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A Mouse Model of Delayed Rotator Cuff Repair Results in Persistent Muscle Atrophy and Fatty Infiltration.

ABSTRACT: 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.

SUBMITTER: Wang Z

PROVIDER: S-EPMC6730552 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A Mouse Model of Delayed Rotator Cuff Repair Results in Persistent Muscle Atrophy and Fatty Infiltration.

Wang Zili Z Liu Xuhui X Davies Michael R MR Horne Devante D Kim Hubert H Feeley Brian T BT

The American journal of sports medicine 20180910 12

<h4>Background</h4>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.<h4>Purpose</h4>To develop a highly clinically relevant mouse model of delayed RC repair.<h ...[more]

PMID: 30198747

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Project description:Current evaluation of muscle fatty infiltration has been limited by subjective classifications. Quantitative fat evaluation through magnetic resonance imaging (MRI) may allow for an improved longitudinal evaluation of the effect of surgical repair on the progression of fatty infiltration.We hypothesized that (1) patients with isolated full-thickness supraspinatus tendon tears would have less progression in fatty infiltration compared with patients with full-thickness tears of multiple tendons and (2) patients with eventual failed repair would have higher baseline levels of fatty infiltration.Cohort study; Level of evidence, 2.Thirty-five patients with full-thickness rotator cuff tears were followed longitudinally. All patients received a shoulder MRI, including the iterative decomposition of echoes of asymmetric length (IDEAL) sequence for fat measurement, prior to surgical treatment and at 6 months after surgical repair. Fat fractions were recorded for all 4 rotator cuff muscles from measurements on 4 sagittal slices centered at the scapular-Y. Demographics and tear characteristics were recorded. Baseline and follow-up fat fractions were compared for patients with isolated supraspinatus tears versus multitendon tears and for patients with intact repairs versus failed repairs. Statistical significance was set at P < .05.The mean fat fractions were significantly higher at follow-up than at baseline for the supraspinatus (9.8% ± 7.0% vs 8.3% ± 5.7%; P = .025) and infraspinatus (7.4% ± 6.1% vs 5.7% ± 4.4%; P = .027) muscles. Patients with multitendon tears showed no significant change for any rotator cuff muscle after repair. Patients with isolated supraspinatus tears showed a significant progression in the supraspinatus fat fraction from baseline to follow-up (from 6.8% ± 4.9% to 8.6% ± 6.8%; P = .0083). Baseline supraspinatus fat fractions were significantly higher in patients with eventual failed repairs compared with those with intact repairs (11.7% ± 6.8% vs 7.1% ± 4.8%; P = .037).Contrary to our initial hypothesis, patients with isolated supraspinatus tears showed a significant progression of fatty infiltration. Patients with eventual repair failure had higher baseline fat fractions in the supraspinatus.

Project description:Rotator cuff tears are a common cause for pain and reduced function. Tears of the tendons of the cuff can be a result of a degenerative process or as a consequence of trauma. Management of cuff tears are surrounded by controversy from indications for surgical management to rehabilitation protocol post-surgical repair. The aim of post surgical rehabilitation is to improve functional outcome, reduce pain and promote tendon healing. In the case of rotator cuff repair, rehabilitation can be broadly divided into early passive range of motion (EPM) and delayed range of motion (DRM). The EPM regime is defined by minimal immobilisation of the shoulder and passive mobilisation of the joint within the first post-operative period. In contrast, DRM immobilises the shoulder joint up to six weeks post-operatively. Proponents of EPM state various advantages of their rehabilitation protocol including improved range of motion and earlier return to normal activities of daily living. However, there has also been concern that this rehabilitation regime may result in an increased rate of re-rupture. Since this is a highly controversial issue, various high quality literature have been published looking to clarify which regime is best following rotator cuff surgery. Reviewing these articles, it appears that there is an increase rate of re-tear of the repaired rotator cuff tendon when the EPM regime is employed. Statistical significance however was limited by small sample sizes. Range of motion post-repair also appears to be associated with post-operative rehabilitation regime. As expected, the EPM regime has been shown to improve range of motion post-repair. Despite this, literature reports patients managed with the DPM showed a statistically better patient reported outcome measure. We conclude that based on the evidence we currently have, early range of motion post rotator cuff repair is related with an increase risk of re-tear. The DPM regime reduces this risk with the possible complication of reduced range of shoulder movement. This problem is thought to be an easier clinical issue to deal with compared to re-rupture of the repaired rotator cuff tendon. There is however lack of data to achieve statistical significance in most of these analysis. There is a definite need for a large, multi-centre single blinded randomised controlled trial to further shed light on this controversial topic.

