Fibroblast Growth Factor 2 Enhances Tendon-to-Bone Healing in a Rat Rotator Cuff Repair of Chronic Tears.

BACKGROUND: The effects of fibroblast growth factor 2 (FGF-2) on healing after surgical repair of chronic rotator cuff (RC) tears remain unclear. HYPOTHESIS: FGF-2 enhances tenogenic healing response, leading to biomechanical and histological improvement of repaired chronic RC tears in rats. STUDY DESIGN: Controlled laboratory study. METHODS: Adult male Sprague-Dawley rats (n = 117) underwent unilateral surgery to refix the supraspinatus tendon to its insertion site 3 weeks after detachment. Animals were assigned to either the FGF-2 group or a control group. The effects of FGF-2 were assessed via biomechanical tests at 3 weeks after detachment and at 6 and 12 weeks postoperatively and were assessed histologically and immunohistochemically for proliferating cell nuclear antigen and mesenchymal stem cell (MSC)-related markers at 2, 6, and 12 weeks postoperatively. The expression of tendon/enthesis-related markers, including SRY-box 9 (Sox9), scleraxis (Scx), and tenomodulin (Tnmd), were assessed by real-time reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry. The effect of FGF-2 on comprehensive gene expressions at the healing site was evaluated by microarray analysis. RESULTS: The FGF-2 group showed a significant increase in mechanical strength at 6 and 12 weeks compared with control; the FGF-2 group also showed significantly higher histological scores at 12 weeks than control, indicating the presence of more mature tendon-like tissue. At 12 weeks, Scx and Tnmd expression increased significantly in the FGF-2 group, whereas no significant differences in Sox9 were found between groups over time. At 2 weeks, the percentage of positive cells expressing MSC-related markers increased in the FGF-2 group. Microarray analysis at 2 weeks after surgery showed that the expression of several growth factor genes and extracellular matrix-related genes was influenced by FGF-2 treatment. CONCLUSION: FGF-2 enhanced the formation of tough tendon-like tissues including an increase in Scx- or Tnmd-expressing cells at 12 weeks after surgical repair of chronic RC tears. The increase in mesenchymal progenitors and the changes in gene expression upon FGF-2 treatment in the early phase of healing appear to be related to a certain favorable microenvironment for tenogenic healing response of chronic RC tears. CLINICAL RELEVANCE: These findings may provide advantages in therapeutic strategies for patients with RC tears.

Rotator cuff tendon-to-bone healing at 12 months after patch grafting of acellular dermal matrix in an animal model.

There is no report to investigate the histology and biomechanical strength of remodeled tendon-to-bone junction more than 6 months after patch grafting with acellular dermal matrix (ADM) on rotator cuff defect. We investigated those 12 months after surgery and hypothesized that a new native enthesis is not regenerated and the biomechanical strength is inferior to normal control. Adult male Sprague-Dawley rats underwent ADM patch grafting for the rotator cuff defect. Quantitative histological analysis, immunohistochemical analysis for collagen type I and III, and biomechanical testing were performed 12 months after surgery. The controls were unoperated age-matched rats. In the grafted rats, the collagen arrangement was more irregular and the fibrocartilage layer was smaller at the tendon-bone interface than in the controls although dense collagen fibers in the remodeled tendon were observed; the number of chondrocytes, the percentage of chondrocytes aligned in rows, and the area of the fibrocartilage layer were significantly smaller than in the control group (p = 0.0252, 0.0039, and 0.0252, respectively). Grafted specimens showed significantly lower collagen organization in the midsubstance and tendon-bone interface than the controls (p = 0.0252 and 0.0374, respectively). Immunohistochemical analysis demonstrated that the remodeled tendon fibers were stained more strongly for type III than type I. At 12 months postoperatively, the ultimate load to failure was significantly lower in the graft group than normal control (p = 0.0026); that was 47.8% of normal controls. 12 months after rotator cuff patch grafting with ADM, the formation of a new enthesis grossly resembled the native structure but there was poor cellular organization and the biomechanical strength of remodeled tendon-to-bone was only 48% of normal controls. Advances in tissue engineering and postoperative rehabilitation are needed to promote the healing process after rotator cuff patch grafting.

Local rhBMP-12 on an Absorbable Collagen Sponge as an Adjuvant Therapy for Rotator Cuff Repair-A Phase 1, Randomized, Standard of Care Control, Multicenter Study: Part 2-A Pilot Study of Functional Recovery and Structural Outcomes.

