Development of a next-generation wound-healing scaffold integrating decellularized dermis with tailored mesenchymal stromal cell secretomes

Chronic wounds are difficult to treat due to impaired cell proliferation, persistent inflammation, and delayed tissue remodeling. To address these challenges, biologically active scaffolds were developed by combining human decellularized dermis, obtained from cadaveric donors, with a standardized, freeze-dried secretome derived from mesenchymal stromal cells (MSC). Dermis scaffolds were prepared using five decellularization protocols, resulting in acellular matrices (DNA content <50 ng/mg) that preserved the extracellular matrix (ECM) architecture. These matrices were subsequently loaded with secretomes isolated from MSCs that were serum-starved alone or in combination with IL-1β or hypoxia. In vitro wound-healing assays demonstrated that secretomes from serum-starved and IL-1β-primed cells accelerated fibroblast and human umbilical vein endothelial cells closure (e.g., IL-1β-primed secretomes significantly reduced fibroblast wound area as early as 16 h, versus 45.1% residual wound area in untreated controls at 48 h), whereas secretomes derived from hypoxic conditions had a minimal effect. These differences correlated with the proteomic composition of MSC-secretomes (1051 proteins identified overall, 26% shared across all three conditions): IL-1β enhanced matrix remodeling and wound repair proteins, serum starvation enriched ECM components, and hypoxia favored cytoprotective proteins. Together, these results demonstrate that combining tailored MSC-secretomes with decellularized dermis provides a ready-to-use, off-the-shelf system capable of overcoming multiple barriers in chronic wound healing, offering a promising strategy for regenerative therapy.