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Influence of a nerve injury proximal to the suprascapular nerve on healing of repaired rotator cuff tear
Journal of Orthopaedic Science 25 (2020) 96e103
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Journal of Orthopaedic Science journal homepage: http://www.elsevier.com/locate/jos
Original Article
Influence of a nerve injury proximal to the suprascapular nerve on healing of repaired rotator cuff tear Koji Akimoto*, Nobuyasu Ochiai, Eiko Hashimoto, Yasuhito Sasaki, Daisuke Nojima, Daisuke Kajiwara, Yusuke Matsuura, Yu Sasaki, Takeshi Yamaguchi, Takehiro Kijima, Seiji Ohtori Department of Orthopaedic Surgery, Chiba University After Graduate School of Medicine, Japan
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Article history: Received 13 October 2018 Received in revised form 9 January 2019 Accepted 12 February 2019 Available online 8 March 2019
Background: Massive rotator cuff tears have a high rate of re-injury because of severe fatty infiltration. Our data showed that injuries proximal to the suprascapular nerve may be one cause of massive rotator cuff tears. The purpose of this study was to evaluate, using a rat model, how brachial plexus injury associated with a massive rotator cuff tear influences healing of the rotator cuff repair. Methods: Seventy SpragueeDawley rats were divided into three groups: rotator cuff tear with BP injury (DT group) (n ¼ 28), rotator cuff tear without brachial plexus injury (T group) (n ¼ 28), and a shamoperated group (n ¼ 14). In the DT group, the rotator cuff tear was made and repaired 4 weeks after brachial plexus ligation. The gross assessment (evaluated the wet weight), biomechanical testing (evaluated the yield stress and the Young's modulus) and histological analyses (using the Bonar scale) were performed at baseline in the sham group, and at 4 and 12 weeks postoperatively in the DT and T groups (n ¼ 7/group/time). Results: Mean wet weight and yield stress were significantly lower in the DT group than in the T group. Additionally, the mean Young's modulus was significantly higher in the DT group than in the T group. Histologically, greater tendon degeneration was observed around the musculotendinous junction in the DT group than in the T group. Conclusion: The gross, biomechanical and histological data show that the repaired rotator cuff tendon with brachial plexus injury in rats does not heal as well as a repaired tendon without an accompanying brachial plexus injury. This suggests that more proximal neuropathy is one risk factor for re-tear of a repaired rotator cuff tendon. © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.
1. Background Rotator cuff (RC) tears are one of the most common shoulder injuries, and result in shoulder pain and joint dysfunction. The treatments for RC tears include both conservative and operative treatments, and when the conservative treatment fails, a RC repair often is performed. However, the re-tear rate after repair has been reported to range from 7 to 57% [1,2]. Re-tear is one of the most influential factors for clinical outcome after surgery [3]. The prognostic factors for re-tear consist of the size of the RC tear and the
* Corresponding author. Department of Orthopaedic Surgery, Chiba University after Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Fax: þ81 43 226 2116. E-mail address: [email protected] (K. Akimoto).
quality of the RC tendon [4,5]. Cofield et al. reported that the postoperative clinical result was rated as good or excellent for 94% of patients with a small RC tear, but poor for 73% of patients with a massive RC tear, suggesting that the size of the RC tear was correlated with postoperative outcome [4]. Khair et al. reported in a systematic review that RCs with moderate or significant preoperative fatty infiltration (Goutallier grades 2e4) correlated with a significantly higher re-tear rate than those with no or minimal fatty infiltration (grades 0e1) [5]. Fatty infiltration of rotator cuff muscles is irreversible and thought to be one prognostic indicator of poor postoperative shoulder function [6]. Suprascapular nerve entrapment at the suprascapular notch or spino-glenoid notch due to a change of the nerve tract caused by a massive RC tear is thought to cause fatty infiltration of the RC muscles [7,8]. However, our previous study
https://doi.org/10.1016/j.jos.2019.02.007 0949-2658/© 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.
K. Akimoto et al. / Journal of Orthopaedic Science 25 (2020) 96e103
showed that a nerve injury proximal to the suprascapular nerve was related to massive RC tears [9,10]. Ochiai et al., using an electromyogram, reported that 48.8% of pseudo-paralyzed shoulders with massive RC tear coexisted with cervical spine lesion while and suggested that proximal neuropathies such as cervical spondylotic amyotrophy, were more common as the size of the tear increased [9]. Furthermore, Vad et al. also reported RC tears concomitant with cervical radiculotpathy and brachial plexopathy using electromyographic examinations [11]. From these studies, neuropathy such as cervical spondylotic amyotrophy and brachial plexopathy concomitant with RC tears would be recognized. Regarding to retear rate after RC repairs, a higher re-tear rate has been reported with massive RC tears [12]. Therefore, we hypothesized that nerve injury proximal to the suprascapular nerve may impair primary healing of affected rotator cuff, which might be one risk factor for postoperative rotator cuff re-tear. The purpose of this study was to evaluate the influence of a nerve injury proximal to the suprascapular nerve on the repaired RC using a rat model of a massive RC tear with brachial plexus (BP) injury. 2. Materials and methods This study has been approved by the ethics committee of the authors' affiliated institutions. 2.1. Materials Seventy 8-week-old SpragueeDawley rats (Charles River Laboratories, Inc., Wilmington, MA), weighing 300e380 g, were randomly divided into a massive RC tear group with BP injury (DT group, n ¼ 28), a massive RC tear group without BP injury (T group, n ¼ 28), and a sham-operated group (n ¼ 14) in which the BP and RC were only exposed surgically (Fig. 1). The rats were housed in a semi-barrier system with a controlled environment (lighting, 12-h light/dark cycle; temperature, 21e23 C; humidity, 45e65%) throughout the study.
