Cell‐based tissue engineering augments tendon‐to‐bone healing in a rat supraspinatus model

Rotator cuff pathology causes substantial pain/disability and health care costs. Cell‐based tissue engineering offers promise for improved outcomes in tendon to bone healing. Cells from the tendon‐bone interface were used here to amplify surgical defect healing in a rat model. Cells from tendon‐to‐bone interface of the rotator cuff were seeded in sponges and implanted into critical rotator cuff defects: Group I, control; II, surgical defect only; III, suture‐repaired defect; IV, surgical defect, repair with sponge only; V, surgical defect, repair with sponge with cells. Three, 6‐, and 12‐week results were assessed for histologic features. At 3 weeks, histologic indices in Group V were significantly increased versus other treatment groups. Group V (12 weeks) showed significantly improved collagen organization versus other treatment groups; there was no difference in collagen organization in Group I versus V. In summary, increased cellularity, inflammation, vascularity, and collagen organization were present at 3 weeks; increased collagen organization at 12 weeks in Group V provides evidence for improved healing with cells. Data further support the utility of tendon‐bone interface cells in rotator cuff healing. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 407–412, 2013     

A rat model of massive rotator cuff tears

Rotator cuff tears (RCTs) are the most common tendon injury seen in orthopedic patients. Massive RCT does not heal spontaneously and results in poor clinical outcomes. Muscle atrophy and fatty infiltration in rotator cuff muscles are major complications of chronic massive RCT and are thought to be the key factors responsible for the failure of attempted massive RCT repair. However, the pathophysiology of rotator cuff muscle atrophy and fat infiltration remains largely unknown, and no small animal model has been shown to reproduce the histologic and molecular changes seen in massive RCT. In this article, we report a novel rat massive RCT model, in which significant and consistent muscle atrophy and fat infiltration were observed in the rotator cuff muscles after rotator cuff tendon transection and denervation. The supraspinatus and infraspinatus muscle lost 25.4% and 28.9% of their wet weight 2 weeks after complete tendon transection, respectively. Six weeks after surgery, the average wet weight of supraspinatus and infraspinatus muscles decreased 13.2% and 28.3%, respectively. Significant fat infiltration was only observed in infraspinatus 6 weeks after tendon transection. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:588–595, 2011     

Results of reconstruction of massive irreparable rotator cuff tears using a fascia lata allograft

Background:Despite the advances in surgical treatment options, massive rotator cuff (r-c) tears still represent a challenge for orthopedic surgeons. This study assesses the effectiveness of fascia lata allograft in reconstruction of massive and irreparable r-c tear and to evaluate the healing and functional outcomes.Results:Postoperative constant score increased from 32.5 preoperatively to 88.7 postoperatively. The most important was the pain relief from 2.4 preoperatively to 14.1 postoperatively and range of motion. The results of the MRI were not reliable, but the ultrasound was satisfactory. Finally, there was no infection or rejection of the graft in any of the patients.Conclusions:Despite advances in surgical methods, there is still not a universally accepted treatment for massive and irreparable rotator cuff tears, because the standard methods have dubious results, with excessive retear rates and poor outcomes, necessitating the need for new repair strategies. We documented significant clinical improvement using fascia lata allograft in the repair of massive irreparable r-c tear, acting as scaffold to bridge the defect, enhancing the healing at the repair site.     

Pulsed electromagnetic field therapy improves tendon‐to‐bone healing in a rat rotator cuff repair model

Rotator cuff tears are common musculoskeletal injuries often requiring surgical intervention with high failure rates. Currently, pulsed electromagnetic fields (PEMFs) are used for treatment of long‐bone fracture and lumbar and cervical spine fusion surgery. Clinical studies examining the effects of PEMF on soft tissue healing show promising results. Therefore, we investigated the role of PEMF on rotator cuff healing using a rat rotator cuff repair model. We hypothesized that PEMF exposure following rotator cuff repair would improve tendon mechanical properties, tissue morphology, and alter in vivo joint function. Seventy adult male Sprague–Dawley rats were assigned to three groups: bilateral repair with PEMF (n = 30), bilateral repair followed by cage activity (n = 30), and uninjured control with cage activity (n = 10). Rats in the surgical groups were sacrificed at 4, 8, and 16 weeks. Control group was sacrificed at 8 weeks. Passive joint mechanics and gait analysis were assessed over time. Biomechanical analysis and μCT was performed on left shoulders; histological analysis on right shoulders. Results indicate no differences in passive joint mechanics and ambulation. At 4 weeks the PEMF group had decreased cross‐sectional area and increased modulus and maximum stress. At 8 weeks the PEMF group had increased modulus and more rounded cells in the midsubstance. At 16 weeks the PEMF group had improved bone quality. Therefore, results indicate that PEMF improves early tendon healing and does not alter joint function in a rat rotator cuff repair model. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:902–909, 2017.

