Bone Tissue Engineering: Scaffold Design Principles, Biomaterial Advances, and Strategies for Functional Regeneration and Clinical Translation.

Bone is a hierarchically organized composite material with unique mechanical properties and an intrinsic regenerative capacity that conventional repair strategies, including autografts, allografts, xenografts, and metallic or ceramic implants, fail to fully replicate due to donor scarcity, immunogenicity, mechanical mismatch, and poor long-term integration. Bone tissue engineering (TE) offers a biologically informed alternative by integrating osteoconductive scaffolds, osteogenic progenitor cells, and osteoinductive signaling molecules into a unified regenerative framework. Unlike existing reviews that evaluate these components in isolation, this review provides a mechanistically integrated analysis that repositions scaffold design as a biologically instructive platform whose topography, stiffness, porosity, and surface chemistry collectively govern cell adhesion, mechanotransduction, osteogenic differentiation, and extracellular matrix remodeling. Critically, it moves beyond cataloging materials and fabrication approaches to evaluate how specific scaffold features drive biological outcomes and to identify frequently understated limitations, including polymer-ceramic degradation kinetics and the inadequacy of small-animal models for clinical translation. By synthesizing advances in biomaterials, additive manufacturing, and smart scaffold technologies within this integrative framework, this review provides researchers and clinicians with a structured framework for evaluating emerging strategies and prioritizing future directions in functional bone regeneration.