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kg, midazolam (Dormicum, Astellas Pharma Inc., Japan) at a dose of 2 mg/kg, and butorphanol (Vetorphale, Meiji Seika Pharma Co., Ltd. Japan) at a dose of 2.5 mg/kg [13]. The BP injury model was created according to the method reported by Sasaki [10]. After skin incision, a longitudinal incision was made through the trapezius muscle, and the part of the muscle attaching to the medial border of the scapula was detached. The BP was exposed by drawing the scapula laterally (Fig. 2a). Ligature of both the superior and inferior trunks of the BP was performed using 4-0 nylon suture (Nescosuture, Alfresa Pharma Corp., Japan) using a force of 1N (Fig. 2b). In the sham group, the BP was exposed by the same procedure, but the ligature of the BP was not performed. 2.3. Creation of the massive RC tear model The massive RC tear model was created according to the method previously reported by Thomopoulos [14] and Liu [15]. In the similar way of creating the BP injury model, rats in the prone position were anesthetized with the anesthesia mixture. A longitudinal skin incision was made from the anterolateral corner of the acromion, and a T-shaped incision was made through the deltoid muscle, exposing the RC, including the supraspinatus (SSP), the infraspinatus (ISP) and the subscapularis (SSC) muscle tendons (Fig. 3a). Each tendon was sharply detached from its attachment to the humerus, and 5 mm long fragments of each tendon were removed (Fig. 3b). Each tendon of the SSP, ISP and SSC were grasped with a doubled armed 4-0 nylon suture using the technique reported by Thomopoulos [14]. The bone tunnels of the greater and lesser tuberosity were created using 23G needle (TERUMO Corp. Japan) at the position where the tendon was anatomically repaired. Trans-osseous reattachment of the SSP, ISP and SSC to the humerus was then performed (Fig. 3c). In the DT group, the detachment and reattachment of the RC tendons were performed 4 weeks after the BP injury. In the sham group, the RC was exposed by the same procedure, but detachment of the RC was not performed (Fig. 1). 2.4. Gross and biomechanical assessment
2.2. Creation of the BP injury model Rats were intraperitoneally anesthetized while in the prone position with a mixture of three types of anesthesia that included medetomidine (Domitor, Orion Corp., Finland) at a dose of 0.15 mg/
Seven rats in each group were sacrificed using an overdose of the three mixed types of anesthesia at 4 and 12 weeks after reattachment of the RC in the T and DT group, and at 4 weeks after exposure of the BP and the RC in the sham group, and both the
Fig. 1. Protocol of this study.
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Fig. 2. The brachial plexus injury model (left shoulder). a. The brachial plexus. b. The ligature of both the superior and inferior trunk of the brachial plexus. Arrowhead (open white): the superior trunk. Arrowhead (black): the inferior trunk. Asterisk: the back of scapula.
Fig. 3. The massive rotator cuff tear model (left shoulder). a. White and black arrowhead indicate the supraspinatus and infraspinatus muscle tendon. Black arrow indicates the greater tuberosity. b. The tendons were detached sharply. c. The tendons were trans-osseously reattached to the humerus.
posterior at the adhesion between the repaired SSP and the tuberosity were evaluated. Microscopy was performed by using a digital microscope (Axioskop 2 Plus, Carl Zeiss, Germany), and a modified Bonar scale was used to evaluate tendon degeneration at the musculotendinous junction which was randomly chosen. This semi-quantitative scoring system consists of four subcategories, including tenocytes, ground substance, collagen and vascularity [10,17]. Each subcategory was scored between 0 and 3, with a higher score indicating more degeneration. We calculated the score for each subcategory and the sum of all subcategory scores. All sections were reviewed by two blinded researchers.
operated and normal sides of the humeral head with attached RC tendons were harvested after removal of the other soft tissue. The specimens were assessed for the condition of adhesion between the repaired RC and the greater and lesser tuberosity and the ratio of operated side to normal side wet weight of RC muscles (wet weight ratio) as gross assessment, and the yield stress and the Young's modulus of the RCs calculated from the tensile test using Autograph® (Shimadzu Corp., Japan) [10] as biomechanical assessment (Fig. 4). For the tensile testing, the tendon was fixed to the custom-made clamp while the humeral head was fixed using a clip. The specimens were stretched to failure at a rate of 10 mm/ min, and both maximum displacement and tear force were recorded on a load-displacement curve. The results were analyzed using the software TRAPEZIUM X (Shimadzu Corp). Each assessment was performed individually on the SSP-ISP complex and the SSC because of the difference in muscle direction and direction of the RC tear. The SSP-ISP complex was assessed, not each of SSP or ISP individually, because the footprint of SSP and ISP partially overlapped at the greater tuberosity [16].
The results were presented as the mean ± standard deviation. The statistical analyses were conducted using SPSS version 19.0® (SPSS Inc., Chicago, IL) and performed using a KruskaleWallis Test and Steel-Dwass test as post-hoc analysis; P values < 0.05 were considered statistically significant for all tests.
2.5. Histological assessment
3. Results
Seven rats in each group were sacrificed and the humerus with RC tendons was harvested at 4 and 12 weeks postoperatively in the same manner as for biomechanical assessment. The humeri were fixed in 10% neutral buffered formalin for 48e72 h, were decalcified with 20% ethylenediamine tetra-acetic acid (EDTA) for 6 weeks, and then were embedded in paraffin. The continuous sections (5 um thick) were cut parallel to the SSP tendon and stained with Masson's trichrome, and 10 sections equally spaced from anterior to
3.1. Gross assessment
2.6. Statistical analysis
No rats died during surgery or postoperatively. In addition, no infection was found in any rats, then all rats were used for each assessment. No rats experienced a re-tear, as the SSP and ISP tendon was attached to the footprint of the greater tuberosity and the SSC tendon was done to the footprint of the lesser one in all groups.
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Fig. 4. Biomechanical assessment. a. The tensile test. The tendon was fixed to the custom-made clamp while the humeral head was fixed using a clip. b. Black arrowhead indicates the rotator cuff tear at the musculotendinous junction.
