Bone Extracellular Matrix-Inspired Biomaterials for Enhanced Bone Repair

Treatment of critical-sized large bone defects arising from severe trauma, tumor resection, infectious osteomyelitis and congenital skeletal malformations has long been a prominent and intractable clinical challenge in orthopedic surgery. Conventional autologous and allogeneic bone grafts suffer from unavoidable limitations including donor site complications, insufficient bone volume and immune rejection, driving urgent demands for advanced artificial bone repair materials. Functionalized bone substitute biomaterials capable of stimulating mesenchymal stem cell osteogenic differentiation and remarkably improving local bone regeneration efficiency represent a promising therapeutic candidate to overcome existing clinical bottlenecks. The native extracellular matrix (ECM) constructs a dynamic, hierarchically structured and biochemically complex microenvironment to sustain diverse cellular physiological behaviors. It delivers synergistic biochemical signaling and biomechanical stimuli to directly or indirectly modulate cell proliferation, adhesion, migration and lineage differentiation, thus exerting an irreplaceable regulatory function in sustaining bone metabolic homeostasis and orchestrating the whole cascade of bone regeneration. As researchers gain deeper understanding of the unique biological functions and underlying molecular signaling mechanisms of ECM constituents in bone defect reconstruction, ECM-mimicking biomaterials have garnered tremendous research interest in regenerative medicine. By precisely recapitulating native bone's chemical composition, porous microstructure and mechanical characteristics via delicate biomimetic engineering, such biomaterials successfully reproduce the physiological cascade of bone repair and achieve satisfying regenerative outcomes across abundant in vitro and preclinical in vivo investigations. This review systematically elaborates the multifaceted biological roles and core molecular mechanisms of ECM during bone reconstruction, thoroughly summarizes state-of-the-art fabrication and functional modification strategies of ECM-inspired biomaterials, as well as their repair performance against critical-sized bone defects. It intends to offer integrated theoretical foundations and innovative design guidelines for the exploitation of high-performance bone graft substitutes for clinical bone defect treatment.