Editorial Commentary: Monitoring Tendon and Muscle Recovery After Rotator Cuff Repair Using Diagnostic Ultrasound Demonstrates that Early Repair is Beneficial for Many Patients With Reparable Tears

Rotator cuff repair is performed to effect healing of the enthesis; to restore shoulder comfort, strength, and function; to prevent tear propagation; and to prevent progression of atrophic muscle changes (fatty degeneration, fatty infiltration, and fatty atrophy) that eventually occur. Non-retracted and moderately retracted rotator cuff tears usually heal after repair, and muscle atrophy may recover over time. It follows that early rotator cuff repair is beneficial for many patients with chronic but reparable rotator cuff tears. Diagnostic ultrasound can provide quantitative information about the recovery of both muscle and tendon and represents a viable alternative to magnetic resonance imaging for evaluating healing after rotator cuff repair.     

Rat rotator cuff muscle responds differently from hindlimb muscle to a combined tendon‐nerve injury

Rotator cuff tears (RCTs) are among the most common musculoskeletal injuries seen by orthopaedic surgeons. Clinically, massive cuff tears lead to unique pathophysiological changes in rotator cuff muscle, including atrophy, and massive fatty infiltration, which are rarely seen in other skeletal muscles. Studies in a rodent model for RCT have demonstrated that these histologic findings are accompanied by activation of the Akt/mammalian target of rapamycin (mTOR) and transforming growth factor‐β (TGF‐β) pathways following combined tendon‐nerve injury. The purpose of this study was to compare the histologic and molecular features of rotator cuff muscle and gastrocnemius muscle—a major hindlimb muscle, following combined tendon‐nerve injury. Six weeks after injury, the rat gastrocnemius did not exhibit notable fatty infiltration compared to the rotator cuff. Likewise, the adipogenic markers SREBP‐1 and PPARγ as well as the TGF‐β canonical pathway were upregulated in the rotator cuff, but not the gastrocnemius. Our study suggests that the rat rotator cuff and hindlimb muscles differ significantly in their response to a combined tendon‐nerve injury. Clinically, these findings highlight the unique response of the rotator cuff to injury, and may begin to explain the poor outcomes of massive RCTs compared to other muscle‐tendon injuries. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1046–1053, 2015.     

Lysophosphatidic acid‐induced RhoA signaling and prolonged macrophage infiltration worsens fibrosis and fatty infiltration following rotator cuff tears

Previous studies have suggested that macrophage‐mediated chronic inflammation is involved in the development of rotator cuff muscle atrophy and degeneration following massive tendon tears. Increased RhoA signaling has been reported in chronic muscle degeneration, such as muscular dystrophy. However, the role of RhoA signaling in macrophage infiltration and rotator muscle degeneration remains unknown. Using a previously established rat model of massive rotator cuff tears, we found RhoA signaling is upregulated in rotator cuff muscle following a massive tendon‐nerve injury. This increase in RhoA expression is greatly potentiated by the administration of a potent RhoA activator, lysophosphatidic acid (LPA), and is accompanied by increased TNFα and TGF‐β1 expression in rotator cuff muscle. Boosting RhoA signaling with LPA significantly worsened rotator cuff muscle atrophy, fibrosis, and fatty infiltration, accompanied with massive monocytic infiltration of rotator cuff muscles. Co‐staining of RhoA and the tissue macrophage marker CD68 showed that CD68+ tissue macrophages are the dominant cell source of increased RhoA signaling in rotator cuff muscles after tendon tears. Taken together, our findings suggest that LPA‐mediated RhoA signaling in injured muscle worsens the outcomes of atrophy, fibrosis, and fatty infiltration by increasing macrophage infiltraion in rotator cuff muscle. Clinically, inhibiting RhoA signaling may represent a future direction for developing new treatments to improve muscle quality following massive rotator cuff tears. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1539–1547, 2017.

