3D-printed manganese dioxide incorporated scaffold promotes osteogenic-angiogenic coupling for refractory bone defect by remodeling osteo-regenerative microenvironment

The treatment of refractory bone defects is a major clinical challenge, especially in steroid-associated osteonecrosis (SAON), which is characterized by insufficient osteogenesis and angiogenesis. Herin, a microenvironment responsiveness scaffold composed of poly-L-lactide (PLLA), and manganese dioxide (MnO 2 ) nanoparticles is designed to enhance bone regeneration by scavenging endogenous reactive oxygen species (ROS) and modulating immune microenvironment in situ. A catalase-like catalytic reaction between MnO 2 and endogenous hydrogen peroxide (H 2 O 2 ) generated at the bone defect area, which typically becomes acidic and ROS-rich, triggers on-demand release of oxygen and Mn 2+ , significantly ameliorating inflammatory response by promoting M2-type polarization of macrophages, reprograming osteoimmune microenvironment conducive to angiogenesis and osteogenesis. Furthermore, the fundamental mechanisms were explored through transcriptome sequencing analysis, revealing that PLLA/MnO 2 scaffolds (PMns) promote osteogenic differentiation by upregulating the TGF-β/Smad signaling pathway in human bone marrow mesenchymal stem cells (hBMSCs). Overall, the PMns exhibit superior immunomodulatory, excellent osteogenic-angiogenic properties and promising candidates as bone graft substitutes for therapy clinical refractory bone defects. • A multifunctional composite scaffold fabricated by an innovative low-temperature rapid prototyping 3D-printing technology. • The study emphasizes the designing of bone grafting substitute based on orchestrating refractory bone healing microenvironment. • The composite scaffold promotes hBMSCs osteogenic differentiation via upregulation TGF-β/Smad signaling pathway. • The composite scaffold promotes bone regeneration and neovascularization of SAON via multi-step coordination.