A 3D-printed scaffold featuring oxygen generation and osteoimmunity regulation for challenging bone regeneration

The repair of large-segment bone defects (LSBD) remains a major clinical challenge owing to the hypoxic microenvironment coupled with immune microenvironment dysregulation. Thus, the development of dual-targeting strategies that simultaneously modulate both pathological microenvironments holds great promise for addressing this clinical challenge. In this study, highly catalytically active nanozymes were constructed, which effectively anchored manganese dioxide (MnO 2 ) onto the surface of hydroxyapatite. Subsequently, a low-temperature 3D printing technique was employed to fabricate PLGA/HA@MnO 2 (PHM) composite scaffolds. In vitro experiments demonstrated that the PHM scaffolds potently scavenged endogenous reactive oxygen species (ROS), facilitated localized oxygen release, and ameliorated the osteogenic microenvironment. Concurrently, the PHM scaffolds promote a pro-regenerative osteoimmune microenvironment. Proteomic and functional analyses preliminarily revealed that the PHM scaffolds modulated extracellular matrix composition and integrin receptor expression, thereby activating the integrin αvβ3-mediated focal adhesion signaling pathway, which may promote macrophage TGF-β secretion to facilitate BMSC osteogenesis. In vivo experiments further corroborated the favorable immunomodulatory capacity and pronounced bone repair efficacy. These findings demonstrate that the functional repair of LSBD can be achieved through synergistic regulation of hypoxic and immune microenvironments. This work implicates a potential mechanism through which manganese-based materials modulate the osteoimmune microenvironment and offers a promising strategic framework for the treatment of LSBD.