This review elucidates the complex interplay among oxidative stress (OS), macrophage polarization, and stem cell-driven osteogenesis, emphasizing the regulatory influence of reactive oxygen species (ROS) on bone repair and regeneration. It demonstrates that an imbalance in ROS can impede bone healing by disrupting the equilibrium between pro-inflammatory (M1) and pro-repair (M2) macrophage phenotypes. Furthermore, the review delineates the mechanisms through which ROS can influence mesenchymal stem cell differentiation and osteoclast activity, while also highlighting the body’s antioxidant defenses that counteract OS. Innovative strategies are explored, particularly the use of biomaterials and nanomedicine, which aim to modulate ROS levels and macrophage polarization, thereby fostering a conducive microenvironment for bone regeneration. The integration of nanotechnology, biomaterials, and cellular biology emerges as a promising frontier for advancing bone regeneration therapies, with the necessity for clinical validation underscored throughout.
Impact Statement
This review establishes redox modulation as a paradigm-shifting strategy for bone regeneration. We elucidate how engineered biocomposites precisely recalibrate reactive oxygen species (ROS) to resolve osteo-inflammation, directing macrophage polarization from pro-inflammatory (M1) to pro-regenerative (M2) phenotypes. This immune reprogramming synergistically enhances mesenchymal stem cell osteogenesis and suppresses osteoclastogenesis. By integrating cutting-edge biomaterial design—including enzyme-mimetic nanozymes and organelle-targeted antioxidants—we highlight clinically viable solutions for diabetic bone defects, osteoporosis, and rheumatoid arthritis. Our framework bridges immunology, nanotechnology, and tissue engineering, offering transformative therapeutic avenues for inflammatory osteopathies.
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