The average wet weight ratio of the SSP and ISP muscles in the sham group was 0.98 ± 0.02. The ratio in the DT and T groups at 4 weeks postoperatively was 0.68 ± 0.13 and 0.94 ± 0.02, respectively. The wet weight ratio in the DT group was significantly lower than in the T group (p < 0.05). The wet weight ratio in the DT group (0.63 ± 0.17) at 12 weeks postoperatively was also significantly lower than in the T group (0.95 ± 0.02) (p < 0.05). The average ratio of the SSC muscle in the sham group was 0.99 ± 0.01. The ratio in the DT and T groups 4 weeks postoperatively was 0.54 ± 0.16 and 0.93 ± 0.03, respectively, and at 12 weeks postoperatively was 0.49 ± 0.08 and 0.92 ± 0.03. The ratios of the SSC muscles in the DT
group at both 4 and 12 weeks postoperatively were significantly lower than in the T group, a similar pattern to that found in the SSP and ISP muscles (p < 0.05) (Fig. 5). 3.2. Biomechanical assessment 1. Yield stress The average yield stress of the SSP and ISP tendons in the sham group was 6.82 ± 0.52 N/mm2. The yield stress in the DT group was significantly lower than in the T group at both 4 and 12 weeks
Fig. 5. The wet weight ratios of the supraspinatus, infraspinatus and subscapularis muscles in the DT group were significantly lower than in the T group at both 4 and 12 weeks postoperatively.
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postoperatively (4 weeks: 3.57 ± 0.18 and 6.70 ± 1.26 N/mm2; 12 weeks: 3.10 ± 0.17 and 6.16 ± 0.64 N/mm2; both p < 0.05). The yield stress of the SSC tendon in the sham group was 6.74 ± 0.71 N/mm2. The stress of the SSC tendon in the DT group at both 4 and 12 weeks postoperatively was significantly lower than in the T group (4 weeks: 4.11 ± 0.41 and 5.35 ± 0.56 N/mm2; 12 weeks: 3.44 ± 0.26 and 4.91 ± 0.29 N/mm2; both p < 0.05). The yield stress for all tendons in the DT group 12 weeks postoperatively was significantly lower than at 4 weeks postoperatively (p < 0.05), but the stress in the T group was not significantly different between 4 and 12 weeks postoperatively (SSP, ISP; p ¼ 0.36, SSC; p ¼ 0.10) (Fig. 6). 2. Young's modulus The average Young's modulus of the SSP and ISP tendons in the sham group was 4.49 ± 0.67 N/mm2. Modulus in the DT group 4 weeks postoperatively was 5.25 ± 0.27 N/mm2, significantly higher than in the T group (4.60 ± 0.25 N/mm2), and remained significantly greater 12 weeks postoperatively (DT group: 5.87 ± 0.31 N/ mm2; T group: 4.70 ± 0.21 N/mm2; both p < 0.05). The Young's modulus of the SSC tendon in the sham group was 4.56 ± 0.34 N/ mm2. Modulus in the DT and T groups 4 weeks postoperatively was 5.31 ± 0.30 N/mm2 and 4.61 ± 0.18 N/mm2, respectively, and 12 weeks postoperatively was 6.10 ± 0.31 N/mm2 and 4.69 ± 0.29 N/ mm2. The Young's modulus of the SSC tendon in the DT group at both 4 and 12 weeks postoperatively was significantly higher than in the T group (p < 0.05). Furthermore, the Young's modulus of all tendons in the DT group 12 weeks postoperatively was significantly higher than at 4 weeks postoperatively (p < 0.05). On the contrary, modulus of the T group was not significantly different between 4 and 12 weeks postoperatively (SSP, ISP: p ¼ 0.39; SSC: p ¼ 0.56) (Fig. 7). 3.3. Histological assessment No tendon degeneration was observed histologically in the sham group. Although mild degeneration, such as rounding of the
nuclei and slight vascularity, were found 4 weeks postoperatively in the T group, no progression of tendon degeneration was found by 12 weeks postoperatively. On the other hand, tendon degeneration with nuclear changes and increased vascularity were found 4 weeks postoperatively in the DT group, and progressed by 12 weeks postoperatively with an increase in cytoplasm in the tenocytes (Fig. 8). The total Bonar scale scores in the DT group were significantly higher than in the T group at both 4 and 12 weeks postoperatively (both p < 0.05). Furthermore, the total score in the DT group 12 weeks postoperatively was significantly higher than at 4 weeks postoperatively (p < 0.05). On the contrary, scores in the T group were not significantly different between 4 and 12 weeks postoperatively (p ¼ 0.26) (Fig. 9). 4. Discussion There have been some clinical reports that evaluate the influence of nerve injury on RC tears [9,18,19], but few pre-clinical reports. Liu et al. reported that significant and consistent SSP muscle atrophy with fatty infiltration occurred in a rat massive RC tear model after transection of the suprascapular nerve [15]. Rowshan et al. also showed that chronic RC injuries might be associated with neuronal injury of the affected muscle using a rabbit SSC tear model with transection of the subscapular nerve [20]. However, these reports evaluated the relationship between peripheral nerve injury and RC tear, and to our knowledge there have been few reports that evaluate the influence of a nerve injury proximal to the suprascapular nerve on RC tears. Therefore, the importance of the current study is to show the influence of a nerve injury more proximal than the suprascapular nerve on RC tears using a rat model of a massive RC tear with BP injury. In our study, the wet weight ratio of both SSP and SSC of the massive RC tear model with BP injury was significantly lower than without BP injury both 4 and 12 weeks postoperatively. This means that the repaired RC muscles following a BP injury were more atrophic than without BP injury. On biomechanical assessment, the
Fig. 6. The yield stress in the DT group were significantly lower than in the T group at both 4 and 12 weeks postoperatively. Furthermore, the one in the DT group 12 weeks postoperatively was significantly lower than at 4 weeks postoperatively.
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Fig. 7. The Young's modulus in the DT group were significantly higher than in the T group at both postoperative time points. The ones of all tendons in the DT group 12 weeks postoperatively was significantly higher than at 4 weeks postoperatively.
