RESUMO
Distraction osteogenesis is a unique and effective way to treat limb length inequality resulting from congenital and posttraumatic skeletal defects. However, despite its widespread clinical use, the cellular and molecular mechanisms by which this surgical treatment promotes new bone formation are not well understood. Previous studies in distraction osteogenesis have noted increased blood flow and vessel formation within the zone of distraction. These observations suggest that distraction osteogenesis may be driven in part by an angiogenic process. Using immunohistological analysis, the expression of two different angiogenic factors (VEGF and bFGF) was shown to localize at the leading edge of the distraction gap, where nascent osteogenesis was occurring. These cells were spatially adjacent to new vessels that were identified by staining for factor VIII. Microarray analysis detected maximal mRNA expression for a wide variety of angiogenic factors including angiopoietin 1 and 2, both Tie receptors, VEGF-A and -D, VEGFR2, and neuropilin 1. Expression of these factors was found to be maximal during the phase of active distraction. Expression of mRNA for extracellular matrix proteins and BMPs was also maximal during this period. A comparison between the patterns of gene expression in fracture healing and distraction osteogenesis revealed similarities; however, the expression of a number of genes showed selective expression in these two types of bone healing. These data suggest that bone formation during distraction osteogenesis is accompanied by the robust induction of factors associated with angiogenesis and support further investigations to elucidate the mechanisms by which angiogenic events promote bone repair and regeneration.
Assuntos
Indutores da Angiogênese/metabolismo , Perfilação da Expressão Gênica , Osteogênese por Distração , Angiopoietinas/genética , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas de Transporte/genética , Colágeno/genética , Citocinas/genética , Fêmur/metabolismo , Fêmur/patologia , Fêmur/cirurgia , Fator 2 de Crescimento de Fibroblastos/análise , Fator 2 de Crescimento de Fibroblastos/genética , Consolidação da Fratura/genética , Consolidação da Fratura/fisiologia , Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia , Imuno-Histoquímica , Masculino , Neovascularização Fisiológica/genética , Neuropilinas/genética , Análise de Sequência com Séries de Oligonucleotídeos , Osteocalcina/genética , Osteogênese/genética , Osteopontina , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de TIE/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Sialoglicoproteínas/genética , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta2 , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/genética , Fatores de Crescimento do Endotélio Vascular/genética , Fator de von Willebrand/análiseRESUMO
The control of postoperative pain in the pediatric orthopaedic patient is a challenging endeavor. Several studies have shown the efficacy of ketorolac tromethamine in the pediatric general surgical population, but its efficacy in the pediatric orthopaedic population remains unproven. Twenty-seven consecutive patients (age 6 months to 18 years) who underwent long-bone osteotomies or foot procedures by a group of three pediatric orthopaedic surgeons were given a ketorolac protocol (1 mg/kg loading, 0.5 mg/kg every 6 h for 24 h). Breakthrough pain was managed with morphine until the patient was able to take oral pain medication, as was any pain after the 24-h period for ketorolac expired. Thirty-seven age- and case-matched patients were used as retrospective controls. The patients in the study who received ketorolac required significantly fewer doses of morphine than did the control group (2.29 +/- 3.98 vs. 10.02 +/- 3.39; p < 0.05). In addition the patients on the ketorolac protocol experienced fewer gastrointestinal side effects (4% vs. 32%; p < 0.05). Finally, the patients in the ketorolac group had a significantly shorter length of stay (3.63 +/- 1.64 days vs. 4.74 +/- 1.76 days; p < 0.05). There were no bleeding complications in either group. Ketorolac is thus a safe and effective means of controlling postoperative pain in the pediatric orthopaedic population while avoiding the troubling maleffects seen with the exclusive use of morphine.