Injectable Mn-Icariin-functionalized silk fibroin/PEG hydrogels restore redox homeostasis and reprogram
Yukai Huang1, Shihao Zhang2, Xiaogang Zhou3
1Department of Orthopaedics, Jinshan Hospital, Fudan University, Shanghai 201508, China.
Abstract:
Bone defect repair under hyperglycemic conditions is limited by sustained oxidative stress, chronic low-grade inflammation and disrupted osteoimmune-vascular coupling. In this study, we constructed an injectable and biodegradable silk fibroin/PEG hydrogel incorporating MnO2 honeycomb nanospheres and liposome-encapsulated icariin (FG/Mn@Ica) to rebuild a bioactive and mechanocompatible microenvironment for diabetic bone regeneration. The hydrogel presented an interconnected porous morphology, elastic-dominant rheology, adaptive compressive behavior and controlled degradation with the sustained release of Mn ions and Ica. Functionally, FG/Mn@Ica reprograms the high-glucose microenvironment at multiple levels. In vitro, it enhances the proliferation of bone marrow mesenchymal stem cells and osteogenic commitment while simultaneously attenuating reactive oxygen species accumulation, stabilizing the mitochondrial membrane potential and activating the AMPK-SIRT1-NRF2-mediated antioxidant axis. Moreover, FG/Mn@Ica promoted the migration of human umbilical vein endothelial cells (HUVECs) and angiogenic tube formation, induced the polarization of pro-regenerative M2 macrophages with elevated Arg1, and suppressed senescence-associated and inflammation-associated markers. In vivo, in a rat femoral defect model, FG/Mn@Ica significantly promoted new bone regeneration. Overall, FG/Mn@Ica integrates mechanical support, restoration of redox homeostasis, osteoimmune modulation and osteogenic reinforcement, offering a rational biomaterial strategy for bone regeneration under diabetic stress.
