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...

This study evaluated the effect of local zinc chloride (ZnCl 2 ), an insulin mimetic agent, upon the early and late parameters of fracture healing in rats using a standard femur fracture model. Mechanical testing, radiographic scoring, histomorphometry, qualitative histological scoring, PCNA immunohistochemistry, and local growth factor analysis were performed. Fractures treated with local ZnCl 2 possessed significantly increased mechanical properties compared to controls at 4 weeks post fracture. The radiographic scoring analysis showed increased cortical bridging at 4 weeks in the 1.0 (p ¼ 0.0015) and 3.0 (p < 0.0001) mg/kg ZnCl 2 treated groups. Histomorphometry of the fracture callus at day 7 showed 177% increase (p ¼ 0.036) in percent cartilage and 133% increase (p ¼ 0.002) in percent mineralized tissue with local ZnCl 2 treatment compared to controls. Qualitative histological scoring showed a 2.1Â higher value at day 7 in the ZnCl 2 treated group compared to control (p ¼ 0.004). Cell proliferation and growth factors, VEGF and IGF-I, within fracture calluses treated with local ZnCl 2 were increased at day 7. The results suggest local administration of ZnCl 2 increases cell proliferation, causing increased growth factor production which yields improved chondrogenesis and endochondral ossification. Ultimately, these events lead to accelerated fracture healing as early as 4 weeks post fracture. ß

Objectives: To develop an accurate machine learning (ML) predictive model incorporating patient, fracture, and trauma characteristics to identify individual patients at risk of an (occult) PMF. Methods: Databases of 2 studies including patients with TSFs from 2 Level 1 trauma centers were combined for analysis. Using ten-fold cross-validation, 4 supervised ML algorithms were trained in recognizing patterns associated with PMFs: (1) Bayes point machine; (2) support vector machine; (3) neural network; and (4) boosted decision tree. Performance of each ML algorithm was evaluated and compared based on (1) C-statistic; (2) calibration slope and intercept; and (3) Brier score. The best-performing ML algorithm was incorporated into an online open-access prediction tool. Results: Total data set included 263 patients, of which 28% had a PMF. Training of the Bayes point machine resulted in the best-performing prediction model reflected by good C-statistic, calibration slope, calibration intercept, and Brier score of 0.89, 1.02, −0.06, and 0.106, respectively. This prediction model was deployed as an open-access online prediction tool. Conclusion: A ML-based prediction model accurately predicted the probability of a (occult) PMF in patients with a TSF based on patient- and fracture-specific characteristics. This prediction model can guide surgeons in their diagnostic workup and preoperative planning. Further research is required to externally validate the model before implementation in clinical practice. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

This study evaluated the efficacy of using calcium sulfate (CaSO 4 ) as a carrier for intramedullary delivery of an organic vanadium salt, vanadyl acetylacetonate (VAC) after femoral fracture. VAC can act as an insulin-mimetic and can be used to accelerate fracture healing in rats. A heterogenous mixture of VAC and CaSO 4 was delivered to the fracture site of BB Wistar rats, and mechanical testing, histomorphometry, micro-computed tomography (micro-CT) were performed to measure healing. At 4 weeks after fracture, maximum torque to failure, effective shear modulus, and effective shear stress were all significantly higher (p < 0.05) in rats treated with 0.25 mg/kg VAC-CaSO 4 as compared to carrier control rats. Histomorphometry found a 71% increase in percent cartilage matrix (p < 0.05) and a 64% decrease in percent mineralized tissue (p < 0.05) at 2 weeks after fracture in rats treated with 0.25 mg/kg of VAC-CaSO 4 . Micro-CT analyses at 4 weeks found a more organized callus structure and higher trending maximum connected z-ray. fraction for VAC-CaSO 4 groups. Evaluation of radiographs and serial histological sections at 12 weeks did not show any evidence of ectopic bone formation. As compared to previous studies, CaSO 4 The use of insulin or insulin-mimetic agents can accelerate fracture healing in experimental animal models.1-5 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. 6 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.1 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.2,3 The use of these carriers also improved the therapeutic safety of insulin, evidenced by blood glucose levels within 12-24 h of insulin administration.1-3 Vanadyl acetylacetonate (VAC) is an insulin-mimetic, organic salt of vanadium that can accelerate fracture healing without inducing hypoglycemia, 5 yet concerns over the safety of metallic salts may limit translational approaches. Investigation of carriers that can deliver lower doses of VAC over a longer period at a fracture site could improve efficacy and enhance safety.Because of the long track record of CaSO 4 (use approved by the FDA in 1996) as an osteoconductive carrier in non-diabetic patients, we hypothesized that VAC delivered with CaSO 4 at the fracture site would accelerate fracture healing in experimental animals. To test this hypothesis, early and late parameters of femur fracture healing were measured in non-diabetic BB Wistar rats treated with a single intramedullary injection of VAC mixed with CaSO 4 . MATERIALS AND METHODS Animal ModelHealthy, diabet...

The effective dose of ZnCl2 augmentation for the enhancement of fracture healing in rats was reduced 3-fold in this study compared with previous findings. Furthermore, CaSO4 acted synergistically with ZnCl2 to increase the mechanical strength and stability at the fracture site.