In situ application of xyloglucan hydrogels and extracellular vesicles from amniotic stem cells for diabetic foot ulcer healing.

Diabetic foot ulcers (DFUs) are chronic wounds involving multiple tissue layers and are a frequent complication of diabetes. These ulcers represent a significant health concern with substantial social implications, as they are challenging to treat due to the neuroischemic changes associated with diabetes. DFUs are characterized by chronic inflammation, which impairs angiogenesis and hinders the wound healing process. A promising therapeutic approach involves the use of human multipotent stem cells and their derivatives, such as extracellular vesicles (EVs), which promote tissue repair through their immunomodulatory properties, reducing inflammation and enhancing vascularization. To optimize their therapeutic potential, biocompatible scaffolds, such as functionalized hydrogels, can support stem cells and their EVs, enabling them to fully exert their regenerative effects and promote cell proliferation. Thus, selecting an appropriate hydrogel is critical to improve tissue regeneration outcomes. In this study, we proposed an in vitro DFU model to evaluate the effectiveness of a partially deglycosylated xyloglucan (dXG) hydrogel enriched with EVs derived from human amniotic mesenchymal stem cells (hAMCs) as a wound dressing. We developed dXG hydrogels (4% wt/v) by incorporating a dispersion of EVs isolated from hAMCs using tangential flow filtration. The biocompatibility of the dXG hydrogel was confirmed by seeding EA.hy926 cells, a human endothelial cell line. Additionally, we assessed its antioxidant potential under pro-inflammatory cytokine conditions to simulate the microenvironment of a chronic ulcer. Our findings demonstrated that the EVs-enriched dXG hydrogel protected cells from cytokine-induced damage and highlighted its biocompatibility. The hydrogel enhanced cell proliferation through stem cell-derived EVs and showed its potential for in situ application as a treatment for DFUs.