The effects of simulated airway diseases and affected flow distributions on aerosol deposition.

BACKGROUND: Experimental and theoretical aspects of targeted drug delivery have been addressed several times in this journal. Herein, a computational study of particle deposition patterns within healthy and diseased lungs has been performed, using a validated aerosol dosimetry model and a flow-resistance model. OBJECTIVE: To evaluate to what extent the uneven flow distributions produced by the physical manifestations of respiratory diseases affect the deposition patterns of inhaled aerosolized drugs. METHODS: Diseases were simulated by constrictions and blockages, which caused uneven flow distributions. Respiratory conditions of sedentary and pronounced activities, and of particle sizes ranging from 0.1 microm to 10 microm, were used as the basis for the calculated deposition patterns. RESULTS: Findings are presented that describe flow as a function of airway disease state (eg, flow redistribution). Data on the effects of lung morphologies, healthy and diseased, on compartmental (tracheobronchial and pulmonary) and local (airway generation) aerosol deposition are also given. By formulating these related factors, modeling results show that aerosolized drugs can be effectively targeted to appropriate sites within lungs to elicit positive therapeutic effects. CONCLUSIONS: We have addressed the complexities involved when taking into account interactive effects between diseased airway morphologies and redistributed air flows on the transport and deposition of inhaled particles. Our results demonstrate that respiratory diseases may influence the deposition of inhaled drugs used in their treatment in a systematic and predictable manner. We submit this work as a first step in establishing the use of mathematical modeling techniques as a sound scientific basis to relate airway diseases and aerosolized drug delivery protocols.

Measurements of electrodynamic effects on the deposition of MDI and DPI aerosols in a replica cast of human oral-pharyngeal-laryngeal airways.

Metered dose inhalers (MDIs) and dry powder inhalers (DPIs) are popular drug delivery devices used in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Integrated effects of electrostatic charges and aerodynamic sizes on the deposition of MDI and DPI particles in a replica cast of human oral-pharyngeal-laryngeal (OPL) airways were examined. Experimental aerosols were generated from commercially available MDI and DPI devices. They are the trademarked brands of the same pharmaceutical company, and contain the same amounts of different drugs. Inhalations were administered as boluses and characterized with an Electronic Single Particle Aerodynamic Relaxation Time (ESPART) analyzer before and after passing through the cadaver-based OPL cast. The MDI and DPI aerosols were not only of different sizes but also carried different positive, negative and zero electrostatic charges; 42.2% of the total number of DPI particles was charged in comparison to 6% of those produced by the MDI. Electrodynamic properties (e.g., charges and sizes) played significant roles on the behavior and deposition of aerosols in the OPL airways. As detailed herein, deposition fractions of the total (charged and uncharged) DPI aerosols were 21.5% in contrast to 2.8% for the MDI aerosols, whereas the charged particle deposition for the DPI was 46.7% in contrast to 22.5% for the MDI. Particle losses in the OPL passages were greater for the DPI than the MDI as the former generated more charged particles than the latter. This finding is consistent with results reported by other researchers but contradicts the observation of another investigator where MDI losses were reported as being higher than those for DPIs. The chief reason for this difference may be that the latter study did not account for the electrical properties of aerosol particles, but only for their mechanical properties. Because the measured deposition efficiencies of MDI and DPI aerosols were different, the data have important implications to inhalation therapy protocols.

Effects of the laryngeal jet on nano- and microparticle transport and deposition in an approximate model of the upper tracheobronchial airways.

The extent to which laryngeal-induced flow features penetrate into the upper tracheobronchial (TB) airways and their related impact on particle transport and deposition are not well understood. The objective of this study was to evaluate the effects of including the laryngeal jet on the behavior and fate of inhaled aerosols in an approximate model of the upper TB region. The upper TB model was based on a simplified numerical reproduction of a replica cast geometry used in previous in vitro deposition experiments that extended to the sixth respiratory generation along some paths. Simulations with and without an approximate larynx were performed. Particle sizes ranging from 2.5 nm to 12 mum were considered using a well-tested Lagrangian tracking model. The model larynx was observed to significantly affect flow dynamics, including a laryngeal jet skewed toward the right wall of the trachea and a significant reverse flow in the left region of the trachea. Inclusion of the laryngeal model increased the tracheal deposition of nano- and micrometer particles by factors ranging from 2 to 10 and significantly reduced deposition in the first three bronchi of the model. Considering localized conditions, inclusion of the laryngeal approximation decreased deposition at the main carina and produced a maximum in local surface deposition density in the lobar-to-segmental bifurcations (G2-G3) for both 40-nm and 4-microm aerosols. These findings corroborate previous experiments and highlight the need to include a laryngeal representation in future computational and in vitro models of the TB region.

