由外伤、肿瘤切除和先天畸形等因素引起的节段性骨缺损带来了重大的临床挑战，通常需要复杂的重建策略。载有多种促进成骨成分的水凝胶已成为骨缺损修复的有前途的工具。虽然之前已经证明了 Piezo1 激动剂 Yoda1 的成骨潜力，但其疏水性对有效负载到水凝胶基质上提出了挑战。在这项研究中，我们通过采用 Yoda1 预处理的骨髓间充质干细胞 (BMSC) 外泌体来解决这一挑战(Exo-Yoda1) 以及源自 BMSC 的外泌体 (Exo-MSC)。相比之下，与对照组和 Exo-MSC 处理的 BMSC 相比，Exo-Yoda1 处理的 BMSC 表现出增强的成骨能力。值得注意的是，Exo-Yoda1 处理的细胞表现出与 Yoda1 本身相似的功能。转录组分析揭示了成骨相关信号通路的激活，表明 Yoda1 介导的信号（例如 ErK）的潜在转导，这一发现在本研究中得到了验证。此外，我们成功地将Exo-Yoda1整合到甲基丙烯酰明胶（GelMA）/甲基丙烯酸海藻酸钠（SAMA）/β-磷酸三钙（β-TCP）水凝胶中。这些负载 Exo-Yoda1 的水凝胶在皮下异位成骨裸鼠模型和大鼠颅骨骨缺损模型中显示出增强的成骨作用。总之，我们的研究介绍了负载 Exo-Yoda1 的 GELMA/SAMA/β-TCP 水凝胶作为促进成骨的一种有前途的方法。这种创新策略为骨缺损重建领域未来广泛的临床应用带来了巨大的希望。© 2024。作者。

Segmental bone defects, arising from factors such as trauma, tumor resection, and congenital malformations, present significant clinical challenges that often necessitate complex reconstruction strategies. Hydrogels loaded with multiple osteogenesis-promoting components have emerged as promising tools for bone defect repair. While the osteogenic potential of the Piezo1 agonist Yoda1 has been demonstrated previously, its hydrophobic nature poses challenges for effective loading onto hydrogel matrices.In this study, we address this challenge by employing Yoda1-pretreated bone marrow-derived mesenchymal stem cell (BMSCs) exosomes (Exo-Yoda1) alongside exosomes derived from BMSCs (Exo-MSC). Comparatively, Exo-Yoda1-treated BMSCs exhibited enhanced osteogenic capabilities compared to both control groups and Exo-MSC-treated counterparts. Notably, Exo-Yoda1-treated cells demonstrated similar functionality to Yoda1 itself. Transcriptome analysis revealed activation of osteogenesis-associated signaling pathways, indicating the potential transduction of Yoda1-mediated signals such as ErK, a finding validated in this study. Furthermore, we successfully integrated Exo-Yoda1 into gelatin methacryloyl (GelMA)/methacrylated sodium alginate (SAMA)/β-tricalcium phosphate (β-TCP) hydrogels. These Exo-Yoda1-loaded hydrogels demonstrated augmented osteogenesis in subcutaneous ectopic osteogenesis nude mice models and in rat skull bone defect model. In conclusion, our study introduces Exo-Yoda1-loaded GELMA/SAMA/β-TCP hydrogels as a promising approach to promoting osteogenesis. This innovative strategy holds significant promise for future widespread clinical applications in the realm of bone defect reconstruction.© 2024. The Author(s).