BACKGROUND: The high failure rate of rotator cuff repairs requires the development of methods to enhance healing at the tendon-bone junction of the repair site. PURPOSE: To assess functional recovery and structural outcomes in detail after implanting recombinant human bone morphogenetic protein-12 (rhBMP-12)/absorbable collagen sponge (ACS) as adjuvant treatment during open rotator cuff repair in patients over a 1-year postoperative follow-up. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: A total of 20 patients were randomized into 2 groups, rhBMP-12/ACS and standard-of-care (SOC) control, with 16 and 4 patients, respectively. The patients underwent open repair of a rotator cuff tear at least 2 to 4 cm wide; in the rhBMP-12/ACS group, this was augmented with a bioscaffold containing rhBMP-12. Follow-up assessments were conducted with a 100-mm visual analog scale (VAS) for pain and active and passive ranges of motion (ROMs) including forward flexion, elevation in the scapular plane, abduction, and external rotation at 12, 16, 26, 39, and 52 weeks after surgery; isometric strength in scapular abduction and external rotation at 16, 26, 39, and 52 weeks; and magnetic resonance imaging (MRI) at 12 and 52 weeks. RESULTS: The mean VAS score decreased from 37.9 mm preoperatively to 13.8 mm at week 52, and ROM and isometric strength recovered at week 52 in the rhBMP-12/ACS group. The mean VAS score decreased from 48.3 mm preoperatively to 1.5 mm at week 52, and ROM (excluding external rotation) and isometric strength recovered by week 52 in the SOC control group. Of the 16 patients in the rhBMP-12/ACS group, 14 showed an intact repair at week 12; the MRI scans of the other 2 patients could not be evaluated because of artifacts. In the SOC control group, 1 patient showed repair failure. At week 52, 14 repairs in the rhBMP-12/ACS group and 2 repairs with available MRI scans in the SOC control group remained intact. CONCLUSION: Functional recovery and structural outcomes in patients in whom rhBMP-12/ACS was used as adjuvant therapy in rotator cuff repair justify conducting future, larger, multicenter, prospective studies. REGISTRATION: NCT00936559, NCT01122498 (ClinicalTrials.gov identifier).

Enhancement of rotator cuff tendon-bone healing with fibroblast growth factor 2 impregnated in gelatin hydrogel sheets in a rabbit model.

BACKGROUND: Application of fibroblast growth factor 2 (FGF-2) may improve the healing response after rotator cuff (RC) surgical repair. This study aimed to determine whether FGF-2-impregnated gelatin hydrogel sheet (GHS) incorporation into the bony trough on the greater tuberosity facilitates healing after RC surgical repair in rabbits. METHODS: We assigned 120 adult male Japanese white rabbits treated with unilateral surgery for supraspinatus tendon repair into the following groups: suture-only group (suture); suture and GHS with phosphate-buffered saline (carrier); suture and GHS with 3 µg of FGF-2 (F3); and suture and GHS with 30 µg of FGF-2 (F30). The effect of FGF-2 was assessed using histologic, biomechanical, and microcomputed tomography evaluations at 2, 6, and 12 weeks. RESULTS: At 12 weeks, loose fibrovascular tissues emerged at the repair site in the suture and carrier groups and dense tendon-like tissues in the F3 and F30 groups, which demonstrated significantly higher ultimate load-to-failure and stress-to-failure at 12 weeks than that in the suture and carrier groups. Microcomputed tomography imaging showed ectopic calcification formation in some specimens from each group. Appearances or frequencies were similar among groups. The histologic and biomechanical effects of FGF-2 on RC healing were obvious at ≥6 weeks postoperatively. CONCLUSION: FGF-2-impregnated GHS incorporation into the bony trough on the greater tuberosity before RC surgical repair is feasible and results in histologic and biomechanical improvements during RC healing in rabbits. No detrimental effect on ectopic calcification was observed.

Neuropathic pain in patients with rotator cuff tears.

