P. Worth Longest

Effectiveness of Direct Lagrangian Tracking Models for Simulating Nanoparticle Deposition in the Upper Airways

Direct Lagrangian particle tracking may provide an effective method for simulating the deposition of ultrafine aerosols in the upper respiratory airways that can account for finite inertia and slip correction effects. However, use of the Lagrangian approach for simulating ultrafine aerosols has been limited due to computational cost and numerical difficulties. The objective of this study is to evaluate the effectiveness of direct Lagrangian tracking methods for calculating ultrafine aerosol transport and deposition in flow fields consistent with the upper respiratory tract. Representative geometries that have been considered include a straight tubular flow field, a 90° tubular bend, and an idealized replica of the human oral airway. The Lagrangian particle tracking algorithms considered include the Fluent Brownian motion (BM) routine, a user-defined BM model, and a user-defined BM model in conjunction with a near-wall interpolation (NWI) algorithm. Lagrangian deposition results have been compared with a chemical species Eulerian model, which neglects particle inertia, and available experimental data. Results indicate that the Fluent BM routine incorrectly predicts the diffusion-driven deposition of ultrafine aerosols by up to one order of magnitude in all cases considered. For the tubular and 90° bend geometries, Lagrangian model results with a user-defined BM routine agreed well with the Eulerian model, available analytic correlations, and experimental deposition data. Considering the oral airway model, the best match to empirical deposition data over a range of particle sizes from 1 to 120 nm was provided by the Lagrangian model with user-defined BM and NWI routines. Therefore, a direct Lagrangian transport model with appropriate user-defined routines provides an effective approach to accurately predict the deposition of nanoparticles in the respiratory tract.

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.

In silico models of aerosol delivery to the respiratory tract — Development and applications☆

This review discusses the application of computational models to simulate the transport and deposition of inhaled pharmaceutical aerosols from the site of particle or droplet formation to deposition within the respiratory tract. Traditional one-dimensional (1-D) whole-lung models are discussed briefly followed by a more in-depth review of three-dimensional (3-D) computational fluid dynamics (CFD) simulations. The review of CFD models is organized into sections covering transport and deposition within the inhaler device, the extrathoracic (oral and nasal) region, conducting airways, and alveolar space. For each section, a general review of significant contributions and advancements in the area of simulating pharmaceutical aerosols is provided followed by a more in-depth application or case study that highlights the challenges, utility, and benefits of in silico models. Specific applications presented include the optimization of an existing spray inhaler, development of charge-targeted delivery, specification of conditions for optimal nasal delivery, analysis of a new condensational delivery approach, and an evaluation of targeted delivery using magnetic aerosols. The review concludes with recommendations on the need for more refined model validations, use of a concurrent experimental and CFD approach for developing aerosol delivery systems, and development of a stochastic individual path (SIP) model of aerosol transport and deposition throughout the respiratory tract.

Condensational Growth May Contribute to the Enhanced Deposition of Cigarette Smoke Particles in the Upper Respiratory Tract

Previous experimental studies have shown that concentrated cigarette smoke particles (CSPs) deposit in the upper airways like much larger 6 to 7 μ m aerosols. Based on the frequent assumption that relative humidity (RH) in the lungs does not exceed approximately 99.5%, the hygroscopic growth of initially submicrometer CSPs is expected to be a relatively minor factor. However, the inhalation of mainstream smoke may result in humidity values ranging from sub-saturated through supersaturated conditions. The objective of this study is to evaluate the effect of condensation particle growth on the transport and deposition of CSPs in the upper respiratory tract under various RH and temperature conditions. To achieve this objective, a computational model of transport in the continuous phase surrounding a CSP was developed for a multicomponent aerosol consisting of water soluble and insoluble species. To evaluate the transport and deposition of dilute hygroscopic CSPs in the upper airways, a model of the human mouth-throat (MT) through approximately respiratory generation G6 was considered with four steady inhalation conditions. These inhalation conditions were representative of inhaled ambient cigarette smoke as well as warm and hot saturated smoke. Results indicate that RH conditions above 100% are possible in the upper respiratory tract during the inhalation of a warm or hot saturated airstream. For sub-saturated inhalation conditions, initial evaporation of the CSPs was observed followed by hygroscopic growth and diameter increases less than approximately 50%. In contrast, the inhalation of warm or hot saturated air resulted in significant particle growth in the MT and tracheobronchial regions. For the inhalation of warm saturated air 3°C above body temperature, initially 200 and 400 nm particles were observed to increase in size to above 3 μ m near the trachea inlet. The upper boundary inhalation condition of saturated 47°C air resulted in 7 to 8 μ m droplets entering the trachea. These results do not prove that the enhanced deposition of CSPs in the upper airways is only a result of condensational growth. However, this study does highlight condensational growth as a potentially significant mechanism in the deposition of smoke particles under saturated inhalation conditions.

