Mathematical Modeling of Pseudomonas Aeruginosa Biofilm Growth and Treatment in the Cystic Fibrosis Lung

摘要

Lung failure due to chronic bacterial infection is the leading cause of death for patients with cystic fibrosis (CF). It is thought that the chronic nature of these infections is, in part, due to the increased tolerance and recalcitrant behavior of bacteria growing as biofilms. Inhalation of Silver Carbene Complex (SCC) antimicrobial, either encased in L-tyrosine polyphosphate (LTP) particles or in aqueous form, has been proposed as a treatment. Through a coordinated experimental and mathematical modeling effort, this dissertation examines this proposed treatment of lung biofilms. Pseudomonas aeruginosa biofilms grown in a flow-cell apparatus irrigated with an artificial CF sputum medium are analyzed as an in vitro model of CF lung infection. A 2D mathematical model of biofilm growth within the flow-cell is developed. Numerical simulations demonstrate that SCC inactivation by the environment is critical in aqueous SCC, but not SCC-LTP, based treatments. LTP particle degradation rate is shown to be a tunable parameter that can be chosen optimally, based on environmental conditions and bacterial susceptibility. In addition, a 2D model of mushroom-like morphology and cavity formation in Pseudomonas aeruginosa biofilms is developed. Iron-signaling is proposed as a plausible mechanism for cavity formation.