BACKGROUND: Recent studies have confirmed the existence of neuropathic pain (NeP) components in patients with musculoskeletal disorders. However, the presence of NeP in patients with rotator cuff tears has not been investigated thus far. Therefore, we studied the prevalence of NeP and the prognostic factors for NeP in patients with rotator cuff tears. METHODS: Data were collected from 110 patients with rotator cuff tears, diagnosed by physical examination and magnetic resonance imaging, who attended an outpatient clinic between August 2013 and August 2014. The measured parameters included visual analog scale (VAS) pain scores, painDETECT questionnaire (PDQ) responses, a physical examination, and magnetic resonance imaging. To evaluate the factors associated with NeP, we performed a two-stage analysis. For univariate analysis, we used the Mann-Whitney U test. For multivariate analysis, forward stepwise regression was performed using factors that demonstrated statistical significance in the univariate analysis. RESULTS: Patients were classified into three groups according to their PDQ score: an NeP group (n = 12; 10.9 %), possible NeP group (n = 33; 30.0 %), and a nociceptive pain (NoP) group (n = 65; 59.1 %). In the univariate analysis between the NeP group and NoP group, NeP was affected by sex (p = 0.034), VAS score (average pain during the past 4 weeks; p = 0.013), and positive Neer and Hawkins impingement signs (p = 0.039). In the multivariate analysis, VAS score (p = 0.031) was an independent prognostic factor for NeP. CONCLUSIONS: Using the PDQ, we found that 10.9 % of patients with rotator cuff tears may have NeP. The VAS score (average pain during the past 4 weeks) was a prognostic factor for NeP. Clinicians should remain vigilant for heterogeneous etiologies of pain in patients with rotator cuff tears.

Hypertrophic teres minor restores shoulder strength and range of external rotation in posterosuperior rotator cuff tears.

BACKGROUND: In posterosuperior rotator cuff tears (PS-RCT), the progression of infraspinatus (ISP) muscle atrophy seems to induce compensatory hypertrophy of the teres minor (TM) muscles. However, the effect of these changes on shoulder strength and range of external rotation (ER) remains unclear. This study determined the strength and range of ER in patients with PS-RCT with atrophic ISP and hypertrophic TM and compared this with patients with PS-RCT and normal or deficient TM. METHODS: We investigated 35 patients with PS-RCT and atrophic ISP. TM muscles were classified as hypertrophic (type A) in 17, normal (type B) in 10, or deficient (type C) in 8. The strength ratio of the affected shoulder to the healthy contralateral shoulder was calculated, and the active range of motion was measured for both shoulders. RESULTS: The strength ratios of ER in types A, B, and C were 60%, 33%, and 7% (P < .01) with the patient's arm at the side and were 60%, 35%, and 5% (P < .001) at 90° abduction, respectively. The average ranges of ER in types A, B, and C were 22.6°, 15.0°, and -12.5° (P < .001) with the patient's arm at the side and were 71.6°, 44.5°, and 21.9° at 90° abduction (P < .01), respectively. The differences between shoulder types in other measures of strength or ER range were not significant. CONCLUSIONS: In patients with PS-RCT and atrophic ISP, shoulders with compensatory hypertrophy of the TM had greater strength and range of ER than shoulders with normal or atrophic TM.

FGF-2 Stimulates the Growth of Tenogenic Progenitor Cells to Facilitate the Generation of Tenomodulin-Positive Tenocytes in a Rat Rotator Cuff Healing Model.

BACKGROUND: Fibroblast growth factor (FGF)-2 has the potential to enhance tendon-to-bone healing after rotator cuff (RC) injury. HYPOTHESIS: FGF-2 stimulates tenogenic differentiation of progenitors to improve the biomechanical strength and histological appearance of repaired RCs in rats. STUDY DESIGN: Controlled laboratory study. METHODS: Adult male Sprague-Dawley rats (N = 156) underwent unilateral surgery to repair the supraspinatus tendon to insertion sites. The FGF-2-treated group (gelatin hydrogel containing 5 µg of FGF-2) and a control group (gelatin hydrogel only) were compared to investigate the effects of FGF-2 at 2, 4, 6, 8, and 12 weeks postoperatively. Biomechanical testing was performed at 6 and 12 weeks. Semiquantitative histological analysis and immunohistochemical analysis for the proliferating cell nuclear antigen (PCNA) were performed, and the expression of tendon-related markers, including Scleraxis (Scx) and Tenomodulin (Tnmd), was monitored by real-time reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization. SRY-box containing gene 9 (Sox9) expression was monitored by RT-PCR and immunohistochemical analysis. At 2 and 4 weeks, immunohistochemical analysis for mesenchymal stem cell (MSC) markers was also performed. RESULTS: The FGF-2-treated group demonstrated a significant improvement in mechanical strength at 6 and 12 weeks and significantly higher histological scores than the control group at ≥4 weeks. The average incidence of PCNA-positive cells was significantly higher at 2 and 4 weeks, and more cells expressing MSC markers were detected at the insertion site in the FGF-2-treated group. The expression level of Scx increased significantly in the FGF-2-treated group from 4 to 8 weeks, while the Tnmd level increased significantly from 4 to 12 weeks postoperatively. The localization of Tnmd overlapped with the locations of reparative tissues accompanying collagen fibers with an aligned orientation. Sox9 expression was significantly upregulated at 4 weeks in the FGF-2-treated group. CONCLUSION: FGF-2 promotes growth of the tenogenic progenitor cells, which participate in tendon-to-bone healing, resulting in biomechanical and histological improvement of the repaired RC. CLINICAL RELEVANCE: These findings provide clues regarding the clinical development of regenerative repair strategies for RC injury.

