19 Gelatin-functionalised hyaluronic acid-based hydrogels with antimicrobial peptides for chronic wound treatment

Abstract Aim Chronic wounds including diabetic foot ulcers (DFU) develop due to impaired healing mechanisms associated with chronic hyperglycaemia, leading to dysregulated inflammatory and angiogenic processes. This condition makes DFUs prone to chronicity and bacterial infection. This study aimed to develop a multifunctional hyaluronic acid (HyA)-based hydrogel to enhance cellular adhesion and provide localised antimicrobial activity to accelerate the healing of DFUs. Methods HyA was chemically modified with acrylate groups (AcHyA) and crosslinked with polyethylene glycol (PEG) dithiol to form stable hydrogels1. Thiolated gelatin was conjugated to the AcHyA (AcHyA-G) to enhance cell adhesion and bioactivity, while the cysteine-terminated peptide PP4-3.1 was incorporated (AcHyA-G-PP4-3.1) for its antimicrobial properties2. The biophysical properties (storage modulus, swelling behaviour, degradation kinetics, and molecular diffusion) of the HyA hydrogels as a function of gelatin concentration were assessed, as well as the response of human dermal fibroblasts (hDFs) and iPSC-derived endothelial cells (iECs). The antimicrobial efficacy of AMP-conjugated AcHyA was assessed against Staphylococcus aureus. Results The biophysical characterisation of AcHyA-G hydrogels revealed rapid gelation, elastic properties, a uniform mesh size, and consistent molecular diffusion across all formulations. Additionally, the presence of gelatin improved stability without altering the hydrogel’s degradation profile. AcHyA-G hydrogels effectively supported the adhesion and spreading of key wound repair cells (HDFs and iECs), with 0.5% gelatin identified as the optimal concentration. Furthermore, incorporating the AMP conferred bactericidal activity against S. aureus, the most prevalent bacteria found in DFU. Conclusion The AcHyA hydrogels functionalised with gelatin and AMPs demonstrate promising potential as multifunctional wound dressings for DFUs. These hydrogels provide structural support, enhanced bioactivity, and localised antimicrobial effect. Future research will focus on evaluating gelatin and AMP-functionalised AcHyA hydrogels in pre-clinical wound models to evaluate their effectiveness and long-term potential in promoting the healing of chronic wounds.