From Vineyard to Hydrogel: Antioxidant, Anti-Inflammatory, and Regenerative Potential of Grape Skin Extract in Diabetic Wound Repair

<b>Background/Objectives:</b> This research aims to offer significant insights into the prospective application of bioactive hydrogels composed of alginate, gelatin, and grape skin extract from Serbia (GSE) for treating diabetic wounds, supporting the circular economy and environmental protection. <b>Methods:</b> An acute dermal irritation study was conducted according to OECD guidelines, revealing no visible signs of erythema or edema, confirming the hydrogel's dermal safety. Afterwards, male Wistar rats were divided into four groups: untreated control (NC), silver sulfadiazine-treated (PC), hydrogel without extract (HG), and hydrogel with GSE (HG + GSE). Wound healing was assessed through a comprehensive approach that included macroscopic wound contraction; biochemical assessment of hydroxyproline content and oxidative stress markers (TBARS, SOD, CAT, GSH); quantification of inflammatory cytokines (TNF-α, IL-6); and histological examination of skin samples using hematoxylin-eosin (H&E) and Masson's trichrome staining. <b>Results:</b> Daily HG+GSE application over 15 days accelerated wound closure, reaching 99.3% by day 15, surpassing PC (91.2%) and HG (87.7 ± 2.1%). Hydroxyproline levels followed a treatment-dependent pattern, with HG+GSE achieving the highest values throughout, reaching 6.78 ± 0.1 µg/mg dry tissue by day 15-more than double NC. The HG+GSE reduced lipid peroxidation while enhancing enzymatic and non-enzymatic antioxidant defenses and markedly lowered pro-inflammatory cytokine levels, indicating systemic anti-inflammatory activity. Histological analysis revealed faster re-epithelialization, increased collagen deposition, and more organized tissue architecture in the HG+GSE group. These outcomes are attributed to the sustained release of bioactive polyphenols such as naringin, caffeic acid, and epicatechin. <b>Conclusions:</b> Overall, this GSE-based hydrogel presents a multifunctional, biocompatible, sustainable, and effective strategy for diabetic wound care.