ISAKOS Congress 2021

2021 ISAKOS Biennial Congress Paper

 

Exercise As A Mechanical Trigger Followed By Collagenase Injections Replicating Intrinsic Factors And The Chronification Of The Pathologic Process: An Evolution Of The Animal Models Of Achilles Tendinopathy

Cesar de Cesar Netto, MD, Iowa City, Iowa UNITED STATES
Nacime Salomao Barbachan Mansur, MD, PhD, Coralville, IA UNITED STATES
Mario H. Lobao, MD, Towson, MD UNITED STATES
Christopher Cychosz, MD, Iowa City, IA UNITED STATES
Kyle R. Duchman, MD, Iowa City, IA UNITED STATES
John E Femino, MD, Iowa City, IA UNITED STATES
Kevin Dibbern, PhD, Iowa City, IA UNITED STATES
Matthieu Lalevee, MD, Iowa City, IA UNITED STATES
Ruth Chimenti, PhD, Iowa City, IA UNITED STATES

University of Iowa, Carver College of Medicine, Iowa City, IA, UNITED STATES

FDA Status Cleared

Summary

When compared to other models and to controls, the proposed Achilles tendinopathy animal model, induced by a mechanical trigger and sustained by chemical stress, demonstrated progressively increased histological tendinopathic scores.

Abstract

Introduction

A variety of Achilles tendinopathy animal models have been proposed in the literature. These models typically involve the induction of tendinopathic findings by either chemical (most commonly with one or more injections of collagenase, mimicking intrinsic factors) or mechanical stress (by repetitive exercise-induced stress with treadmill running exercises, simulating extrinsic risk factors). To date, no study has evaluated the combination of a mechanical trigger followed by collagenase injections, replicating the logical and sequential steps involved in the development the human pathology. Our goal was to develop this novel animal model of Achilles tendinopathy and to compare histological and functional findings with animals subjected to isolated mechanical or chemical stress, as well as to controls.

Methods

Sixty-four Sprague-Dawley rats were divided into four groups (n=16): isolated treadmill running protocol (15o uphill running, 20meters/minute, 1hour/day, 3 weeks duration, weeks 2-4); isolated injections of collagenase (0.1mg each, 3 injections total, weeks 5-7); treadmill protocol (weeks 2-4) followed by three consecutive collagenase injections (weeks 5-7); and controls, no running and three injections of normal saline (weeks 5-7). Five animals from each group were sacrificed at weeks 8 and 10. Six animals by group were sacrificed at week 12. Gait analysis was performed at weeks one (after acclimation), five (following running protocol), eight (following injection protocol) and twelve (just before latest sacrifice time-point). Histological findings were assessed by the Movin Tendinopathy Score (eight parameters, scored from 0-3, total score 0-24), assessing collagen arrangement, structure, and stainability, cellularity, vascularity, nuclear rounding, hyalinization and presence of glycosaminoglycans. Gait parameters included stand and swing times, stride length, duty cycle and swing length.

Results

After 8 weeks, significantly increased tendinopathic scores (p<0.001) were found in animals subjected to collagenase injections (16, CI 13.1-18.9) and to running/collagenase (17.4, CI 14.4-20.3), when compared to running alone (3, CI 0.1-5.9) and controls (1.6, CI -1.3-4.50). Similarly, after 10 weeks, significantly increased scores were found in the same groups, with slight severity regression: controls (1, CI -0.8-2.8), running (2.2, CI 0.4-4.0), collagenase (10, CI 8.2-11.8) and running/collagenase (17.6, CI 15.8-19.4). After 12 weeks, the collagenase group demonstrated reversal of the findings (3.3, CI 1.6-5.1), and was no different than control (2.1, CI 0.4-3.9) and running groups (2.5, CI 0.3-4.7). However, significantly increased pathological findings were noted in the running/collagenase group (20.0, CI 18.2-21.8) consistent with chronification of the tendinopathic process. Gait analysis results are presented in Figure1.

Conclusion

When compared to other models and to controls, the proposed Achilles tendinopathy animal model, induced by a mechanical trigger and sustained by chemical stress, demonstrated progressively increased histological tendinopathic scores after 12 weeks. Findings observed after isolated mechanical or chemical stresses were temporary and not maintained at final follow-up.
The steps involved in the development of the pathology, as well as the observed histological results of the combined running/collagenase model, better replicate the findings of human chronic Achilles tendinopathy.
Applications for this novel model are promising, potentially supporting a better understanding of early/late findings as well as treatment options for Achilles tendinopathy.

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