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Methods: Following confirmation of the extract\u2019s antioxidant activity, hydrogels were synthesized by varying gelatin content and CaCl2 concentration to achieve desirable crosslinking density, mechanical properties, and extract release behavior. Physicochemical characterization of hydrogels included equilibrium swelling analysis, mechanical testing, FTIR analysis, and in vitro release of extract from hydrogel. Moreover, the biocompatibility of hydrogels enriched with extract was assessed via MTT assay, while antimicrobial activity was tested against Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 10145, and Candida albicans ATCC 10231. The antioxidant capacity of the hydrogels was evaluated using DPPH, ABTS, and FRAP assays. Results: Our results showed that higher gelatin and CaCl2 concentrations produced denser crosslinked networks, leading to reduced swelling and increased stiffness. Additionally, the extract exhibited a biphasic release profile from hydrogels, featuring an initial rapid release followed by sustained release over 24 h. Conclusions: The hydrogels maintained high biocompatibility and demonstrated selective antimicrobial activity, particularly against Escherichia coli, and satisfactory antioxidant activity. Obtained multifunctional sustainable hydrogels enriched with grape skin extract represent promising agents for managing skin conditions associated with oxidative stress and bacterial infections.<\/jats:p>","DOI":"10.3390\/pharmaceutics17060790","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T10:45:26Z","timestamp":1750157126000},"page":"790","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Development and Optimization of Grape Skin Extract-Loaded Gelatin\u2013Alginate Hydrogels: Assessment of Antioxidant and Antimicrobial Properties"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5388-6085","authenticated-orcid":false,"given":"Jovana","family":"Bradic","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica, 69, 34000 Kragujevac, Serbia"},{"name":"Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, Zmaj Jovina 30, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3048-4264","authenticated-orcid":false,"given":"Anica","family":"Petrovic","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica, 69, 34000 Kragujevac, Serbia"},{"name":"Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, Zmaj Jovina 30, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9906-436X","authenticated-orcid":false,"given":"Aleksandar","family":"Kocovic","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica, 69, 34000 Kragujevac, Serbia"},{"name":"Center of Excellence for Redox Balance Research in Cardiovascular and Metabolic Disorders, Zmaj Jovina 30, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vukasin","family":"Ugrinovic","sequence":"additional","affiliation":[{"name":"Innovation Center of the Faculty of Technology and Metallurgy Ltd., Karnegijeva 4, 11120 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8690-8495","authenticated-orcid":false,"given":"Suzana","family":"Popovic","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica, 69, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5698-5510","authenticated-orcid":false,"given":"Andrija","family":"Ciric","sequence":"additional","affiliation":[{"name":"Faculty of Science, University of Kragujevac, Radoja Domanovica 12, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5964-049X","authenticated-orcid":false,"given":"Zoran","family":"Markovic","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences and Mathematics, State University of Novi Pazar, Vuka Karadzica bb, 36300 Novi Pazar, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2473-9603","authenticated-orcid":false,"given":"Edina","family":"Avdovic","sequence":"additional","affiliation":[{"name":"Institute for Information Technologies, University of Kragujevac, Jovana Cvijica bb, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"138098","DOI":"10.1016\/j.ijbiomac.2024.138098","article-title":"Hydrogels and Hydrogel-Based Drug Delivery Systems for Promoting Refractory Wound Healing: Applications and Prospects","volume":"285","author":"Lin","year":"2025","journal-title":"Int. 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