     

Botulinum toxin is detrimental to repair of a chronic rotator cuff tear in a rabbit model

Re‐tear continues to be a problem after rotator cuff repair. Intramuscular botulinum toxin (Botox) injection can help optimize tension at the repair site to promote healing but could have an adverse effect on the degenerated muscle in a chronic tear. We hypothesized that Botox injection would improve repair characteristics without adverse effect on the muscle in a chronic rotator cuff tear model. The supraspinatus tendon of both shoulders in 14 rabbits underwent delayed repair 12 weeks after transection. One shoulder was treated with intramuscular Botox injection and the other with a saline control injection. Six weeks after repair, outcomes were based on biomechanics, histology, and magnetic resonance imaging. Botox‐treated repairs were significantly weaker (2.64 N) than control repairs (5.51 N, p = 0.03). Eighty percent of Botox‐treated repairs and 40% of control repairs healed with some partial defect. Fatty infiltration of the supraspinatus was present in all shoulders (Goutallier Grade 3 or 4) but was increased in the setting of Botox. This study provides additional support for the rabbit supraspinatus model of chronic cuff tear, showing consistent fatty infiltration. Contrary to our hypothesis, Botox had a negative effect on repair strength and might increase fatty infiltration. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1152–1157, 2015.     

Graft Augmentation of Repairable Rotator Cuff Tears: An Algorithmic Approach Based on Healing Rates

We provide our algorithm for tissue augmentation of rotator cuff repairs based on the current available evidence regarding rotator cuff healing. A variety of factors are associated with healing following rotator cuff repair. Increasing tear size and retraction as well as severe fatty degeneration have been associated with worsening rates of tendon healing. Given the correlation between tendon healing and postoperative outcomes, it is important to identify patients at high risk for failure and to modify their treatment accordingly to minimize the risk of early biomechanical failure and maximize the potential for structural healing. One approach that may be used to improve healing is tissue augmentation. Tissue augmentation is the use of tissue patches and scaffolds to provide rotator cuff reinforcement. Surgical management for rotator cuff tears (RCTs) continues to be a challenging task in orthopaedic surgery today. Appropriate treatment measures require an in depth understanding and consideration of the patient’s prognostic factors such as age, fatty infiltration of the rotator cuff muscles, bone mineral density, rotator cuff retraction, anteroposterior tear size, work activity, and degenerative changes of the joint. Using these factors within the Rotator Cuff Healing Index, we can determine a patient’s surgical treatment that will yield the maximum healing rate. For nonarthritic RCTs, joint-preserving strategies should be first-line treatment options. For young, active patients with a reparable RCT and minimal fatty infiltration, a complete repair can be effective. For young patients with irreparable RCTs, superior capsular reconstructions, and tendon transfers are viable options. For elderly patients with low work activity, an irreparable RCT and significant fatty infiltration, a partial repair with or without graft augmentation can be attempted if minimal to no arthritic changes are seen.Level of EvidenceLevel V, expert opinion.     

MRI quantification of fatty infiltration and muscle atrophy in a mouse model of rotator cuff tears

Rotator cuff pathology is the most common shoulder problem seen by orthopedic surgeons. Rotator cuff muscle fatty infiltration and muscle atrophy are common in larger tears and are considered predicting factors for the prognosis of cuff repair. Clinically, MRI is the gold standard in determining fatty infiltration and muscle atrophy; however, analysis for MRI imaging is primarily qualitative in nature with the results lacking further validation. We have recently developed a mouse model of rotator cuff tears. The goal of this study is to quantify and verify rotator cuff muscle atrophy and fatty infiltration using high‐resolution MRI in our mouse model. The rotator cuff muscles were analyzed for fat using a triglyceride quantification assay (TQA), muscle volume was measured through water displacement (WD), and histology. The study revealed that MRI had a high correlation with fat as measured with histology and TQA (R² = 098). MRI also correlated well with atrophy measured with WD and wet weight. This suggests that MRI is a reliable modality in evaluating the progression of fatty infiltration and muscle atrophy following rotator cuff tears in a small animal model. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 421–426, 2013     

Einzelreihe, Doppelreihe oder transoss?re Refixation

Arthroscopic rotator cuff repair is an established treatment option for rotator cuff tears. Clinical results are very good regardless of the repair technique. Critical analysis of repair integrity showed a high retear rate for larger tears especially in the earlier series. Apart from biological factors e.g., age, muscle atrophy, and fatty infiltration of the rotator cuff, studies have shown biomechanical deficiencies of single-row repair. Double-row repair with a medial and lateral row of suture anchors was developed as an improvement over single-row repair and showed superior biomechanical properties in most of the recent literature. Clinical results reveal a tendency towards better healing rates compared with single-row repair without further improvement of the clinical result. Transosseous-equivalent repair, which was developed as an alternative to the classic double-row repair, has not clearly shown the same biomechanical superiority or significantly higher healing rates compared to single-row repair.     

