A bilayer hydrogel with a lower layer ROS-responsive Au-CeO₂ antioxidant release and an upper layer sustained release...

Diabetic wound healing remains a formidable clinical challenge, hindered by multifactorial obstacles including chronic inflammation, persistent oxidative stress, impaired angiogenesis and dysfunctional extracellular matrix (ECM) remodeling. Current therapeutic modalities often fail to address these multiple pathological links simultaneously, resulting in limited efficacy. To address this challenge, this study constructs a bilayer hydrogel (Au-CeO₂-bFGF): the lower layer is formed by cross-linking poly(vinyl alcohol) (PVA), tetrakis(4-sulfophenyl)boric acid (TSPBA) and oxidized dextran (PTOD) to create a reactive oxygen species (ROS) responsive network loaded with Au-CeO₂ (PTOD-Au-CeO₂) to dynamically scavenge excessive ROS and alleviate oxidative stress and inflammation; the upper layer, composed of methacrylated hyaluronic acid (HAMA) and sodium alginate (HASA), is loaded with basic fibroblast growth factor (bFGF) (HASA-bFGF) for sustained release to promote ECM remodeling and angiogenesis. PTOD-Au-CeO₂ degrades in response to ROS, releasing antioxidant Au-CeO₂ to exert anti-inflammatory and antioxidant effects, and HASA-bFGF slowly releases bFGF to facilitate cell migration and tube formation in vitro. In a diabetic mouse wound model, the Au-CeO₂-bFGF responds to the high ROS concentration at the wound site, degrading the lower layer network to release Au-CeO₂, thereby scavenging local ROS and resolving inflammation. Following the amelioration of the inflammatory microenvironment, the upper layer continuously releases bFGF, significantly enhancing collagen deposition, ECM remodeling and neovascularization, ultimately achieving wound closure. In summary, the Au-CeO₂-bFGF achieves integrated intervention in the multiple pathological stages of diabetic wounds through a synergistic, spatiotemporal strategy of "anti-inflammation and antioxidant first, pro-repair later" orchestrated by its bilayer structure, providing a novel and intelligent therapeutic strategy with significant potential for clinical translation in the management of complex wounds.