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

A significant number of lower extremity fractures result in mal-union necessitating effective treatments to restore ambulation. Prior research in diabetic animal fracture models demonstrated improved healing following local insulin application to the fracture site and indicated that local insulin therapy can aid bone regeneration, at least within an insulin-dependent diabetic animal model. This study tested whether local insulin therapy could accelerate femur fracture repair in normal, non-diabetic rats. High (20 units) and low (10 units) doses of insulin were delivered in a calcium sulfate carrier which provided sustained release of the exogenous insulin for 7 days after fracture. Histomorphometry, radiographic scoring, and torsional mechanical testing were used to measure fracture healing. The fracture calluses from rats treated with high-dose insulin had significantly more cartilage than untreated rats after 7 and 14 days of healing. After 4 weeks of healing, femurs from rats treated with low-dose insulin had significantly higher radiographic scores and mechanical strength (p < 0.05), compared to the no treatment control groups. The results of this study suggest that locally delivered insulin is a potential therapeutic agent for treating bone fractures. Further studies are necessary, such as large animal proof of concepts, prior to the clinical use of insulin for bone fracture treatment. The effect of insulin on diabetic fracture healing has been well documented.1-3 Diabetes leads to reduced cellular proliferation in the early callus, reduced collagen synthesis and content compared to non-diabetic control animals, and reduced biomechanical properties of the healing fracture.1 Administration of systemic insulin to regulate blood glucose within normal levels ameliorates impaired fracture healing in an insulin-dependent diabetic rat model.2 Remarkably though, local insulin treatment at the fracture site in insulin-dependent diabetic rats that were maintained in a severe hyperglycemic state also ameliorates impaired fracture healing associated with diabetes.1,2 Local insulin therapy improved fracture site cell proliferation, cartilage formation, new bone content, and callus strength in hyperglycemic, insulin-dependent, diabetic rats. 1,4The experiments performed in diabetic animals indicate that insulin acts to positively regulate fracture healing at the systemic and local levels. Use of insulin to augment fracture healing or other bone regeneration processes in normal animal models of bone regeneration has not been investigated. Elevating systemic insulin levels would cause hypoglycemia in normal mammals and thus is not a therapeutic option. However, local application of insulin to a fracture site that would provide locally high yet systemically near normal insulin levels could be a therapeutic strategy to enhance fracture healing.The effects of local insulin therapy on femur fracture healing were measured using a non-diabetic rat model. We hypothesize that in a dose dependent manner, local insulin com...

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The study confirms app validity and usefulness by demonstrating that every cohort's simulator performance improved with consecutive use, and participants with higher levels of training performed better. Also, user confidence in this app's veracity and utility increased with lower levels of training experience.