Amine-Functionalized Gellan Gum-Based Hydrogel Loaded with Adipose Stem Cell-Derived Small Extracellular Vesicles: An In Vitro Proof of Concept for Enhancing Diabetic Foot Ulcer Healing.

Diabetic foot ulcers (DFUs) are chronic wounds and a common complication of diabetes. A promising strategy in the treatment of DFUs involves the use of stem cell derivatives, such as small extracellular vesicles (sEVs), which can enhance cell proliferation and reduce inflammation while avoiding immunogenic responses. In this study, we evaluated the ability of adipose mesenchymal stem cell- (ASC)-derived sEVs to enhance the proliferation of human fibroblasts, which play a crucial role in wound regenerative processes. To mimic the inflammatory environment of DFUs, fibroblasts were cultured into the gellan gum (GG) modified with ethylenediamine (EDA) hydrogel scaffolds loaded with ASC-derived sEVs, under pro-inflammatory cytokines. Our comparative analysis demonstrated that sEVs loaded in GG-EDA hydrogel improved fibroblast viability in pro-inflamed conditions while retaining the anti-inflammatory and immunomodulatory properties of their cells of origin. By modulating the gene expression profile of fibroblasts to promote cell proliferation, wound healing and re-epithelialization, our system presents a promising therapeutic strategy for DFU healing.