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Tissue regeneration is a hot topic in health sciences, particularly because effective therapies promoting the healing of several cell types are lacking, specifically those of the musculoskeletal system. Mesenchymal Stem/Stromal Cells (MSCs) have been identified as crucial players in bone homeostasis, and are considered a promising therapy for diseases such as osteoarthritis (OA) and Rheumatoid Arthritis (RA). However, some known drawbacks limit their use, particularly ethical issues and immunological rejections. Thus, MSCs byproducts, namely Extracellular Vesicles (EVs), are emerging as potential solutions to overcome some of the issues of the original cells. EVs can be modulated by either cellular preconditioning or vesicle engineering, and thus represent a plastic tool to be implemented in regenerative medicine. Further, the use of biomaterials is important to improve EV delivery and indirectly to modulate their content and secretion. This review aims to connect the dots among MSCs, EVs, and biomaterials, in the context of musculoskeletal diseases. ; This research was funded by European Union's Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement No 860462-Project PREMUROSA to H.A. and L.R.; by the Italian Ministry of Education, University and Research (MIUR) program "Departments of Excellence 2018–2022", FOHN to A.C. and AGING Projects to A.C.; Fondazione Cariplo 2019-3277 to A.C., European Union's Horizon 2020 Research and Innovation Program under Grant Agreement No.953121—project FLAMIN-GO to L.R. and A.C.; by FISM—Fondazione Italiana Sclerosi Multipla—cod. 2020/PR-Single/021 and financed or co-financed with the '5 per mille' public funding" to G.C.; by European Union's Horizon 2020 research and innovation programme under grant agreement No 952033—project "Twinning to excel materials engineering for medical devices" —ExcellMater to L.R. and A.C.

From April 2020 to December 2020, 52 hospitalized patients with confirmed SARS-CoV-2 infection were enrolled at Maggiore della Carità University Hospital in Novara, Italy. Patients were hospitalized for acute respiratory or influenza-like symptoms during the two waves of SARS-CoV-2 infection and stratified by the results of molecular analysis on nasal swabs. OPN levels were measured by ELISA and OPN levels were found to be increased in SARS-CoV-2 patients compared to non-comorbid and non-hospitalized healthy controls. ; This study was funded by the Italian Ministry of Education, University and Research (MIUR) program "Departments of Excellence 2018–2022", FOHN to AC and AGING Projects to AC and RV, Fondazione Cariplo 2019-3277 to AC, European Union's Horizon 2020 Research and Innovation Program under Grant Agreement No. 953121—project FLAMIN-GO to AC, and European Union's Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement No 860462-Project PREMUROSA to HA.