     

Restoration of anterior–posterior rotator cuff force balance improves shoulder function in a rat model of chronic massive tears

The rotator cuff musculature imparts dynamic stability to the glenohumeral joint. In particular, the balance between the subscapularis anteriorly and the infraspinatus posteriorly, often referred to as the rotator cuff “force couple,” is critical for concavity compression and concentric rotation of the humeral head. Restoration of this anterior–posterior force balance after chronic, massive rotator cuff tears may allow for deltoid compensation, but no in vivo studies have quantitatively demonstrated an improvement in shoulder function. Our goal was to determine if restoring this balance of forces improves shoulder function after two‐tendon rotator cuff tears in a rat model. Forty‐eight rats underwent detachment of the supraspinatus and infraspinatus. After four weeks, rats were randomly assigned to three groups: no repair, infraspinatus repair, and two‐tendon repair. Quantitative ambulatory measures including medial/lateral forces, braking, propulsion, and step width were significantly different between the infraspinatus and no repair group and similar between the infraspinatus and two‐tendon repair groups at almost all time points. These results suggest that repairing the infraspinatus back to its insertion site without repair of the supraspinatus can improve shoulder function to a level similar to repairing both the infraspinatus and supraspinatus tendons. Clinically, a partial repair of the posterior cuff after a two‐tendon tear may be sufficient to restore adequate function. An in vivo model system for two‐tendon repair of massive rotator cuff tears is presented. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29: 1028–1033, 2011     

Healing rates for challenging rotator cuff tears utilizing an acellular human dermal reinforcement graft

Purpose:

This study presents a retrospective case series of the clinical and structural outcomes (1.5 T MRI) of arthroscopic rotator cuff repair with acellular human dermal graft reinforcement performed by a single surgeon in patients with large, massive, and previously repaired rotator cuff tears.

Materials and Methods:

Fourteen patients with mean anterior to posterior tear size 3.87 ± 0.99 cm (median 4 cm, range 2.5–6 cm) were enrolled in the study and were evaluated for structural integrity using a high-field (1.5 T) MRI at an average of 16.8 months after surgery. The Constant-Murley scores, the Flexilevel Scale of Shoulder Function (Flex SF), scapular plane abduction, and strength were analyzed.

Results:

MRI results showed that the rotator cuff repair was intact in 85.7% (12/14) of the patients studied. Two patients had a Sugaya Type IV recurrent tear (2 of 14; 14.3%), which were both less than 1 cm. The Constant score increased from a preoperative mean of 49.72 (range 13–74) to a postoperative mean of 81.07 (range 45–92) (P value = 0.009). Flexilevel Scale of Shoulder Function (Flex SF) Score normalized to a 100-point scale improved from a preoperative mean of 53.69 to a postoperative mean of 79.71 (P value = 0.003). The Pain Score improved from a preoperative mean of 7.73 to a postoperative mean of 13.57 (P value = 0.008). Scapular plane abduction improved from a preoperative mean of 113.64° to a postoperative mean of 166.43° (P value = 0.010). The strength subset score improved from a preoperative mean of 1.73 kg to a postoperative mean of 7.52 kg (P value = 0.006).

Conclusions:

This study presents a safe and effective technique that may help improve the healing rates of large, massive, and revision rotator cuff tears with the use of an acellular human dermal allograft. This technique demonstrated favorable structural healing rates and statistically improved functional outcomes in the near term.

Level of Evidence:

4. Retrospective case series.     

Long-term outcome and structural integrity following open repair of massive rotator cuff tears

Background:

Surgical repair of massive rotator cuff tears is associated with less favorable clinical results and a higher retear rate than repair of smaller tears, which is attributed to irreversible degenerative changes of the musculotendinous unit.

Materials and Methods:

During the study period, 25 consecutive patients with a massive rotator cuff tear were enrolled in the study and the tears were repaired with an open suture anchor repair technique. Preoperative and postoperative clinical assessments were performed with the Constant score, the simple shoulder test (SST) and a pain visual analog scale (VAS). At the final follow-up, rotator cuff strength measurement was evaluated and assessment of tendon integrity, fatty degeneration and muscle atrophy was done using a standardized magnetic resonance imaging protocol.

Results:

The mean follow-up period was 70 months. The mean constant score improved significantly from 42.3 to 73.1 points at the final follow-up. Both the SST and the pain VAS improved significantly from 5.3 to 10.2 points and from 6.3 to 2.1, respectively. The overall retear rate was 44% after 6 years. Patients with an intact repair had better shoulder scores and rotator cuff strength than those with a failed repair, and also the retear group showed a significant clinical improvement (each P<0.05). Rotator cuff strength in all testing positions was significantly reduced for the operated compared to the contralateral shoulder. Muscle atrophy and fatty infiltration of the rotator cuff muscles did not recover in intact repairs, whereas both parameters progressed in retorn cuffs.