Comparing MDI and DPI Aerosol Deposition Using In Vitro Experiments and a New Stochastic Individual Path (SIP) Model of the Conducting Airways

PurposeDeposition characteristics of MDI and DPI aerosols were compared throughout the conducting airways for the first time using a combination of in vitro experiments and a newly developed stochastic individual path (SIP) model for different inhalation profiles.MethodsIn vitro experiments were used to determine initial particle distribution profiles and to validate computational fluid dynamics (CFD) model results for a MDI and DPI delivering the same dose of drug in a geometry of the mouth-throat and tracheobronchial airways. The validated CFD model was then used to predict the transport and deposition of the drug using correct and incorrect inhalation profiles for each inhaler.ResultsThe MDI delivered approximately two times more drug to the tracheobronchial region compared with the DPI for both correct and incorrect inhalation profiles. Errors in inhalation reduced the deposited tracheobronchial dose by approximately 30% for both inhalers. The DPI delivered the largest dose to the mouth-throat (~70%) and the MDI delivered the largest dose to the alveolar airways (~50%).ConclusionsThe developed in silico model provides new insights into the lung delivery of pharmaceutical aerosols and can be applied in future studies in combination with pharmacokinetic analysis to establish bioequivalence between devices.

Effects of Oral Airway Geometry Characteristics on the Diffusional Deposition of Inhaled Nanoparticles

The deposition of ultrafine aerosols in the respiratory tract presents a significant health risk due to the increased cellular-level response that these particles may invoke. However, the effects of geometric simplifications on local and regional nanoparticle depositions remain unknown for the oral airway and throughout the respiratory tract. The objective of this study is to assess the effects of geometric simplifications on diffusional transport and deposition characteristics of inhaled ultrafine aerosols in models of the extrathoracic oral airway. A realistic model of the oral airway with the nasopharynx (NP) included has been constructed based on computed tomography scans of a healthy adult in conjunction with measurements reported in the literature. Three other geometries with descending degrees of physical realism were then constructed with successive geometric simplifications of the realistic model. A validated low Reynolds number k-omega turbulence model was employed to simulate laminar, transitional, and fully turbulent flow regimes for the transport of 1-200 nm particles. Results of this study indicate that the geometric simplifications considered did not significantly affect the total deposition efficiency or maximum local deposition enhancement of nanoparticles. However, particle transport dynamics and the underlying flow characteristics such as separation, turbulence intensity, and secondary motions did show an observable sensitivity to the geometric complexity. The orientation of the upper trachea was shown to be a major factor determining local deposition downstream of the glottis and should be retained in future models of the respiratory tract. In contrast, retaining the NP produced negligible variations in airway dynamics and could be excluded for predominantly oral breathing conditions. Results of this study corroborate the use of existing diffusion correlations based on a circular oral airway model. In comparison to previous studies, an improved correlation for the deposition of nanoparticles was developed based on a wider range of particle sizes and flow rates, which captures the dependence of the Sherwood number on both Reynolds and Schmidt numbers.

Numerical Simulations of Capillary Aerosol Generation: CFD Model Development and Comparisons with Experimental Data

For a capillary aerosol generation system, the mechanisms governing droplet transport from the capillary tip through deposition in an enclosed geometry have not been previously explored. The objective of this study was to develop and validate a CFD model of transport and deposition for capillary-generated albuterol in water aerosols in a standard USP induction port used for pharmaceutical aerosol testing. Within this system, comparisons have been made between experimental measurements and numerical predictions of the jet angle, aerosol deposition in a sectioned induction port model, and size distributions of exiting particles. The CFD model employed accounts for multiscale and multicomponent flow initialized at the 57 μ m capillary tip and extending through the USP induction port with 30 L/min of co-flow air. A discrete Lagrangian particle tracking algorithm with corrections for near-wall anisotropic turbulence has been implemented to model the polydisperse particle phase including the effects of turbulent dispersion and evaporation. Results indicated good agreement between predictions of the numerical model and experimental in vitro measurements. The experimental mean (SD) total mass fraction of drug deposited in the sectioned induction port was 14.6 (1.1)%. Numerical predictions of deposited mass fraction for non-evaporating particles and evaporating droplets were 13.1% and 13.3%, respectively, resulting in relative differences of 10.3% and 8.9%. Comparisons between in vitro measurements and predictions within individual sections of the induction port resulted in relative differences as low at 0.75%. The predicted mass median diameters exiting the induction port for the particle and evaporating droplet models were 3.07 and 3.45 μ m, respectively, in comparison to an experimental value of 3.06 μ m. The numerical model developed in this study can be applied to optimize the capillary aerosol generation process and improve its delivery of aerosols to the lung.

