Visualization of Murine Intranasal Dosing Efficiency Using Luminescent Francisella tularensis: Effect of Instillation Volume and Form of Anesthesia

Intranasal instillation is a widely used procedure for pneumonic delivery of drugs, vaccine candidates, or infectious agents into the respiratory tract of research mice. However, there is a paucity of published literature describing the efficiency of this delivery technique. In this report we have used the murine model of tularemia, with Francisella tularensis live vaccine strain (FTLVS) infection, to evaluate the efficiency of pneumonic delivery via intranasal dosing performed either with differing instillation volumes or different types of anesthesia. FTLVS was rendered luminescent via transformation with a reporter plasmid that constitutively expressed the Photorhabdus luminescens lux operon from a Francisella promoter. We then used an IVIS Spectrum whole animal imaging system to visualize FT dissemination at various time points following intranasal instillation. We found that instillation of FT in a dose volume of 10 µl routinely resulted in infection of the upper airways but failed to initiate infection of the pulmonary compartment. Efficient delivery of FT into the lungs via intranasal instillation required a dose volume of 50 µl or more. These studies also demonstrated that intranasal instillation was significantly more efficient for pneumonic delivery of FTLVS in mice that had been anesthetized with inhaled (isoflurane) vs. parenteral (ketamine/xylazine) anesthesia. The collective results underscore the need for researchers to consider both the dose volume and the anesthesia type when either performing pneumonic delivery via intranasal instillation, or when comparing studies that employed this technique

Multi-objective robust optimization of multi-directional carbon/glass fibre-reinforced hybrid composites with manufacture related uncertainties under flexural loading

© 2017 Elsevier Ltd Multi-objective robust optimization of multi-directional carbon/glass fibre-reinforced epoxy hybrid composites has been presented in this study. Two conflicting objectives, namely minimizing the density and minimizing the cost under the constraint of a specified minimum flexural strength, were considered with the design variables being the fibre type, fibre orientation angle and fibre volume fraction of each lamina. A modified version of the non-dominated sorting genetic algorithm (NSGA-II) was used in order to find the Pareto optimal solutions. Furthermore, robust optimization problems were defined by including manufacturing related uncertainties in the thickness and orientation of each lamina. These uncertain variables were considered as uncertain-but-bounded with the worst case for the minimum flexural strength being determined through an internal anti-optimization solver. The optimization and anti-optimization problems were solved with Pareto optimal and robust solutions being presented for carbon/glass fibre hybrid composites with different levels of minimum flexural strength. The results showed that, in general, consideration of uncertainties in thickness and fibre orientation angle increased the material cost and/or density with this effect being more important for high strength composites