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运输机制并准确预测其在真实人体气道中的沉积具有很大的意义。需要经过实验验证的计算机模拟结果来评估环境中以及现在工作场所中更频繁出现的吸入有毒纳米颗粒对健康的影响，以及用于治疗目的的纳米药物的命运。该提案的总体目标是开发一个经过验证的、全面的、公众可访问的计算机模拟模型，模拟吸入空气颗粒动力学和沉积/清除的代表性、特定主题的情况。新的计算机模型将产生逼真和准确的结果，以获得新的物理见解，并提供一系列有用的应用。示例包括：该研究计划要求采用计算和实验相结合的方法来理解相互关联的流体-颗粒相互作用机制，并开发预测性计算机模拟模型。基于PI及其研究团队在肺-气溶胶动力学建模和模拟方面20年的经验，将在NC州立大学的MAE系开发双向耦合流体-结构相互作用、非球形颗粒动力学和空气-粘液传输和颗粒清除机制的新型子模型。实验工作将在美世大学进行，重点是在相同的受试者特定气道模型中沉积纳米材料。预期结果：（i）与技术创新有关（即，应用于获得专利的智能吸入器系统的虚拟测试以实现最佳药物-气雾剂递送）;（ii）具有多种应用（参见列出的更广泛的影响）;以及（iii）接口工程和生命科学（例如，智力优点：所提出的研究将提供新的物理见解，更好地理解和新的数学和计算机模型，关于空气粘液流动和颗粒运输，现实世界的纳米颗粒（特别是椭圆体，碳纳米管和纳米纤维）在现实的，特定于受试者的人类气道中在具有流体-结构相互作用的现实的循环呼吸条件下的沉积和清除。将为环境专家、毒理学家、医疗保健提供者开发基本免费的开放获取软件和代码，以预测特定对象人体气道中局部和区域纳米颗粒的沉积/清除。更广泛的影响：开发的代码和软件免费向公众开放。它们将很容易通过一个特定的网站沿着手册和模拟示例获得和更新。与纳米颗粒吸入相关的现代医学和环境问题可以容易地解决，例如，（a）主要可靠的颗粒沉积数据，以分析吸入的有毒纳米颗粒或用于药代动力学建模的新药的影响（B）以及，使用专利的智能吸入器系统对用于受控药物气雾剂吸入的新方法的虚拟测试和（c）评估局部气道阻塞的影响，例如，由于严重哮喘、COPD、OSAS或CF对空气颗粒流的影响。拟议的研究活动还通过以下方式对研究/教育产生了其他更广泛的影响：（i）促进本科生和研究生的教学和研究培训;（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，以扩大他们的硕士课程，并可能创建博士级工程项目。

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.