Local rhBMP-12 on an Absorbable Collagen Sponge as an Adjuvant Therapy for Rotator Cuff Repair - A Phase 1, Randomized, Standard of Care Control, Multicenter Study: Safety and Feasibility.

BACKGROUND: Recombinant human bone morphogenetic protein-12 (rhBMP-12) has been shown to induce tendon and ligament formation in rats and to improve tendon healing; however, the safety and feasibility of implanting rhBMP-12/absorbable collagen sponge (ACS) in humans are not known. PURPOSE: To investigate the safety and feasibility of rhBMP-12 on an ACS as an adjuvant therapy in open rotator cuff repair. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: This study consisted of 20 patients with full-thickness rotator cuff tears. Patients were randomized either to standard of care (SOC) treatment (open rotator cuff repair) or to receive 0.015 mg/mL rhBMP-12/ACS and SOC treatment during their open rotator cuff repair (rhBMP-12/ACS group) at a rate of 1/4 SOC/rhBMP-12/ACS. The feasibility of implanting the product and the safety of the product were evaluated during the 1-year follow-up period. The evaluation involved up to 10 postoperative visits, which included physical examinations, radiographs, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans with an emphasis on heterotopic ossification (HO), pharmacokinetics, immunogenicity, laboratory evaluations, and local and systemic adverse events at specified time points. RESULTS: Small amounts of HO were seen on follow-up CT scans in 10 of 16 patients in the rhBMP-12/ACS group and in 2 of 3 patients in the SOC group. HO did not increase at 26 weeks and was not associated with any adverse events or unsatisfactory clinical outcomes. Pharmacokinetics demonstrated that circulating levels of rhBMP-12 were not detectable after administration. Five of 16 patients showed a postoperative immunogenic response but did not show any correlating adverse events. Complete healing of the rotator cuff was observed in 14 of 16 patients; 2 of 16 imaging results could not be analyzed because of artifacts in the rhBMP-12 group on MRI scans. In the SOC group, 1 of 4 patients showed a retear at 12 weeks after surgery. CONCLUSION: The use of rhBMP-12/ACS has been shown to be feasible and safe in a concentration of 0.015 mg/mL when used in open rotator cuff repair. Higher dose concentrations of rhBMP-12 should be evaluated in the future to evaluate their safety and potential to increase rotator cuff healing after open surgical repair.

Functional and structural comparisons of the arthroscopic knotless double-row suture bridge and single-row repair for anterosuperior rotator cuff tears.

BACKGROUND: We compared the outcomes of knotless double-row suture bridge and single-row repairs in patients undergoing arthroscopic repair for anterosuperior rotator cuff tears. METHODS: We included 61 full-thickness anterosuperior rotator cuff tears treated by arthroscopic repair, namely, single-row repair (group 1: 25 shoulders; mean patient age, 64 years) and the knotless double-row suture bridge repair (group 2: 36 shoulders; mean patient age, 62 years). Preoperative and postoperative magnetic resonance imaging was performed for all shoulders. Clinical outcomes were evaluated for mean follow-up periods of 81 months (range, 72-96 months) in group 1 and 34 months (range, 24-42 months) in group 2, using the University of California, Los Angeles and Japanese Orthopaedic Association assessments. RESULTS: At the final follow-up, both groups showed improvement in the average University of California, Los Angeles and Japanese Orthopaedic Association scores and range of motion, although no intergroup differences were observed. Both groups showed improved abduction strength, and the average score was higher in group 2 (P = .0112). The lift-off and belly-press test results were improved in both groups. Postoperatively, the incidence of positive lift-off tests tended to be lower (P = .075) and that of positive belly-press tests was lower in group 2, P = .049). The repair failure rate tended to be lower in group 2 (14% [5 of 36]) than in group 1 (32% [8 of 25]; P = .0839). CONCLUSIONS: Arthroscopic knotless double-row suture bridge repair of anterosuperior rotator cuff tears yielded functional outcomes equivalent to those of single-row repair and may be useful for improving subscapularis function, abduction strength, and tendon healing.

