**1. Introduction**

Inhalable aerosols consist of multiple nano-to-micro-scale solid or liquid particulate matters (PMs) with dissolved or embedded compounds, as well as associated vapors. Instead of being spheres with constant diameters, most of these airborne PMs are nonspherical in shape, with everchanging sizes due to evaporation/condensation. Therefore, they are defined as "unconventional aerosol particles". Examples include fiber-like carbon nanotubes (CNTs) [1], hygroscopic cigarette particles [2–4], and pulmonary drug powders [5].

Both active and passive human exposures to ultrafine airborne aerosols are growing. Contributing factors include the increase in nanomaterial generation during product/device manufacturing, handling and use [6], consumptions of conventional and new tobacco products [2– 4], as well as nanoparticle pulmonary drug development [7, 8]. Of great concern are the toxic health risks and therapeutic benefits induced by the inhalation. This is mainly because the small sizes facilitate ultrafine PM transport into deeper lung airways, translocation to the bloodstream crossing body membrane barriers, thus affecting organs and tissues in both pulmonary routes and systemic regions. For example, the transmission of respiratory infectious disease begins from the deposition of pathogens carried by airborne PM into the respiratory tract [9]. Since infection initiation is usually region specific, local dosages (i.e., lung deposited, tissue, and delivered doses) in pulmonary routes and systemic regions are essential for precise risk assessments. Another example is the worker exposure to airborne nanomaterials in the workplace [6]. Furthermore, pulmonary targeted drug delivery is favorable for both lung and systemic disease treatments, owing to the strong capability of the lung to absorb pharmaceuticals. Using ultrafine unconventional particles as drug carriers has also been promoted in medical device design, encapsulation, and drug delivery [7, 8, 10], because of their extraordinary capabilities to penetrate into deeper lung airways by virtue of the nonspherical shape or the hygroscopic growth characteristics. In this case, accurate local dosage information is also essential for the evaluation of drug delivery efficacy to targeted sites.

In light of the above discussion, the primary goal of relevant researches is to provide highresolution data and enhance the fundamental understanding of the physical and chemical mechanisms for the dynamics of unconventional inhaled aerosols in human respiratory systems and systemic regions. Data of interests include: transport, deposition, dissolution, absorption, distribution, and clearance of unconventional aerosols in lung airways and systemic regions under various exposure conditions. These data will also help to answer the key question: "*What type of inhaled aerosols deposits where at what surface concentrations in subjectspecific human respiratory systems under distinct breathing conditions, and what delivered dose into the site of interest in systemic regions*?"

Experiments or clinical tests are not able to provide such high-resolution data on human subjects, because of ethical reasons and lack of reliable measurements. Hence, developing and applying an accurate and realistic computer simulation model is desired. Different types of numerical models have been developed specifically to determine the fate of inhaled aerosols in human bodies, as has been reviewed recently by Phalen and Raabe [11]. To simulate particle trajectories, interactions, and lung deposition of unconventional inhaled aerosols, computational fluid-particle dynamics (CFPD) models based on Euler-Lagrange and Euler-Euler methods are the best options compared to other numerical models such as empirical and semiempirical ones [11]. Specifically, accurate prediction of the fate of such aerosols requires the model to be able to capture the effects of particle shape and size change on their trajectories before deposition. Based on more underlying physics and less extrapolations and simplifications, CFPD models are able to describe the fundamental behaviors of fluids and particles with high-resolution local data by solving conservation laws with constitutive equations [3, 4, 10]. Hence, these validated noninvasive, cost-effective, and accurate CFPD models will complement in vitro and in vivo studies on unconventional lung aerosol dynamics by simulating fluid-particle flows that are difficult to be reproduced experimentally. They will be able to deliver new perspectives of scientific knowledge and healthcare data for medical device improvements for effective and targeted drug deliveries, novel lung therapeutics, noninvasive disease diagnostic methodologies, and exposure health risk evaluations. Accordingly, CFPD models are expected to contribute to the following aspects:


