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MgFe-Layered Double Hydroxide-Reinforced Injectable GelMA Hydrogels Promote Calvarial Bone Regeneration with
Jiajie Zheng1, Kang Wang2, Hao Xu1
1Department of Neurosurgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People's Republic of China.
Background:
Critical-sized calvarial defects remain challenging because conventional grafting strategies often fail to conform to irregular defect geometries and insufficiently regulate the immune-osteogenic microenvironment. This study developed an injectable MgFe-layered double hydroxide (LDH)-reinforced gelatin methacryloyl (GelMA) hydrogel and compared it with MgAl-LDH to evaluate the influence of LDH cation composition on calvarial bone regeneration.
Methods:
MgFe-LDH and MgAl-LDH nanoplatelets were synthesized and incorporated into photocrosslinkable GelMA hydrogels. Nanoparticle characterization, cellular uptake, cytocompatibility, macrophage responses, and bone marrow stromal cell osteogenic differentiation were evaluated in vitro. Regenerative efficacy was further assessed in a murine critical-sized calvarial defect model for 12 weeks using micro-computed tomography, histology, immunofluorescence staining, qRT-PCR, and transcriptomic analysis.
Results:
Both LDH formulations showed comparable nanoplatelet morphology, positive surface charge, efficient cellular internalization, and favorable cytocompatibility. Compared with LPS-stimulated macrophages, MgFe-LDH reduced TNF-α and IL-1β expression by 55.7% and 57.8%, respectively, while increasing IL-10 and TGF-β expression by 4.2-fold and 3.9-fold. MgFe-LDH also enhanced BMSC osteogenic differentiation, increasing ALP activity, mineralized matrix deposition, RUNX2 expression, and OCN expression by 2.3-fold, 1.7-fold, 2.4-fold, and 1.8-fold, respectively. In vivo, GelMA-MgFe-LDH produced the strongest defect bridging and mineralized tissue formation, increasing BV/TV and BMD by 1.5-fold and 1.6-fold compared with GelMA alone. Transcriptomic and qRT-PCR analyses suggested that IL-10RA-JAK1-STAT3-associated signaling may participate in MgFe-LDH-mediated osteoimmune remodeling and bone repair.
Conclusion:
MgFe-LDH-reinforced injectable GelMA hydrogels promote calvarial bone regeneration and are associated with pro-resolving immune responses and osteogenic remodeling. These findings support cation-engineered LDH hydrogels as promising injectable biomaterials, although pathway inhibition, protein-level validation, ion-release profiling, and long-term biosafety studies are needed to clarify the proposed mechanism.