Biologic and pharmacologic augmentation of rotator cuff repairs

As rotator cuff repair techniques have improved, failure of the tendon to heal to the proximal humerus is less likely to occur from weak tendon-to-bone fixation. More likely causes of failure include biologic factors such as intrinsic tendon degeneration, fatty atrophy, fatty infiltration of muscle, and lack of vascularity of the tendons. High failure rates have led to the investigation of biologic augmentation to potentially enhance the healing response. Histologic studies have shown that restoration of the rotator cuff footprint during repair can help reestablish the enthesis. In animal models, growth factors and their delivery scaffolds as well as tissue engineering have shown promise in decreasing scar tissue while maintaining biomechanical strength. Platelet-rich plasma may be a safe adjuvant to rotator cuff repair, but it has not been shown to improve healing or function. Many of these strategies need to be further defined to permit understanding of, and to optimize, the biologic environment; in addition, techniques need to be refined for clinical use.     

Correlation of atrophy and fatty infiltration on strength and integrity of rotator cuff repairs: a study in thirteen patients

In 13 patients, the development of supraspinatus muscle atrophy and fatty infiltration after rotator cuff tendon repair was quantified prospectively via magnetic resonance imaging. Intraoperative electrical nerve stimulation at repair showed that the maximal supraspinatus tension (up to 200 N) strongly correlated with the anatomic cross-sectional muscle area and with muscle fatty infiltration (ranging from 12 N/cm(2) in Goutallier stage 3 to 42 N/cm(2) in Goutallier stage 0). Within 1 year after successful tendon repair (n = 8), fatty infiltration did not recover, and atrophy improved partially at best; however, if the repair failed (n = 5), atrophy and fatty infiltration progressed significantly. The ability of the rotator cuff muscles to develop tension not only correlates with their atrophy but also closely correlates with their degree of fatty infiltration. With current repair techniques, atrophy and fatty infiltration appear to be irreversible, despite successful tendon repair. Unexpectedly, not only weak but also very strong muscles are at risk for repair failure.     

Degenerative changes of the deltoid muscle have impact on clinical outcome after reversed total shoulder arthroplasty

Introduction  

Despite a high complication rate, subjective and objective results of reversed shoulder arthroplasty for severe rotator cuff lesions associated with osteoarthritis, fracture sequelae, or revision of hemiarthroplasty are favorable. However, whether the changes in biomechanics of the joint may lead to structural changes in the remaining rotator cuff and the deltoid muscle, and may thereby alter the clinical result, has rarely been described. This study investigates the context between postoperative fatty infiltration of the remaining rotator cuff and the deltoid muscle, and the clinical outcome after reversed shoulder arthroplasty.     

Current Biomechanical Concepts for Rotator Cuff Repair

For the past few decades, the repair of rotator cuff tears has evolved significantly with advances in arthroscopy techniques, suture anchors and instrumentation. From the biomechanical perspective, the focus in arthroscopic repair has been on increasing fixation strength and restoration of the footprint contact characteristics to provide early rehabilitation and improve healing. To accomplish these objectives, various repair strategies and construct configurations have been developed for rotator cuff repair with the understanding that many factors contribute to the structural integrity of the repaired construct. These include repaired rotator cuff tendon-footprint motion, increased tendon-footprint contact area and pressure, and tissue quality of tendon and bone. In addition, the healing response may be compromised by intrinsic factors such as decreased vascularity, hypoxia, and fibrocartilaginous changes or aforementioned extrinsic compression factors. Furthermore, it is well documented that torn rotator cuff muscles have a tendency to atrophy and become subject to fatty infiltration which may affect the longevity of the repair. Despite all the aforementioned factors, initial fixation strength is an essential consideration in optimizing rotator cuff repair. Therefore, numerous biomechanical studies have focused on elucidating the strongest devices, knots, and repair configurations to improve contact characteristics for rotator cuff repair. In this review, the biomechanical concepts behind current rotator cuff repair techniques will be reviewed and discussed.     

