Alveolar Bone Regeneration: Smart Biomaterials and Physical Stimulation.

Large-area bone loss from disease, trauma, or congenital defects requires surgical procedures and bone grafting. Alveolar bone loss from severe periodontal disease and non-unions often demands immediate grafting. Treating large alveolar bone defects using grafts and substitutes is challenging due to the complex oral environment, infection risks, and unstable graft properties, which may compromise strength and bioactivity. Successful grafts must promote vasculature development and osteogenesis while maintaining mechanical stability at the graft site. Current bone graft substitutes are inadequate for optimal alveolar bone healing. New biomaterial technologies including additive manufacturing techniques enhance repair processes by developing anatomically equivalent implants that integrates better with host tissues, provide mechanical stability and activate innate healing mechanisms. Smart stimuli-responsive materials (SSMs), combined with exogenous physical stimulation, further advance this by triggering cell regulatory pathways, promoting bone mineralization, blood vessel development, and mechanical integrity. Electrical, magnetic, mechanical, ultrasound, and shockwave stimulations activate Ras, p38 kinase, PI3K/Akt, JNK, NF-κB, MAPK/ERK, Wnt, BMP, and VEGF pathways, enhancing osteogenic genes like Runx2, YAP, osteopontin, and osteocalcin to promote osteoinduction and osteogenesis. This article provides an in-depth literature analysis of smart biomaterials and stimuli-mediated alveolar bone repair and regeneration mechanisms. It also highlights the unmet needs of innovative biomaterials such as SSMs and explores strategies to manage the bone microenvironment, aiming to enhance clinical translation for large-area bone defects regeneration.