Fig. 8. Histologic assessment of tendon degeneration. Each subcategory of Bonar scale (a: tenocytes, b: ground substance, c: collagen, d: vascularity) was showed in the figure.
yield stress of both SSP and SSC tendons with BP injury were significantly lower than without BP injury, and the Young's modulus of both tendons with BP injury was significantly higher than without BP injury both 4 and 12 weeks postoperatively. This means that RC tendons repaired following BP injury were weaker and less flexible than without BP injury. Furthermore, on histological assessment the Bonar scale scores of both SSP and SSC tendons with BP injury were significantly higher than without BP
injury, suggesting that degeneration of repaired RC tendons following BP injury progressed more than without BP injury. In a previous study using the rat RC tear model, Buchmann et al. found macroscopically that SSP tendon defects showed an increasing coverage with scar tissue over time, with a complete closure in 73% of rats after 9 weeks postoperatively [21]. Gimbel et al. found that degeneration of a torn SSP tendon was significant 2 weeks after the tear, but was nearly healed by 8 weeks after surgery [22]. In this
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Fig. 9. Total scores on the Bonar scale in the DT group were significantly higher than in the T group at both 4 and 12 weeks postoperatively. Furthermore, the total score in the DT group 12 weeks postoperatively was significantly higher.
study using a rat model, there were no significant differences in the yield stress or the Young's modulus of any of the tendons, nor a significant change in the Bonar scale of the SSC tendon between 4 and 12 weeks after a massive RC tear without BP injury. However, when the RC tear was paired with BP injury, the yield stress of the tendons at 12 weeks was significantly lower, and the Young's modulus of all tendons, and the Bonar score of the SSC tendon, were significantly higher than at 4 weeks postoperatively. Thus, degeneration of the repaired RC tendon with the BP injury progressively worsened over time. The results of this study suggest that a nerve injury more proximal than the suprascapular nerve might be one risk factor for postoperative RC re-tear. The best treatment for the massive RC tears with severe fatty infiltration caused by a more proximal nerve injury has not been established clinically. Although the RC repair has been performed for those cases, higher re-tear rates ranging from 20 to 60% have been reported [23,24]. In addition, our study shows that the repaired RC tendon with a nerve injury proximal to the suprascapular nerve is biomechanically and histologically more likely to degenerate. Therefore, for these massive RC tears with proximal nerve injury, we suggest the surgeon consider reconstructions that do not depend on residual RC tendons for good postoperative shoulder function, such as superior capsule reconstruction (Mihata et al. [25]) or reverse total shoulder arthroplasty [26]. There were several limitations to this study. First, the anatomy and function of the shoulder in rat, which is a quadrupedal animal, differ from those of human shoulders [27]. However, the rat has been reported to be an appropriate model for experiments involving RC tears [28]. Second, the mechanism of an RC tear in humans is different than in an experimental animal model because human RC tears are typically multi-factorial, and may involve longterm RC degeneration or chronic sub-acromial impingement [29,30]. Rat RC tears were created in this study by a surgical detachment of the RC tendon from the humerus. However, it is difficult or impossible to reproduce human RC tears completely in a rat model. Third, we used a BP injury model, not a cervical spine lesion model. If possible, it would have been better to use the cervical disease model which is similar to the clinical condition. However, a cervical spondylotic amyotrophy model has not been established, and this BP injury model was thought to be useful for evaluating neuropathy proximal to the suprascapular nerve. This study is the first basic science report to evaluate the influence of a nerve injury proximal to the suprascapular nerve on a
repaired RC, and thus the results of this study provide insight into the treatment of patients with massive RC tears that have severe fatty infiltration caused by a more proximal nerve injury. 5. Conclusion The gross, biomechanical and histological data of this study showed that the repaired rotator cuff tendon of the rat massive rotator cuff tear model with brachial plexus injury does not heal as well as one without brachial plexus injury. Further, it suggests that a more proximal neuropathy, such as a cervical spondylotic amyotrophy or brachial plexopathy, may be one risk factor for retear of the repaired rotator cuff tendon. Conflicts of interest These authors, their immediate family, and any research foundation with which they are affiliated did not receive any financial payments or other benefits from any commercial entity related to the subject of this article. References [1] Lee YS, Jeong JY, Park CD, Kang SG, Yoo JC. Evaluation of the risk factors for a rotator cuff retear after repair surgery. Am J Sports Med 2017 Jul;45(8): 1755e61. [2] Zumstein MA, Jost B, Hempel J, Hodler J, Gerber C. The clinical and structural long-term results of open repair of massive tears of the rotator cuff. J Bone Joint Surg Am 2008 Nov;90(11):2423e31. [3] Sugaya H, Maeda K, Matsuki K, Moriishi J. Repair integrity and functional outcome after arthroscopic double-row rotator cuff repair. A prospective outcome study. J Bone Joint Surg Am 2007 May;89(5):953e60. [4] Cofield RH, Parvizi J, Hoffmeyer PJ, Lanzer WL, Ilstrup DM, Rowland CM. Surgical repair of chronic rotator cuff tears. A prospective long-term study. J Bone Joint Surg Am 2001 Jan;83-A(1):71e7. [5] Khair MM, Lehman J, Tsouris N, Gulotta LV. A systematic review of preoperative fatty infiltration and rotator cuff outcomes. HSS J 2016 Jul;12(2):170e6. [6] Gladstone JN, Bishop JY, Lo IK, Flatow EL. Fatty infiltration and atrophy of the rotator cuff do not improve after rotator cuff repair and correlate with poor functional outcome. Am J Sports Med 2007 May;35(5):719e28. [7] Cummins CA, Messer TM, Nuber GW. Suprascapular nerve entrapment. J Bone Joint Surg Am 2000 Mar;82(3):415e24. [8] Warner JP, Krushell RJ, Masquelet A, Gerber C. Anatomy and relationships of the suprascapular nerve: anatomical constraints to mobilization of the supraspinatus and infraspinatus muscles in the management of massive rotator-cuff tears. J Bone Joint Surg Am 1992 Jan;74(1):36e45. [9] Ochiai N, Hashimoto E, Sasaki Y, Akimoto K, Sugaya H, Takahashi N, Matsuki K. Prevalence of concomitant neuropathy in large to massive rotator cuff tear using needle electromyography. J Shoulder Elbow Surg 2017 Apr;26(4):e111.
