Multifunctional Hydrogel with Phytochemicals and Silver Nanoparticles for Promoting Scar-Free Wound Healing

Background/objectives: Delayed wound healing, along with excessive scar formation, is the major clinical drawback due to the presence of stubborn bacteria, oxidative stress, prolonged inflammation, and irregular tissue regeneration. Utilizing nanomaterial-based wound dressings offers significant advancements and minimal cytotoxicity, but also presents issues such as poor biocompatibility, low solubility, and reduced permeability. These factors limit the effectiveness of nanomaterial-based wound dressings in promoting complete tissue regeneration. To overcome these limitations, plant-derived bioactives are integrated with nanomaterials within a hydrogel cage to enhance antibacterial activity, mitigate oxidative stress and inflammation, and promote tissue regeneration. Methods: A multifunctional alginate–gelatin hydrogel incorporating silver nanoparticles and plant extracts (AG-AgNP-PE) was developed to promote scar-free wound healing, alongside a plant extract-free silver nanoparticles-loaded hydrogel for comparative evaluation of the functional contribution of plant bioactives. The biological performance of the formulated hydrogels was systematically evaluated through antioxidant, antimicrobial, and antibiofilm assays, while in vitro cytocompatibility and proregenerative activity were assessed using MTT and Alamar Blue assays, live/dead cell imaging, and a scratch-wound assay, complemented by in vivo evaluation in zebrafish embryos. Results: Pro-angiogenic activity was further investigated using the CAM model, and therapeutic efficacy was validated in an in vivo rat burn wound model through microscopic wound assessment, histopathological examination, and biochemical assays. Conclusions: Among the hydrogels, AG-AgNP-PE exhibited superior performance across all key properties, highlighting the synergistic effect of the nanomaterial combined with plant extracts within hydrogel cages and positioning it as a promising multifunctional wound dressing for rapid tissue regeneration and scar-free wound healing, suitable for advanced wound management.