Local Application of Gelatin Hydrogel Sheets Impregnated With Platelet-Derived Growth Factor BB Promotes Tendon-to-Bone Healing After Rotator Cuff Repair in Rats.

PURPOSE: To determine whether the local application of platelet-derived growth factor BB (PDGF-BB) in hydrogel sheets would promote healing and improve histologic characteristics and biomechanical strength after rotator cuff (RC) repair in rats. METHODS: To assess the effect of PDGF-BB on tendon-to-bone healing we divided 36 adult male Sprague-Dawley rats treated with bilateral surgery to repair the supraspinatus tendon at its insertion site into 3 groups: group 1 = suture-only group; group 2 = suture and gelatin hydrogel sheets impregnated with phosphate-buffered saline (PBS); and group 3 = suture and gelatin hydrogel sheets impregnated with PDGF-BB (0.5 µg). Semiquantitative histologic evaluation was carried out 2, 6, and 12 weeks later; cell proliferation was assessed 2 and 6 weeks postoperatively by immunostaining for proliferating cell nuclear antigen (PCNA), and biomechanical testing, including ultimate load to failure, stiffness, and ultimate stress to failure, was performed 12 weeks after the operation. RESULTS: At 2 weeks, the average percentage of PCNA-positive cells at the insertion site was significantly higher in group 3 (40.5% ± 2.4%) than in group 1 (32.1% ± 6.9%; P = .03) and group 2 (31.9% ± 3.7%; P = .02). At 2 and 6 weeks, the histologic scores were similar among the 3 groups. At 12 weeks, the histologic score was significantly higher in group 3 (10.3 ± 0.8) than in group 1 (8.5 ± 0.5; P = .002) or group 2 (8.8 ± 0.8; P = .009), whereas ultimate load to failure, stiffness, and ultimate load to stress (normal control population, 44.73 ± 9.75 N, 27.59 ± 4.32 N/mm, and 21.33 ± 4.65 N/mm(2), respectively) were significantly higher in group 3 (28.28 ± 6.28 N, 11.05 ± 2.37 N/mm, and 7.99 ± 2.13 N/mm(2), respectively) than in group 1 (10.44 ± 1.98 N, 4.74 ± 1.31 N/mm, and 3.28 ± 1.27 N/mm(2), respectively; all P < .001) or group 2 (11.85 ± 2.89 N, 5.86 ± 1.75 N/mm, and 3.31 ± 0.80 N/mm(2), respectively; all P < .001). CONCLUSIONS: The placement of a PDGF-BB-impregnated hydrogel sheet just lateral to a transected and acutely reattached supraspinatus tendon produced significantly more PCNA-positive cells at 2 weeks and greater collagen fiber orientation, ultimate failure loads, stiffness, and stress to failure at 12 weeks than did a PBS-impregnated hydrogel sheet. No differences in vascularity or cellularity were observed. CLINICAL RELEVANCE: The local application of PDGF-BB-impregnated gelatin hydrogel may help to promote tendon-to-bone healing after RC repair in humans.

Hypertrophic changes of the teres minor muscle in rotator cuff tears: quantitative evaluation by magnetic resonance imaging.

BACKGROUND: Few reports have assessed the teres minor (TM) muscle in rotator cuff tears. This study aimed to quantitatively analyze the morphologic changes of the TM muscle in patients with or without rotator cuff tears by magnetic resonance imaging (MRI). METHODS: This retrospective study consisted of 279 subjects classified on the basis of interpretations of conventional MRI observations into 6 groups: no cuff tear; partial-thickness supraspinatus (SSP) tear; full-thickness SSP tear; SSP and subscapularis tears; SSP and infraspinatus (ISP) tears; and SSP, ISP, and subscapularis tears. With use of ImageJ software (National Institutes of Health, Bethesda, MD, USA) for oblique sagittal MRI, we measured the areas of ISP, TM, and anatomic external rotation (ISP + TM) muscles on the most lateral side in which the scapular spine was in contact with the scapular body. The occupational ratios of the TM muscle area to the anatomic external rotation muscle area were calculated. Ratios above the maximum of the 95% confidence intervals of the occupational ratio in the no-tear group were defined as hypertrophy of the TM muscle. RESULTS: Occupational ratios of the TM muscle in the no-tear group followed a normal distribution, and ratios >0.288 were defined as hypertrophic. Hypertrophic changes of the TM muscle were confirmed in rotator cuff tears involving the ISP tendon. A negative correlation was found between the occupational ratios of TM and ISP (P < .001). CONCLUSION: The TM muscle appeared hypertrophic in rotator cuff tears involving the ISP, and the progression of ISP muscle atrophy seemed to induce the development of this compensatory hypertrophy.