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Journal of Orthopaedic Science journal homepage: http://www.elsevier.com/locate/jos
Original Article
Influence of a nerve injury proximal to the suprascapular nerve on healing of repaired rotator cuff tear Koji Akimoto*, Nobuyasu Ochiai, Eiko Hashimoto, Yasuhito Sasaki, Daisuke Nojima, Daisuke Kajiwara, Yusuke Matsuura, Yu Sasaki, Takeshi Yamaguchi, Takehiro Kijima, Seiji Ohtori Department of Orthopaedic Surgery, Chiba University After Graduate School of Medicine, Japan
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a b s t r a c t
Article history: Received 13 October 2018 Received in revised form 9 January 2019 Accepted 12 February 2019 Available online 8 March 2019
Background: Massive rotator cuff tears have a high rate of re-injury because of severe fatty infiltration. Our data showed that injuries proximal to the suprascapular nerve may be one cause of massive rotator cuff tears. The purpose of this study was to evaluate, using a rat model, how brachial plexus injury associated with a massive rotator cuff tear influences healing of the rotator cuff repair. Methods: Seventy SpragueeDawley rats were divided into three groups: rotator cuff tear with BP injury (DT group) (n ¼ 28), rotator cuff tear without brachial plexus injury (T group) (n ¼ 28), and a shamoperated group (n ¼ 14). In the DT group, the rotator cuff tear was made and repaired 4 weeks after brachial plexus ligation. The gross assessment (evaluated the wet weight), biomechanical testing (evaluated the yield stress and the Young's modulus) and histological analyses (using the Bonar scale) were performed at baseline in the sham group, and at 4 and 12 weeks postoperatively in the DT and T groups (n ¼ 7/group/time). Results: Mean wet weight and yield stress were significantly lower in the DT group than in the T group. Additionally, the mean Young's modulus was significantly higher in the DT group than in the T group. Histologically, greater tendon degeneration was observed around the musculotendinous junction in the DT group than in the T group. Conclusion: The gross, biomechanical and histological data show that the repaired rotator cuff tendon with brachial plexus injury in rats does not heal as well as a repaired tendon without an accompanying brachial plexus injury. This suggests that more proximal neuropathy is one risk factor for re-tear of a repaired rotator cuff tendon. © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.
1. Background Rotator cuff (RC) tears are one of the most common shoulder injuries, and result in shoulder pain and joint dysfunction. The treatments for RC tears include both conservative and operative treatments, and when the conservative treatment fails, a RC repair often is performed. However, the re-tear rate after repair has been reported to range from 7 to 57% [1,2]. Re-tear is one of the most influential factors for clinical outcome after surgery [3]. The prognostic factors for re-tear consist of the size of the RC tear and the
* Corresponding author. Department of Orthopaedic Surgery, Chiba University after Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Fax: þ81 43 226 2116. E-mail address: [email protected] (K. Akimoto).
quality of the RC tendon [4,5]. Cofield et al. reported that the postoperative clinical result was rated as good or excellent for 94% of patients with a small RC tear, but poor for 73% of patients with a massive RC tear, suggesting that the size of the RC tear was correlated with postoperative outcome [4]. Khair et al. reported in a systematic review that RCs with moderate or significant preoperative fatty infiltration (Goutallier grades 2e4) correlated with a significantly higher re-tear rate than those with no or minimal fatty infiltration (grades 0e1) [5]. Fatty infiltration of rotator cuff muscles is irreversible and thought to be one prognostic indicator of poor postoperative shoulder function [6]. Suprascapular nerve entrapment at the suprascapular notch or spino-glenoid notch due to a change of the nerve tract caused by a massive RC tear is thought to cause fatty infiltration of the RC muscles [7,8]. However, our previous study
https://doi.org/10.1016/j.jos.2019.02.007 0949-2658/© 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.
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showed that a nerve injury proximal to the suprascapular nerve was related to massive RC tears [9,10]. Ochiai et al., using an electromyogram, reported that 48.8% of pseudo-paralyzed shoulders with massive RC tear coexisted with cervical spine lesion while and suggested that proximal neuropathies such as cervical spondylotic amyotrophy, were more common as the size of the tear increased [9]. Furthermore, Vad et al. also reported RC tears concomitant with cervical radiculotpathy and brachial plexopathy using electromyographic examinations [11]. From these studies, neuropathy such as cervical spondylotic amyotrophy and brachial plexopathy concomitant with RC tears would be recognized. Regarding to retear rate after RC repairs, a higher re-tear rate has been reported with massive RC tears [12]. Therefore, we hypothesized that nerve injury proximal to the suprascapular nerve may impair primary healing of affected rotator cuff, which might be one risk factor for postoperative rotator cuff re-tear. The purpose of this study was to evaluate the influence of a nerve injury proximal to the suprascapular nerve on the repaired RC using a rat model of a massive RC tear with brachial plexus (BP) injury. 2. Materials and methods This study has been approved by the ethics committee of the authors' affiliated institutions. 2.1. Materials Seventy 8-week-old SpragueeDawley rats (Charles River Laboratories, Inc., Wilmington, MA), weighing 300e380 g, were randomly divided into a massive RC tear group with BP injury (DT group, n ¼ 28), a massive RC tear group without BP injury (T group, n ¼ 28), and a sham-operated group (n ¼ 14) in which the BP and RC were only exposed surgically (Fig. 1). The rats were housed in a semi-barrier system with a controlled environment (lighting, 12-h light/dark cycle; temperature, 21e23 C; humidity, 45e65%) throughout the study.
