Novel preclinical murine model of trauma-induced elbow stiffness

Abstract

BackgroundPeri-articular injury may result in functional deficits and pain. In particular, post-traumatic elbow stiffness is a debilitating condition, precluding patients from performing activities of daily living. As such, clinicians and basic scientists alike, aim to develop novel therapeutic interventions to prevent and treat elbow stiffness; thereby reducing patient morbidity. Yet, there is a paucity of pre-clinical models of peri-articular stiffness, especially of the upper extremity, necessary to develop and test the efficacy of therapeutics. We set out to develop a pre-clinical murine model of elbow stiffness, resulting from soft tissue injury, with features characteristic of pathology observed in these patients.MethodsA soft tissue peri-elbow injury was inflicted in mice using cardiotoxin. Pathologic tissue repair was induced by creating an investigator-imposed deficiency of plasminogen, a protease essential for musculoskeletal tissue repair. Functional testing was conducted through analysis of grip strength and gait. Radiography, microcomputed tomography, and histological analyses were employed to quantify development of heterotopic ossification.ResultsAnimals with peri-elbow soft tissues injury in conjunction with an investigator-imposed plasminogen deficiency, developed a significant loss of elbow function measured by grip strength (2.387 ± 0.136 N vs 1.921 ± 0.157 N, ****, p < 0.0001) and gait analysis (35.05 ± 2.775 mm vs 29.87 ± 2.075 mm, ***, p < 0.0002). Additionally, plasminogen deficient animals developed capsule thickening, delayed skeletal muscle repair, fibrosis, chronic inflammation, and heterotopic ossification; all features characteristic of pathology observed in patients with trauma-induced elbow stiffness.ConclusionA soft tissue injury to the peri-elbow soft tissue with a concomitant deficiency in plasminogen, instigates elbow stiffness and pathologic features similar to those observed in humans. This pre-clinical model is valuable for translational studies designed to investigate the contributions of pathologic features to elbow stiffness or as a high-throughput model for testing therapeutic strategies designed to prevent and treat trauma-induced elbow stiffness.Electronic supplementary materialThe online version of this article (10.1186/s40634-018-0155-3) contains supplementary material, which is available to authorized users.

Functional Measures of Grip Strength and Gait Remain Altered Long-Term in a Rat Model of Post-Traumatic Elbow Contracture

“…Interestingly, injured limb grip strength and injured-contralateral differences never appeared to plateau, suggesting these parameters might return to control levels at a later time point. A recently developed mouse model of elbow contracture evaluated grip strength at 28-days postinjury [22] and observed significant differences between injured and control animals, similar to our results. To the best of our knowledge, this is the only other small animal model of elbow joint contracture.…”

“…Thus, spatial symmetry and injured limb step distance are likely better indicators of reduced ROM. Only one previous study has evaluated gait in an animal model of elbow contracture [22]. Using a murine model of PTJC, significantly decreased mean step distances were observed at 28-days postinjury, similar to this study.…”

“…2). Unlike typical devices for measuring grip strength in rodents [13,22,29], our device consists of two sets of custom-made grip bars/ladders, each of which is secured via linear slides and connected to separate load cells (Loadstar Sensors, Fremont, CA). During the first week after bandage removal, animals were familiarized to the grip strength device by performing six practice trials.…”

“…Similar to grip strength, gait analysis has been used previously to quantify functional changes in rodent models of a variety of injury conditions including knee instability and osteoarthritis [15][16][17], patellar tendon degeneration [18], Achilles tendon injury [19], rotator cuff damage [20], and spinal cord injury [21]. Additionally, a recent study evaluated gait changes due to elbow contracture in a murine model [22]; however, in this study animals were only evaluated at a single time point for a single gait parameter. In this study, spatiotemporal gait compensations were investigated longitudinally in our rat PTJC model using an open source, fully automated technique validated to detect rodent gait abnormalities with high sensitivity [23,24].…”

Animal Models of Peripheral Pain: Biology Review and Application for Drug Discovery

“…Since this model closely recapitulates characteristic pathology observed in patients clinically, the results suggest utility of the model for assessment of novel therapeutics aimed at preventing traumainduced elbow stiffness, with the goal of achievement of greater success rates. 92 No single model would serve the purpose of addressing all the questions posed in a human musculoskeletal pain condition. Nonetheless, these models have the potential to allow investigators to define the mechanisms that generate and maintain pain and to serve as a platform to test the efficacy and side effects profile of novel treatments.…”