Musculoskeletal connective tissues form the mechanical connections in the skeleton that enable human-powered mobility. These tissues have impressive properties, often serving their function for millions of loading cycles over decades of years, due in part to their intricate structural hierarchy. However, subfailure injuries and connective tissue diseases disrupt this organization and compromise tissue function. Clinical treatment of subfailure injuries is difficult because the mechanisms and locations of damage within the tissue structure remain unclear, and effective therapeutic targets have not been identified. The objective of this dissertation was to investigate molecular-level damage to collagen during mechanical loading of tendons as a potential mechanism underlying subfailure connective tissue injuries.

Experiments using monotonic tension loading and a novel technique to detect and label denatured collagen, using triple-helical peptide hybridization, demonstrated collagen molecular damage at subfailure levels of loading. Computational simulations revealed that mechanical unfolding of the collagen triple helix likely occurs by shear load transfer via intermolecular crosslinks. Subfailure connective tissue injuries often result from overuse, rather than individual acute loading events, and are thought to be caused by accumulating “microdamage” in the tissue. Therefore, mechanical damage to the collagen molecule was investigated in creep-fatigue loaded tendons. Denatured collagen accumulated with increasing fatigue loading cycles and correlated with permanent tissue elongation. Tendons exhibit well-known viscoelastic behavior across the range of physiological loading rates, including strain-rate strengthening. Fatigue experiments that accounted for this rate-dependent strength, by cycling samples to the same stress relative to their tensile strength at the applied strain rate, revealed that the accumulation of denatured collagen and the amount of damage at failure were rate dependent. Tendons cycled at faster strain rates were able to endure greater amounts of creep strain and collagen denaturation before failing. The results in this dissertation present compelling evidence that molecular-level damage to collagen via mechanical unfolding of the collagen triple helix is a fundamental mechanism of damage in tendons and the mechanism of structural microdamage accumulation due to repeated loading. These findings present a new understanding of mechanical damage in connective tissues that can inform progress toward improved prevention and treatment of connective tissue injuries.