Peptide GAM immunoadsorption therapy in primary membranous nephropathy (PRISM): Phase II trial investigating the safety and feasibility of peptide GAM immunoadsorption in anti-PLA2 R positive primary membranous nephropathy.

INTRODUCTION: Membranous nephropathy (MN) is among the most common causes of nephrotic syndrome in adults worldwide. Most patients have primary MN (PMN), an autoimmune condition associated with the IgG anti-PLA2 R autoantibody. For patients with severe disease, standard of care continues to be a 6-month regime of rotating high dose steroids and immunosuppression that comes with a significant side-effect profile. Immunoadsorption is a relatively safe procedure for the extracorporeal removal of specific immunoglobulins without the need for medications. DESIGN: This is a Phase II multi-centre, single arm prospective clinical trial carried out across Northwest region of the United Kingdom to assess the safety and clinical effectiveness of immunoadsorption therapy in PMN. 12 adult patients with biopsy proven MN, nephrotic range proteinuria and serum anti-PLA2 R antibody titers of more than 170 µ/mL will undergo 5 consecutive daily sessions of immunoadsorption. Primary outcome is the reduction of serum anti-PLA2 R antibodies at day 14. Secondary outcomes are the safety and tolerability of immunoadsorption therapy in patients with primary MN at all-time points, reduction of serum anti-PLA2 R levels, proteinuria and improvement in renal function. Quality of life and Cost-effectiveness of treatment will be assessed from a UK National Health Service perspective. DISCUSSION: With proven efficacy in removing IgG antibodies and its use as a relatively safe treatment option in a multitude of conditions, immunoadsorption has the potential to offer patients with primary MN a more directed therapy free from the short and long-term side-effects generally seen in this condition.

Growth factor release by vesicular phospholipid gels: in-vitro results and application for rotator cuff repair in a rat model.

BACKGROUND: Biological augmentation of rotator cuff repair is of growing interest to improve biomechanical properties and prevent re-tearing. But intraoperative single shot growth factor application appears not sufficient to provide healing support in the physiologic growth factor expression peaks. The purpose of this study was to establish a sustained release of granulocyte-colony stimulating factor (G-CSF) from injectable vesicular phospholipid gels (VPGs) in vitro and to examine biocompatibility and influence on histology and biomechanical behavior of G-CSF loaded VPGs in a chronic supraspinatus tear rat model. METHODS: G-CSF loaded VPGs were produced by dual asymmetric centrifugation. In vitro the integrity, stability and release rate were analyzed. In vivo supraspinatus tendons of 60 rats were detached and after 3 weeks a transosseous refixation with G-CSF loaded VPGs augmentation (n = 15; control, placebo, 1 and 10 µg G-CSF/d) was performed. 6 weeks postoperatively the healing site was analyzed histologically (n = 9; H&E by modified MOVIN score/Collagen I/III) and biomechanically (n = 6). RESULTS: In vitro testing revealed stable proteins after centrifugation and a continuous G-CSF release of up to 4 weeks. Placebo VPGs showed histologically no negative side effects on the healing process. Histologically in vivo testing demonstrated significant advantages for G-CSF 1 µg/d but not for G-CSF 10 µg/d in Collagen III content (p = 0.035) and a higher Collagen I/III ratio compared to the other groups. Biomechanically G-CSF 1 µg/d revealed a significant higher load to failure ratio (p = 0.020) compared to control but no significant differences in stiffness. CONCLUSIONS: By use of VPGs a continuous growth factor release could be obtained in vitro. The in vivo results demonstrate an improvement of immunohistology and biomechanical properties with a low dose G-CSF application via VPG. The VPG itself was well tolerated and had no negative influence on the healing behavior. Due to the favorable properties (highly adhesive, injectable, biocompatible) VPGs are a very interesting option for biologic augmentation. The study may serve as basis for further research in growth factor application models.

Arthroscopically assisted 2-bundle anatomic reduction of acute acromioclavicular joint separations: 58-month findings.

