Volumetric MicroCT Intensity Histograms of Fatty Infiltration Correlate with the Mechanical Strength of Rotator Cuff Repairs: An Ex Vivo Rabbit Model

Background: Rotator cuff (RC) tears are common tendon injuries seen in orthopaedic patients. Successful repair of large and massive RC tears remains a challenge due to our limited understanding of the pathophysiological features of this injury. Clinically relevant small animal models that can be used to study the pathophysiological response to repair are limited by the lack of chronic repair models. Purpose: To develop a highly clinically relevant mouse model of delayed RC repair. Study Design: Controlled laboratory study. Methods: Three-month-old C57BL/6J mice underwent unilateral supraspinatus (SS) and infraspinatus (IS) tendon tear with immediate, 2-week delayed, or 6-week delayed tendon repair. Animals with no repair or sham surgery served as controls. Gait analysis was conducted to measure shoulder function at 2 weeks and 6 weeks after surgery. Animals were sacrificed 6 weeks after the last surgery. Shoulder joint, SS, and IS muscles were harvested and analyzed histologically. Ex vivo mechanical testing of intact and repaired SS and IS tendons was conducted. Reverse-transcriptase polymerase chain reaction was performed on SS and IS muscles to quantify atrophy, fibrosis, and fatty infiltration–related gene expression. Results: Histological and tendon mechanical testing showed that torn tendons could be successfully repaired as late as 6 weeks after transection. However, significant atrophy and fatty infiltration of muscle, with impaired shoulder function, were persistent in the 6-week delayed repair group. Shoulder function correlated with the severity of RC muscle weight loss and fatty infiltration. Conclusion: We successfully developed a clinically relevant mouse model of delayed RC repair. Six-week delayed RC repair resulted in persistent muscle atrophy and fatty infiltration with inferior shoulder function compared with acute repair. Clinical Relevance: Our novel mouse model could serve as a powerful tool to understand the pathophysiological and cellular/molecular mechanisms of RC muscle and tendon degeneration, eventually improving our strategies for treating and repairing RC tears.

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Effect of hypercholesterolemia on fatty infiltration and the quality of tendon-to-bone healing in a rabbit model of a chronic rotator cuff tear: Electrophysiological, biomechanical, and histological analyses

Asia-Pacific Journal of Sports Medicine Arthroscopy Rehabilitation and Technology ◽

10.1016/j.asmart.2016.07.011 ◽

2016 ◽

Vol 6 ◽

pp. 15

Author(s):

Seok Won Chung ◽

H. Park ◽

Jieun Kwon ◽

Sae Hoon Kim ◽

Joo Han Oh

Keyword(s):

Rotator Cuff ◽

Rotator Cuff Tear ◽

Bone Healing ◽

Fatty Infiltration ◽

Rabbit Model ◽

Cuff Tear

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Fatty Infiltration Does Not Progress After Rotator Cuff Repair in a Rabbit Model

Arthroscopy The Journal of Arthroscopic and Related Surgery ◽

10.1016/j.arthro.2008.03.004 ◽

2008 ◽

Vol 24 (8) ◽

pp. 936-940 ◽

Cited By ~ 24

Author(s):

L. Joseph Rubino ◽

Dominic C. Sprott ◽

Harold F. Stills ◽

Lynn A. Crosby

Keyword(s):

Rotator Cuff ◽

Rotator Cuff Repair ◽

Fatty Infiltration ◽

Rabbit Model ◽

Cuff Repair

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Adipose Stem Cell–Derived Exosomes Decrease Fatty Infiltration and Enhance Rotator Cuff Healing in a Rabbit Model of Chronic Tears

The American Journal of Sports Medicine ◽

10.1177/0363546520908847 ◽

2020 ◽

Vol 48 (6) ◽

pp. 1456-1464 ◽

Cited By ~ 3

Author(s):

Chongyang Wang ◽

Qingxiang Hu ◽

Wei Song ◽

Weilin Yu ◽

Yaohua He

Keyword(s):

Stem Cell ◽

Rotator Cuff ◽

Bone Healing ◽

Fatty Infiltration ◽

Biomechanical Testing ◽

Rabbit Model ◽

Saline Group ◽

Adipose Stem Cell ◽

Sham Surgery ◽

Cuff Repair

Background: Fatty infiltration and poor tendon-bone healing in chronic rotator cuff tears (RCTs) are associated with unsatisfactory prognosis. Adipose stem cell–derived exosomes (ASC-Exos), having multiple biological effects, can prevent muscle degeneration in acute RCTs. However, the effects of ASC-Exos on fatty infiltration and tendon-bone healing in chronic RCTs remain unknown. Purpose: To study the effects of ASC-Exos on fatty infiltration and tendon-bone healing in a chronic RCT rabbit model. Study Design: Controlled laboratory study. Methods: At week 0, we randomly allocated 35 rabbits to receive sham surgery (14 rabbits) or establish a bilateral RCT model (21 rabbits, detachment of the supraspinatus tendon). At week 6, a total of 7 rabbits received sham surgery, and 7 rabbits with RCT were sacrificed for fatty infiltration assay. The remaining 14 rabbits with bilateral RCTs were randomly assigned to a saline group (7 rabbits that received local saline injection and rotator cuff repair) or an ASC-Exos group (7 rabbits that received local ASC-Exos injection and rotator cuff repair). At week 18, all rabbits were sacrificed for histological examination and biomechanical testing. Results: At week 18, the ASC-Exos group showed significantly lower fatty infiltration (14.01% ± 2.85%) compared with the saline group (21.79% ± 3.07%) ( P < .001), and no statistical difference compared with the time of repair (10.88% ± 2.64%) ( P = .127). For tendon-bone healing, the ASC-Exos group showed a higher histological score and more newly regenerated fibrocartilage at the repair site than did the saline group. Regarding biomechanical testing, the ASC-Exos group showed significantly higher ultimate load to failure, stiffness, and stress than the saline group. Conclusion: Local injection of ASC-Exos in chronic RCTs at the time of repair could prevent the progress of fatty infiltration, promote tendon-bone healing, and improve biomechanical properties. Clinical Relevance: ASC-Exos injection may be used as a cell-free adjunctive therapy to inhibit fatty infiltration and improve rotator cuff healing in the repair of chronic RCTs.