Effect of Postoperative Passive Motion on Rotator Cuff Reconstruction With Acellular Dermal Matrix Grafts in a Rat Model.

BACKGROUND: Although postoperative rehabilitation is critical for rotator cuff tendon-to-bone healing and shoulder function recovery, no standardized protocol has been established. HYPOTHESIS: Postoperative immediate passive motion is detrimental to tendon-to-bone remodeling and tendon maturation after rotator cuff acellular dermal matrix (ADM) grafting, although postoperative delayed passive motion does no harm. STUDY DESIGN: Controlled laboratory study. METHODS: Male Sprague-Dawley rats underwent rotator cuff reconstruction with ADM grafts. Their shoulders were immobilized for 2 weeks thereafter. The rats were assigned to 3 different rehabilitation protocols: (1) immobilization without passive motion (nonpassive motion [N-PM], controls), (2) immobilization with immediate passive motion (I-PM), and (3) immobilization with delayed passive motion (D-PM). Specimens obtained 2, 6, and 12 weeks postoperatively were analyzed histologically, and semiquantitative histomorphological measurements of collagen organization, vascularity, and cellularity were obtained; the area of interest was divided into 2 zones, the midsubstance of the graft and the graft-bone interface. Another set of samples taken at 12 weeks was subjected to biomechanical analysis. RESULTS: At 2 weeks, there was no significant difference among the groups in terms of semiquantitative histomorphological measurements of collagen organization, vascularity, and cellularity. At 6 weeks, collagen organization at the insertion site was significantly poorer in I-PM than in N-PM and D-PM rats (P = .0095). At 12 weeks, collagen organization at the insertion site and midsubstance of ADM grafts was also significantly poorer in I-PM rats (P = .0125 and P = .0018, respectively), and ultimate load-to-failure was lower in this group (P = .0043). CONCLUSION: While postoperative immediate passive motion was detrimental to remodeled tendon-to-bone healing and to the tendon maturation of ADM grafts placed in the rotator cuff tendon defects, delayed passive motion did no harm. CLINICAL RELEVANCE: For patients with 6-week immobilization after rotator cuff reconstruction, we recommend that early passive motion be started no sooner than 3 weeks after surgery. Immediate early passive motion should be avoided.

Effect of immobilization on rotator cuff reconstruction with acellular dermal matrix grafts in an animal model.

INTRODUCTION: Using a rat model we determined whether immobilization improves tendon-to-bone healing and tendon maturation after rotator cuff reconstruction with acellular dermal matrix (ADM) grafts. METHODS: Sprague-Dawley rats were randomly assigned to 3 equal groups. All rats were subjected to rotator cuff reconstruction and their shoulder was not immobilized (N-IM controls) or immobilized for 2- or 6 weeks immediately thereafter (2- and 6-IM groups, respectively). After detaching the rotator cuff including the full-thickness supraspinatus tendon at its insertion on the greater tuberosity, a defect was created. ADM patches were used for rotator cuff reconstruction. Specimens obtained 2, 6, and 12 weeks after surgery were subjected to semiquantitative histomorphological measurements to assess cellularity, vascularity, and collagen organization. In addition, specimens at 12 weeks were submitted for biomechanical analysis. RESULTS: Cell density decreased over time in all 3 groups; there was no significant difference among the groups at 2 weeks. However, the 6-IM group harbored more cells in the tendon-to-bone interface than the 2-IM group at 6 weeks and the N-IM group at 12 weeks. Vascularity in the interface decreased over time in the N-IM and 2-IM groups but not the 6-IM rats. At 6 and 12 weeks, the 2-IM group manifested better collagen organization than the other groups. The 2-IM group exhibited higher ultimate load-to-failure than the other groups. Stiffness was similar in the 3 groups. CONCLUSION: Remodeling of ADM grafts placed in rat rotator cuff defects was promoted by 2- but not 6-week immobilization.

Wild-type transthyretin-derived amyloidosis in various ligaments and tendons.

