Growth factor release following femoral nailing.

The aim of this study was to investigate whether growth factors essential for fracture healing are substantially increased in the immediate aftermath following reaming of the intramedullary cavity for stabilisation of femoral shaft fractures. Consecutive adult patients whose femoral shaft fractures stabilised with either reamed (10 patients) or unreamed (10 patients) intramedullary nailing were studied. Peripheral blood samples and samples from the femoral canal before and after reaming and nail insertion were collected. Serum was extracted and using Elisa colorimetric assays the concentration of Platelet Derived Growth Factor-BetaBeta (PDGF), Vascular Endothelial Growth Factor (VEGF), Insulin-like Growth Factor-I (IGF-I), Transforming Growth Factor beta 1 (TGF-beta1) and Bone Morphogenetic Protein-2 (BMP-2) was measured. The mean age of the twenty patients who participated in the study was 38 years (range 20-63). Reaming substantially increased all studied growth factors (p<0.05) locally in the femoral canal. VEGF and PDGF were increased after reaming by 111.2% and 115.6% respectively. IGF-I was increased by 31.5% and TGF-beta1 was increased by 54.2%. In the unreamed group the levels of PDGF-BB, VEGF, TGF-beta1 remained unchanged while the levels of IGF-I decreased by 10%. The levels of these mediators in the peripheral circulation were not altered irrespectively of the nail insertion technique used. BMP-2 levels during all time points were below the detection limit of the immunoassay. This study indicates that reaming of the intramedullary cavity is associated with increased liberation of growth factors. The osteogenic effect of reaming could be secondary not only to grafting debris but also to the increased liberation of these molecules.

[1]  E. McCarty,et al.  Reamed intramedullary nailing of the femur: 551 cases. , 1999, The Journal of trauma.

[2]  Sigvard T. Hansen,et al.  Closed Intramedullary Nailing of Femoral Fractures , 2001 .

[3]  D. Hose,et al.  Human reaming debris: a source of multipotent stem cells. , 2005, Bone.

[4]  T A Einhorn,et al.  Growth Factor Regulation of Fracture Repair , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

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

[6]  P. Ruppel,et al.  Platelet-derived growth factor potentiates cellular responses of articular chondrocytes to interleukin-1. , 1991, Arthritis and rheumatism.

[7]  F. W. Rhinelander.  Effects of medullary nailing on the normal blood supply of diaphyseal cortex. 1973. , 1998, Clinical orthopaedics and related research.

[8]  Dekang Lin,et al.  The Release and Activation of Transforming Growth Factor β2 Associated with Apoptosis of Chick Hypertrophic Chondrocytes , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[9]  S. Ljunghall,et al.  The bone mineral density in acquired growth hormone deficiency correlates with circulating levels of insulin‐like growth factor I , 1992, Journal of internal medicine.

[10]  L. Donahue,et al.  Insulin-Like Growth Factors and Bone: The Osteoporosis Connection Revisited , 1998, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[11]  Stephen M Warren,et al.  Factors in the fracture microenvironment induce primary osteoblast angiogenic cytokine production. , 2002, Plastic and reconstructive surgery.

[12]  P. Giannoudis,et al.  Enhancement of fracture healing with parathyroid hormone: preclinical studies and potential clinical applications , 2007, Expert opinion on investigational drugs.

[13]  D. Macdonald,et al.  Reamed against unreamed nailing of the femoral diaphysis: a retrospective study of healing time. , 1997, Injury.

[14]  D. Cromack,et al.  TGF-beta and PDGF mediated tissue repair: identifying mechanisms of action using impaired and normal models of wound healing. , 1991, Progress in clinical and biological research.

[15]  M. Clatworthy,et al.  Reamed versus unreamed femoral nails. A randomised, prospective trial. , 1998, The Journal of bone and joint surgery. British volume.

[16]  N. Haas,et al.  Cell proliferation and differentiation during fracture healing are influenced by locally applied IGF-I and TGF-beta1: comparison of two proliferation markers, PCNA and BrdU. , 2003, Journal of biomedical materials research. Part B, Applied biomaterials.

[17]  F. W. Rhinelander.  The normal microcirculation of diaphyseal cortex and its response to fracture. , 1968, The Journal of bone and joint surgery. American volume.

[18]  F. Kummer,et al.  Intramedullary Nailing of the Lower Extremity: Biomechanics and Biology , 2007, The Journal of the American Academy of Orthopaedic Surgeons.

[19]  R. Maier,et al.  Timing of femur fracture fixation: effect on outcome in patients with thoracic and head injuries. , 2002, The Journal of trauma.

[20]  P. Giannoudis,et al.  Current concepts of the inflammatory response after major trauma: an update. , 2003, Injury.

[21]  Y. Cui,et al.  rhBMP‐2, rhVEGF165, rhPTN and thrombin‐related peptide, TP508 induce chemotaxis of human osteoblasts and microvascular endothelial cells , 2005 .

