A bioactive microflower doped triple-network hydrogel for immunomodulation-mediated angio/osteogenesis coordination in mandibular bone regeneration

Abstract

Maxillofacial bone defects pose significant clinical challenges due to unresolved inflammation, mechanical instability, and insufficient vascular integration. To address these limitations, we designed a multifunctional Ca/SrP microflower-doped triple-network hydrogel (MFs@PPB) engineered with polyethylene glycol diacrylate (PEGDA), poly(vinyl alcohol) (PVA), and borax to create a hydrogel with superior mechanical strength, self-healing properties, and adhesive interfaces. The triple-network structure enables dynamic self-healing under mechanical stress, while its bioactive ionic release, particularly strontium (Sr²⁺), modulates macrophage polarization, suppressing pro-inflammatory M1 macrophages and promoting pro-regenerative M2 polarization. This coordinated immunomodulation fosters angiogenesis and osteogenesis. The hydrogel's unique composition allows precise conformance to irregular mandibular defects, ensuring stable scaffold integration. In vivo, MFs@PPB effectively initiates immunomodulation to suppress chronic inflammation, followed by functional vascular network formation and biomimetic bone deposition, outperforming conventional strategies in structural and functional restoration. This study introduces a biomaterial strategy that bridges immune reprogramming with bioactive material properties, offering a transformative solution for mandibular reconstruction by overcoming the inflammation-regeneration paradox. The harmonized integration of immune modulation, angiogenic activation, and osteoinductive signaling within a single platform has broad implications for regenerative medicine.