This study quantified the effects of local intramedullary delivery of an organic vanadium salt, which may act as an insulin-mimetic on fracture healing. Using a BB Wistar rat femoral fracture model, local vanadyl acetylacetonate (VAC) was delivered to the fracture site and histomorphometry, mechanical testing, and immunohistochemistry were performed. Callus percent cartilage was 200% higher at day 7 (p < 0.05) and 88% higher at day 10 (p < 0.05) in the animals treated with 1.5 mg/kg of VAC. Callus percent mineralized tissue was 37% higher at day 14 (p < 0.05) and 31% higher at day 21 (p < 0.05) in the animals treated with 1.5 mg/kg of VAC. Maximum torque to failure was 104% and 154% higher at 4 weeks post-fracture (p < 0.05) for the healing femurs from the VACtreated (1.5 and 3.0 mg/kg) animals. Animals treated with other VAC doses demonstrated increased mechanical parameters at 4 weeks (p < 0.05). Immunohistochemistry detected 62% more proliferating cells at days 7 (p < 0.05) and 94% more at day 10 (p < 0.05) in the animals treated with 1.5 mg/kg VAC. Results showed 100% more vascular endothelial growth factor-C (VEGF-C) positive cells and 80% more blood vessels at day 7 (p < 0.05) within the callus subperiosteal region of VAC-treated animals (1.5 mg/kg) compared to controls. The results suggest that local VAC treatment affects chondrogenesis and angiogenesis within the first 7-10 days post-fracture, which leads to enhanced mineralized tissue formation and accelerated fracture repair as early as 3-4 weeks post-fracture. ß

Local insulin delivery has been shown to improve osseous healing in diabetic animals. The purpose of this study was to quantify the effects of local intramedullary delivery of saline or Ultralente insulin (UL) on various fracture healing parameters using an in vivo non-diabetic BB Wistar rat model. Quantitation of local insulin levels showed a rapid release of insulin from the fractured femora, demonstrating complete release at 2 days. RT-PCR analysis revealed that the expression of early osteogenic markers (Col1a2, osteopontin) was significantly enhanced with UL treatment when compared with saline controls (p < 0.05). Significant differences in VEGF þ cells and vascularity were evident between the treatment and control groups at day 7 (p < 0.05). At day 21, histomorphometric analysis demonstrated a significant increase in percent mineralized tissue in the UL-treated animals compared with controls (p < 0.05), particularly within the subperiosteal region of the fracture callus. Mechanical testing at 4 weeks showed significantly greater mechanical strength for UL-treated animals (p < 0.05), but healing in control animals caught up at 6 weeks post-fracture. These results suggest that the primary osteogenic effect of UL during the early stages of fracture healing (1-3 weeks) is through an increase in osteogenic gene expression, subperiosteal angiogenesis, and mineralized tissue formation. ß

Each year, over one million orthopedic operations are performed which a bony defect is presence, requiring the use of further augmentation in addition to bony fixation. Application of autogenous bone graft is the standard of care to promote healing of these defects, but several determents exist in using autogenous bone graft exist including limited supply and donor site morbidity. Prior work has demonstrated that local insulin application to fracture sites promote fracture healing, but no work has been performed to date in its effects upon defect healing/allograft incorporation. The goal of this study was to examine the potential role of local insulin application upon allograft incorporation. Microradiographic, histologic, and histomorphometric analysis outcome parameters showed that local insulin significantly accelerated new bone formation. Histological comparisons using predetermined scoring systems demonstrated significantly greater healing in femora treated with insulin compared to control femora (p < 0.001). Quantitatively more bone production was also observed, specifically in areas of endosteal (p = 0.010) and defect (p = 0.041) bone in femora treated with local insulin, compared to control femora, 6 weeks after implantation. This study demonstrates the potential of local insulin as an adjunct for the treatment of segmental defect and allograft incorporation.

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