A Bioactive Coating Enhances Bone Allografts in Rat Models of Bone Formation and Critical Defect Repair

Bone allografts are inferior to autografts for the repair of critical‐sized defects. Prior studies have suggested that bone morphogenetic protein‐2 (BMP‐2) can be combined with allografts to produce superior healing. We created a bioactive coating on bone allografts using polycondensed deoxyribose isobutyrate ester (PDIB) polymer to deliver BMP‐2 ± the bisphosphonate zoledronic acid (ZA) and tested its ability to enhance the functional utility of allografts in preclinical Wistar rat models. One ex vivo and two in vivo proof‐of‐concept studies were performed. First, PDIB was shown to be able to coat bone grafts (BGs). Second, PDIB was used to coat structural allogenic corticocancellous BG with BMP‐2 ± ZA ± hydroxyapatite (HA) microparticles and compared with PDIB‐coated grafts in a rat muscle pouch model. Next, a rat critical defect model was performed with treatment groups including (i) empty defect, (ii) BG, (iii) collagen sponge + BMP‐2, (iv) BG + PDIB/BMP‐2, and (v) BG + PDIB/BMP‐2/ZA. Key outcome measures included detection of fluorescent bone labels, microcomputed tomography (CT) quantification of bone, and radiographic healing. In the muscle pouch study, BMP‐2 did not increase net bone volume measured by microCT, however, fluorescent labeling showed large amounts of new bone. Addition of ZA increased BV by sevenfold (p < 0.01). In the critical defect model, allografts were insufficient to promote reliable union, however, union was achieved in collagen/BMP‐2 and all BG/BMP‐2 groups. Statement of clinical significance: These data support the concept that PDIB is a viable delivery method for BMP‐2 and ZA delivery to enhance the bone forming potential of allografts. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2278–2286, 2019     

Editorial Commentary: Dermal Allografts Are Indicated for Repair of Irreparable Rotator Cuff Tears and for Revision Surgery,and May Be Cost-Effective for Primary Repair

Improving rotator cuff repair results is the goal of all shoulder surgeons. The addition of a biologic graft may speed healing, allow accelerated rehabilitation, and increase healing rates. Recent research suggests that augmentation of rotator cuff repair using dermal allograft may be cost-effective. Indications for dermal allografts are revision rotator cuff repairs and primary cuff repairs in which a tensionless repair cannot be accomplished. Allografts act as a load-sharing device to allow tendons to heal without tension. They also serve to fill the gap in irreparable cuff tears. It is important to understand that augmentation will not compensate for advanced muscle fatty atrophy or neurapraxia. Precautions to prevent Cutibacterium acne nosocomial infection are essential. The healing time or dermal grafts is considerably longer than the repaired native cuff tendon, requiring supervised rehabilitation. Dermal allografts are a crucial tool for repair of irreparable rotator cuff tears and for revision surgery. From an economic standpoint, they now also may be considered for use in primary rotator cuff repair surgery.     

Skeletal muscle fibrosis and stiffness increase after rotator cuff tendon injury and neuromuscular compromise in a rat model

Rotator cuff tears can cause irreversible changes (e.g., fibrosis) to the structure and function of the injured muscle(s). Fibrosis leads to increased muscle stiffness resulting in increased tension at the rotator cuff repair site. This tension influences repairability and healing potential in the clinical setting. However, the micro‐ and meso‐scale structural and molecular sources of these whole‐muscle mechanical changes are poorly understood. Here, single muscle fiber and fiber bundle passive mechanical testing was performed on rat supraspinatus and infraspinatus muscles with experimentally induced massive rotator cuff tears (Tenotomy) as well as massive tears with chemical denervation (Tenotomy + BTX) at 8 and 16 weeks post‐injury. Titin molecular weight, collagen content, and myosin heavy chain profiles were measured and correlated with mechanical variables. Single fiber stiffness was not different between controls and experimental groups. However, fiber bundle stiffness was significantly increased at 8 weeks in the Tenotomy + BTX group compared to Tenotomy or control groups. Many of the changes were resolved by 16 weeks. Only fiber bundle passive mechanics was weakly correlated with collagen content. These data suggest that tendon injury with concomitant neuromuscular compromise results in extra‐cellular matrix production and increases in stiffness of the muscle, potentially complicating subsequent attempts for surgical repair. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1111–1116, 2014.     

