统有效缓解了炎症，加速了再血管化，并促进了组织矿化。我们进一步使用大鼠股骨髁缺损模型评估了 Ost-EVs/水凝胶系统的成骨能力。总的来说，我们的结果表明，Ost-EVs 与基于生物材料的水凝胶的结合具有治疗骨缺损的巨大潜力。