BACKGROUND: Currently, no clinical midterm results have been reported on arthroscopically assisted reduction of the acutely dislocated acromioclavicular (AC) joint using suture-button devices for fixation. HYPOTHESIS: Athroscopically assisted reduction of the acutely dislocated AC joint yields satisfactory clinical outcomes without loss of reduction, clavicle migration, or AC joint degeneration at midterm follow-up evaluation. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The clinical and radiographic outcomes of 23 of 30 consecutive patients (21 men, 2 women) who underwent anatomic reduction for acute AC joint dislocation using 2 suture-button devices between 2006 and 2007 were reviewed. Radiographic evaluation was performed by measurement of coracoclavicular (CC) distance and AC displacement. Clinical evaluation included a visual analog scale (VAS) for pain, the Constant score, the simple shoulder test, and the Short Form-36. Previously, this same patient collective was reviewed after 2 years of follow-up using similar methods. RESULTS: All 23 patients were available for midterm follow-up examination 58 months postoperatively. There were 3 Rockwood type III, 3 type IV, and 17 type V acromioclavicular joint separations. Mean ± SD follow-up was 58 ± 5.6 months (range, 51-67 months). Most patients (96%) remained very satisfied or satisfied with the procedure outcome. The VAS and Constant score improved significantly when compared with baseline (0.3 ± 0.6 and 91.5 ± 4.7 at 58 months postoperatively vs 4.5 ± 1.9 and 34.5 ± 6.9 at baseline) and remained essentially unchanged when compared with the 2-year outcome scores (0.3 ± 0.6 and 91.5 ± 4.7 at 58 months postoperatively vs 0.25 ± 0.5 and 94.3 ± 3.2 at 2 years). Radiographs showed 8 radiographic failures (undercorrection, posterior displacement, or both) and 4 additional overcorrections of the CC distance. When comparing with 24-month data, 17 of 20 radiographs remained unchanged; 1 case of previous overcorrection drifted into normal AC alignment and 2 cases increased in posterior subluxation of the clavicle. CONCLUSION: Arthroscopically assisted reduction of the acutely dislocated AC joint provides satisfactory clinical results 58 months after surgery. Compared with the baseline, all patients improved significantly. Two of 23 patients revealed an increased posterior dislocation compared with evaluation 24 months after surgery. No further migration of the clavicle or AC joint degeneration was observed.

Refixation of the supraspinatus tendon in a rat model--influence of continuous growth factor application on tendon structure.

The purpose was to evaluate histological changes of the supraspinatus tendon (SSP) after refixation under continuous growth factor application over 20 days in comparison to the native healing process. In a chronic rat tendon tear model (15 rats/group), a transosseous SSP refixation was performed and growth factors (control, G-CSF, b-FGF, combination) were continuously released into the subacromial space by an osmotic pump. Tendon healing was evaluated histologically by a modified MOVIN-Score, and Collagen I/III content was determined by immunohistology at 6 weeks. A modified MOVIN sum score showed significant lower counts for G-CSF and b-FGF in comparison to the control group (p = 0.050/p = 0.027) and the combined group (p = 0.050/p = 0.043). Collagen III was significantly reduced in the combined group compared to the control group (p = 0.028). Collagen I showed no significant differences. The Collagen I/III ratio was nearly doubled for b-FGF and the combined group compared to the control. At the study endpoint, 33% of pump dislocations were detected. The continuous application of both isolated growth factors (G-CSF/b-FGF) achieved improved tendon-remodeling. However, the continuous application via an osmotic pump showed a relative high dislocation rate when applied in the rat model.

Rotator cuff changes in a full thickness tear rat model: verification of the optimal time interval until reconstruction for comparison to the healing process of chronic lesions in humans.

BACKGROUND: The aim of the study was to develop a standardized rat model for chronic rotator cuff tears. Therefore, a time point of degenerative changes that shows comparable histological changes to the chronic tendon tears in humans had to be determined. The rat shoulder has already been described as a standardized model for investigation of the healing behavior in acute supraspinatus lesions. Little data exist about the possibility of generating a chronic rotator cuff lesion. METHODS: We performed a complete detachment of the supraspinatus tendon in 45 Sprague-Dawley rats. After an interval of 3, 6 and 9 weeks (15 rats in each group), the macroscopic and histological changes were analyzed. The histological investigation included atrophy and fatty muscle degeneration, tendon degeneration and the grade of inflammatory changes. For evaluation of tendon degeneration, a modified MOVIN-Score was used. The contralateral shoulder provided as control group. RESULTS: Macroscopically the defect showed an increasing coverage with scar tissue over time with a complete closure in 73% after 9 weeks. The 3 week group showed the highest rate of persisting defects (80%). The atrophy of the supraspinatus muscle decreased from initial slight atrophy to a nearly normal muscle status in the 9 week group. Fatty infiltration was found in three animals per group regardless of the time interval after detachment. Tendon degeneration (modified MOVIN-Score) showed no significant difference between 3 and 6 weeks (p = 0.93) whereas after 9 weeks a significant increased degeneration was found (p < 0.01). In the early phase (3 and 6 weeks), inflammatory cells could be detected more frequently. CONCLUSIONS: The results show that a chronic tear of the human rotator cuff can be imitated in the rat model with some exclusion. The rapid self-healing response in the rat and the fatty infiltration of the human muscle are the main differences. However, tendon degeneration, inflammation and muscle atrophy combined with a persisting defect at 3 weeks after detachment are comparable to the chronic tendon tears in humans. This model can serve as a basis for further research in the field of rotator cuff repair for chronic lesions.

Arthroscopically assisted 2-bundle anatomical reduction of acute acromioclavicular joint separations.