[22]  C. A. Rockwood,et al.  THE AMERICAN Academy of Orthopaedic Surgeons. , 1988, The Journal of bone and joint surgery. American volume.

[23]  T. Sakou.  Bone morphogenetic proteins: from basic studies to clinical approaches. , 1998, Bone.

[24]  Britt Wildemann,et al.  Synergistic effect of IGF-I and TGF-ß1 on fracture healing in ratsSingle versus combined application of IGF-I and TGF-ß1 , 2003 .

[25]  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.

[26]  P. Tornetta,et al.  Reamed versus nonreamed anterograde femoral nailing. , 2000, Journal of orthopaedic trauma.

[27]  M. Müller.  [Classification and international AO-documentation of femur fractures]. , 1980, Unfallheilkunde.

[28]  H. Oxlund,et al.  Local injection of TGF-beta increases the strength of tibial fractures in the rat. , 1994, Acta orthopaedica Scandinavica.

[29]  P. Lips,et al.  In Vivo Mechanical Loading Modulates Insulin-Like Growth Factor Binding Protein-2 Gene Expression in Rat Osteocytes , 2007, Calcified Tissue International.

[30]  Jörg Fiedler,et al.  BMP‐2, BMP‐4, and PDGF‐bb stimulate chemotactic migration of primary human mesenchymal progenitor cells , 2002, Journal of cellular biochemistry.

[31]  G. Hofmann,et al.  Interlocking compression nailing: a report on 402 applications , 1998, Archives of Orthopaedic and Trauma Surgery.

[32]  H. Oxlund,et al.  Local injection of TGF-β increases the strength of tibial fractures in the rat , 1994 .

[33]  Thomas A. Mustoe, MD, FACS,et al.  Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms , 1989, The Journal of cell biology.

[34]  W. Richter,et al.  TGF-β1 as a marker of delayed fracture healing , 2005 .

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

[36]  L. Handolin,et al.  Early intramedullary nailing of lower extremity fracture and respiratory function in polytraumatized patients with a chest injuryA retrospective study of 61 patients , 2004, Acta orthopaedica Scandinavica.

[37]  J. K. Nulend,et al.  Viable osteoblastic potential of cortical reamings from intramedullary nailing , 2004, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[38]  B. Olsen,et al.  Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. , 2002, Development.

[39]  G. Regel,et al.  Primary intramedullary femur fixation in multiple trauma patients with associated lung contusion--a cause of posttraumatic ARDS? , 1993, The Journal of trauma.

[40]  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.

[41]  P. Giannoudis,et al.  Surgical stress response. , 2006, Injury.

[42]  F. Bakker,et al.  Reaming debris in osteotomized sheep tibiae. , 2001, The Journal of trauma.

[43]  Gerhard Küntscher,et al.  Die Marknagelung von Knochenbrüchen , 1940, Klinische Wochenschrift.

[44]  P. Giannoudis,et al.  Application of clinical proteomics in diagnosis and management of trauma patients. , 2007, Injury.

[45]  C. Court-Brown,et al.  Reamed or unreamed nailing for closed tibial fractures. A prospective study in Tscherne C1 fractures. , 1996, The Journal of bone and joint surgery. British volume.

[46]  S. Perren,et al.  Reaming versus non-reaming in medullary nailing: Interference with cortical circulation of the canine tibia , 2004, Archives of Orthopaedic and Trauma Surgery.

[47]  M. Leunig,et al.  Thermal necrosis after tibial reaming for intramedullary nail fixation. A report of three cases. , 1996, The Journal of bone and joint surgery. British volume.

[48]  Y. Cui,et al.  rhBMP-2, rhVEGF(165), rhPTN and thrombin-related peptide, TP508 induce chemotaxis of human osteoblasts and microvascular endothelial cells. , 2005, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[49]  R. Sanders,et al.  Trochanteric Nail Insertion for the Treatment of Femoral Shaft Fractures , 2005, Journal of orthopaedic trauma.

[50]  Robert Peter,et al.  Bone debris: dead matter or vital osteoblasts. , 2004, The Journal of trauma.

[51]  C. Tabin,et al.  BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing , 2006, Nature Genetics.

[52]  M. Eriksen,et al.  The influence of a one-step reamer-irrigator-aspirator technique on the intramedullary pressure in the pig femur. , 2006, Injury.

[53]  M. Itoman,et al.  Deep infection and fracture healing in immediate and delayed locked intramedullary nailing for open femoral fractures. , 1999, Orthopedics.

[54]  Thomas A. Mustoe, MD, FACS,et al.  Role of platelet‐derived growth factor in wound healing , 1991, Journal of cellular biochemistry.

[55]  D. Clawson,et al.  Closed intramedullary nailing of femoral fractures. A report of five hundred and twenty cases. 1984. , 1984, The Journal of bone and joint surgery. American volume.

[56]  Müller Me.  [Classification and international AO-documentation of femur fractures]. , 1980 .

[57]  P. Diggle,et al.  Factors affecting rates of infection and nonunion in intramedullary nailing. , 2004, The Journal of bone and joint surgery. British volume.