Comparison of SPECT aerosol deposition data with twenty-four-hour clearance measurements.

Three-dimensional (3D) radionuclide imaging provides detailed information on the distribution of inhaled aerosol material within the body. Analysis of the data can provide estimates of the deposition per airway generation. Information on regional distribution of deposited aerosol can also be obtained from 24-hour clearance measurements. In this study, a nebulizer was used to deliver a radiolabeled aerosol to nine human subjects. Single photon emission computed tomography (SPECT) has been used to assess the distribution of aerosol deposition per airway generation. The deposition pattern was also estimated using measurements of the aerosol remaining in the lung 24 h after inhalation. The error in the SPECT value was assessed by simulation and that in the 24-h clearance value by repeat analysis. The mean fraction of lung deposition in the conducting airway (CADF) from SPECT was 0.21. The corresponding 24-h clearance value was 0.23. These values were not significantly different. There was a weak but non-significant correlation between the SPECT and 24-h measurements (r = 0.49). The standard error of the difference was 0.11. The corresponding errors on the SPECT and 24-h clearance measurements were 0.04 and 0.05, respectively. There was no systematic difference between the values of conducting airways deposition obtained from 24-h measurements and SPECT. However, there were random differences on individual subjects, which were larger than the estimated measurement errors.

Comparison of SPECT aerosol deposition data with a human respiratory tract model.

Three-dimensional (3D) radionuclide imaging provides detailed information on the distribution of inhaled aerosol material within the body. Analysis of the data can provide estimates of the deposition per airway generation. In this study, two different nebulizers have been used to deliver radiolabeled aerosols of different particle size to 12 human subjects. Medical imaging has been used to assess the deposition in the body. The deposition pattern has also been estimated using the International Commission on Radiological Protection (ICRP) empirical model and compared to values obtained by experiment. The results showed generally good agreement between model and experiment for both aerosols for the deposition in the extrathoracic and conducting airways. However, there were significant differences in the fate of the remainder of the aerosol between the amount deposited in the alveolar region and that exhaled. The inter-subject variability of deposition predicted by the model was significantly less than that measured, for all regions of the body. The model predicted quite well the differences in deposition distribution pattern between the two aerosols. In conclusion, this study has shown that the ICPR model of inhaled aerosol deposition shows areas of good agreement with results from experiment. However, there are also areas of disagreement, which may be explained by hygroscopic particle growth and individual variation in airway anatomy.

Three-dimensional computational fluid dynamics simulations of particle deposition in the tracheobronchial tree.

Simulation of the dynamics and disposition of inhaled particles within human lungs is an invaluable tool in both the development of inhaled pharmacologic drugs and the risk assessment of environmental particulate matter (PM). The goal of the present focused study was to assess the utility of three-dimensional computational fluid dynamics (CFD) models in studying the local deposition patterns of PM in respiratory airways. CFD models were validated using data from published experimental studies in human lung casts. The ability of CFD to appropriately simulate trends in deposition patterns due to changing ventilatory conditions was specifically addressed. CFD simulations of airflow and particle motion were performed in a model of the trachea and main bronchi using Fluent Inc.'s FIDAP CFD software. Particle diameters of 8 microm were considered for input flow rates of 15 and 60 L/min. CFD was able to reproduce the observed spatial heterogeneities of deposition within the modeled bifurcations, and correctly predicted the "hot-spots" of particle deposition on carinal ridges. The CFD methods also predicted observed differences in deposition for high-versus-low flow rates. CFD models may provide an efficient means of studying the complex effects of airway geometry, particle characteristics, and ventilatory parameters on particle deposition and therefore aid in the design of human subject experiments.

