Osteoimmunity‐Regulating Biomimetically Hierarchical Scaffold for Augmented Bone Regeneration

TLDR

Proper immune response engineering is essential for bone tissue regeneration after biomaterial implantation. The study fabricated a biomimetically hierarchical scaffold to augment bone repair by balancing immune response and bone metabolism. The scaffold combines a 3D‑printed stiff gradient core with an infused soft hydrogel, uses MnCO‑mediated Fenton‑like reactions to release CO and Mn²⁺ that shift macrophages to an M2 phenotype and secrete VEGF, activates HIF‑1α via Mn²⁺ and DFO@PCL nanoparticles to promote angiogenesis, and DFO inhibits osteoclast differentiation while HA supplies osteoinductive activity. In vitro and in vivo studies show the scaffold strongly modulates immunity, promotes angiogenesis, suppresses osteoclastogenesis, and enhances osteogenesis, markedly improving bone regeneration and offering a promising platform for large‑scale bone defect repair.

Abstract

Engineering a proper immune response following biomaterial implantation is essential to bone tissue regeneration. Herein, a biomimetically hierarchical scaffold composed of deferoxamine@poly(ε-caprolactone) nanoparticles (DFO@PCL NPs), manganese carbonyl (MnCO) nanosheets, gelatin methacryloyl hydrogel, and a polylactide/hydroxyapatite (HA) matrix is fabricated to augment bone repair by facilitating the balance of the immune system and bone metabolism. First, a 3D printed stiff scaffold with a well-organized gradient structure mimics the cortical and cancellous bone tissues; meanwhile, an inside infusion of a soft hydrogel further endows the scaffold with characteristics of the extracellular matrix. A Fenton-like reaction between MnCO and endogenous hydrogen peroxide generated at the implant-tissue site triggers continuous release of carbon monoxide and Mn2+ , thus significantly lessening inflammatory response by upregulating the M2 phenotype of macrophages, which also secretes vascular endothelial growth factor to induce vascular formation. Through activating the hypoxia-inducible factor-1α pathway, Mn2+ and DFO@PCL NP further promote angiogenesis. Moreover, DFO inhibits osteoclast differentiation and synergistically collaborates with the osteoinductive activity of HA. Based on amounts of data in vitro and in vivo, strong immunomodulatory, intensive angiogenic, weak osteoclastogenic, and superior osteogenic abilities of such an osteoimmunity-regulating scaffold present a profound effect on improving bone regeneration, which puts forward a worthy base and positive enlightenment for large-scale bone defect repair.