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Effect of Hypercholesterolemia on Fatty Infiltration and Quality of Tendon-to-Bone Healing in a Rabbit Model of a Chronic Rotator Cuff Tear

The American Journal of Sports Medicine ◽

10.1177/0363546515627816 ◽

2016 ◽

Vol 44 (5) ◽

pp. 1153-1164 ◽

Cited By ~ 36

Author(s):

Seok Won Chung ◽

HaeBong Park ◽

Jieun Kwon ◽

Ghee Young Choe ◽

Sae Hoon Kim ◽

...

Keyword(s):

Rotator Cuff ◽

Rotator Cuff Tear ◽

Bone Healing ◽

Fatty Infiltration ◽

Rabbit Model ◽

Cuff Tear

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Fatty Infiltration Does Not Progress After Rotator Cuff Repair in a Rabbit Model

Yearbook of Hand and Upper Limb Surgery ◽

10.1016/s1551-7977(10)79464-4 ◽

2010 ◽

Vol 2010 ◽

pp. 203-204

Author(s):

J.C. Macy

Keyword(s):

Rotator Cuff ◽

Rotator Cuff Repair ◽

Fatty Infiltration ◽

Rabbit Model ◽

Cuff Repair

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Fatty Infiltration of the Torn Rotator Cuff Worsens Over Time in a Rabbit Model

Arthroscopy The Journal of Arthroscopic and Related Surgery ◽

10.1016/j.arthro.2007.01.023 ◽

2007 ◽

Vol 23 (7) ◽

pp. 717-722 ◽

Cited By ~ 63

Author(s):

L. Joseph Rubino ◽

Harold F. Stills ◽

Dominic C. Sprott ◽

Lynn A. Crosby

Keyword(s):

Rotator Cuff ◽

Fatty Infiltration ◽

Rabbit Model ◽

Over Time

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Retinoic Acid Receptor Agonists Suppress Muscle Fatty Infiltration in Mice

The American Journal of Sports Medicine ◽

10.1177/0363546520984122 ◽

2021 ◽

Vol 49 (2) ◽

pp. 332-339

Author(s):

Hideyuki Shirasawa ◽

Noboru Matsumura ◽

Masaki Yoda ◽

Kazumasa Okubo ◽

Masayuki Shimoda ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Rotator Cuff ◽

Rotator Cuff Tear ◽

Gene Expression Analysis ◽

Retinoic Acid Receptor ◽

Adipogenic Differentiation ◽

Fatty Infiltration ◽

Cuff Tear

Background: The infiltration of fat tissue into skeletal muscle, a condition referred to as muscle fatty infiltration or fatty degeneration, is regarded as an irreversible event that significantly compromises the motor function of skeletal muscle. Purpose: To investigate the effect of retinoic acid receptor (RAR) agonists in suppressing the adipogenic differentiation of fibroadipogenic progenitors (FAPs) in vitro and fatty infiltration after rotator cuff tear in mice. Study Design: Controlled laboratory study. Methods: FAPs isolated from mouse skeletal muscle were cultured in adipogenic differentiation medium in the presence or absence of an RAR agonist. At the end of cell culture, adipogenic differentiation was evaluated by gene expression analysis and oil red O staining. A mouse model of fatty infiltration—which includes the resection of the rotator cuff, removal of the humeral head, and denervation the supraspinatus muscle—was used to induce fatty infiltration in the supraspinatus muscle. The mice were orally or intramuscularly administered with an RAR agonist after the surgery. Muscle fatty infiltration was evaluated by histology and gene expression analysis. Results: RAR agonists effectively inhibited the adipogenic differentiation of FAPs in vitro. Oral and intramuscular administration of RAR agonists suppressed the development of muscle fatty infiltration in the mice after rotator cuff tear. In accordance, we found a significant decrease in the number of intramuscular fat cells and suppressed expression in adipogenic markers. RAR agonists also increased the expression of the transcripts for collagens; however, an accumulation of collagenous tissues was not histologically evident in the present model. Conclusion: Muscle fatty infiltration can be alleviated by RAR agonists through suppressing the adipogenic differentiation of FAPs. The results also suggest that RAR agonists are potential therapeutic agents for treating patients who are at risk of developing muscle fatty infiltration. The consequence of the increased expression of collagen transcripts by RAR agonists needs to be clarified. Clinical Relevance: RAR agonists can be used to prevent the development of muscle fatty infiltration after rotator cuff tear. Nevertheless, further studies are mandatory in a large animal model to examine the safety and efficacy of intramuscular injection of RAR agonists.

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