4D-printed Fe3O4-PLLA scaffolds modulate osteoimmune microenvironment for oral bone repair

Craniomaxillofacial bone repair remains a major clinical challenge. Conventional static scaffolds, which retain a fixed geometry after implantation, lack adaptability to complex and irregular defects. In contrast, 4D-printed shape-memory polymer (SMP) scaffolds enable minimally invasive delivery and stimuli-responsive shape adaptation in vivo. When combined with traditional Chinese medicinal monomers, these scaffolds circumvent the immunogenicity of conventional growth factors, reduce treatment costs, and facilitate slow release when loaded into a hydrogel. In this study, naringin-loaded methacrylated chitosan (CSMA) was integrated with 4D-printed Fe₃O₄-PLLA scaffolds to construct hybrid systems featuring long-term drug release and magnetically controlled shape transformation. The resulting scaffolds exhibited excellent magnetic responsiveness, biocompatibility, mechanical robustness, and rapid shape recovery. They exhibited over 98 % shape recovery with rapid recovery time (<40s), indicating potential for minimally invasive implantation and new bone formation. Enhanced polarization of M2 macrophages and osteogenic differentiation of bone marrow mesenchymal stem cells (rBMSCs) were confirmed in vitro. Transcriptome analysis revealed downregulation of the NLRP3 inflammasome, supporting M2 macrophage polarization and bone regeneration in vivo. This study illustrates that 4D-printed NG-CSMA/Fe₃O₄-PLLA scaffolds promote bone regeneration through the polarization of macrophages towards the M2 phenotype, presenting potential strategies for the development of functional scaffolds in bone defect repair.