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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZGM1)
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Somers, Scott D
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Montana State University - Bozeman
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
United States
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Wu, Yilin; Klapper, Isaac; Stewart, Philip S (2018) Hypoxia arising from concerted oxygen consumption by neutrophils and microorganisms in biofilms. Pathog Dis 76:
Simkins, Jeffrey W; Stewart, Philip S; Seymour, Joseph D (2018) Spatiotemporal mapping of oxygen in a microbially-impacted packed bed using 19F Nuclear magnetic resonance oximetry. J Magn Reson 293:123-133
Stewart, Philip S; Zhang, Tianyu; Xu, Ruifang et al. (2016) Reaction-diffusion theory explains hypoxia and heterogeneous growth within microbial biofilms associated with chronic infections. NPJ Biofilms Microbiomes 2:16012
James, Garth A; Ge Zhao, Alice; Usui, Marcia et al. (2016) Microsensor and transcriptomic signatures of oxygen depletion in biofilms associated with chronic wounds. Wound Repair Regen 24:373-83
Pabst, Breana; Pitts, Betsey; Lauchnor, Ellen et al. (2016) Gel-Entrapped Staphylococcus aureus Bacteria as Models of Biofilm Infection Exhibit Growth in Dense Aggregates, Oxygen Limitation, Antibiotic Tolerance, and Heterogeneous Gene Expression. Antimicrob Agents Chemother 60:6294-301
Aristotelous, A C; Klapper, I; Grabovsky, Y et al. (2015) Diffusive transport through a model host-biofilm system. Phys Rev E Stat Nonlin Soft Matter Phys 92:022703
Ammons, Mary Cloud B; Morrissey, Kathryn; Tripet, Brian P et al. (2015) Biochemical association of metabolic profile and microbiome in chronic pressure ulcer wounds. PLoS One 10:e0126735
Stewart, Philip S (2015) Antimicrobial Tolerance in Biofilms. Microbiol Spectr 3:
Stewart, Philip S; Franklin, Michael J; Williamson, Kerry S et al. (2015) Contribution of stress responses to antibiotic tolerance in Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother 59:3838-47
Stewart, Philip S (2014) Biophysics of biofilm infection. Pathog Dis 70:212-8

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