Conclusions:

Open repair of massive rotator tears achieved high patient satisfaction and a good clinical outcome at the long-term follow-up despite a high retear rate. Also, shoulders with retorn cuffs were significantly improved by the procedure. Muscle atrophy and fatty muscle degeneration could not be reversed after repair and rotator cuff strength still did not equal that of the contralateral shoulder after 6 years.

Level of evidence:

Level IV     

Sustained delivery of transforming growth factor beta three enhances tendon‐to‐bone healing in a rat model

Despite advances in surgical technique, rotator cuff repairs are plagued by a high rate of failure. This failure rate is in part due to poor tendon‐to‐bone healing; rather than regeneration of a fibrocartilaginous attachment, the repair is filled with disorganized fibrovascular (scar) tissue. Transforming growth factor beta 3 (TGF‐β3) has been implicated in fetal development and scarless fetal healing and, thus, exogenous addition of TGF‐β3 may enhance tendon‐to‐bone healing. We hypothesized that: TGF‐β3 could be released in a controlled manner using a heparin/fibrin‐based delivery system (HBDS); and delivery of TGF‐β3 at the healing tendon‐to‐bone insertion would lead to improvements in biomechanical properties compared to untreated controls. After demonstrating that the release kinetics of TGF‐β3 could be controlled using a HBDS in vitro, matrices were incorporated at the repaired supraspinatus tendon‐to‐bone insertions of rats. Animals were sacrificed at 14–56 days. Repaired insertions were assessed using histology (for inflammation, vascularity, and cell proliferation) and biomechanics (for structural and mechanical properties). TGF‐β3 treatment in vivo accelerated the healing process, with increases in inflammation, cellularity, vascularity, and cell proliferation at the early timepoints. Moreover, sustained delivery of TGF‐β3 to the healing tendon‐to‐bone insertion led to significant improvements in structural properties at 28 days and in material properties at 56 days compared to controls. We concluded that TGF‐β3 delivered at a sustained rate using a HBDS enhanced tendon‐to‐bone healing in a rat model. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29: 1099–1105, 2011     

Outcome analysis of arthroscopic treatment of partial thickness rotator cuff tears

Background:

Partial thickness rotator cuff tears occupy an important position in the spectrum of rotator cuff disease. The development of a more comprehensive classification has been sought to address both the tear location and extent, which may influence clinical results. The purpose of this study is to classify partial thickness rotator cuff tears according to the arthroscopic findings and to evaluate the clinical outcomes after arthroscopic repair of partial thickness tears.

Materials and Methods:

One hundred and two patients had arthroscopic treatment of partial thickness rotator cuff tears. The inclusion criterion for the study was a partially torn supraspinatus tendon involving articular or bursal side, verified by direct arthroscopic visualization. Outcome analysis was exclusively applied to patients who underwent transtendon repair, using the shoulder index of American Shoulder and Elbow Society and the University of California Los Angeles (UCLA) rating system.

Results:

Partial thickness rotator cuff tears were divided into five groups according to arthroscopic findings. There was significant improvement after surgery in all parameters of clinical evaluation in the tears that warranted repair. Arthroscopic repair in situ (transtendon technique) may be the preferred option in unstable partial thickness tear.

Conclusion:

The proposed classification system may assist decision making in the treatment of partial thickness rotator cuff tears.     

Assessment of pain‐related behavior and pro‐inflammatory cytokine levels in the rat rotator cuff tear model

The cause of pain following rotator cuff tear has not been fully elucidated. The purpose of this study was to evaluate behavior and inflammatory cytokines in a rat unstabilized rotator cuff defect (UCD) model. Forty‐five Sprague–Dawley rats were divided into three groups: sham; UCD; and stabilized rotator cuff defect (SCD). Gait analysis was examined using CatWalk. Tumor necrosis factor (TNF)‐α, interleukin(IL)‐1β, and IL‐6 were measured within the subacromial bursa and the glenohumeral joint synovium at 21 and 56 days after surgery using an enzyme‐linked immunosorbent assay (ELISA). Stride length, print area and contact intensity in the UCD group was significantly lower than in the sham group after surgery. Stride length, print area and contact intensity in the SCD group was significantly higher than in the UCD group. In contrast, TNF‐α, IL‐1β, and IL‐6 in the UCD group was significantly higher than in the sham group at days 21 and 56. However, TNF‐α, IL‐1β, and IL‐6 in the SCD group was significantly lower than in the UCD group at days 21 and 56. The present results suggest that SCD is effective not only in improving shoulder function but also in reducing inflammatory cytokines, which may serve as one source of pain due to rotator cuff tear. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:286–290, 2014.     

