Using load to improve tendon/ligament tissue engineering and develop novel treatments for tendinopathy

• Tendon, ligament, fascia, and cartilage are connective tissues that develop in response to diverse mechanical demands and pathology may result from alterations in the load placed any of these tissues. • Loads can be generally categorized into tension, compression, and shear. Each of these regulate distinct molecular pathways that are involved in matrix remodeling. • The response to load is stage-specific, meaning that the activation of mechanically sensitive pathways changes during development and maturation. • The perspectives provided here draw from studies spanning in vitro , animal, and human experiments of healthy and diseased tendon to propose a more targeted approach to advance rehabilitation, orthobiologics, and tissue engineering. Tendon and ligament injuries are highly prevalent but heal poorly, even with proper care. Restoration of native tissue function is complicated by the fact that these tissues vary anatomically in terms of their mechanical properties, composition, and structure. These differences develop as adaptations to diverse mechanical demands; however, pathology may alter the loads placed on the tissue. Musculoskeletal loads can be generally categorized into tension, compression, and shear. Each of these regulate distinct molecular pathways that are involved in tissue remodeling, including many of the canonical tenogenic genes. In this review, we provide a perspective on the stage-specific regulation of mechanically sensitive pathways during development and maturation of tendon and ligament tissue, including scleraxis, mohawk, and others. Furthermore, we discuss structural features of healing and diseased tendon that may contribute to aberrant loading profiles, and how the associated disturbance in molecular signaling may contribute to incomplete healing or the formation of degenerative phenotypes. The perspectives provided here draw from studies spanning in vitro , animal, and human experiments of healthy and diseased tendon to propose a more targeted approach to advance rehabilitation, orthobiologics, and tissue engineering.