Scalable Pathogen Extraction Platform for the Treatment of Blood-borne Infections
Miller, Sinead Emily
Sepsis is a life threatening syndrome caused by infection, affecting over 1 million Americans per year and accounting for over 250,000 deaths annually. Treatment of sepsis relies on appropriate antibiotic therapy targeted towards a specific bacteria type or strain. However, pathogen identification requires 3 to 5 days, delaying effective antibiotic therapy. Early broad spectrum antibiotic therapy is suboptimal and ineffective in many cases, especially due to emerging multi-drug resistant pathogens. Acinetobacter baumannii is a pathogen of particular concern due to its prominent multi-drug resistant phenotype and persistence. A baumannii is a leading cause of sepsis worldwide with an associated mortality rate reaching 72%. The development of new approaches to inhibit the progression of blood-borne A. baumannii infection in the earliest stages of sepsis represent an urgent need with broad potential impact. Effective removal of A. baumannii can be achieved through rational design of hemoperfusion technologies. The goal of this dissertation was to develop a fluidic platform for blood-borne pathogen removal, including drug resistant variants. Initially, a synthesis strategy was implemented to fabricate colistin functionalized nanoparticles. Colistin can be used as an A. baumannii targeting motif (Chapter II). A computational model was later developed for the study of A. baumannii biodistribution during bacterial sepsis. The potential benefit of extracorporeal bacterial isolation and removal from blood, in terms of bacterial load by compartment, was assessed using this model (Chapter III). Finally, a model-based fluidic device was designed for bacterial capture and removal. Previous modeling predictions were incorporated into the design of this fluidic platform, which was decorated with a colistin-based ligand for effective removal of A. baumannii from blood (Chapter IV). This technology can be used to successfully separate and remove bacteria from blood, avoiding translational obstacles that limit other blood purification therapies. Furthermore, this technology has the potential to improve sepsis-associated outcomes by treating sepsis rapidly at the source and potentially decrease the current threat of the ‘post-antibiotic era’ through effective treatment of multi-drug resistant pathogens.