Development of Drug-Loaded Gelatin-Based Hydrogel Films for Impaired Wound Healing in Simulated Chronic Conditions

Background/Objectives: Chronic wounds are considered a silent epidemic, affecting a significant portion of the global population and often leading to severe complications. In particular, wounds resulting from burns or trauma can give rise to squamous cell carcinoma (SCC), a form of skin cancer that arises under chronic inflammatory conditions. This study aims to develop and evaluate pH-responsive gelatin-based hydrogel films incorporating 5-fluorouracil (5-FU) for targeted treatment of SCC in chronic wound environments. Methods: Hydrogel films were formulated using gelatin and loaded with 5-FU. The design leveraged the pH differences between healthy skin and chronic wounds to enable stimuli-responsive drug release. The hydrofilms were characterized by evaluating their surface properties, including transparency, contact angle, and nanoscale morphology. In vitro swelling and dissolution behaviors were analyzed under varying pH conditions. Hemocompatibility was assessed through standard blood interaction assays. Cytotoxicity and selective toxicity were tested using both non-tumoral and tumoral representative skin cell lines. Results: The hydrogel films demonstrated pH-dependent swelling and dissolution, aligning with the neutral and basic environment of chronic wounds. Surface analysis revealed suitable transparency, wettability, and nanoscale uniformity for wound application. In vitro studies showed excellent hemocompatibility. Cytotoxicity assays confirmed good selective toxicity against the A431 skin carcinoma cell line, with minimal effects on healthy cells. Conclusions: The developed gelatin-based hydrogel films exhibit promising characteristics for targeted SCC therapy in chronic wounds. Their pH responsiveness, biocompatibility, and selective antitumor activity support their potential as effective and safe delivery systems. This platform may offer a novel therapeutic approach for managing malignancies arising in non-healing wound environments.