Engineering of biomaterials for advanced skin tissue regeneration requires optimization of critical parameters including interconnected porous structure, biomaterial stability, hydrophilicity, biocompatibility, and bioactivity. These features enable the mimicry of the skin tissue microenvironment and support the key phases of the regeneration process, which are crucial for effective tissue repair. Another important requirement for successful skin tissue regeneration is the modulation of oxidative stress, as excessive accumulation of reactive oxygen species (ROS) at the site of the skin lesion can hinder healing and cause chronic inflammation and scarring. To address these challenges, we propose a reductionist therapeutic approach to skin tissue regeneration by developing bio-sourced scaffolds that replicate the native extracellular matrix (ECM), neutralize ROS levels, and actively promote tissue regeneration at both structural and molecular levels. These nano ZnO-embedded gelatin/alginate bioscaffolds were prepared via a simple crosslinking reaction and loaded with carefully selected active agents with antioxidant and skin tissue regenerative potential. Characterization studies of the bioscaffolds confirmed their porous interconnected morphology with tunable porosity (92%-94%), mechanical strength (1.95-3.22 MPa), hydrophilicity, stable adhesion to skin tissue, and ROS-scavenging activity. Additionally, the bioscaffolds demonstrated simultaneous release of quercetin, allantoin, and caffeic acid, and both biocompatibility-in vitro on human fibroblasts (MRC5) and in vivo on Caenorhabditis elegans. Overall, these findings provide valuable insight into the design of multifunctional bioscaffolds as a promising therapeutic platform for skin tissue regeneration application, which simultaneously modulates oxidative stress, replicates ECM architecture, and stimulates the healing cascade, ultimately enhancing skin tissue repair and reducing scarring.
