Dataset Information

Enthesis trauma as a means for the development of translatable chronic rotator cuff degeneration in an ovine model.

ABSTRACT:

Background

Untreated rotator cuff tears lead to irreversible tendon degeneration, resulting in unacceptable repair prognosis. The inability of current animal models of degenerated rotator cuff tendons to more fully emulate the manifestation and degree of pathology seen in humans with a previously torn rotator cuff tendon (s) significantly impairs the development of novel therapeutics. Therefore, the objective of this study was to develop a large-animal translational model of enthesis damage to the rotator cuff tendons to mimic the chronic degenerative changes that occur in patients that demonstrate clinical manifestations of tendinopathy.

Methods

A partial enthesis tear model (i.e., sharp transection) in adult sheep was created by cutting the tendon fibers perpendicularly through the enthesis midpoint, while leaving the other portion of the tendon in-tact. To assess tendon integrity, non-destructive biomechanical tests were performed, followed by histopathological, histomorphological, and gene expression analysis. Samples of degenerated human rotator cuff tendons obtained from patients undergoing reverse total shoulder arthroplasty to use for comparative pathological analysis.

Results

In the sheep model, transected tendons at all timepoints had significantly decreased mechanical properties. Histopathologic evaluation and Bonar scoring revealed that the tendons in sheep underwent degenerative changes similar in magnitude and manifestation as the degenerated human tendon samples. Furthermore, similar levels of collagen disorganization were noted between the 6 and 12-week ovine samples and the degenerated human samples.

Conclusions

These findings indicate that the new sheep model of rotator cuff injury reliably recapitulates the structural and cellular changes that occur clinically in humans with chronic rotator cuff tendon injuries and suggest that this new model is well suited to evaluation of new therapeutic interventions.

SUBMITTER: Johnson J

PROVIDER: S-EPMC8246224 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundChronic degeneration of rotator cuff tendons is a major contributing factor to the unacceptably high prevalence of rotator cuff repair surgery failures. The etiology of chronic rotator cuff degeneration is not well understood, and current therapies are not effective, necessitating preclinical research to fill this knowledge gap. Unfortunately, current large animal models rely on enthesis disruption as a means of model generation, which is not representative of human patients with chronic rotator cuff degeneration prior to full-thickness tears. Following, the goal of this study was to develop and characterize a translational large-animal model of chronic rotator cuff degeneration without enthesis release.MethodsA midsubstance damage model [i.e., "combed fenestration" (CF)] in adult sheep was generated by creating 16 longitudinal cuts within the top third of the infraspinatus tendon thickness. Tendon integrity was characterized through exhaustive non-destructive biomechanical stress relaxation testing [peak stress, peak load, percent relaxation, and cross-sectional area (CSA)], followed by histopathological degeneration scoring and analysis (Bonar score), histomorphological analysis of collagen organization and fatty atrophy (percent adipose area), and gene expression analyses.ResultsThe CF model tendons exhibited significantly decreased mechanical properties as evidenced by decreased peak stress (P<0.025) and increased percent relaxation (18-week vs. Control, P<0.035) at multiple strain magnitudes and across all timepoints. At all timepoints, the CF tendons exhibited pathological changes aligned with tendon degeneration, as evidenced by increased Bonar scoring (P<0.001) and decreased collagen organization (6-week vs. Control, P=0.013). Increases in intramuscular adipose content were also documented through histomorphology analysis (6- and 18-week vs. Control, P<0.077). Significant changes in gene expression were noted at all timepoints.ConclusionsThese data reveal that this new ovine CF model of chronic rotator cuff degeneration results in tendons with decreased mechanical properties, degenerative pathology characteristics, and gene expression profiles that aligned with the degenerative changes that have been noted in humans with tendinopathy. For these reasons, we believe this novel large animal model of chronic rotator cuff degeneration is a translational platform in which to test devices, therapies, and/or technologies aimed at repairing damage to the shoulder.