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kg, midazolam (Dormicum, Astellas Pharma Inc., Japan) at a dose of 2 mg/kg, and butorphanol (Vetorphale, Meiji Seika Pharma Co., Ltd. Japan) at a dose of 2.5 mg/kg [13]. The BP injury model was created according to the method reported by Sasaki [10]. After skin incision, a longitudinal incision was made through the trapezius muscle, and the part of the muscle attaching to the medial border of the scapula was detached. The BP was exposed by drawing the scapula laterally (Fig. 2a). Ligature of both the superior and inferior trunks of the BP was performed using 4-0 nylon suture (Nescosuture, Alfresa Pharma Corp., Japan) using a force of 1N (Fig. 2b). In the sham group, the BP was exposed by the same procedure, but the ligature of the BP was not performed. 2.3. Creation of the massive RC tear model The massive RC tear model was created according to the method previously reported by Thomopoulos [14] and Liu [15]. In the similar way of creating the BP injury model, rats in the prone position were anesthetized with the anesthesia mixture. A longitudinal skin incision was made from the anterolateral corner of the acromion, and a T-shaped incision was made through the deltoid muscle, exposing the RC, including the supraspinatus (SSP), the infraspinatus (ISP) and the subscapularis (SSC) muscle tendons (Fig. 3a). Each tendon was sharply detached from its attachment to the humerus, and 5 mm long fragments of each tendon were removed (Fig. 3b). Each tendon of the SSP, ISP and SSC were grasped with a doubled armed 4-0 nylon suture using the technique reported by Thomopoulos [14]. The bone tunnels of the greater and lesser tuberosity were created using 23G needle (TERUMO Corp. Japan) at the position where the tendon was anatomically repaired. Trans-osseous reattachment of the SSP, ISP and SSC to the humerus was then performed (Fig. 3c). In the DT group, the detachment and reattachment of the RC tendons were performed 4 weeks after the BP injury. In the sham group, the RC was exposed by the same procedure, but detachment of the RC was not performed (Fig. 1). 2.4. Gross and biomechanical assessment
2.2. Creation of the BP injury model Rats were intraperitoneally anesthetized while in the prone position with a mixture of three types of anesthesia that included medetomidine (Domitor, Orion Corp., Finland) at a dose of 0.15 mg/
Seven rats in each group were sacrificed using an overdose of the three mixed types of anesthesia at 4 and 12 weeks after reattachment of the RC in the T and DT group, and at 4 weeks after exposure of the BP and the RC in the sham group, and both the
Fig. 1. Protocol of this study.
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Fig. 2. The brachial plexus injury model (left shoulder). a. The brachial plexus. b. The ligature of both the superior and inferior trunk of the brachial plexus. Arrowhead (open white): the superior trunk. Arrowhead (black): the inferior trunk. Asterisk: the back of scapula.
Fig. 3. The massive rotator cuff tear model (left shoulder). a. White and black arrowhead indicate the supraspinatus and infraspinatus muscle tendon. Black arrow indicates the greater tuberosity. b. The tendons were detached sharply. c. The tendons were trans-osseously reattached to the humerus.
posterior at the adhesion between the repaired SSP and the tuberosity were evaluated. Microscopy was performed by using a digital microscope (Axioskop 2 Plus, Carl Zeiss, Germany), and a modified Bonar scale was used to evaluate tendon degeneration at the musculotendinous junction which was randomly chosen. This semi-quantitative scoring system consists of four subcategories, including tenocytes, ground substance, collagen and vascularity [10,17]. Each subcategory was scored between 0 and 3, with a higher score indicating more degeneration. We calculated the score for each subcategory and the sum of all subcategory scores. All sections were reviewed by two blinded researchers.
operated and normal sides of the humeral head with attached RC tendons were harvested after removal of the other soft tissue. The specimens were assessed for the condition of adhesion between the repaired RC and the greater and lesser tuberosity and the ratio of operated side to normal side wet weight of RC muscles (wet weight ratio) as gross assessment, and the yield stress and the Young's modulus of the RCs calculated from the tensile test using Autograph® (Shimadzu Corp., Japan) [10] as biomechanical assessment (Fig. 4). For the tensile testing, the tendon was fixed to the custom-made clamp while the humeral head was fixed using a clip. The specimens were stretched to failure at a rate of 10 mm/ min, and both maximum displacement and tear force were recorded on a load-displacement curve. The results were analyzed using the software TRAPEZIUM X (Shimadzu Corp). Each assessment was performed individually on the SSP-ISP complex and the SSC because of the difference in muscle direction and direction of the RC tear. The SSP-ISP complex was assessed, not each of SSP or ISP individually, because the footprint of SSP and ISP partially overlapped at the greater tuberosity [16].
The results were presented as the mean ± standard deviation. The statistical analyses were conducted using SPSS version 19.0® (SPSS Inc., Chicago, IL) and performed using a KruskaleWallis Test and Steel-Dwass test as post-hoc analysis; P values < 0.05 were considered statistically significant for all tests.
2.5. Histological assessment
3. Results
Seven rats in each group were sacrificed and the humerus with RC tendons was harvested at 4 and 12 weeks postoperatively in the same manner as for biomechanical assessment. The humeri were fixed in 10% neutral buffered formalin for 48e72 h, were decalcified with 20% ethylenediamine tetra-acetic acid (EDTA) for 6 weeks, and then were embedded in paraffin. The continuous sections (5 um thick) were cut parallel to the SSP tendon and stained with Masson's trichrome, and 10 sections equally spaced from anterior to
3.1. Gross assessment
2.6. Statistical analysis
No rats died during surgery or postoperatively. In addition, no infection was found in any rats, then all rats were used for each assessment. No rats experienced a re-tear, as the SSP and ISP tendon was attached to the footprint of the greater tuberosity and the SSC tendon was done to the footprint of the lesser one in all groups.
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Fig. 4. Biomechanical assessment. a. The tensile test. The tendon was fixed to the custom-made clamp while the humeral head was fixed using a clip. b. Black arrowhead indicates the rotator cuff tear at the musculotendinous junction.
