# Novel Mechanism for Repair of Tendon Fatigue Damage Injuries

> **NIH NIH R56** · CORNELL UNIVERSITY · 2020 · $475,855

## Abstract

Tendinopathies are common musculoskeletal injuries that lead to tendon rupture and disuse. Degenerative
changes in ruptured tendons suggest that subrupture fatigue damage accumulation from wear and tear is an
integral component in the pathogenesis of tendinopathy. Consequently, we have previously developed an in vivo
model of sub-rupture fatigue damage accumulation using the rat patellar tendon to investigate the onset and
pathogenesis of tendinopathy. We have shown that even just one bout of fatigue loading leads to development
of collagen damage kinks and a 20% decrease in stiffness of the tendon that is not recovered out to at least 8-
weeks. A major hurdle to progress in management of developing chronic tendinopathies is that the mechanism
of tendon repair is unknown, largely because it does not naturally occur. Our previous work investigating the
utility of exercise as a therapeutic showed that exercise leads to repair when initiated 2-weeks after onset of sub-
rupture fatigue injury but promotes further degeneration when initiated 1-day after sub-rupture fatigue injury.
Generation of these two contrasting models (effective therapeutic exercise and detrimental therapeutic exercise
of fatigue damaged tendons) will be invaluable to unraveling the mechanisms that drive the response of fatigue
damaged tendons to conservative treatment. Interestingly, the main difference in the degenerative versus
reparative outcome from therapeutic exercise is the time of initiation even though the fatigue damaged tendons
at both timepoints exhibit similar macroscopic mechanical properties. It is therefore critical to determine the
biomechanical conditions wherein conservative treatment, such as exercise, will promote repair and not further
degeneration. In addition, an increase in population of myofibroblasts and integrin α5 was uniquely associated
with repair of fatigue damaged tendons from effective therapeutic exercise leading to generation of a novel
mechanistic hypothesis for repair of sub-rupture fatigue damaged tendons. We hypothesize that repair of fatigue
damage follows 3-phases. In phase 1, regions of matrix damage are repopulated with tenocytes that have re-
established cell-ECM interactions. In phase 2, myofibroblasts are activated in regions of matrix damage, likely
driven by integrin α5 and the fibronectin splice variant, FN-EDA. In phase 3, myofibroblasts tension the damage
kinks and increase cross-linking. The proposed studies will interrogate our mechanistic hypothesis by evaluating
the cell-ECM interactions that evolve over the 2-weeks after onset of injury (Aim 1) and interrogating the role of
myofibroblasts in repair of fatigue damage injury (Aim 2). Lastly, the role of integrin α5 (dependent or independent
of myofibroblasts) in repair of sub-rupture fatigue injuries will be interrogated (Aim 3). The proposed studies will
(A) identify biological and mechanical factors that should be considered prior to initiation of conservative
treatment su...

## Key facts

- **NIH application ID:** 10255875
- **Project number:** 1R56AR077239-01
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** NELLY Andarawis-Puri
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $475,855
- **Award type:** 1
- **Project period:** 2020-09-21 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10255875

## Citation

> US National Institutes of Health, RePORTER application 10255875, Novel Mechanism for Repair of Tendon Fatigue Damage Injuries (1R56AR077239-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10255875. Licensed CC0.

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