Project description:Myosteatosis is the pathological accumulation of lipid that occurs in conjunction with atrophy and fibrosis following skeletal muscle injury or disease. Little is known about the mechanisms by which lipid accumulates in myosteatosis, but many studies have demonstrated the degree of lipid infiltration negatively correlates with muscle function and regeneration. Our goal was to identify biochemical pathways that lead to muscle dysfunction and lipid accumulation in injured rotator cuff muscles, a model that demonstrates severe myosteatosis. Adult rats were subjected to a massive tear to the rotator cuff musculature. After a period of either 0 (healthy control), 10, 30, or 60 days, muscles were prepared for RNA sequencing, shotgun lipidomics, metabolomics, biochemical measures, electron microscopy, and muscle fiber contractility. Following rotator cuff injury, there was a decrease in muscle fiber specific force production that was lowest at 30d. There was a dramatic time dependent increase in triacylglyceride content. Interestingly, genes related to not only triacylglyceride synthesis, but also lipid oxidation were largely downregulated over time. Using bioinformatics techniques, we identified that biochemical pathways related to mitochondrial dysfunction and reactive oxygen species were considerably increased in muscles with myosteatosis. Long chain acyl-carnitines and L-carnitine, precursors to beta-oxidation, were depleted following rotator cuff tear. Electron micrographs showed injured muscles displayed large lipid droplets within mitochondria at early time points, and an accumulation of peripheral segment mitochondria at all time points. Several markers of oxidative stress were elevated following rotator cuff tear. The results from this study suggest that the accumulation of lipid in myosteatosis is not a result of canonical lipid synthesis, but occurs due to decreased lipid oxidation in mitochondria. A failure in lipid utilization by mitochondria would ultimately cause an accumulation of lipid even in the absence of increased synthesis. Further study will identify whether this process is required for the onset of myosteatosis.

Project description:PurposeAcute trauma-related rotator cuff tears are believed to have better healing potential than chronic tears due to less degenerative changes of the tendons. However, the histopathological condition of tendons from trauma-related tears is not well investigated. The purpose of this study was to explore specific histopathological features in tendons from acute trauma-related full-thickness rotator cuff tears and to compare them to findings in tendons from nontraumatic, chronic tears.MethodsIn a prospective cohort study, 62 previously asymptomatic patients [14 women, median age 61 years (range 42-75)] with trauma-related full-thickness rotator cuff tears were consecutively included. Arthroscopic repair was performed within 30 (median, IQR 25-37) days after the injury. During surgery, tissue biopsies were harvested from the supraspinatus tendons in 53 (86%) of the patients. In addition, similar biopsies were harvested from 10 patients undergoing surgery for chronic tears without history of trauma. All tissue samples were examined by a well-experienced pathologist under light microscope. Tendon degeneration was determined using the Bonar score whereas immunostaining was used for proliferation (Ki67), inflammation (CD45), apoptosis (p53) and haemosiderin staining to study traces of bleeding.ResultsThe median (IQR) Bonar score for the acute trauma-related biopsies was 10.5 (7.5-14.5) compared to 11 (5-12.8) for the control group with no statistically significant difference between the groups. No statistically significant between-group difference was found for the inflammatory index whereas tendons from patients with trauma-related full-thickness rotator cuff tears had statistically significantly higher apoptosis [3.1 (0.5-8.9) vs. 0.1 (0-1.5), p = 0.003] and proliferation [4.0 (1.8-6.9) vs. 0.4 (0-2.0), p = 0.001) indices than those undergoing surgery for chronic tears. Positive haemosiderin staining was found in 34% of tissue samples from patients with trauma-related tears compared to 10% in the control group (n.s).ConclusionThis study suggests that there is no difference with regard to degenerative changes between supraspinatus tendons harvested from patients with acute, trauma-related rotator cuff tears and patients with nontraumatic, chronic tears.Level of evidenceII.