Transthyretin-derived amyloid deposition is commonly found in intercarpal ligaments of patients with senile systemic amyloidosis. However, the frequency of transthyretin-derived amyloid deposits in ligaments of other tissues remains to be elucidated. This study aimed to determine the frequency of amyloid deposition and the precursor proteins of amyloid found in orthopedic disorders. We studied 111 specimens from patients with carpal tunnel syndrome (flexor tenosynovium specimens), rotator cuff tears (rotator cuff tendon specimens), and lumbar canal stenosis (yellow ligament specimens). To identify amyloid precursor proteins, we used immunohistochemical staining with antibodies that react with transthyretin, immunoglobulin light chain, amyloid A protein, and ß(2)-microglobulin. By means of Congo red staining, we identified 47 (42.3%) amyloid-positive samples, 39 of which contained transthyretin-derived amyloid (18 flexor tenosynovium specimens, 5 rotator cuff tendon specimens, and 16 yellow ligament specimens). Genetic testing and/or clinical findings suggested that all patients with transthyretin amyloid deposits did not have familial amyloidotic polyneuropathy. The occurrence of amyloid deposition in those tissues depended on age. These results suggest that transthyretin-derived amyloid deposits may occur more frequently in various ligaments and tendons than originally expected. In the future, such amyloid deposits may aid determination of the pathogenesis of ligament and tendon disorders in older patients.

Prediction of postoperative ambulatory status 1 year after hip fracture surgery.

UNLABELLED: Hirose J, Ide J, Yakushiji T, Abe Y, Nishida K, Maeda S, Anraku Y, Usuku K, Mizuta H. Prediction of postoperative ambulatory status 1 year after hip fracture surgery. OBJECTIVES: To assess the validity of Estimation of Physiologic Ability and Surgical Stress (E-PASS) for predicting the postoperative risk and ambulatory status long-term follow-up after hip fracture surgery and to establish an algorithm for predicting their ambulatory status. DESIGN: Cohort study. SETTING: Twelve hospitals belonging to the regional network for hip fracture in Japan. PARTICIPANTS: The study population was composed of 421 patients; 268 underwent surgery between April 2004 and March 2006 (group A), and 153 were treated surgically between April 2006 and March 2007 (group B). All were operated at 3 surgical hospitals and, subsequently, transferred to 9 rehabilitation centers. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We evaluated various factors, including their E-PASS scores to determine whether there was a correlation with the patients' mortality rate and their ability to walk at discharge and 1 year after surgery (group A). Using multiple regression analysis, we then developed algorithms to predict the ability of elderly patients to walk after hip fracture surgery. We applied the algorithms to group B patients and compared their actual and predicted ambulatory status. RESULTS: In group A patients, the postoperative walking ability and mortality rate were highly correlated with their E-PASS scores and dementia status. In group B, our algorithms exhibited good correlations between the predicted and actual walking ability at both time points (rho=0.6, P<.001). CONCLUSIONS: In candidates for hip fracture surgery, the E-PASS scores exhibited a good correlation with the patients' functional and survival prognoses, and the algorithm including E-PASS scores and dementia status can accurately estimate the ambulatory status at discharge and 1 year after surgery.

New equations for predicting postoperative risk in patients with hip fracture.

UNLABELLED: Predicting the postoperative course of patients with hip fractures would be helpful for surgical planning and risk management. We therefore established equations to predict the morbidity and mortality rates in candidates for hip fracture surgery using the Estimation of Physiologic Ability and Surgical Stress (E-PASS) risk-scoring system. First we evaluated the correlation between the E-PASS scores and postoperative morbidity and mortality rates in all 722 patients surgically treated for hip fractures during the study period (Group A). Next we established equations to predict morbidity and mortality rates. We then applied these equations to all 633 patients with hip fractures treated at seven other hospitals (Group B) and compared the predicted and actual morbidity and mortality rates to assess the predictive ability of the E-PASS and Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM) systems. The ratio of actual to predicted morbidity and mortality rates was closer to 1.0 with the E-PASS than the POSSUM system. Our data suggest the E-PASS scoring system is useful for defining postoperative risk and its underlying algorithm accurately predicts morbidity and mortality rates in patients with hip fractures before surgery. This information then can be used to manage their condition and potentially improve treatment outcomes. LEVEL OF EVIDENCE: Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

The effects of fibroblast growth factor-2 on rotator cuff reconstruction with acellular dermal matrix grafts.