Issues in drug delivery: concepts and practice.

Understanding the transport and deposition of inhaled aerosols is of fundamental importance to inhalation therapy. Herein we address issues that affect drug delivery from experimental and theoretical perspectives. Accordingly, we shall limit our comments to a focused review of laboratory work (ie, an in vitro perspective) and the development of a computer-based 3-dimensional (3D) oral morphology with related computational fluid dynamics (CFD) and particle deposition studies (ie, an "in silico" perspective). To describe the oral region, morphometric data from the literature were employed. With Maya Unlimited, a third-party animation software package, coronal images were used to create initial spline curves, which served as the foundation of a nonuniform rational B-spline surface, representing a 3D morphology. To the best of our knowledge, this study is the first medical application of Maya Unlimited. We have demonstrated that the code can be employed to construct 3D biological structures and perform 3D CFD simulations of aerosols from dry powder inhalers and metered-dose inhalers. A study was also conducted using Fluent, a commercially available software package that has been used extensively in our laboratory for 3D CFD computations. The Maya Unlimited software can generate physiologically realistic oral structures; it has great potential for use in the medical arena, because it requires neither advance technical training nor substantial peripheral ( eg, hardware) support, it allows for the introduction of medical devices ( eg, dry powder inhalers) into simulations, and it predicts 3D CFDpatterns consistent with experimental observations and results of more rigorous software ( Fluent). In the in vitro perspective we considered numerous salient topics, including the performances of dry powder inhalers and metered-dose inhalers, their respective operating characteristics, and relevance to in vivo data. We advocate that 3D CFD software be employed in a complementary manner, in real time, with aerosol therapy protocols in the medical arena, to promote the targeted delivery of inhaled drugs and thereby enhance their efficacies.

Airway identification within planar gamma camera images using computer models of lung morphology.

PURPOSE: Quantification of inhaled aerosols by planar gamma scintigraphy could be improved if a more comprehensive assessment of aerosol distribution patterns among lung airways were obtained. The analysis of planar scans can be quite subjective because of overlaying of small, peripheral airways with large, conducting airways. Herein, a computer modeling technique of the three-dimensional (3-D) branching structure of human lung airways was applied to assist in the interpretation of planar gamma camera images. METHODS: Airway dimensions were derived from morphometric data, and lung boundaries were formulated from scintigraphy protocols. Central, intermediate, and peripheral regions were superimposed on a planar view of the 3-D simulations, and airways were then tabulated by type, number, surface area, and volume in each respective region. RESULTS: These findings indicate that the central region, for example, consists mostly of alveolated airways. Specifically, it was found that alveolated airways comprise over 99% of the total number of airways, over 95% of the total airway surface area, and approximately 80% of the total airway volume in the central region. CONCLUSIONS: The computer simulations are designed to serve as templates that can assist in the interpretation of aerosol deposition data from scintigraphy images.

Particle deposition in children's lungs: theory and experiment.

A mathematical model of inhaled aerosol particle deposition for children is presented and validated with data from two published experimental studies. The model accurately predicts deposition fraction (DF) in children as a function of particle size for particles in the size range 1-3 microns for both sedentary and exercise breathing conditions. When the experimental data are grouped according to age, the model is able to predict age-dependent trends in DF at the studied particle sizes under sedentary breathing conditions. The model predicts that when ventilatory conditions are held constant, age-dependent changes in morphology result in decreasing DF with age; however, under realistic conditions these changes may be masked by age-dependent changes in ventilation. Despite the fact that mean DF differs significantly from adult values only in children younger than 9, the model predicted that dose-per-surface area may still be greater in children due to smaller lung sizes.

Computer reconstruction of a human lung boundary model from magnetic resonance images.

A mathematical description of the morphology of the lung is necessary for modeling and analyzing the deposition of inhaled aerosols A model of the lung boundary was generated from magnetic resonance images, with the goal of creating a framework for anatomically realistic morphological models of the human airway network. We used data visualization and analysis software to reconstruct the lung volume from a series of transverse magnetic resonance images collected at many vertical locations in the lung, ranging from apex to base. The lung model was then built using isosurface extraction techniques. These modeling methods may facilitate the creation of customized morphological models for individual subjects, resulting in improved interpretation of aerosol distribution data from single-photon-emission computed tomography (SPECT). Such customized models could be developed for children and for patients with respiratory diseases, thus aiding in the study of inhaled medications and environmental aerosols in these populations.

