Temporally Controlled Therapeutic Strategies for Critical-Sized Bone Defects: Integrating Materials Engineering and...

Critical-sized bone defects exceed the endogenous self-healing capacity of bone tissue and remain one of the most intractable clinical challenges in orthopedic reconstruction. Conventional therapeutic regimens, including autologous/allogeneic bone grafts and the Masquelet technique, are severely restricted by donor shortage, immune rejection, high infection risk, and insufficient functional regeneration efficacy. As an emerging paradigm, temporally controlled therapy precisely mimics the staged physiological demands of natural bone healing by programming the release timing, sequence, and dosage of therapeutic factors, thereby achieving dynamic regulation of bone regenerative microenvironments and bringing new breakthroughs for defect repair. This review systematically summarizes the biological basis, core material systems, key technological platforms, and molecular mechanisms of temporally controlled bone regeneration. We comprehensively discuss state-of-the-art delivery strategies based on smart biomaterials, including microenvironment-responsive hydrogels, multilayered gradient scaffolds, micro/nanoparticle carriers, and genetically engineered cell therapies. The spatiotemporal synergistic effects of core growth factors (BMPs, VEGF, PDGF) and innovative dynamic regulation technologies, such as 4D bioprinting and closed-loop feedback systems, are further highlighted. Distinct from conventional sustained-release systems that provide static drug supplementation, temporally controlled strategies enable stage-matched modulation of biological cascades covering inflammation, vascularization, osteogenesis, and bone remodeling. Notably, emerging rare-earth nanoparticle-integrated platforms offer unique advantages in responsive drug delivery, imaging-guided precise regulation, and adaptive tissue regeneration. Finally, we critically elaborate the current progress, translational bottlenecks, biosafety concerns, and future prospects of temporal therapeutic systems, aiming to provide comprehensive theoretical support and innovative perspectives for the design of advanced clinical repair strategies for critical-sized bone defects.