Naringin-based hydrogel decorated 3D printed scaffold modulates immunity and angiogenesis for diabetic bone regeneration

Abstract

Hyperglycemia and inflammation within the diabetic microenvironment impair the healing of bone defects in diabetic patients. A key limitation of current therapeutic approaches is their lack of efficacy in restoring immune homeostasis. Herein, a novel 3D-printed PHSN composite scaffold is designed to regulate the immune microenvironment. PHSN is fabricated by integrating poly (lactic-co-glycolic acid) (PLGA) with hydroxyapatite (HA) via 3D printing technology, yielding a structure that combines osteogenic potential with mechanical strength. Loaded with naringin and SupGels, PHSN promotes macrophage repolarization toward the M2 phenotype via the JAK/STAT signaling pathway, thereby upregulating anti-inflammatory mediators and tissue-regeneration factors, stimulating angiogenesis and osteogenesis. In diabetic models, PHSN inhibits M1 macrophage polarization, drives reprogramming toward the M2 phenotype, and upregulates the expression of CD31, ALP, and OCN at bone defect sites, indicating enhanced angiogenesis and osteogenesis. Collectively, this study establishes a strategy of synergistically modulating immunity, vascularization, and bone formation, offering a promising and translatable solution for diabetic bone regeneration.