Validation of the conceptual anatomical model of the lung airway.

The conceptual anatomical model of the lung airway considers each lung volume divided into ten concentric shells. It specifies the volume of each airway generation in each shell, using Weibel morphometry. This study updates and validates the model and evaluates the errors obtained when using it to estimate inhaled aerosol deposition per generation from spatial imaging data. A comparison of different airway models describing the volume per generation, including data from CT images of a lung cast and a human subject, was performed. A revised version of the conceptual model was created, using the average volume per generation from these data. The new model was applied to derive the aerosol deposition per generation from 24 single photon emission computed tomography (SPECT) studies. Analysis errors were assessed by applying the same calculations but using airway models based on the minimum and maximum volumes per generation. The mean shell position of each generation in the average model was not significantly different from either CT model. However there were differences between the volumes per generation of the different models. The root mean square differences between bronchial airways deposition fraction (generations 2-8) obtained from the maximum and minimum models compared to the new average model was 0.66 percentage points (14%). For the conducting airways deposition fraction (generations 2-15) this was 1.66 percentage points (12%). The conceptual model is consistent with CT measurements of airway geometry. The errors resulting from using a generic airway model to interpret 3D radionuclide image data have been defined.

Fine particle deposition within human nasal airways.

An original mathematical model describing particle diffusion in human nasal passages is presented. A unique feature of the model is that it combines effects of both turbulent and laminar flows. To account for turbulence, concentration equations written in cylindrical coordinates are first simplified by a scaling technique and then solved analytically based on momentum/mass transfer analogy. To describe laminar motion, the work of Martonen et al. (1995a) is modified for application to nasal passages. The predictions of the new model agree well with particle deposition data from experiments using human replica nasal casts over a wide range of flow rates (4-30 L/min) and particle sizes (0.001-0.1 micro m). The results of our study suggest that a complex fluid dynamics situation involving a natural transition from laminar to turbulent motion may exist within human nasal passages during inspiration. The model may be used to predict deposition efficiencies of inhaled particles for inhalation toxicology (e.g., the risk assessment of air pollutants) and aerosol therapy (e.g., the treatment of lung diseases) applications.

Risk assessment dosimetry model for inhaled particulate matter: I. Human subjects.

Pollutant particulate matter (PM) is a serious global problem, presenting a threat to the health and well being of human subjects. Inhalation exposures tests with surrogate animals can be performed to estimate the threat. However, it is difficult to extrapolate the findings of animal tests to human conditions. In this two-part series, interspecies dosimetry models especially designed for implementation with risk assessment protocols are presented. In Part I, the mathematical integrity of the source model per se was tested with data from human subjects, and theoretical predictions agreed well with experimental measurements. In Part II, for surrogate (rat) simulations, appropriate algorithms for morphologies and ventilatory parameters were used as subroutines in the validated model. We conducted a comprehensive series of computer simulations describing the behavior of a representative air pollutant, secondary cigarette smoke. For risk assessment interests, a range of states from rest to exercise was considered. PM hygroscopicity had a pronounced effect on deposition in a complex but systematic manner, in humans and rats: deposition was increased for particles larger than about 1 microm, but was decreased for particles smaller than about 0.1 microm. The results clearly indicate that dosimetry models can be effectively used to a priori determine the laboratory conditions necessary for animals tests to accurately mimic human conditions. Moreover, the use of interspecies models is very cost effective. We propose, therefore, that mathematical models be used in a complementary manner with inhalation exposure experiments and be actively integrated into PM risk assessment protocols.

Risk assessment dosimetry model for inhaled particulate matter: II. Laboratory surrogates (rat).

