Clinical-Scale Mesenchymal Stem Cell-Derived Extracellular Vesicle Therapy for Wound Healing.

We developed an extracellular vesicle (EV) bioprocessing platform for the scalable production of human Wharton's jelly mesenchymal stem cell (MSC)-derived EVs. The effects of clinical-scale MSC-EV products on wound healing were tested in two different wound models: subcutaneous injection of EVs in a conventional full-thickness rat model and topical application of EVs using a sterile re-absorbable gelatin sponge in the chamber mouse model that was developed to prevent the contraction of wound areas. In vivo efficacy tests showed that treatment with MSC-EVs improved the recovery following wound injury, regardless of the type of wound model or mode of treatment. In vitro mechanistic studies using multiple cell lines involved in wound healing showed that EV therapy contributed to all stages of wound healing, such as anti-inflammation and proliferation/migration of keratinocytes, fibroblasts, and endothelial cells, to enhance wound re-epithelialization, extracellular matrix remodeling, and angiogenesis.