A Predictive Open-Source Computer Model for Inhaled Nanoparticle Transport and Deposition in Subject-specific Upper Airways

了解吸入的天然和人造纳米颗粒的转运机制，准确预测其在真实人体气道中的沉积具有重要意义。需要经过实验验证的计算机模拟结果，以评估在环境中出现的、现在更频繁地出现在工作场所的吸入有毒纳米粒子对健康的影响，以及为治疗目的而施用的纳米药物的命运。本提案的总体目标是开发一个经过验证的、全面的、公众可访问的吸入空气颗粒动力学和沉积/清除的计算机模拟模型，用于具有代表性的、特定主题的病例。新的计算机模型将产生真实和准确的结果，以获得新的物理见解，并提供一系列有用的应用。例子包括：专注于肺肿瘤药物气溶胶靶向的卫生保健提供者，评估人造来源的有毒纳米颗粒沉积的联邦监管机构，以及对纳米颗粒清除方面感兴趣的科学家。该研究计划要求采用计算和实验相结合的方法来了解相互关联的流体-颗粒相互作用机制，并开发预测的计算机模拟模型。基于PI和他的研究团队在肺部气溶胶动力学建模和模拟方面20年的经验，北卡罗莱纳州立大学的MAE部门将开发双向耦合流固相互作用，非球形颗粒动力学以及空气-粘液输送和颗粒清除机制的新子模型。这项实验工作将在美世大学进行，重点是纳米材料在同一受试者特定气道模型中的沉积。预期结果：(i)与技术创新有关（即应用于专利智能吸入器系统的虚拟测试，以实现最佳药物气溶胶输送）；（ii）有多个用途（见所列的更广泛影响）；（三）界面工程和生命科学（例如，保健和/或环境法规）。智力优势：提出的研究将提供新的物理见解，更好地理解和新颖的数学和计算机模型，以研究真实的、受试者特定的人类气道中在流体结构相互作用的真实循环呼吸条件下的空气-粘液流动和颗粒运输、沉积和清除的真实纳米颗粒（特别是椭球、碳纳米管和纳米纤维）。将开发开放获取的软件和代码，为环境专家、毒理学家、卫生保健提供者预测局部和区域纳米颗粒在特定受试者的人体气道中的沉积/清除，基本上是免费的。更广泛的影响：开发的代码和软件是免费向公众开放的。它们将很容易获得，并通过一个特定的网站与手册和模拟的例子一起更新。与纳米颗粒吸入有关的现代医学和环境问题可以很容易地得到解决，例如：(a)主要可靠的颗粒沉积数据，用于分析吸入有毒纳米颗粒或新药的影响，以进行药代动力学建模；(b)使用专利智能吸入器系统对受控药物气溶胶吸入的新方法进行虚拟测试；(c)评估局部气道阻塞的影响，例如，由于严重哮喘、慢性阻塞性肺病、阻塞性呼吸暂停综合征、或CF对空气颗粒流动的影响。建议的研究活动亦透过以下途径对研究/教育产生更广泛的影响：(i)促进本科生和研究生的教学和研究训练；（ii）来自代表性不足群体的学生的参与；（iii）与本科院校的学生和教师建立研究和教育合作，以扩大其硕士水平的课程设置，并有可能创建博士水平的工程项目。

CBET - 1232988Understanding the transport mechanisms of inhaled natural and man-made nanoparticles and accurately predicting the deposition in realistic human airways are of great interest. Experimentally validated computer simulation results are needed to assess health effects of inhaled toxic nanoparticles appearing in the environment and now more frequently in the workplace, as well as the fate of administered nanodrugs for therapeutic purposes. The overall goal of this proposal is to develop a validated, comprehensive, public-access computer simulation model of inhaled air-particle dynamics and deposition/clearance for representative, subject-specific cases. The new computer model will produce realistic and accurate results to gain new physical insight and provide an array of useful applications. Examples include: health-care providers focusing on drug-aerosol targeting of lung tumors, federal regulators assessing toxic nanoparticle deposition from man-made sources, and scientists interested in nanoparticle clearance aspects.The research plan calls for a combined computational and experimental approach to understand interrelated fluid-particle interaction mechanisms and to develop a predictive computer simulation model. Building on two decades of experience in lung-aerosol dynamics modeling and simulation by the PI and his Research Team, the novel submodels for two-way coupled fluid-structure interactions, non-spherical particle dynamics and air-mucus transport and particle clearance mechanism will be developed in the MAE Department at NC State University. The experimental work, focusing on nanomaterial depositions in the same subject-specific airway models, will be carried out at Mercer University.The anticipated results: (i) are related to technology innovation (i.e., applied to virtual testing of a patented smart inhaler system for optimal drug-aerosol delivery); (ii) have multiple applications (see broader impacts listed); and (iii) interface engineering and life sciences (e.g., health-care and/or environmental regulations).Intellectual Merit: The proposed study will provide new physical insights, a better understanding and novel mathematical and computer models on air-mucus flow and particle transport, deposition and clearance of real-world nanoparticles (especially ellipsoids, carbon nanotubes, and nanofibers) in realistic, subject-specific human airways under realistic, cyclic breathing conditions with fluid-structure interactions. Open-access software and codes will be developed to predict both local and regional nanoparticle deposition/clearance in subject-specific human airways for environmental specialists, toxicologists, health-care providers, basically free-of-charge.Broader Impacts: The developed codes and software are free and open to the public. They will be easily available and updated via a specific website along with manuals and simulation examples. Modern medical and environmental problems related to nanoparticle inhalation could be readily solved, for example,(a) primarily reliable particle-deposition data to analyze the impact of inhaled toxic nanoparticles or new drugs for pharmacokinetics modeling (b) also, virtual testing of the new methodology for controlled drug-aerosol inhalation using a patented smart inhaler system and (c) evaluating the effect of local airway obstruction, e.g., due to severe asthma, COPD, OSAS, or CF on air-particle flow. The proposed research activity also has other broader impacts on research/education via: (i) promoting the teaching and research training of undergraduate and graduate students; (ii) involvement of students from underrepresented groups; (iii) establishing research and education collaborations with students and faculty from an undergraduate institution to expand their masters-level course offerings and to potentially create a PhD-level engineering program.