The average wet weight ratio of the SSP and ISP muscles in the sham group was 0.98 ± 0.02. The ratio in the DT and T groups at 4 weeks postoperatively was 0.68 ± 0.13 and 0.94 ± 0.02, respectively. The wet weight ratio in the DT group was significantly lower than in the T group (p < 0.05). The wet weight ratio in the DT group (0.63 ± 0.17) at 12 weeks postoperatively was also significantly lower than in the T group (0.95 ± 0.02) (p < 0.05). The average ratio of the SSC muscle in the sham group was 0.99 ± 0.01. The ratio in the DT and T groups 4 weeks postoperatively was 0.54 ± 0.16 and 0.93 ± 0.03, respectively, and at 12 weeks postoperatively was 0.49 ± 0.08 and 0.92 ± 0.03. The ratios of the SSC muscles in the DT
group at both 4 and 12 weeks postoperatively were significantly lower than in the T group, a similar pattern to that found in the SSP and ISP muscles (p < 0.05) (Fig. 5). 3.2. Biomechanical assessment 1. Yield stress The average yield stress of the SSP and ISP tendons in the sham group was 6.82 ± 0.52 N/mm2. The yield stress in the DT group was significantly lower than in the T group at both 4 and 12 weeks
Fig. 5. The wet weight ratios of the supraspinatus, infraspinatus and subscapularis muscles in the DT group were significantly lower than in the T group at both 4 and 12 weeks postoperatively.
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postoperatively (4 weeks: 3.57 ± 0.18 and 6.70 ± 1.26 N/mm2; 12 weeks: 3.10 ± 0.17 and 6.16 ± 0.64 N/mm2; both p < 0.05). The yield stress of the SSC tendon in the sham group was 6.74 ± 0.71 N/mm2. The stress of the SSC tendon in the DT group at both 4 and 12 weeks postoperatively was significantly lower than in the T group (4 weeks: 4.11 ± 0.41 and 5.35 ± 0.56 N/mm2; 12 weeks: 3.44 ± 0.26 and 4.91 ± 0.29 N/mm2; both p < 0.05). The yield stress for all tendons in the DT group 12 weeks postoperatively was significantly lower than at 4 weeks postoperatively (p < 0.05), but the stress in the T group was not significantly different between 4 and 12 weeks postoperatively (SSP, ISP; p ¼ 0.36, SSC; p ¼ 0.10) (Fig. 6). 2. Young's modulus The average Young's modulus of the SSP and ISP tendons in the sham group was 4.49 ± 0.67 N/mm2. Modulus in the DT group 4 weeks postoperatively was 5.25 ± 0.27 N/mm2, significantly higher than in the T group (4.60 ± 0.25 N/mm2), and remained significantly greater 12 weeks postoperatively (DT group: 5.87 ± 0.31 N/ mm2; T group: 4.70 ± 0.21 N/mm2; both p < 0.05). The Young's modulus of the SSC tendon in the sham group was 4.56 ± 0.34 N/ mm2. Modulus in the DT and T groups 4 weeks postoperatively was 5.31 ± 0.30 N/mm2 and 4.61 ± 0.18 N/mm2, respectively, and 12 weeks postoperatively was 6.10 ± 0.31 N/mm2 and 4.69 ± 0.29 N/ mm2. The Young's modulus of the SSC tendon in the DT group at both 4 and 12 weeks postoperatively was significantly higher than in the T group (p < 0.05). Furthermore, the Young's modulus of all tendons in the DT group 12 weeks postoperatively was significantly higher than at 4 weeks postoperatively (p < 0.05). On the contrary, modulus of the T group was not significantly different between 4 and 12 weeks postoperatively (SSP, ISP: p ¼ 0.39; SSC: p ¼ 0.56) (Fig. 7). 3.3. Histological assessment No tendon degeneration was observed histologically in the sham group. Although mild degeneration, such as rounding of the
nuclei and slight vascularity, were found 4 weeks postoperatively in the T group, no progression of tendon degeneration was found by 12 weeks postoperatively. On the other hand, tendon degeneration with nuclear changes and increased vascularity were found 4 weeks postoperatively in the DT group, and progressed by 12 weeks postoperatively with an increase in cytoplasm in the tenocytes (Fig. 8). The total Bonar scale scores in the DT group were significantly higher than in the T group at both 4 and 12 weeks postoperatively (both p < 0.05). Furthermore, the total score in the DT group 12 weeks postoperatively was significantly higher than at 4 weeks postoperatively (p < 0.05). On the contrary, scores in the T group were not significantly different between 4 and 12 weeks postoperatively (p ¼ 0.26) (Fig. 9). 4. Discussion There have been some clinical reports that evaluate the influence of nerve injury on RC tears [9,18,19], but few pre-clinical reports. Liu et al. reported that significant and consistent SSP muscle atrophy with fatty infiltration occurred in a rat massive RC tear model after transection of the suprascapular nerve [15]. Rowshan et al. also showed that chronic RC injuries might be associated with neuronal injury of the affected muscle using a rabbit SSC tear model with transection of the subscapular nerve [20]. However, these reports evaluated the relationship between peripheral nerve injury and RC tear, and to our knowledge there have been few reports that evaluate the influence of a nerve injury proximal to the suprascapular nerve on RC tears. Therefore, the importance of the current study is to show the influence of a nerve injury more proximal than the suprascapular nerve on RC tears using a rat model of a massive RC tear with BP injury. In our study, the wet weight ratio of both SSP and SSC of the massive RC tear model with BP injury was significantly lower than without BP injury both 4 and 12 weeks postoperatively. This means that the repaired RC muscles following a BP injury were more atrophic than without BP injury. On biomechanical assessment, the
Fig. 6. The yield stress in the DT group were significantly lower than in the T group at both 4 and 12 weeks postoperatively. Furthermore, the one in the DT group 12 weeks postoperatively was significantly lower than at 4 weeks postoperatively.
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Fig. 7. The Young's modulus in the DT group were significantly higher than in the T group at both postoperative time points. The ones of all tendons in the DT group 12 weeks postoperatively was significantly higher than at 4 weeks postoperatively.