**1. Introduction**

50 Aerosols - Science and Case Studies

Inhalable aerosols consist of multiple nano-to-micro-scale solid or liquid particulate matters (PMs) with dissolved or embedded compounds, as well as associated vapors. Instead of being spheres with constant diameters, most of these airborne PMs are nonspherical in shape, with everchanging sizes due to evaporation/condensation. Therefore, they are defined as "unconventional aerosol particles". Examples include fiber-like carbon nanotubes (CNTs) [1],

Both active and passive human exposures to ultrafine airborne aerosols are growing. Contributing factors include the increase in nanomaterial generation during product/device manufacturing, handling and use [6], consumptions of conventional and new tobacco products [2– 4], as well as nanoparticle pulmonary drug development [7, 8]. Of great concern are the toxic health risks and therapeutic benefits induced by the inhalation. This is mainly because the small sizes facilitate ultrafine PM transport into deeper lung airways, translocation to the bloodstream crossing body membrane barriers, thus affecting organs and tissues in both pulmonary routes and systemic regions. For example, the transmission of respiratory infectious disease begins from the deposition of pathogens carried by airborne PM into the respiratory tract [9]. Since infection initiation is usually region specific, local dosages (i.e., lung deposited, tissue, and delivered doses) in pulmonary routes and systemic regions are essential for precise risk assessments. Another example is the worker exposure to airborne nanomaterials in the workplace [6]. Furthermore, pulmonary targeted drug delivery is favorable for both lung and systemic disease treatments, owing to the strong capability of the lung to absorb pharmaceuticals. Using ultrafine unconventional particles as drug carriers has also been promoted in medical device design, encapsulation, and drug delivery [7, 8, 10], because of their extraordinary capabilities to penetrate into deeper lung airways by virtue of the nonspherical shape or the hygroscopic growth characteristics. In this case, accurate local dosage information

hygroscopic cigarette particles [2–4], and pulmonary drug powders [5].

is also essential for the evaluation of drug delivery efficacy to targeted sites.

*the site of interest in systemic regions*?"

In light of the above discussion, the primary goal of relevant researches is to provide highresolution data and enhance the fundamental understanding of the physical and chemical mechanisms for the dynamics of unconventional inhaled aerosols in human respiratory systems and systemic regions. Data of interests include: transport, deposition, dissolution, absorption, distribution, and clearance of unconventional aerosols in lung airways and systemic regions under various exposure conditions. These data will also help to answer the key question: "*What type of inhaled aerosols deposits where at what surface concentrations in subjectspecific human respiratory systems under distinct breathing conditions, and what delivered dose into*

Experiments or clinical tests are not able to provide such high-resolution data on human subjects, because of ethical reasons and lack of reliable measurements. Hence, developing and applying an accurate and realistic computer simulation model is desired. Different types of numerical models have been developed specifically to determine the fate of inhaled aerosols in human bodies, as has been reviewed recently by Phalen and Raabe [11]. To simulate particle trajectories, interactions, and lung deposition of unconventional inhaled aerosols, computa**5.** Establish guidelines for limiting workplace exposure to new nanoparticles and micron fibers, considering both short-term and long-term exposures.

This chapter is intended to serve as an overview of advanced CFPD models for unconventional inhaled aerosols and a demonstration of how to build and apply CFPD models on lung aerosol dynamics simulations. It also shows a roadmap to the next-generation multiscale lung dosimetry models. Specifically, fundamental mathematics of advanced CFPD modeling techniques is introduced in Section 2, focusing on predicting unconventional aerosol transport and deposition in human upper airways, i.e., nonspherical fiber, hygroscopic droplet, vapor mixture, etc. Basic steps of CFPD modeling are also discussed in this section. Section 3 presents applications of different advanced CFPD models with parametric sensitivity analyses on particle transport and deposition characteristics in airways. Challenges and future directions are discussed in Section 4 on developing next-generation multiscale numerical models, which will be able to simulate unconventional aerosol transport, deposition, and translocation from the complete pulmonary routes into systemic regions. Structured literature reviews on the above topics are also integrated in the following sections. Other reviews can be found in [12, 13].
