Stem cell-derived small extracellular vesicles embedded into methacrylated hyaluronic acid wound dressings accelerate wound repair in a pressure model of diabetic ulcer

Over the past years, the development of innovative smart wound dressings is revolutionizing wound care
management and research. Specifically, in the treatment of diabetic foot wounds, three-dimensional (3D)
bioprinted patches may enable personalized medicine therapies. In the present work, a methacrylated hyaluronic
acid (MeHA) bioink is employed to manufacture 3D printed patches to deliver small extracellular vesicles (sEVs)
obtained from human mesenchymal stem cells (MSC-sEVs). The production of sEVs is maximized culturing MSCs
in bioreactor. A series of in vitro analyses are carried out to demonstrate the influence of MSC-sEVs on functions
of dermal fibroblasts and endothelial cells, which are the primary functional cells in skin repair process. Results
demonstrate that both cell populations are able to internalize MSC-sEVs and that the exposure to sEVs stimulates
proliferation and migration. In vivo experiments in a well-established diabetic mouse model of pressure ulcer
confirm the regenerative properties of MSC-sEVs. The MeHA patch enhances the effectiveness of sEVs by enabling
controlled release of MSC-sEVs over 7 days, which improve wound epithelialization, angiogenesis and innervation.
The overall findings highlight that MSC-sEVs loading in 3D printed biomaterials represents a powerful technique,
which can improve the translational potential of parental stem cell in terms of regulatory and economic impact.