Functionalized mesenchymal stem cells for enhanced bone regeneration: advances and challenges

Bone fracture continues to pose a significant clinical challenge in regenerative medicine due to limited repair capacity and inadequate therapeutic options. Among the various therapeutic strategies, mesenchymal stem cells have shown strong potential due to their ability to promote bone formation, modulate inflammation, and migrate to injury sites. However, clinical outcomes have been limited by issues like low survival rates, poor integration, and non-specific distribution after transplantation. Functionalized mesenchymal cells enhanced through genetic, chemical, or material-based modifications have emerged as an advanced strategy to overcome these limitations and significantly improve bone regeneration. This review explores recent developments in the functionalization of stem cells to increase their bone-forming potential. It covers techniques of gene modification, preconditioning, nanoparticle integration, and scaffold-based delivery. The role of these engineered cells is in activating key pathways involved in bone repair, including bone morphogenetic proteins and Wnt signaling. Furthermore, the study highlights current delivery platforms, including injectable gels, printed scaffolds, and bioactive coatings that support targeted, sustained cell activity. Despite encouraging preclinical outcomes, unresolved challenges in manufacturing, immune compatibility, and regulatory pathways persist, prompting the exploration of emerging solutions like precision-engineered implants and artificial intelligence-driven design to guide the future of advanced bone regeneration therapies.