BME School Chair Candidate 

Todd Giorgio 

Professor of Biomedical Engineering 

Professor of Chemical and Biomolecular Engineering 

Professor of Cancer Biology 

Vanderbilt University 

 "The Design of Nanoparticle-Based Treatments for Bacteremia: Model-Based Insights" 

 Progressive emergence of multi-drug resistance (MDR) is a significant and growing factor in fatal bacterial toxemia. To combat decreasing antibiotic effectiveness, a number of approaches founded on separation biophysics have been demonstrated to isolate bacteria from simple fluids. Design-based development of such approaches is required to understand the parameters and conditions that control performance for potential translation to clinical practice. We developed a mathematical model that quantitatively describes the kinetics of pathogenesis and progression of symptomatic bacteremia under various conditions to better understand disease mechanisms and quantitatively assess the biological impact of bacterial separation therapy. The design goal of this interdisciplinary research project is the reduction of pathogen load during sepsis under conditions that are estimated to provide clinical benefit. Results from our mathematical model describing symptomatic bacteremia was used to inform the design of colistin-functionalized nanoparticles. Colistin is an antibiotic with an uncommon mechanism of action due, in part, to polycationicity. Colistin-functionalized nanoparticles and microparticles rapidly bind the cell envelope of Gram-negative pathogens. A quantitative assessment of wild-type (WT) and colistin-resistant (CR) Gram-negative bacterium interaction with colistin-functionalized particles estimated that complexation reaches half-maximum saturation in approximately seven minutes regardless of phenotype. This rate of nanoparticle binding to bacteria is among the fastest reported and is essential to inform the design of devices intended for the separation of bacteria from blood, including the dangerous CR and, potentially, MDR phenotypes. Electron micrographs superimposed with elemental information from energy-dispersive X-ray (EDX) spectroscopy confirm localization of colistin-functionalized particles on the bacterial surface. Quantitative characterization of nanoparticle-bacteria association mediated through colistin enables the design-based consideration of new approaches to bacterial detection and isolation with the potential for human benefit. 

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