Local insulin therapy affects fracture healing in a rat model

Abstract

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...

The Convergence of Fracture Repair and Stem Cells: Interplay of Genes, Aging, Environmental Factors and Disease

“…Other data suggests that insulin is directly anabolic for bone formation . BB Wistar rats develop spontaneous insulin‐dependent diabetes.…”

Local vanadium release from a calcium sulfate carrier accelerates fracture healing

“…The use of insulin or insulin‐mimetic agents can accelerate fracture healing in experimental animal models . The evaluation of scaffolds for appropriate drug delivery of these therapeutic modalities may combat the annual 5–10% of fractures that result in non‐union .…”

“…We previously showed that local insulin delivery to bone fracture sites promotes osteogenesis during the first 4–7 days of healing, but the effectiveness is limited when insulin is directly injected into the intramedullary (IM) canal . The use of palmitic acid and calcium sulfate (CaSO 4 ) as insulin carriers prolonged local bioavailability of insulin at bone fracture sites and improved healing as compared to insulin treatment without a carrier based upon biomechanical and histological healing outcomes . The use of these carriers also improved the therapeutic safety of insulin, evidenced by blood glucose levels within 12–24 h of insulin administration .…”

“…The use of palmitic acid and calcium sulfate (CaSO 4 ) as insulin carriers prolonged local bioavailability of insulin at bone fracture sites and improved healing as compared to insulin treatment without a carrier based upon biomechanical and histological healing outcomes . The use of these carriers also improved the therapeutic safety of insulin, evidenced by blood glucose levels within 12–24 h of insulin administration . Vanadyl acetylacetonate (VAC) is an insulin‐mimetic, organic salt of vanadium that can accelerate fracture healing without inducing hypoglycemia, yet concerns over the safety of metallic salts may limit translational approaches.…”

Sodium Tungstate for Promoting Mesenchymal Stem Cell Chondrogenesis

“…Previous studies have found systemic insulin treatment increased cell proliferation, soft callus formation/chondrogenesis, biomechanical properties, and callus bone content in diabetes mellitus rats [12]. Furthermore, local administration of insulin has been found to improve healing and bone regeneration in animal models [13,14]. However, insulin is difficult to deliver locally due to its high molecular weight (MW) (51 amino acids and 5,808 Da MW) and stability; insulin goes through hydrolysis/ degradation or intermolecular transformation during storage and use [15].…”