Multifunctional pH-responsive HA-c-FZ1 hydrogel presents a promising therapeutic strategy for diabetic skin wounds

Abstract

Background: Diabetic foot ulcers remain a major clinical challenge, driven by the convergent effects of microbial infection, chronic inflammation, oxidative stress, and inadequate neovascularization that collectively disrupt tissue repair. Although the integrin α v β3 agonist peptide FZ1 exhibits promising pro-healing activity, limited delivery control and insufficient functional versatility have restricted its clinical translation. To overcome these constraints, a pH-responsive hyaluronic acid (HA)-based hydrogel, hyaluronic acid conjugated with FZ1 peptide (HA-c-FZ1), was developed to enable intelligent acidity-triggered peptide release while integrating antimicrobial activity, reactive oxygen species (ROS) scavenging, and inflammation control within a single wound dressing platform for diabetic wound repair. Methods: Photo-crosslinkable oxidized methacrylated HA was synthesized and covalently linked to FZ1 through a pH-labile Schiff base bond, yielding HA-c-FZ1 hydrogel at three concentrations (2%, 3%, and 4%). HA-c-FZ1 hydrogel morphology, swelling behavior, mechanical properties, peptide-loading efficiency, pH-responsive release, antioxidant activity, antibacterial activity, biocompatibility, and anti-inflammatory effects were systematically evaluated in vitro. Therapeutic efficacy was then assessed in a diabetic mouse model with infected full-thickness skin wounds through wound closure analysis, histological staining, immunofluorescence detection of macrophage polarization markers (inducible nitric oxide synthase and arginase) and angiogenic markers (alpha-smooth muscle actin and vascular endothelial growth factor), and laser speckle imaging of blood perfusion. Transcriptomic profiling, RT-qPCR, and western blotting were performed to define the molecular mechanisms underlying HA-c-FZ1-mediated wound repair. Results: HA-c-FZ1 hydrogel formed a homogeneous porous hydrogel network with predictable swelling behavior, tunable mechanical performance, high FZ1 loading efficiency, and accelerated peptide release under acidic conditions. In vitro, HA-c-FZ1 hydrogel promoted keratinocyte proliferation and migration, reduced ROS accumulation, and inhibited Staphylococcus aureus and Escherichia coli survival. In infected diabetic wounds, HA-c-FZ1 hydrogel suppressed bacterial burden and accelerated wound closure, accompanied by enhanced re-epithelialization, collagen deposition, angiogenesis, and local blood perfusion. Mechanistic analyses indicated that HA-c-FZ1 hydrogel attenuated nuclear factor kappa B-associated inflammatory signaling, promoted M2 macrophage polarization, and activated focal adhesion kinase–protein kinase B-dependent angiogenic responses. Conclusions: HA-c-FZ1 functions as a pH-responsive hydrogel dressing that combines peptide delivery with antimicrobial, redox-regulatory, immunomodulatory, and pro-angiogenic functions. These findings position it as a therapy for chronic diabetic wound repair by simultaneously addressing infection, inflammation, oxidative stress, and vascular regeneration.

Keywords

Diabetic foot ulcers / Bioactive peptide FZ1 / Hyaluronic acid hydrogel / Photo-crosslinking / Anti-inflammation / Oxidative stress

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