3D Imaging & Computer Model of the Respiratory Tract

描述（由申请人提供）：呼吸系统是身体与外部环境之间的主要界面之一。因此，它可能成为一系列环境因子的目标，导致发病率和死亡率增加。医学领域还利用呼吸系统/空气界面作为将药物递送靶向至呼吸道的特定区域或为可能无法通过其他手段有效施用的药物提供快速进入体循环的途径。此外，各种疾病，如COPD或间质性肺病，可改变呼吸系统的结构和功能，并显著影响空气传播的药剂或药物如何被吸入、沉积或吸收。目前还不存在能够有效预测剂量测定以及最终预测动物或人类在健康或疾病条件下暴露于空气传播剂的后果的计算模型。因此，该生物工程研究伙伴关系正在开发必要的成像和计算工具，用于构建和验证最先进的，基于生物学的，多尺度的呼吸系统计算模型，该模型包含固有的物种差异和结构和功能关系的异质性以及疾病对气流和剂量预测的影响。通过这种方式，计算预测可以得到更严格的测试，并对人类健康风险评估和治疗干预产生更广泛的影响。鉴于人们对纳米材料在医疗应用中的兴趣越来越大，以及对潜在人类健康风险的担忧，我们的模型验证研究将利用我们的新型3D成像方法关注颗粒物。因此，我们的具体目标是围绕模型开发、实验评价和模型优化来预测：a）健康大鼠中的部位特异性气流（目标1）; B）患有间质性肺病和COPD的大鼠中的部位特异性气流（目标2）; c）健康和患病大鼠中的气溶胶沉积（目标3）;以及d）健康和患病人体中的气溶胶沉积（目标4）。最终，我们期望提供现实的，全面的，预测性的呼吸系统模型，将解剖学，生理学和疾病的固有异质性结合起来。此外，这项工作将为研究人员和临床医生提供一套独特的成像和计算工具，用于了解物种特异性肺结构-功能关系及其对颗粒沉积和清除的影响。 公共卫生相关性：该项目将通过开发逼真的呼吸系统计算模型来影响人类健康，这些模型将提高我们对疾病引起的气流不均匀性变化的理解，这些变化会影响大鼠和人类的气溶胶沉积。这些模型将改进环境暴露和药物输送方法的人类健康风险评估。该项目还将为呼吸解剖，气流和生命系统中的纳米颗粒产生新颖的定量3D成像方法，以及一套用于图像处理，网格生成/细化的计算工具，以及一个多尺度计算框架，包括3D计算流体动力学模型与组织特性和颗粒跟踪的低维模型的双向耦合。

DESCRIPTION (provided by applicant): The respiratory system is one of the major interfaces between the body and the external environment. As a result, it can become a target for a broad range of environmental agents that can lead to increased morbidity and mortality. The medical field has also exploited the respiratory system/air interface as a way for either targeting drug delivery to specific regions of the respiratory tract or to provide rapid access to the systemic circulation for drugs that may not be effectively administered by other means. Furthermore, various diseases, such as COPD, or interstitial lung disease, can alter the structure and function of the respiratory system and dramatically affect how airborne agents or drugs are inhaled, deposited, or absorbed. Computational models that can effectively predict the dosimetry and ultimately the consequences of exposure to airborne agents under healthy or disease conditions in either animals or humans do not exist. As a result, this Bioengineering Research Partnership is developing the imaging and computational tools necessary for constructing and validating state-of-the-art, biologically based, multi-scale computational models of the respiratory system that incorporates the inherent species differences and heterogeneities in structure and functional relationships and the influence of disease on airflows and dosimetry predictions. In this way, computational predictions can be more rigorously tested and have a broader impact on human health risk assessments and therapeutic interventions. In light of increasing interest in nanomaterials for medical applications as well as concerns over potential human health risks, our model validation studies will focus on particulates utilizing our novel 3D imaging approaches. Our specific aims are therefore organized around model development, experimental evaluation, and model refinement to predict: a) site-specific airflows in health rats (Aim 1); b) site-specific airflows in rats with interstitial lung disease and COPD (Aim 2); c) aerosol deposition in healthy and diseased rats (Aim 3); and d) aerosol deposition in healthy and diseased humans (Aim 4). Ultimately, we expect to deliver realistic, comprehensive, predictive models of the respiratory system that incorporate the inherent heterogeneities in anatomy, physiology, and disease. In addition, this effort will provide researchers and clinicians with a unique suite of imaging and computational tools for understanding species-specific pulmonary structure-function relationships and their effects on particle deposition and clearance. PUBLIC HEALTH RELEVANCE: This project will impact human health through the development of realistic, computational models of the respiratory system that improves our understanding of disease-induced changes in airflow heterogeneities that impact aerosol deposition in rats and humans. Such models will improve human health risk assessments for environmental exposures and methods for drug delivery. This project will also produce novel, quantitative 3D imaging methods for respiratory anatomy, airflows, and nanoparticles in living systems and a suite of computational tools for image processing, mesh generation/refinement, and a multi-scale computational framework that includes bi-directional coupling of 3D computational fluid dynamics models with lower dimensional models of tissue properties and particle tracking.