Development of a Multiscale Numerical Model with Two Human Pulmonary Health Applications

Determination of the site-specific dosimetry and clearance of deposited aerosols in the human airways is critical in health risk assessment studies such as toxicant exposure evaluation and inhaled medication delivery with pulmonary topical or systemic actions. However, comprehensive evaluation still lacks informative data, i.e., high-resolution local dosimetry of inhaled aerosols in airways and systemic regions, due to the limited imaging resolutions, restricted operational flexibilities, and invasive nature of experimental and clinical examinations. Computational simulations, on the other hand, can provide a detailed explanation for the chemical dynamics in the respiratory system, intrapulmonary and extrapulmonary tissues, and systemic regions using multiscale platforms. In this study, two experimentally validated multiscale numerical analyses were developed for the post-deposition calculation of the respirable aerosols, which expands the application of mathematical models in the respiratory system to the health endpoint. First, computational fluid-particle dynamics (CFPD) is coupled with a physiologically based toxicokinetic (PBTK) model to predict the in tissue translocation and systemic disposition of inhaled volatile organic compound and toxicant constituents in an electronic cigarette (EC). The proposed framework can be used as a benchmark to identify drug or toxicant dynamics in the human body, significantly applicable in the fields of pharmacokinetics and toxicokinetics. Second, an epidemiological computational approach was programmed and optimized by connecting CFPD and host cell dynamics (HCD) models to simulate the transport and deposition of low-strain influenza A virus (IAV)-laden droplets in subject-specific human lung airways and to predict the regional responses of targeted host cells to IAV infection. Furthermore, the hygroscopic growth and shrinkage of multicomponent droplets were considered by examining the thermodynamic equilibrium between the phases. These frameworks overcome the limitation of the experimental studies by connecting levels of biological dynamics that are not measurable using clinical studies. The influence of repetitive exposure incidents on the post-deposition dynamics was determined, which is valuable for assessing the chronic health effects of inhaled airborne particles.Chemical Engineerin

Computational Fluid-Particle Dynamics Modeling for Unconventional Inhaled Aerosols in Human Respiratory Systems

The awareness is growing of health hazards and pharmaceutical benefits of micro-/nano-aerosol particles which are mostly nonspherical and hygroscopic, and categorized as “unconventional” vs. solid spheres. Accurate and realistic numerical models will significantly contribute to answering public health questions. In this chapter, fundamentals and future trends of computational fluid-particle dynamics (CFPD) models for lung aerosol dynamics are discussed, emphasizing the underlying physics to simulate unconventional inhaled aerosols such as fibers, droplets, and vapors. Standard simulation procedures are presented, including reconstruction of the human respiratory system, CFPD model formulation, finite-volume mesh generation, etc. Case studies for fiber and droplet transport and deposition in lung are also provided. Furthermore, challenges and future directions are discussed to develop next-generation models. The ultimate goal is to establish a roadmap to link different numerical models, and to build the framework of a new multiscale numerical model, which will extend exposure and lung deposition predictions to health endpoints, e.g., tissue and delivered doses, by calculating absorption and translocation into alveolar regions and systemic regions using discrete element method (DEM), lattice Boltzmann method (LBM), and/or physiologically based pharmacokinetic (PBPK) models. It will enable simulations of extremely complex airflow-vapor-particle-structure dynamics in the entire human respiratory system at detailed levels

Development of a hybrid CFD-PBPK model to predict the transport of xenon gas around a human respiratory system to systemic regions

Administering incorrect doses of conventional anesthetic agents through the pulmonary route can cause potential health risks such as blood coagulation, platelet dysfunction, and deteriorating organ function. As an alternative, xenon can minimize the impact on the cardiovascular system and provide the neuroprotective effect, hemodynamic stability, and fast recovery. However, the inhalation pattern still needs to be carefully monitored and controlled to avoid health risks caused by over administering xenon to patients during unconsciousness. Thus, high-resolution lung absorption and whole-body translocation data are critically needed to fully understand how to administer the gas and coordinate with the patient to accurately control the dose. Clinical studies are not able to provide accurate dosimetry data due to their limited operational flexibility and imaging resolution. Therefore, a computational fluid dynamics (CFD) model was employed in this study to simulate the transport and absorption of the inhaled xenon which is connected with a physiologically based pharmacokinetic (PBPK) model to predict the translocation into the systemic regions. To study the effects of different breathing patterns on xenon transport dynamics in the human body, a realistic breathing waveform and two steady-state flow rates with inhalation durations of 2 and 1.5 seconds were selected. For the realistic breathing cycle, the inhalation-exhalation periods are defined for a human at rest and the other two cases have a fixed volumetric flow rate of 15 L/min. As the two latter cases only simulate the inspiratory phase, a 1-second holding time was applied to represent the missing periods of the full breathing time. Simulations were performed in a subject-specific human upper airway configuration from mouth to G6. Numerical results show that with the accurate lung uptake predictions obtained from the CFD model, the hybrid CFD-PBPK model with TRANSIT compartments generates more precise and breath-specific trends compared to simple PBPK models. Numerical results demonstrate that breathing pattern can significantly influence the xenon uptake in the human body, which can be utilized as a critical factor to be coordinated by clinicians to achieve the optimized xenon dose. Furthermore, parametric analyses were performed for the influence of breathing patterns on local airflow distributions, gas species translocations, and lung elimination mechanisms followed by species diffusion into the systemic regions

Computational analysis of deposition and translocation of inhaled nicotine and acrolein in the human body with e-cigarette puffing topographies

<p>Recently, toxicants such as formaldehyde and acrolein were detected in electronic cigarette (EC) aerosols. It is imperative to conduct research and provide sufficient quantitative evidence to address the associated potential health risks. However, it is still a lack of informative data, i.e., high-resolution local dosimetry of inhaled aerosols in lung airways and other systemic regions, due to the limited imaging resolutions, restricted operational flexibilities, and invasive nature of experimental and clinical studies. In this study, an experimentally validated multiscale numerical model, i.e., Computational Fluid-Particle Dynamics (CFPD) model combined with a Physiologically Based Toxicokinetic (PBTK) model is developed to predict the systemic translocation of nicotine and acrolein in the human body after the deposition in the respiratory system. <i>In-silico</i> parametric analysis is performed for puff topography influence on the deposition and translocation of nicotine and acrolein in human respiratory systems and the systemic region. Results indicate that the puff volume and holding time can contribute to the variations of the nicotine and acrolein plasma concentration due to enhanced aerosol deposition in the lung. The change in the holding time has resulted in significant difference in the chemical translocation which was neglected in a large group of experimental studies. The capability of simulating multiple puffs of the new CFPD-PBTK model paves the way to a valuable computational simulation tool for assessing the chronic health effects of inhaled EC toxicants.</p> <p>Copyright © 2018 American Association for Aerosol Research</p