Rotator cuff repair using cell sheets derived from human rotator cuff in a rat model

To achieve biological regeneration of tendon‐bone junctions, cell sheets of human rotator‐cuff derived cells were used in a rat rotator cuff injury model. Human rotator‐cuff derived cells were isolated, and cell sheets were made using temperature‐responsive culture plates. Infraspinatus tendons in immunodeficient rats were resected bilaterally at the enthesis. In right shoulders, infraspinatus tendons were repaired by the transosseous method and covered with the cell sheet (sheet group), whereas the left infraspinatus tendons were repaired in the same way without the cell sheet (control group). Histological examinations (safranin‐O and fast green staining, isolectin B4, type II collagen, and human‐specific CD31) and mRNA expression (vascular endothelial growth factor; VEGF, type II collagen; Col2, and tenomodulin; TeM) were analyzed 4 weeks after surgery. Biomechanical tests were performed at 8 weeks. In the sheet group, proteoglycan at the enthesis with more type II collagen and isolectin B4 positive cells were seen compared with in the control group. Human specific CD31‐positive cells were detected only in the sheet group. VEGF and Col2 gene expressions were higher and TeM gene expression was lower in the sheet group than in the control group. In mechanical testing, the sheet group showed a significantly higher ultimate failure load than the control group at 8 weeks. Our results indicated that the rotator‐cuff derived cell sheet could promote cartilage regeneration and angiogenesis at the enthesis, with superior mechanical strength compared with the control. Treatment for rotator cuff injury using cell sheets could be a promising strategy for enthesis of tendon tissue engineering. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:289–296, 2017.

     

Treatment of massive irreparable rotator cuff tears without arthritis: a comparison of superior capsular reconstruction,partial rotator cuff repair,and reverse total shoulder arthroplasty

BackgroundTo compare outcomes of superior capsular reconstruction (SCR), partial rotator cuff repair (PR), and reverse total shoulder arthroplasty (rTSA) for massive irreparable rotator cuff tear (MIRCT) without arthritis at more than 2 years follow-up.MethodsA retrospective analysis of prospectively collected data of consecutive patients undergoing surgical treatment for intraoperatively confirmed MIRCT without arthritis using SCR, PR, or rTSA. Preoperative and postoperative data were collected and multivariate analysis performed.ResultsThirty two patients met inclusion criteria for SCR, 24 for PR, and 42 for rTSA (mean follow-up years: SCR 3.2; PR 4.0; rTSA 3.5; P = .02). The rTSA patients were older (66.2 years; SCR 57.3; PR 59.0; P = .0001) and more likely to be female (61.9%; SCR 12.5%; PR 25.0%; P < .001). Intraoperative evaluation demonstrated full thickness subscapularis tear in 37.5% for SCR, 4.2% for PR, and 21.4% for rTSA (P = .01). Pseudoparalysis was present in 18.8% of SCR, 0% of PR, and 14.3% of rTSA patients (P = .08). All groups saw postoperative improvement in strength and patient-reported outcomes (P < .036). SCR and rTSA demonstrated an improved forward elevation range of motion (ROM) postoperatively while PR did not (P = .96). No group experienced improvement in rotation ROM (P > .12). rTSA had worse postoperative ROM in all planes compared to SCR and PR (P < .003). There were no differences between groups in postoperative strength (P > .16) or patient-reported outcomes (American Shoulder and Elbow Surgeons P = .14; visual analog scale P = .86; single assessment numeric evaluation P = .61). Patients were satisfied in 81.2% of SCR cases, 87.5% of PR, and 95.3% of rTSA (P = .33). Three of 32 (9.4%) SCR patients required conversion to rTSA, while 3 of 24 (12.5%) PR patients required reoperation (2 revision repairs; 1 conversion to rTSA). There were 3 additional surgical complications among 42 rTSA patients (7.1%). There were 4 nonsurgical complications in the SCR group and 1 in the rTSA group. One SCR patient and 3 rTSA patients were deceased. Multivariate analysis demonstrated no independent predictors of revision surgery. An increased acromiohumeral interval distance was an independent predictor of improved postoperative strength for all groups (P < .02).ConclusionSCR, PR, and rTSA for the treatment of MIRCT without arthritis all significantly improved postoperative strength and outcomes scores with >80% patient satisfaction but with rTSA having worse postoperative motion and a higher complication rate. There were no independent predictors for revision surgery. SCR, PR and rTSA are all viable operations for MIRCT without arthritis with satisfactory results maintained at 2 years postoperatively.