Organs-on-a-chip as model systems for multifactorial musculoskeletal diseases.

Multifactorial diseases affecting musculoskeletal tissues are characterized by the interactions between multiple tissues, such as muscle and nerves in neuromuscular diseases, or multiple cellular components in a tissue, as in the case of bone tumors, interacting with bone cells. For these diseases also the influence of different biophysical and biochemical stimuli, such as mechanical overload and inflammatory molecules in osteoarthritis, play a key role. To investigate these complex phenomena, organ-on-a-chip systems have been developed, taking into account specific disease characteristics such as being directly derived from patients, the presence of specifically mutated cells, or a combination of relevant biophysical and/or biochemical stimuli. Depending on the envisaged application, different issues remain to be addressed. In particular, improving automation and output sensors are key for drug screening applications, while refining model microarchitecture to enhance physiological fidelity is needed for more basic science studies.