The overall goal of this project is to develop the first mathematical models of chronic biofilm infection that integrate processes from both host and microbe. A special focus will be the spatiotemporal distribution of oxygen which we hypothesize is critical to the persistence of the infection. Oxygen concentration is important for host healin, clearance of bacteria by neutrophils, and microbial growth and antibiotic susceptibility. Mathematical model development will occur in parallel with experimental measurements of oxygen distributions in novel in vitro biofilm models using microelectrodes and 19F magnetic resonance imaging oximetry.
Specific aims of this project are to: 1) Derive integrated mathematical models for cystic fibrosis lung and chronic wound biofilm infection and characterize model behaviors including diffusion properties of heterogeneous reactive biomaterials, bistable outcomes, hysteresis, and responses to perturbations such as hyperbaric oxygen therapy and antimicrobial chemotherapy, and 2) Develop in vitro experimental models of biofilm-infected lung or wound tissues and apply experimental techniques to map spatiotemporal distributions of oxygen in these systems. The mathematical models will describe oxygen dynamics during biofilm infection by incorporating these processes: tissue delivery and host respiration of oxygen, air-liquid gas exchange, biofilm consumption of oxygen, bacterial growth and death, neutrophil invasion and oxygen utilization, and oxygen-dependence of the antimicrobial efficacy of phagocytes and antibiotics. The model is expected to predict the spatiotemporal distribution of oxygen in a biofilm-infected tissue and the persistence of the infection. The development of MRI oximetry for these systems is innovative and paves the way for the application of this technique in animal models in future work. A strong interdisciplinary team of mathematicians, engineers, and four MDs combine expertise with modeling in heterogeneous biological materials including biofilms, biofilm science and technology, magnetic resonance microscopy, wound healing, animal models of biofilm infection, tissue oxygenation, and cystic fibrosis pulmonology.
This project is relevant to understanding the pathogenesis of persisent infections involving microbial biofilms. These include: cystic fibrosis pneumonia, chronic wounds such as diabetic foot ulcers, chronic rhinosinusitis, and numerous infections associated with indwelling medical devices. Improved understanding of the role of oxygen dynamics during biofilm development could lead to new diagnostic and therapeutic approaches.