Smart nanocomposite scaffolds for bone regeneration: Mechanobiological regulation and translational perspectives.
Critical-sized and load-bearing bone defects remain major clinical challenges. The intrinsic regenerative capacity of bone is frequently insufficient to achieve complete functional repair. Recent advances in smart nanocomposite scaffolds have shifted bone tissue engineering from passive structural support toward biologically instructive platforms capable of dynamically regulating cellular behavior and tissue repair. These advances represent a major conceptual and mechanobiological transformation in scaffold design; however, they should not be interpreted as indicating widespread clinical readiness. Despite encouraging preclinical outcomes, most smart scaffold systems remain in the preclinical or early translational stage because critical challenges related to mechanical reliability, scalable manufacturing, long-term biosafety, and regulatory approval remain unresolved. This review examines the mechanobiological mechanisms by which smart nanocomposite scaffolds regulate bone regeneration, with particular emphasis on interactions between scaffolds and stem cells, immune modulation, angiogenic coupling, and translational feasibility. Key regenerative pathways involving osteoconduction, mechanotransduction, ion-mediated signaling, electrical conductivity, and stimuli-responsive activation are analyzed in relation to scaffold composition, nanotopography, and microenvironmental regulation. Comparative translational analysis is provided for bone marrow-derived mesenchymal stem cells, adipose-derived stem cells, induced pluripotent stem cell-derived progenitors, and emerging exosome-based acellular regenerative strategies. In addition, major translational barriers, including manufacturing scalability, mechanical limitations in load-bearing environments, regulatory complexity, long-term biosafety, and reproducibility of cell-based therapies, are critically analyzed. Overall, this review provides a mechanobiological and translational framework for development of clinically applicable smart biomaterials for next-generation bone regenerative engineering. This review presents an evidence-stratified translational framework linking mechanistic pathways to supporting study types and corresponding translational barriers.