Fig. 8. Histologic assessment of tendon degeneration. Each subcategory of Bonar scale (a: tenocytes, b: ground substance, c: collagen, d: vascularity) was showed in the figure.
yield stress of both SSP and SSC tendons with BP injury were significantly lower than without BP injury, and the Young's modulus of both tendons with BP injury was significantly higher than without BP injury both 4 and 12 weeks postoperatively. This means that RC tendons repaired following BP injury were weaker and less flexible than without BP injury. Furthermore, on histological assessment the Bonar scale scores of both SSP and SSC tendons with BP injury were significantly higher than without BP
injury, suggesting that degeneration of repaired RC tendons following BP injury progressed more than without BP injury. In a previous study using the rat RC tear model, Buchmann et al. found macroscopically that SSP tendon defects showed an increasing coverage with scar tissue over time, with a complete closure in 73% of rats after 9 weeks postoperatively [21]. Gimbel et al. found that degeneration of a torn SSP tendon was significant 2 weeks after the tear, but was nearly healed by 8 weeks after surgery [22]. In this
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Fig. 9. Total scores on the Bonar scale in the DT group were significantly higher than in the T group at both 4 and 12 weeks postoperatively. Furthermore, the total score in the DT group 12 weeks postoperatively was significantly higher.
study using a rat model, there were no significant differences in the yield stress or the Young's modulus of any of the tendons, nor a significant change in the Bonar scale of the SSC tendon between 4 and 12 weeks after a massive RC tear without BP injury. However, when the RC tear was paired with BP injury, the yield stress of the tendons at 12 weeks was significantly lower, and the Young's modulus of all tendons, and the Bonar score of the SSC tendon, were significantly higher than at 4 weeks postoperatively. Thus, degeneration of the repaired RC tendon with the BP injury progressively worsened over time. The results of this study suggest that a nerve injury more proximal than the suprascapular nerve might be one risk factor for postoperative RC re-tear. The best treatment for the massive RC tears with severe fatty infiltration caused by a more proximal nerve injury has not been established clinically. Although the RC repair has been performed for those cases, higher re-tear rates ranging from 20 to 60% have been reported [23,24]. In addition, our study shows that the repaired RC tendon with a nerve injury proximal to the suprascapular nerve is biomechanically and histologically more likely to degenerate. Therefore, for these massive RC tears with proximal nerve injury, we suggest the surgeon consider reconstructions that do not depend on residual RC tendons for good postoperative shoulder function, such as superior capsule reconstruction (Mihata et al. [25]) or reverse total shoulder arthroplasty [26]. There were several limitations to this study. First, the anatomy and function of the shoulder in rat, which is a quadrupedal animal, differ from those of human shoulders [27]. However, the rat has been reported to be an appropriate model for experiments involving RC tears [28]. Second, the mechanism of an RC tear in humans is different than in an experimental animal model because human RC tears are typically multi-factorial, and may involve longterm RC degeneration or chronic sub-acromial impingement [29,30]. Rat RC tears were created in this study by a surgical detachment of the RC tendon from the humerus. However, it is difficult or impossible to reproduce human RC tears completely in a rat model. Third, we used a BP injury model, not a cervical spine lesion model. If possible, it would have been better to use the cervical disease model which is similar to the clinical condition. However, a cervical spondylotic amyotrophy model has not been established, and this BP injury model was thought to be useful for evaluating neuropathy proximal to the suprascapular nerve. This study is the first basic science report to evaluate the influence of a nerve injury proximal to the suprascapular nerve on a
repaired RC, and thus the results of this study provide insight into the treatment of patients with massive RC tears that have severe fatty infiltration caused by a more proximal nerve injury. 5. Conclusion The gross, biomechanical and histological data of this study showed that the repaired rotator cuff tendon of the rat massive rotator cuff tear model with brachial plexus injury does not heal as well as one without brachial plexus injury. Further, it suggests that a more proximal neuropathy, such as a cervical spondylotic amyotrophy or brachial plexopathy, may be one risk factor for retear of the repaired rotator cuff tendon. Conflicts of interest These authors, their immediate family, and any research foundation with which they are affiliated did not receive any financial payments or other benefits from any commercial entity related to the subject of this article. References [1] Lee YS, Jeong JY, Park CD, Kang SG, Yoo JC. Evaluation of the risk factors for a rotator cuff retear after repair surgery. Am J Sports Med 2017 Jul;45(8): 1755e61. [2] Zumstein MA, Jost B, Hempel J, Hodler J, Gerber C. The clinical and structural long-term results of open repair of massive tears of the rotator cuff. J Bone Joint Surg Am 2008 Nov;90(11):2423e31. [3] Sugaya H, Maeda K, Matsuki K, Moriishi J. Repair integrity and functional outcome after arthroscopic double-row rotator cuff repair. A prospective outcome study. J Bone Joint Surg Am 2007 May;89(5):953e60. [4] Cofield RH, Parvizi J, Hoffmeyer PJ, Lanzer WL, Ilstrup DM, Rowland CM. Surgical repair of chronic rotator cuff tears. A prospective long-term study. J Bone Joint Surg Am 2001 Jan;83-A(1):71e7. [5] Khair MM, Lehman J, Tsouris N, Gulotta LV. A systematic review of preoperative fatty infiltration and rotator cuff outcomes. HSS J 2016 Jul;12(2):170e6. [6] Gladstone JN, Bishop JY, Lo IK, Flatow EL. Fatty infiltration and atrophy of the rotator cuff do not improve after rotator cuff repair and correlate with poor functional outcome. Am J Sports Med 2007 May;35(5):719e28. [7] Cummins CA, Messer TM, Nuber GW. Suprascapular nerve entrapment. J Bone Joint Surg Am 2000 Mar;82(3):415e24. [8] Warner JP, Krushell RJ, Masquelet A, Gerber C. Anatomy and relationships of the suprascapular nerve: anatomical constraints to mobilization of the supraspinatus and infraspinatus muscles in the management of massive rotator-cuff tears. J Bone Joint Surg Am 1992 Jan;74(1):36e45. [9] Ochiai N, Hashimoto E, Sasaki Y, Akimoto K, Sugaya H, Takahashi N, Matsuki K. Prevalence of concomitant neuropathy in large to massive rotator cuff tear using needle electromyography. J Shoulder Elbow Surg 2017 Apr;26(4):e111.
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