Spatiotemporal Distribution of Oxygen in Biofilm Infections

描述（由申请人提供）：该项目的总体目标是开发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时空分布的氧气，我们假设是至关重要的持续感染。氧浓度对于宿主愈合、嗜中性粒细胞清除细菌、微生物生长和抗生素敏感性是重要的。数学模型的开发将与使用微电极和19 F磁共振成像血氧测定法在新型体外生物膜模型中对氧分布的实验测量并行进行。该项目的具体目标是：1）导出囊性纤维化肺和慢性伤口生物膜感染的集成数学模型，并表征模型行为，包括异质反应性生物材料的扩散性质、生物学结果、滞后和对扰动（例如高压氧治疗和抗微生物化疗）的响应，和2）开发生物膜感染的肺或伤口组织的体外实验模型，并应用实验技术来绘制这些系统中氧的时空分布。数学模型将通过合并这些过程来描述生物膜感染期间的氧动力学：组织递送和宿主呼吸的氧、空气-液体气体交换、生物膜消耗的氧、细菌生长和死亡、中性粒细胞侵入和氧利用以及吞噬细胞和抗生素的抗微生物功效的氧依赖性。该模型预计将预测时空分布的氧气在生物膜感染的组织和感染的持续性。这些系统的MRI血氧饱和度的发展是创新的，并在未来的工作中，该技术在动物模型中的应用铺平了道路。由数学家、工程师和四位医学博士组成的强大跨学科团队将联合收割机专业知识与异质生物材料建模相结合，包括生物膜、生物膜科学和技术、磁共振显微镜、伤口愈合、生物膜感染的动物模型、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.