Tissue‐engineered tendon constructs for rotator cuff repair in sheep

Current rotator cuff repair commonly involves the use of single or double row suture techniques, and despite successful outcomes, failure rates continue to range from 20 to 95%. Failure to regenerate native biomechanical properties at the enthesis is thought to contribute to failure rates. Thus, the need for technologies that improve structural healing of the enthesis after rotator cuff repair is imperative. To address this issue, our lab has previously demonstrated enthesis regeneration using a tissue‐engineered graft approach in a sheep anterior cruciate ligament (ACL) repair model. We hypothesized that our tissue‐engineered graft designed for ACL repair also will be effective in rotator cuff repair. The goal of this study was to test the efficacy of our Engineered Tissue Graft for Rotator Cuff (ETG‐RC) in a rotator cuff tear model in sheep and compare this novel graft technology to the commonly used double row suture repair technique. Following a 6‐month recovery, the grafted and contralateral shoulders were removed, imaged using X‐ray, and tested biomechanically. Additionally, the infraspinatus muscle, myotendinous junction, enthesis, and humeral head were preserved for histological analysis of muscle, tendon, and enthesis structure. Our results showed that our ETC‐RCs reached 31% of the native tendon tangent modulus, which was a modest, non‐significant, 11% increase over that of the suture‐only repairs. However, the histological analysis showed the regeneration of a native‐like enthesis in the ETG‐RC‐repaired animals. This advanced structural healing may improve over longer times and may diminish recurrence rates of rotator cuff tears and lead to better clinical outcomes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:289–299, 2018.     

Bone morphogenetic proteins 2, 5, and 6 in combination stimulate osteoblasts but not osteoclasts in vitro

Bone regeneration is required for fracture healing. Various procedures have been used to promote osteogenesis with bone morphogenetic proteins (BMPs). We assessed the effects of BMP‐2, BMP‐5, and BMP‐6 in isolated and combined use on the generation of osteoblasts and osteoclasts by comparing the osteoclastic potency of each on osteoclasts of primary murine bone marrow cells. Subsequently, cells were stained for tartrate‐resistant acid phosphatase, and real time PCR analysis of receptor activator of NKκB ligand and osteoprotegerin was conducted. The same combination of BMPs was used to assess their potential to enhance osteoblasts, employing a mineralization assay and real‐time PCR analysis of collagen type‐1, runx2, and osterix. While BMP‐2 alone and the combination of BMP‐2 and BMP‐5 significantly enhanced osteoclastogenesis, BMP‐2, BMP‐5, and BMP‐6 in combination did not have additional effects. However, the combined use of BMP‐2, BMP‐5, and BMP‐6 had an additive effect on matrix mineralization and osterix expression in osteoblasts. Our study shows that the combination of BMP‐2, BMP‐5, and BMP‐6 stimulates osteoblasts but not osteoclastogenesis. Thus, the synergistic use of various BMPs might improve effective bone regeneration in the clinical setting. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res     

Effect of tamoxifen on fatty degeneration and atrophy of rotator cuff muscles in chronic rotator cuff tear: An animal model study

Fatty degeneration of the rotator cuff muscles is an irreversible change resulting from chronic rotator cuff tear and is associated with poor clinical outcomes following rotator cuff repair. We evaluated the effect of Tamoxifen, a competitive estrogen receptor inhibitor, on fatty degeneration using a mouse model for chronic rotator cuff tear. Sixteen adult mice were divided into two diet groups (Tamoxifen vs. Regular) and subjected to surgical creation of a large rotator cuff tear and suprascapular nerve transection in their left shoulder with the right shoulder serving as a control. The rotator cuff muscles were harvested at 16 weeks and subjected to histology and RT‐PCR for adipogenic and myogenic markers. Histology showed substantially decreased atrophy and endomysial inflammation in Tamoxifen group, but no significant differences in the amount of intramuscular adipocytes and lipid droplets compared to the Regular group. With RT‐PCR, the operated shoulders showed significant upregulation of myogenin and PPAR‐γ, and downregulation of myostatin compared to the nonsurgical shoulder. No significant differences of gene expression were found between the two diet groups. Our study demonstrated that tamoxifen diet leads to decreased muscle atrophy and inflammatory changes following chronic rotator cuff tear, but has no apparent effect on adipogenesis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1846–1853, 2015.