been suggested to avoid systemic distribution and toxicity as well as to promote longer survival of the cells 48. Currently, mostly autologous MSCs and adipose-derived stem cells (ASCs) are applied for knee OA therapy, but very few approaches are targeting hip OA. Almost all of the trials are phase Ia/b safety and dose-finding studies with a low number of participants. About 45 of the listed studies are completed, but only six of them report results. A total of 55 of the trials that are recruiting or not yet recruiting indicate strongly increasing interest in stem cell therapy not only for traumatic cartilage injury but also for late-stage OA.Extracellular vesicles derived from stem cells Our literature search shows that stem cells, specifically autologous stem cells derived from bone marrow (BMSCs) and adipose tissue (ASCs), are preferred over other cell types for regenerative strategies. However, there is doubt among surgeons and researchers about whether or not stem cells are really the optimal tool for regenerative therapy. After administration, stem cells tend to disappear quickly from the target tissue; however, their chondroprotective and immunomodulatory effects are long lasting. Presumably, the therapeutic effects are mainly mediated in a paracrine manner, as they appear to be independent of the engrafted cells 49. When exposed to inflammatory signals, MSCs develop and show a rich secretory profile. After stimulation of these cells with tumor necrosis factor (TNF)-α, a proteomic approach identified 118 proteins, which were differentially expressed by human ASCs 50. However, paracrine effects are not limited to soluble factors, as stem cells and other cell types produce extracellular vesicles (EVs), which are small phospholipid-bilayer-enclosed particles carrying many cytoplasmic components 51, 52. EVs play a role in a number of different cellular activities, such as communication between cells via horizontal transfer of mRNA and proteins, and they are distinguished according to size. EVs are attractive options for therapeutic use because of their unique physical and biological characteristics, which include high biocompatibility and intrinsic targeting activity 53. Exosomes, the most-studied group of EV, can be as small as 30–150 nm in diameter, so it may be possible for them to passively diffuse through tissues 54. Overall, the consensus is that stem cell secretomes and EVs applied for the treatment of cartilage pathology and knee OA had pleiotropic and overall positive effects 55. In vitro, anti-catabolic, immunomodulatory, and regenerative properties were assigned to the secretome and EVs. Pre-clinical in vivo studies resulted in positive effects on the joint and confirmed the effectiveness of EV injections as a minimally invasive therapy 56. injections partially improved the gait abnormality patterns in an OA mouse model 57, and MSC secretome injections provided early (day seven) pain reduction in treated mice 58. All together, these data support the translational potential of this regenerative approach. The promising in vitro and in vivo results support the potential of this new treatment strategy, opening up new perspectives for cell component-based therapies. EVs are proposed as next-generation biomarkers to predict the pathophysiological state of the joint 55, assigning an important role for EVs in future therapies for the treatment of joint disorders. Remarkably, they constitute a simpler, and most of all safer, alternative to actual cell-based therapeutic strategies, as they are cell derived but not living cells and thus cannot proliferate or form tumors. As known for cells, EVs can also be combined with scaffolds, either bound on their surface or embedded within the biomaterial matrices. Specific activation signals such as ultrasound may enable the controlled release of specific subpopulations of EVs, i.e. exosomes. Besides nutrient supply and metabolism, physiological and non-physiological shock absorption and support of overlying cartilage are the main functions of subchondral bone 59, 60. Therefore, any changes affecting bone cell