Evaluation of the Respimat Soft Mist Inhaler using a Concurrent CFD and In Vitro Approach

BACKGROUND The Respimat Soft Mist Inhaler is reported to generate an aerosol with low spray momentum and a small droplet size. However, the transport characteristics of the Respimat aerosol are not well understood. The objective of this study was to characterize the transport and deposition of an aerosol emitted from the Respimat inhaler using a combination of computational fluid dynamics (CFD) modeling and in vitro experiments. METHODS Deposition of the Respimat aerosol was assessed in the inhaler mouthpiece (MP), a standard induction port (IP), and a more realistic mouth-throat (MT) geometry at an inhalation flow rate of 30 L/min. Aerosols were generated using an albuterol sulfate (0.6%) solution, and the drug deposition was quantified using both in vitro experiments and a CFD model of the Respimat inhaler. Laser diffraction experiments were used to determine the initial polydisperse aerosol size distribution. RESULTS AND CONCLUSIONS It was found that the aerosol generated from the highly complex process of jet collision and breakup could be approximated in the model using effective spray conditions. Computational predictions of deposition fractions agreed well with in vitro results for both the IP (within 20% error) and MT (within 10% error) geometries. The experimental results indicated that the deposition fraction of drug in the MP ranged from 27 to 29% and accounted for a majority of total drug loss. Based on the CFD solution, high MP deposition was due to a recirculating flow pattern that surrounded the aerosol spray and entrained a significant number of small droplets. In contrast, deposition of the Respimat aerosol in both the IP (4.2%) and MT (7.4%) geometries was relatively low. Results of this study indicate that modifications to the current Respimat MP and control of specific patient variables may significantly reduce deposition in the device and may decrease high oropharyngeal drug loss observed in vivo.

Numerical Simulation of Wall Shear Stress Conditions and Platelet Localization in Realistic End-to-Side Arterial Anastomoses

Research studies over the last three decades have established that hemodynamic interactions with the vascular surface as well as surgical injury are inciting mechanisms capable of eliciting distal anastomotic intimal hyperplasia (IH) and ultimate bypass graft failure. While abnormal wall shear stress (WSS) conditions have been widely shown to affect vascular biology and arterial wall self-regulation, the near-wall localization of critical blood particles by convection and diffusion may also play a significant role in IH development. It is hypothesized that locations of elevated platelet interactions with reactive or activated vascular surfaces, due to injury or endothelial dysfunction, are highly susceptible to IH initialization and progression. In an effort to assess the potential role of platelet-wall interactions, experimentally validated particle-hemodynamic simulations have been conducted for two commonly implemented end-to-side anastomotic configurations, with and without proximal outflow. Specifically, sites of significant particle interactions with the vascular surface have been identified by a novel near-wall residence time (NWRT) model for platelets, which includes shear stress-based factors for platelet activation as well as endothelial cell expression of thrombogenic and anti-thrombogenic compounds. Results indicate that the composite NWRT model for platelet-wall interactions effectively captures a reported shift in significant IH formation from the arterial floor of a relatively high-angle (30 deg) graft with no proximal outflow to the graft hood of a low-angle graft (10 deg) with 20% proximal outflow. In contrast, other WSS-based hemodynamic parameters did not identify the observed system-dependent shift in IH formation. However, large variations in WSS-vector magnitude and direction, as encapsulated by the WSS-gradient and WSS-angle-gradient parameters, were consistently observed along the IH-prone suture-line region. Of the multiple hemodynamic factors capable of eliciting a hyperplastic response at the cellular level, results of this study indicate the potential significance of platelet-wall interactions coinciding with regions of low WSS in the development of IH.

Aerosolization characteristics of dry powder inhaler formulations for the excipient enhanced growth (EEG) application: Effect of spray drying process conditions on aerosol performance

The aim of this study was to develop a spray dried submicrometer powder formulation suitable for the excipient enhanced growth (EEG) application. Combination particles were prepared using the Buchi Nano spray dryer B-90. A number of spray drying and formulation variables were investigated with the aims of producing dry powder formulations that were readily dispersed upon aerosolization and maximizing the fraction of submicrometer particles. Albuterol sulfate, mannitol, L-leucine, and poloxamer 188 were selected as a model drug, hygroscopic excipient, dispersibility enhancer and surfactant, respectively. Formulations were assessed by scanning electron microscopy and aerosol performance following aerosolization using an Aerolizer dry powder inhaler (DPI). In vitro drug deposition was studied using a realistic mouth-throat (MT) model. Based on the in vitro aerosolization results, the best performing submicrometer powder formulation consisted of albuterol sulfate, mannitol, L-leucine and poloxamer 188 in a ratio of 30:48:20:2, containing 0.5% solids in a water:ethanol (80:20%, v/v) solution which was spray dried at 70 °C. The submicrometer particle fraction (FPF(1 μm/ED)) of this final formulation was 28.3% with more than 80% of the capsule contents being emitted during aerosolization. This formulation also showed 4.1% MT deposition. The developed combination formulation delivered a powder aerosol developed for the EEG application with high dispersion efficiency and low MT deposition from a convenient DPI device platform.