Spatiotemporal Distribution of Oxygen in Biofilm Infections

描述（由申请人提供）：该项目的总体目标是建立第一个慢性生物膜感染的数学模型，该模型整合了宿主和微生物的过程。一个特别的焦点将是氧气的时空分布，我们假设这是感染持续的关键。氧浓度对宿主愈合、中性粒细胞清除细菌、微生物生长和抗生素敏感性都很重要。数学模型的发展将与使用微电极和19F磁共振成像血氧仪对新型体外生物膜模型中的氧分布进行实验测量同时进行。该项目的具体目标是：1)推导囊性纤维化肺和慢性伤口生物膜感染的综合数学模型，并表征模型行为，包括异质反应性生物材料的扩散特性、双稳态结果、迟滞以及对诸如高压氧治疗和抗菌化疗等扰动的反应；2)建立生物膜感染肺或伤口组织的体外实验模型，并应用实验技术绘制这些系统中氧的时空分布。数学模型将通过结合以下过程来描述生物膜感染过程中的氧动力学：组织输送和宿主氧气呼吸，空气-液体气体交换，生物膜氧气消耗，细菌生长和死亡，中性粒细胞入侵和氧气利用，以及吞噬细胞和抗生素抗菌功效的氧依赖性。该模型有望预测氧气在生物膜感染组织中的时空分布和感染的持久性。磁共振血氧仪在这些系统中的发展是创新的，为该技术在未来动物模型中的应用铺平了道路。一个由数学家、工程师和四名医学博士组成的强大跨学科团队，将专业知识与异质生物材料建模相结合，包括生物膜、生物膜科学与技术、磁共振显微镜、伤口愈合、生物膜感染动物模型、组织氧合和囊性纤维化肺病学。

DESCRIPTION (provided by applicant): 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.