BACKGROUND: To achieve reduction of an acute acromioclavicular (AC) joint separation, novel procedures aim to provide stability and function by restoring the coracoclavicular anatomy. HYPOTHESIS: Anatomical reconstruction for acute AC joint disruption using 2 flip-button devices results in satisfactory clinical function and provides a stable fixation. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The outcome of 23 consecutive patients (21 men, 2 women; mean age, 37.5 +/- 10.2 years; range, 21-59 years) who underwent anatomical reduction for an acute AC joint dislocation using 2 flip-button devices, each separately replacing 1 coracoclavicular ligament, was evaluated clinically and radiographically preoperatively and 6, 12, and 24 months postoperatively. The evaluation included a visual analog scale for pain, the Constant score, the simple shoulder test, and the Short Form-36. An additional 7 patients had similar surgery during the same period, but 4 were lost to follow-up, 2 required surgical revision, and 1 developed postoperative infection. RESULTS: There were 3 Rockwood type III, 3 type IV, and 17 type V separations. Mean follow-up was 30.6 +/- 5.4 months (range, 24-40 months). The visual analog scale and Constant score showed significant improvements from preoperative 4.5 +/- 1.9 (range, 1-7) and 34.3 +/- 6.9 (range, 22-44) to postoperative 0.25 +/- 0.5 (range, 0-1) and 94.3 +/- 3.2 (range, 88-98) at 24 months, respectively. Postoperative radiographic AC joint alignment was unsatisfactory in 8 cases, either in the coronal, axillary, or both planes, with no different clinical outcome when compared with the remaining patients. CONCLUSION: Immediate anatomical reduction of an acute AC separation with flip-button devices provides satisfactory clinical results at intermediate-term follow-up. This technique should be performed by an experienced arthroscopist; tunnel and button placement are of utmost importance to avoid postoperative failure or loss of reduction.

The anatomic reconstruction of acromioclavicular joint dislocations using 2 TightRope devices: a biomechanical study.

BACKGROUND: For the reconstruction of acromioclavicular (AC) joint separation, several operative procedures have been described; however, the anatomic reconstruction of both coracoclavicular ligaments has rarely been reported. PURPOSE: The aim of this biomechanical study is to describe a new procedure for anatomic reconstruction of the AC joint. STUDY DESIGN: Controlled laboratory study. MATERIALS AND METHODS: Forty fresh-frozen cadaveric shoulders were tested. Cyclic loading and a load-to-failure protocol was performed in vertical (native, n = 10; reconstructed, n = 10) and anterior directions (native, n = 10; reconstructed, n = 10) on 20 AC joints and repeated after anatomic reconstruction. Reconstruction of conoid and trapezoid ligaments was achieved by 2 TightRope devices (Arthrex, Naples, Florida). Dynamic, cyclic, and static loading until failure in vertical (n = 5) and horizontal (n = 5) directions were tested in native as well as reconstructed joints in a standardized setting. RESULTS: The native coracoclavicular ligaments in static load for vertical force measured 598 N (range, 409-687), elongation 10 mm (range, 6-14), and stiffness 99 N/mm (range, 67-130); static load for anterior force was 338 N (range, 186-561), elongation 4 mm (range, 3-7), and stiffness 140 N/mm (range, 70-210). The mean maximum static load until failure in reconstruction for vertical force was 982 N (range, 584-1330) (P =.001), elongation 4 mm (range, 3-6) (P < .001), and stiffness 80 N/mm (range, 66.6-105) (P = .091); and for anterior static force 627 N (range, 364-973) (P < .001), elongation 6.5 mm (range, 4-10) (P = .023), and stiffness 78 N/mm (range, 46-120) (P = .009). During dynamic testing of the native coracoclavicular ligaments, the mean amount of repetitions (100 repetitions per stage, stage 0-100 N, 100-200 N, 200-300 N, etc, and a frequency of 1.5 Hz) in native vertical direction was 593 repetitions (range, 426-683) and an average of 552 N (range, 452-683) load until failure. In vertical reconstructed testing, there were 742 repetitions (range, 488-893) (P = .222) with a load until failure of 768 N (range, 486-900) (P = .095). In the anterior direction load, the native ligament failed after an average of 365 repetitions (range, 330-475) and an average load of 360 N (range, 307-411), while reconstructed joints ended in 549 repetitions (range, 498-566) (P = .008) with a load until failure of 547 N (range, 490-585) (P = .008). In all testing procedures, a preload of 5 N was performed. CONCLUSION: The anatomic reconstruction of the AC joint using TightRope is a stable and functional anatomic reconstruction procedure. The reconstruction technique led to favorable in vitro results with equal or even higher forces than native ligaments. CLINICAL RELEVANCE: Through anatomic repair, stable function of the AC joint can be achieved in an anatomic manner.

Arthroscopic anatomical reconstruction of the acromioclavicular joint.

Traditional techniques for restoration of a separated acromioclavicular joint are afflicted with various complications and often lead to recurrent dislocation. Lately, anatomic as well as minimally-invasive repair techniques with major focus on restoration of the coracoclavicular ligaments have been described for acromioclavicular joint reconstruction. We present a technique for an arthroscopically-assisted anatomical acromioclavicular joint reconstruction by replacing the conoid and trapezoid separately with nonabsorbable sutures and titanium buttons.