Project description:BackgroundThe injection of mesenchymal stem cells (MSCs) mitigates fat accumulation in released rotator cuff muscle after tendon repair in rodents.PurposeTo investigate whether the injection of autologous MSCs halts muscle-to-fat conversion after tendon repair in a large animal model for rotator cuff tendon release via regional effects on extracellular fat tissue and muscle fiber regeneration.Study designControlled laboratory study.MethodsInfraspinatus (ISP) muscles of the right shoulder of Swiss Alpine sheep (n = 14) were released by osteotomy and reattached 16 weeks later without (group T; n = 6) or with (group T-MSC; n = 8) electropulse-assisted injection of 0.9 Mio fluorescently labeled MSCs as microtissues with media in demarcated regions; animals were allowed 6 weeks of recovery. ISP volume and composition were documented with computed tomography and magnetic resonance imaging. Area percentages of muscle fiber types, fat, extracellular ground substance, and fluorescence-positive tissue; mean cross-sectional area (MCSA) of muscle fibers; and expression of myogenic (myogenin), regeneration (tenascin-C), and adipogenic markers (peroxisome proliferator-activated receptor gamma [PPARG2]) were quantified in injected and noninjected regions after recovery.ResultsAt 16 weeks after tendon release, the ISP volume was reduced and the fat fraction of ISP muscle was increased in group T (137 vs 185 mL; 49% vs 7%) and group T-MSC (130 vs 166 mL; 53% vs 10%). In group T-MSC versus group T, changes during recovery after tendon reattachment were abrogated for fat-free mass (-5% vs -29%, respectively; P = .018) and fat fraction (+1% vs +24%, respectively; P = .009%). The area percentage of fat was lower (9% vs 20%; P = .018) and the percentage of the extracellular ground substance was higher (26% vs 20%; P = .007) in the noninjected ISP region for group T-MSC versus group T, respectively. Regionally, MCS injection increased tenascin-C levels (+59%) and the water fraction, maintaining the reduced PPARG2 levels but not the 29% increased fiber MCSA, with media injection.ConclusionIn a sheep model, injection of autologous MSCs in degenerated rotator cuff muscle halted muscle-to-fat conversion during recovery from tendon repair by preserving fat-free mass in association with extracellular reactions and stopping adjuvant-induced muscle fiber hypertrophy.Clinical relevanceA relatively small dose of MSCs is therapeutically effective to halt fatty atrophy in a large animal model.

Project description:PurposeTo use a large, contemporary database to perform a cross-sectional analysis of current practice trends in rotator cuff repair (RCR) for the treatment of full-thickness rotator cuff tear (RCT) and determine outcomes of arthroscopic and open RCR, including hospital readmissions and 2-year reoperation rates with accurate laterality tracking using International Classification of Diseases, Tenth Revision (ICD-10) codes.MethodsThe PearlDiver Mariner dataset was used to query patients with full-thickness RCTs from 2010 to 2017. Propensity-score matching was performed to account for differences in age and comorbidities and allow for comparison between those undergoing open RCR and arthroscopic RCR. Subsequent procedures were tracked using ICD-10 codes to identify ipsilateral surgery within 2 years of index surgery. Hospital and emergency department admission within 30 days of surgery were investigated.ResultsOf 534,076 patients diagnosed with full-thickness RCT, 37% underwent RCR; 73% of which were arthroscopic. From 2010 to 2017, arthroscopic RCRs increased from 65% to 80%, whereas open RCRs decreased from 35% to 20% (P < .0001). Younger patients underwent arthroscopic RCR more frequently, and patients who underwent open RCR had greater rates of 30-day emergency department (7.0%) and hospital readmission (2.0%) compared with arthroscopic RCR (6.3%, 1.0%, respectively) (P < .0001). For 24,392 patients with ICD-10 coding and 2-year follow-up, 10.4% of patients required reoperation, with the most common procedure being revision RCR, and 1.3% required conversion to arthroplasty. Open RCRs were more likely to require subsequent surgery (11.3%) compared with arthroscopic RCR (9.5%) (P < .0001). Patients aged 50 to 59 had the greatest rate of reoperation (14.0%), but no patients younger than age 40 years required reoperation, and no patients younger than age 50 years required conversion to arthroplasty.ConclusionsThe frequency of arthroscopic RCR has continued to increase compared to open RCR. In this large cross-sectional analysis, arthroscopic RCR demonstrated lower 2-year reoperation rates and 30-day readmission rates compared to open RCR.Level of evidenceIII, cross-sectional study.

Dataset Information

A Mouse Model of Delayed Rotator Cuff Repair Results in Persistent Muscle Atrophy and Fatty Infiltration.

Publications

A Mouse Model of Delayed Rotator Cuff Repair Results in Persistent Muscle Atrophy and Fatty Infiltration.

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