Mechanobiology and therapeutic applications of mesenchymal stem cells in distraction osteogenesis

Distraction osteogenesis (DO) is a powerful reconstructive technique for bone lengthening and reconstruction, but its utility is limited by prolonged consolidation and complications. Mesenchymal stem cells (MSCs) show promise as adjunctive therapies, yet their functions are highly dependent on the dynamic mechanical and biological microenvironment. This review summarizes the phase-specific roles of MSCs during DO, focusing on mechanotransduction pathways (e.g., integrin-FAK, Wnt/β-catenin, Hippo-YAP/TAZ, Piezo1), paracrine mechanisms, and immunomodulation. We evaluate current therapeutic strategies, including local transplantation, endogenous recruitment, cell-free therapies, and molecular modulation. We also discuss key knowledge gaps and technical challenges hindering clinical translation, such as MSC heterogeneity and optimal delivery parameters. We propose that emerging tools like single-cell sequencing and artificial intelligence will be crucial for developing personalized, targeted interventions to accelerate bone regeneration. Ultimately, a deeper understanding of MSC mechanobiology is essential to translate their therapeutic potential into improved clinical outcomes in distraction osteogenesis.