Accumulation of collagen molecular unfolding is the mechanism of cyclic fatigue damage and failure in collagenous tissues

Abstract

Overuse injuries to dense collagenous tissues are common, but their etiology is poorly understood. The predominant hypothesis that micro-damage accumulation exceeds the rate of biological repair is missing a mechanistic explanation. Here, we used collagen hybridizing peptides to measure collagen molecular damage during tendon cyclic fatigue loading and computational simulations to identify potential explanations for our findings. Our results revealed that triple-helical collagen denaturation accumulates with increasing cycles of fatigue loading, and damage is correlated with creep strain independent of the cyclic strain rate. Finite-element simulations demonstrated that biphasic fluid flow is a possible fascicle-level mechanism to explain the rate dependence of the number of cycles and time to failure. Molecular dynamics simulations demonstrated that triple-helical unfolding is rate dependent, revealing rate-dependent mechanisms at multiple length scales in the tissue. The accumulation of collagen molecular denaturation during cyclic loading provides a long-sought “micro-damage” mechanism for the development of overuse injuries.

Toughening mechanisms for the attachment of architectured materials: The mechanics of the tendon enthesis

“…To identify potential nanoscale mechanisms that could explain this behavior, we quantified molecular damage under the various loading regimes using fluorescein-labeled collagen hybridizing peptide (F-CHP) (30,31). Whole-sample imaging of F-CHP fluorescence intensity, indicative of collagen damage, increased with applied load or number of cycles (Fig.…”

Molecular origin of viscoelasticity in mineralized collagen fibrils

“…Crack propagation and catastrophic failure of bone and tendons are the most predominant topics that have been widely investigated, but the origins of microdamages are still under debate 21,22 . The most accredited hypotheses relate to the heterogeneity of the microstructural composition that is affected by several factors (e.g., gender) 23 , and to atomic-scale structural changes due to shearing by accumulating the damages from cyclic loadings on tendon 24 .…”

“…, gender), 23 and atomic-scale structural changes due to shearing by accumulating the damage from cyclic loadings on tendon. 24 …”

Sustained mechanical tension governs fibrogenic activation of tendon stromal cells in systemic sclerosis

“…(19)(20)(21) In tendon, repetitive overloading disturbs the underlying homeostatic tension that is critical for maintaining matrix structure and function. (22) Injury responses are intimately linked to celland tissue-level mechanical homeostasis, with the extracellular matrix providing biophysical signals for appropriate remodeling and resolution responses. (22)(23)(24) For instance, it is now evident that matrix stiffening precedes the onset of clinical fibrosis.…”

“…(22) Injury responses are intimately linked to celland tissue-level mechanical homeostasis, with the extracellular matrix providing biophysical signals for appropriate remodeling and resolution responses. (22)(23)(24) For instance, it is now evident that matrix stiffening precedes the onset of clinical fibrosis. (21,25,26) Whereas matrix mechanical cues are instrumental in the successful transition from activated wound healing programs to successful resolution, persistent aberrant matrix stiffening is implicated in instilling fibroblast activation and pathological tissue remodeling.…”