Herbal Extract-loaded Biomaterials for Bone Regeneration: Mechanisms of Action, Delivery Platform Optimization, and...

Bone regeneration remains a major clinical challenge due to the limited bioactivity, high cost, and adverse effects associated with current grafts and synthetic therapeutics. Herbal phytometabolites, including flavonoids, alkaloids, and terpenoids, have emerged as promising multitarget agents capable of modulating key pathways involved in skeletal repair. These natural compounds exert osteoinductive effects by activating Runx2/Osterix and stimulating BMP2/Smad and Wnt/β- catenin signaling; reducing bone resorption through RANKL/OPG regulation and NFATc1/NF-κB suppression; enhancing angiogenesis via VEGF upregulation and HIF-1α stabilization; and supporting osteoconduction by promoting collagen synthesis and alkaline phosphatase-mediated mineralization. This review systematically evaluates the structural diversity, biological mechanisms, and therapeutic potential of phytochemicals in bone healing, along with advancements in their delivery through polymeric nanoparticles/microspheres, bioactive glass and calcium phosphate scaffolds, thermosensitive hydrogels, functionalized implants, and emerging stimuli-responsive and 3D/4Dprinted biomaterials. By integrating traditional botanical knowledge with modern biomaterial engineering, we provide a comprehensive translational framework for developing phytochemical-based bone therapeutics as cost-effective, biocompatible alternatives to recombinant growth factors in the expanding global bone graft market.