Manufacture of extracellular vesicles derived from mesenchymal stromal cells

Extracellular vesicles derived from mesenchymal stromal cells (MSC-EVs) are an off-the-shelf product for treating a broad range of diseases and are a valuable alternative to cell therapy. MSC-EVs have higher stability, better delivery efficiency, lower immunogenicity, and prolonged shelf-life compared to MSCs.Since MSC-EVs are considered biopharmaceuticals, manufacturing is based on the principle that ‘the process is the product’. Depending on the cultivation and isolation methods, the therapeutic mode of action of MSC-EVs can be changed.Large-scale manufacturing of MSC-EVs is the major challenge in the field. Most applied technologies for upscaling cell cultivation and subsequent EV isolation and purification from conditioned cell media are hollow-fiber bioreactors and tangential flow filtration. Mesenchymal stromal cells (MSCs) are a promising therapy for various diseases ranging from ischemic stroke to wound healing and cancer. Their therapeutic effects are mainly mediated by secretome-derived paracrine factors, with extracellular vesicles (EVs) proven to play a key role. This has led to promising research on the potential of MSC-EVs as regenerative, off-the-shelf therapeutic agents. However, the translation of MSC-EVs into the clinic is hampered by the poor scalability of their production. Recently, new advanced methods have been developed to upscale MSC cultivation and EV production yields, ranging from new cell culture devices to priming procedures. This review gives an overview of these innovative strategies for manufacturing MSC-EVs.