Musculoskeletal tissue repair still represents a challenge in orthopedics. Stem cell-based regenerative therapies have been widely explored using a variety of approaches, from targeted delivery of stem cells and their derivatives to advanced manufacturing of tissue grafts. Although several studies support the potential of stem cells in musculoskeletal tissue repair, few approaches have been successfully translated into clinics, attributable in part to a lack of well-defined standards of care in preclinical and clinical studies. This translational delay also depends on the intrinsic variability and complexity of the regulatory and legal frameworks worldwide.

Stem cell therapy-based strategies vary significantly depending on the musculoskeletal tissue damage to be restored. Among them, tissue engineering approaches localize stem cells at the site of injury, thus diminishing the risk of free transplanted cells infiltrating other tissues. On the other hand, the use of therapeutic strategies based on alternative delivery routes for stem cells or their derivatives (i.e., secretome, microvesicles, and exosomes) involve limited manipulation and lower processing costs compared to tissue engineering. Both tissue engineering and stem cell therapy can take advantage of recent nanotechnology-based strategies to achieve a targeted and controlled delivery of cells and bioactive molecules.

In this landscape, it is implicit to verify the safety and efficacy of stem cell-based approaches. Relevant preclinical studies should be developed, both in vitro and in vivo, and a multidisciplinary approach is required to better elucidate the mechanisms of stem cell differentiation, function, and tissue healing. Even more importantly, a good design of clinical trials should be implemented for the final validation of stem cell-based therapies in orthopedics.

This special issue aims at collecting original basic and preclinical research articles, clinical studies, and review articles that address the recent advancements regarding the use of stem cell-based approaches to treat musculoskeletal tissue disorders.

Potential topics include but are not limited to the following:

• Preclinical studies testing the efficacy of stem cell-based therapies in orthopedic animal models and their relevance in respect to the human pathology
• Clinical applications of stem cell-based therapies for musculoskeletal tissue repair
• New biologically relevant biomaterials and strategies for using nanotechnologies as carrier systems for stem cells and bioactive molecules derived from them with the potential to promote musculoskeletal tissue regeneration
• Use of pluripotent stem cells as opposed to the use of adult progenitor cells (e.g., ASC, BMSCs, and synovial MSCs), in orthopedic applications
• In vitro and in vivo strategies to improve differentiation capacity of stem cells into musculoskeletal tissue(s)
• In vitro and in vivo models to investigate the immunomodulatory function of stem cells in the context of musculoskeletal disorders