PURPOSE: Our purpose was to determine whether the local application of fibroblast growth factor (FGF) 2 accelerates regeneration and remodeling of rotator cuff tendon defects reconstructed with acellular dermal matrix (ADM) grafts in rats. METHODS: Thirty adult male Sprague-Dawley rats were divided into equal groups undergoing FGF-treated and FGF-untreated repairs. All rats underwent placement of an ADM graft for the supraspinatus defect (3 x 5 mm). FGF-2 (100 microg/kg) in a fibrin sealant was applied to both shoulders in the FGF-treated group, whereas only fibrin sealant was applied in untreated group. At 2, 6, and 12 weeks after surgery, 5 rats (10 shoulders) in each group were sacrificed for histologic analysis (3 shoulders) and biomechanical testing (7 shoulders). The controls were 5 unoperated rats (3 histologic and 7 biomechanical control specimens). RESULTS: Unoperated control tendons inserted into the bone by direct insertion; there was a zone of fibrocartilage between the tendon and bone. At 2 weeks, the FGF-treated group had tendon maturing scores similar to those in the untreated group (P > .05). At 6 and 12 weeks, the FGF-treated group had significantly higher scores (P < .05). At 2 weeks, specimens in both the treated and untreated groups exhibited similar strength; the ultimate tensile failure load was 6.0 +/- 4.0 N and 5.8 +/- 2.0 N, respectively (P > .05). At 6 weeks, the FGF-treated specimens were stronger, with an ultimate tensile failure load of 10.2 +/- 3.1 N compared with 7.2 +/- 2.2 N in the untreated group (P = .02). At 12 weeks, the FGF-treated specimens were stronger, with an ultimate tensile failure load of 15.9 +/- 1.6 N compared with 13.2 +/- 2.0 N in the untreated group (P = .0072), and there were no significant differences in strength compared with the controls (17.8 +/- 2.6 N) (P > .05). CONCLUSIONS: The remodeling of ADM grafts placed in rat rotator cuff tendon defects was accelerated by the local administration of FGF-2. CLINICAL RELEVANCE: The application of FGF-2 may result in improved histologic characteristics and biomechanical strength in ADM graft constructs in humans.

The effect of a local application of fibroblast growth factor-2 on tendon-to-bone remodeling in rats with acute injury and repair of the supraspinatus tendon.

METHODS: We investigated the effect of application of fibroblast growth factor (FGF)-2 on the tendon-to-bone remodeling of repaired supraspinatus tendon in rats subjected to bilateral detachment. FGF-2 (100 mg/kg) in a fibrin sealant or sealant alone was applied on the right and left shoulders, respectively. Twelve animals each at 2, 4, and 6 weeks after surgery were sacrificed for histological analysis (n = 5) and biomechanical Q1 testing (n = 7). RESULTS: Histologically, at 2 weeks, FGF-treated specimens had significantly higher tendon-to-bone insertion maturing scores then untreated specimens (P < .002). At 4 and 6 weeks, the scores of FGF-treated and untreated specimens were similar (P > .05). Biomechanically, FGF-treated specimens were stronger at 2 weeks (P = .001); at 4 and 6 weeks, both specimens exhibited similar strength (P > .05). CONCLUSIONS: The initial tendon-to-bone remodeling was accelerated by a local application of FGF-2. This may represent a clinically important improvement in rotator cuff repair.

Morphological study, by teasing examination, of the communication from the musculocutaneous to median nerves.

Nine specimens with communications from the musculocutaneous to the median nerves were investigated, by teasing examination, from their origins in the brachial plexus to their final destinations in nerve fibers. The nerve fibers of the communications were derived from the sixth and seventh cervical ventral rami of the spinal nerves. The distributions of the nerve fibers of the communications were divided into four types. In Type A, the nerve fibers reached the thenar muscles and the lateral digital nerves. In Type B, they reached the pronator teres or flexor carpi radialis muscles in addition to Type A. In Type C, they reached the anterior interosseous nerve area in addition to Type B. Finally in Type D, they also reached the distal muscle belly of the index of the flexor digitorum superficialis. It was revealed that there was a definite rule in the distribution of the nerve fibers in the communications from the musculocutaneous to median nerves. The area of the distributions was expanded in order from the thenar muscles to the flexor muscles of the forearm. The results in this study are useful for proper diagnosis and treatment of the peripheral nerve injuries involving the musculocutaneous and median nerves.

Morphological study of the communication between the musculocutaneous and median nerves.

We investigated the incidence of each pattern of the communications between the musculocutaneous and median nerves and discussed its morphological significance. The communications between both nerves were seen in 188 (41.5%) of 453 specimens. They were classified into five regular patterns according to their directions and formations. The incidence of the communication was significantly higher in those with excessive heads of biceps brachii than in those without them (p < 0.05). As a result, we established a classification of the regular pattern of the communications and revealed that the musculocutaneous and median nerves had the possibility of forming plexuses in the humeral area. The musculocutaneous nerves are regarded as the bundles that arise from the median nerve with the lateral cutaneous nerve of forearm and the branches to the biceps brachii and brachialis muscles.