Glycosaminoglycan-mediated fibril sliding and its role in fatigue-induced microdamage and rupture in aged and healing Achilles tendons

Project Summary/Abstract
Injuries to soft tissues represent 45% of all musculoskeletal injuries per year. Fatigue loading causes damage
at the microscale to collagen fibrils, which makes the tendon more susceptible to rupture. Changes to the
native tendon composition are often associated with injury risk. In the aging tendon, interfibrillar structures
between fibrils (e.g., glycosaminoglycans (GAGs)) have been shown to decrease, in association with
alterations to interfibrillar mechanics and rupture rates. While GAGs may not play a direct role in elastic
mechanics, they have been postulated to promote fibril sliding by retaining water and increasing fibril spacing
and lubrication, meaning that they provide an important load-bearing mechanism in tissues with aligned fibrils.
This sliding mechanism may protect against repetitive, viscoelastic processes that cause tendon damage,
namely fatigue, by reducing overall load to individual collagen fibrils. Yet, the connection between GAGs and
fatigue-induced rupture remains unelucidated. The goal of this proposal is to define the multiscale interplay
between GAGs, interfibrillar load transmission, and fatigue rupture in intact and healing mature and aged
tendons. Our overall hypothesis is that GAGs modulate fibril spacing which enables sliding between aligned
fibrils and protects against fatigue-induced microdamage and eventual rupture in intact and late-stage healing
tendons. The proposed aims would innovate preclinical evaluations of multiscale tendon mechanics and
augment the scientific understanding of micromechanical changes that precede injury in aging and healing
tendons. The Aims are: Specific Aim 1: In mature and aged Achilles tendons, define the role of GAGs in
preventing damage accumulation and eventual rupture during fatigue loading. Specific Aim 2: In the healing
Achilles tendon, define the role of GAGs in preventing damage accumulation and eventual rupture during
fatigue loading. In both aims, we will couple state-of-the-art biomechanical testing of a high-throughput rodent
model with rigorous micromechanical and histological measures of interfibrillar sliding and structures. We will
use findings from these techniques to inform and refine computational shear-lag models of tendons to further
explore the role of GAGs in fatigue loading. These exciting and innovative studies will elucidate the role of
GAGs in interfibrillar sliding, microdamage, and eventual rupture in Achilles tendons undergoing fatigue
loading. Further, these studies will increase our understanding of mechanisms that lead to injury in aging and
healing tendons, which is essential to our understanding of how tendon injuries occur, to improve interventions
preceding injury, and enhance future therapeutic strategies following tendon injury.

Grant Number: 5F32AR082671-02
NIH Institute/Center: NIH
Principal Investigator: Jonathon Blank