The enhancement of bone allograft incorporation by the local delivery of the sphingosine 1-phosphate receptor targeted drug FTY720.

Poor vascularization coupled with mechanical instability is the leading cause of post-operative complications and poor functional prognosis of massive bone allografts. To address this limitation, we designed a novel continuous polymer coating system to provide sustained localized delivery of pharmacological agent, FTY720, a selective agonist for sphingosine 1-phosphate receptors, within massive tibial defects. In vitro drug release studies validated 64% loading efficiency with complete release of compound following 14 days. Mechanical evaluation following six weeks of healing suggested significant enhancement of mechanical stability in FTY720 treatment groups compared with unloaded controls. Furthermore, superior osseous integration across the host-graft interface, significant enhancement in smooth muscle cell investment, and reduction in leukocyte recruitment was evident in FTY720 treated groups compared with untreated groups. Using this approach, we can capitalize on the existing mechanical and biomaterial properties of devitalized bone, add a controllable delivery system while maintaining overall porous structure, and deliver a small molecule compound to constitutively target vascular remodeling, osseous remodeling, and minimize fibrous encapsulation within the allograft-host bone interface. Such results support continued evaluation of drug-eluting allografts as a viable strategy to improve functional outcome and long-term success of massive cortical allograft implants.

The effects of dietary caloric restriction on antioxidant status and lipid peroxidation in mild and severe streptozotocin-induced diabetic rats.

BACKGROUND: Dietary caloric restriction (CR) without malnutrition is effective in the control of diabetes mellitus by stabilizing glucose homeostasis and enhancing glycemic control. Mild and severe streptozotocin-induced diabetic and non-diabetic rats were subjected to caloric restriction and ad libitum feeding to evaluate their effects on oxidative stress and lipid profile in the plasma of experimental animals. METHODS: Mild and severe diabetes were induced in Male Wistar rats by intraperitoneal injection of 35 and 65 mg/kg streptozotocin respectively. The experimental animals were subjected to 40% caloric restriction and ad libitum feeding for 9 weeks. RESULTS: CR was effective in significantly reducing body weight, blood glucose, HbA IC and TG concentrations (all p < 0.001) in mild diabetic rats and non-significantly improving the plasma HDL-cholesterol concentrations. However, CR did not produce any significant effect on the antioxidant enzyme activities and MDA concentrations in all the groups nor in any of the parameters measured in non-diabetic rats except their overall weight change. There were significant (p < 0.001) decreases in body weight and non-significant fluctuating results in HbA IC and HDL-cholesterol in severe diabetic animals. CONCLUSIONS: These results demonstrate that caloric restriction is most effective in mild than in non-diabetic or severe diabetic animals.