Refixation of the Supraspinatus Tendon in a Rat Model—Influence of Continuous Growth Factor Application on Tendon Structure Stefan Buchmann, 1,2 Gunther H. Sandmann, 3 Lars Walz, 4 Henriette Hoppe, 1 Knut Beitzel, 1,5 Gabriele Wexel, 6 Weiwei Tian, 7 Gerhard Winter, 7 Andreas B. Imhoff 1 1 Department of Orthopaedic Sports Medicine, Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr. 22, 81675 Munich, Germany, 2 Department of Orthopaedic Surgery, Schulthess Clinic, Lengghalde 2, 8008 Zurich, Switzerland, 3 Department of Traumatology, Klini- kum rechts der Isar, Technical University of Munich, Ismaningerstr. 22, 81675 Munich, Germany, 4 Clinical Trial Unit, University Hospital Basel, Schanzenstr. 55, 4031 Basel, Switzerland, 5 Department of Trauma and Orthopaedic Surgery, Berufsgenossenschaftliche Unfallklinik Murnau, Prof.-Ku ¨ntschner-Str. 8, 82418 Murnau, Germany, 6 Department of Experimental Oncology, Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr. 22, 81675 Munich, Germany, 7 Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig Maximilians University, Butenandstr. 5-13, 81377 Munich, Germany Received 6 April 2012; accepted 23 July 2012 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jor.22211 ABSTRACT: 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 ¼ 0.050/p ¼ 0.027) and the combined group (p ¼ 0.050/p ¼ 0.043). Collagen III was significantly reduced in the combined group compared to the control group (p ¼ 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. ß 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res Keywords: rat model; chronic tear; rotator cuff repair; growth factor; collagen Tears of the rotator cuff tendon are a common cause of debilitating pain, reduced shoulder function, and weakness in the elderly population. 1 The technical approach to surgical reconstruction experienced a vast progress in the last years and biomechanically primary stable constructs can be achieved. 2 Nevertheless, a retear rate between 25% and 94% is documented in the recent literature. 3–5 Patient age, tear size, tendon/ muscle quality, and biologic healing response are described as important risk factors for retear. 6 Sum- marizing these risk factors the insufficient healing capacity of these degenerative lesions is likely the main factor for failure of reconstruction in rotator cuff surgery and therefore it gains understandingly increasing interest. Growth factors (GFs) that appear during the wound healing process have been reported to promote tissue regeneration and healing. 7,8 The choice of GFs for this study was based on following factors: previous data for improvement of tendon healing in animal trials, availability and reported clinical experience in humans. Additionally, growth factors used in clinical practice were favored because of the already existing pharma- cological approvals and therefore a shortened time for transfer of the results into clinical routine. 9 The GFs used in the present study were also chosen because of their differing pharmacological effects to investigate a potential benefit of a combined treatment. Granulocyte colony stimulating factor (G-CSF) affects the inflammatory process by direct activation of neutrophile granulocytes and promotes chemotaxis of mesenchymal stem cells and neutrophile granulocytes. Additionally, enhancement of microvessel formation is described. 10 Animal studies using G-CSF by Sasaki et al. 9 demonstrated improvement of ACL graft to bone integration. Basic fibroblast growth factor (b-FGF) supports fibroblast proliferation and—migration as well as angiogenesis and collagen expression. 11 Animal stud- ies revealed positive effects on early tendon healing in different used models. 12,13 In current studies, an individual timepoint for GF peak expression is described (e.g., b-FGF with 7– 9 days after injury). 14,15 Bolus application of growth factors typically leads to clearance from the wound site within 48 h. We developed a model for continuous GF application by an osmotic pump to avoid the early clearance or required repetitive local injections. To evaluate the effects in chronic tendon degeneration, we used a previously evaluated chronic tear model in rats. 16 The aim of the study was to evaluate histological changes of the chronically torn supraspinatus tendon (SSP) following refixation under the influence of con- tinuous G-CSF and b-FGF application over 20 days in comparison to the native healing process of a chronic The authors state that there is no conflicts of interest. Grant sponsor: Deutsche Arthrosehilfe e.V. (German Society for Support of Osteoarthritic Patients—Non-profit association with main focus on education and research granting); Grant number: p47-A196-Imhoff-EP4-walz1-schulter-ko–60k-2005-08. Correspondence to: Stefan Buchmann (T: 49-89-41407840; F: 49- 89-4140-7841; E-mail: s_buchmann17@hotmail.com) ß 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. JOURNAL OF ORTHOPAEDIC RESEARCH 2012 1