Many musculoskeletal diseases and trauma can potentially be alleviated or cured by stem cell and tissue engineering approaches. Most musculoskeletal tissues are derived from mesenchymal stem cells (MSCs), which natively differentiate into chondrocytes, osteoblasts, adipocytes, fibroblasts, myocytes, etc. Although MSCs are assisted by other cell populations such as the hematopoietic lineages, there is no doubt that MSCs are the progenitors of the building blocks of the musculoskeletal system during development. The roles of MSCs in musculoskeletal regeneration have been demonstrated numerous times in various musculoskeletal tissues, and yet are not completely understood. Nonetheless, musculoskeletal regeneration often, but not always, requires biomaterial scaffolds that need to accommodate various cellular functions such as adherence, proliferation, and differentiation. Musculoskeletal scaffolds must also provide the structural similarity, mechanical strength, diffusion, and gas exchange needs of the tissues or organs to be regenerated. These conflicting needs of musculoskeletal scaffolds for cellular function and physical attributes of the regenerating tissue remain a challenge. Although a great deal can and should be learned from in vitro systems, follow-up in vivo studies are needed as a testing bed for cell-scaffold constructs. Additionally, there is a need to test the efficacy of musculoskeletal constructs in frequently inflammatory and diseased models. Furthermore, musculoskeletal regeneration often requires the engineering of two or more cell types, such as osteochondral, fibro-osseous, fibromyogenic, and myo-osseous tissues. This review provides a glimpse of selected approaches for the engineering of complex musculoskeletal tissue.
