The Tendon Extracellular Matrix: From Hierarchical Architecture to Systemic Regulation and Therapeutic Translation

The tendon extracellular matrix (ECM) is a complex and dynamic structure essential for transmitting force and ensuring musculoskeletal integrity. It is primarily composed of a hierarchy of collagen fibrils, whose assembly and stability are regulated by enzymatic and non-enzymatic cross-linking. Various non-collagenous proteins further modulate its organization and functional properties. The mechanical behavior of tendons is directly dictated by this specialized ECM, which in turn dynamically adapts to physiological loads. A continuous bidirectional dialogue exists between tenocytes and the surrounding matrix, crucial for tissue homeostasis. Furthermore, ECM remodeling is influenced by systemic and temporal factors, including circadian rhythms, hormones, aging, exercise, and genetics. Metabolic diseases, notably diabetes and hyperlipidemia disrupt ECM equilibrium by fueling chronic inflammation and pathological remodeling. Given its central role, the tendon ECM has emerged as a key target for innovative strategies in regenerative medicine, such as biologic therapies and the design of biomimetic scaffolds. This review synthesizes current knowledge on the composition, mechanobiology, regulation, and translational applications of the tendon ECM, providing an integrated perspective for advancing therapeutic approaches in tendinopathy and tendon repair.