Role of sildenafil in acceleration of delayed union fracture healing on Sprague-Dawley rats model.

Introduction: Delayed union with its subsequent morbidity remains a major problem in fracture healing. Angiogenesis plays an important role in fracture healing. Sildenafil has been shown to be a potent stimulator of angiogenesis through upregulation of pro-angiogenic factors known as vascular endothelial growth factor (VEGF). This study evaluated the role of sildenafil in accelerating the healing process in delayed union model. Methods: This was an experimental study in delayed union femoral fracture model in male Sprague Dawley rats evaluated by histomorphometry and immunohistochemistry. Twenty four rats Original Research Article Fauzi et al.; BJMMR, 8(5): 419-428, 2015; Article no.BJMMR.2015.464 420 were randomized into four groups; control (group 1), administration of sildenafil 3.5 mg/kgbw (group 2), sildenafil 5 mg/kgbw (group 3), and sildenafil 7.5 mg/kgbw (group 4). The parameters evaluated were total area of callus, osseous, cartilage, fibrous tissue, and VEGF expression. The evaluation was carried out at week-2 and -4 after intervention. Results: On week-2 evaluation, ANOVA test showed a significant difference in the total callus area with the p-value of 0.004. ANOVA test also found significant difference among groups in the osseous, cartilage, and fibrous tissue area with p-value of 0.001, 0.015 and 0.005 respectively. On week-4, ANOVA test found no significant difference among all groups in the total callus area with p-value of 0.192. However, in ANOVA test, we found significant difference between groups in the osseous and fibrous tissue area with p-value of 0.015 and 0.001 respectively. Conclusion: Sildenafil is proven to accelerate fracture healing of delayed union and to increase VEGF expression.

[1]  A. Bachtiar,et al.  Transplantation of mesenchymal stem cells, recombinant human BMP-2,and their combination in accelerating the union after osteotomy and increasing, the mechanical strength of extracorporeally irradiated femoral autograft in rat models , 2014, Medical journal of the Islamic Republic of Iran.

[2]  A Ignatius,et al.  Rodent animal models of delayed bone healing and non-union formation: a comprehensive review. , 2013, European cells & materials.

[3]  M. Menger,et al.  Sildenafil accelerates fracture healing in mice , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[4]  C. Hettrich,et al.  Vascular Endothelial Growth Factor: An Essential Component of Angiogenesis and Fracture Healing , 2010, HSS Journal.

[5]  A. Rivard,et al.  Sildenafil Increases Endothelial Progenitor Cell Function and Improves Ischemia-Induced Neovascularization in Hypercholesterolemic Apolipoprotein E–Deficient Mice , 2009, Hypertension.

[6]  Ramesh Vidavalur,et al.  Sildenafil-mediated neovascularization and protection against myocardial ischaemia reperfusion injury in rats: role of VEGF/angiopoietin-1 , 2008, Journal of cellular and molecular medicine.

[7]  F. Dammacco,et al.  [Mesenchymal stem cells and bone regeneration]. , 2008, Recenti progressi in medicina.

[8]  P. Giannoudis,et al.  Fracture healing: the diamond concept. , 2007, Injury.

[9]  D. Lefer,et al.  Sildenafil Promotes Ischemia-Induced Angiogenesis Through a PKG-Dependent Pathway , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[10]  P. Giannoudis,et al.  Molecular aspects of fracture healing: which are the important molecules? , 2007, Injury.

[11]  Ramesh Vidavalur,et al.  Sildenafil induces angiogenic response in human coronary arteriolar endothelial cells through the expression of thioredoxin, hemeoxygenase and vascular endothelial growth factor. , 2006, Vascular pharmacology.

[12]  L. Memış,et al.  Demineralized bone matrix and hydroxyapatite/tri-calcium phosphate mixture for bone healing in rats , 2006, International Orthopaedics.

[13]  J. Goulet,et al.  Delayed unions of the tibia. , 2006, Instructional course lectures.

[14]  Eleftherios Tsiridis,et al.  Current concepts of molecular aspects of bone healing. , 2005, Injury.

[15]  I. Hvid,et al.  Recombinant human vascular endothelial growth factor enhances bone healing in an experimental nonunion model. , 2005, The Journal of bone and joint surgery. British volume.

[16]  N. Weidner,et al.  Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors , 2004, Breast Cancer Research and Treatment.

[17]  David J Hak,et al.  Development of an atrophic nonunion model and comparison to a closed healing fracture in rat femur , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[18]  J. Lou,et al.  Engineered allogeneic mesenchymal stem cells repair femoral segmental defect in rats , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[19]  J. Szatkowski,et al.  Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). , 2003, The Journal of bone and joint surgery. American volume.

[20]  H. Redmond,et al.  Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Papapoulos,et al.  Bone Morphogenetic Proteins Stimulate Angiogenesis through Osteoblast-Derived Vascular Endothelial Growth Factor A. , 2002, Endocrinology.

[22]  J. Jośko,et al.  Vascular endothelial growth factor (VEGF) and its effect on angiogenesis. , 2000, Medical science monitor : international medical journal of experimental and clinical research.

[23]  O. Grundnes,et al.  Effects of periosteal stripping on healing of segmental fractures in rats. , 1996, Journal of orthopaedic trauma.

[24]  P. Flecknell,et al.  Recommendations for euthanasia of experimental animals: Part 2. DGXT of the European Commission. , 1996, Laboratory animals.

[25]  D. Lorich,et al.  The pericyte as a possible osteoblast progenitor cell. , 1992, Clinical orthopaedics and related research.