Inhalation toxicology investigations are often performed with laboratory animals to address the potential health effects of inhaled air pollutants on human beings. In Part II of this risk assessment study we have considered the deposition of inhaled particulate matter in the laboratory rat as the surrogate of choice. Calculations were performed in an analogous manner to those conducted in Part I for human subjects. To simulate a wide range of human respiratory intensities associated with different levels of physical activities that must be recognized in the determination of air pollution standards, the CO(2) concentrations within animal inhalation exposure chambers may be controlled. Accordingly, we have regulated rat breathing parameters to correspond to a range of human activities, from rest to work. The results of this interspecies modeling study have been presented in a variety of graphical formats to ease comparisons with findings from experiments and to facilitate integration of the results into risk assessment analyses. The findings of our work clearly demonstrate that interspecies simulations can be employed to design animal tests a priori so that the results can be effectively and efficiently extrapolated to human conditions in a meaningful manner.

Flow simulation in the human upper respiratory tract.

Computer simulations of airflow patterns within the human upper respiratory tract (URT) are presented. The URT model includes airways of the head (nasal and oral), throat (pharyngeal and laryngeal), and lungs (trachea and main bronchi). The head and throat morphology was based on a cast of a medical school teaching model; tracheobronchial airways were defined mathematically. A body-fitted three-dimensional curvilinear grid system and a multiblock method were employed to graphically represent the surface geometries of the respective airways and to generate the corresponding mesh for computational fluid dynamics simulations. Our results suggest that for a prescribed phase of breath (i.e., inspiration or expiration), convective respiratory airflow patterns are highly dependent on flow rate values. Moreover, velocity profiles were quite different during inhalation and exhalation, both in terms of the sizes, strengths, and locations of localized features such as recirculation zones and air jets. Pressure losses during inhalation were 30-35% higher than for exhalation and were proportional to the square of the flow rate. Because particles are entrained and transported within airstreams, these results may have important applications to the targeted delivery of inhaled drugs.

Factors affecting the deposition of inhaled porous drug particles.

Recent findings indicate that the inhalation of large manufactured porous particles may be particularly effective for drug delivery. In this study, a mathematical model was employed to systematically investigate the effects of particle size, particle density, aerosol polydispersity, and patient ventilatory parameters on deposition patterns of inhaled drugs in healthy human lungs. Aerodynamically similar particles with densities of 0.1, 1.0, and 2.0 g/cm(3) were considered. Particle size distributions were defined with mass median aerodynamic diameters (MMADs) ranging from 1 to 3 microm and geometric standard deviations ranging from 1.5 to 2.5, representing particles in the respirable size range. Breathing rates of 30 and 60 L/min with tidal volumes of 500 to 3000 mL were assumed, simulating shallow to deep breaths from a dry powder inhaler. Particles with a high density and a small geometric diameter had slightly greater deposition fractions than particles that were aerodynamically similar, but had lower density and larger geometric size (typical of manufactured porous particles). This can be explained by the fact that particles with a small geometric diameter deposit primarily by diffusion, which is a function of geometric size but is independent of density. As MMAD increased, the effect of density on deposition was less pronounced because of the decreased efficiency of diffusion for large particles. These data suggest that polydisperse aerosols containing a significant proportion of submicron particles will deposit in the pulmonary airways with greater efficiency than aerodynamically similar aerosols comprised of geometrically larger porous particles.

A computer model of lung morphology to analyze SPECT images.

Measurement of the spatial distribution of aerosol deposition in human lungs can be performed using single photon emission computed tomography (SPECT). To relate deposition patterns to real lung structures, a computer model of the airway network has been developed. Computer simulations are presented that are compatible with the analysis of SPECT images. Computational techniques that are consistent with clinical procedures are used to analyze airways by type and number within transverse slices of the lung volume. The computer models serve as customized templates, which when analyzed alongside gamma scintigraphy images, can assist in the interpretation of human test data.

Fundamental effects of particle morphology on lung delivery: predictions of Stokes' law and the particular relevance to dry powder inhaler formulation and development.

Key factors that contribute to the aerodynamic properties of aerosol particles are found in Stokes' law. These factors may be monitored or controlled to optimize drug delivery to the lungs. Predictions of the aerodynamic behavior of therapeutic aerosols can be derived in terms of the physical implications of particle slip, shape and density. The manner in which each of these properties have been used or studied by pharmaceutical scientists to improve lung delivery of drugs is readily understood in the context of aerosol physics. Additional improvement upon current aerosol delivery of particulates may be predicted by further theoretical scrutiny.