Fig. 1. Study overview.

(A) Rat tail tendon fascicles were loaded in creep-fatigue to 40% of the ultimate tensile strength (UTS) until tissue failure. Incremental levels of fatigue were defined as the peak cyclic (creep) strain at 20, 50, and 80% of cycles to failure. (B) To label and quantify denatured collagen, we stained mechanically loaded fascicles with fluorescent CHP, which hybridizes to unfolded collagen α chains. The amount of denatured collagen was quantified on microplate via the fluorescence of bound F-CHP. Computational simulations were used to investigate the potential mechanisms of fascicle- and molecular-level fatigue behavior. (C) Biphasic finite-element simulations were used to study the potential role of fluid flow on strain rate–dependent fatigue behavior at the fascicle level. (D) MD simulations of collagen model peptides were used to identify molecular mechanisms of fatigue damage accumulation and strain rate dependence. GPO, glycine-proline-hydroxyproline.