A robust immersed boundary method for flow in complex geometries: study of aerosol deposition in the human extrathoracic airways

The flow and the transport of particles in the human respiratory system dictate the effectiveness of therapeutic aerosols used in inhaled drug delivery. The aerosol particles are generally inhaled through the mouth, passing by the throat before reaching the targeted areas in the lungs. Therefore, knowledge of the particle deposition in the mouth-throat region is critical in the design of effective inhalation devices for optimum delivery to the lungs. Numerical simulations offer a non-invasive and cost-effective alternative to in vivo and in vitro tests. However, accurate prediction remains a challenge for numerical models due to the complexity of the flow in the extrathoracic airways. A robust immersed boundary method for flow in complex geometries is proposed. This greatly simplifies the task of grid generation and eliminates the problems associated with grid quality that exist for boundary-fitted grid techniques. The proposed method is an extension to the momentum forcing approach onto curvilinear coordinates and applies an iterative procedure to compute the forcing term implicitly, which stabilizes the scheme for higher Reynolds numbers. The use of a curvilinear grid minimizes the number of unused cells outside the geometry and increases the efficiency of the numerical scheme. The method is validated against numerical and experimental data in the literature for a number of test cases on both Cartesian and curvilinear grids. The results show good agreement with previous studies. Direct numerical simulations were performed in a number of realistic mouth and throat geometries obtained from MRI scans. A Lagrangian particle tracking scheme was employed to advance the particles dynamically, and total and regional deposition efficiencies were determined and compared to in vitro data. The effect of inflow turbulence and intersubject variation on deposition was studied. Geometric variation has a large impact on total deposition whereas the effect of inflow turbulence is confined to oral deposition

In silico assessment of mouth-throat effects on regional deposition in the upper tracheobronchial airways

Regional deposition of inhaled medicines is a valuable metric of effectiveness in drug delivery applications to the lung. In silico methods are now emerging as a valuable tool for the detailed description of localized deposition in the respiratory airways. In this context, there is a need to minimize the computational cost of high-fidelity numerical approaches. Motivated by this need, the present study is designed to assess the role of the extrathoracic airways in determining regional deposition in the upper bronchial airways. Three mouth-throat geometries, with significantly different geometric and filtering characteristics, are merged onto the same tracheobronchial tree that extends to generation 8, and Large Eddy Simulations are carried out at steady inhalation flowrates of 30 and View the MathML source. At both flowrates, large flow field differences in the extrathoracic airways across the three geometries largely die out below the main bifurcation. Importantly, localized deposition fractions are found to remain practically identical for particles with aerodynamic diameters of up to View the MathML source and View the MathML source at 30 and View the MathML source, respectively. For larger particles, differences in the localized deposition fractions are shown to be mainly due to variations in the mouth-throat filtering rather than upstream flow effects or differences in the local flow field. Deposition efficiencies in the individual airway segments exhibit strong correlations across the three geometries, for all particle sizes. The results suggest that accurate predictions of regional deposition in the tracheobronchial airways can therefore be obtained if the particle size distribution that escapes filtering in the mouth-throat (ex-cast dose) of a particular patient is known or can be estimated. These findings open the prospect for significant reductions in the computational expense, especially in the context of in silico population studies, where the aerosol size distribution and precomputed flow field from standardized mouth-throat models could be used with large numbers of tracheobronchial trees available in chest-CT databases

Supranormal Expiratory Airflow after Bilateral Lung Transplantation is Associated with Improved Survival

RATIONALE: flow volume loops (FVL) in some bilateral lung transplant (BLT) and heart-lung transplant (HLT) patients suggest variable extrathoracic obstruction in the absence of identifiable causes. These FVLs usually have supranormal expiratory and normal inspiratory flow rates (SUPRA pattern). OBJECTIVES: characterize the relationship of the SUPRA pattern to predicted donor and recipient lung volumes, airway size, and survival. METHODS: we performed a retrospective review of adult BLT/HLT patients. We defined the SUPRA FVL pattern as: (1) mid-vital capacity expiratory to inspiratory flow ratio (Ve50:Vi50) \u3e 1.0, (2) absence of identifiable causes of extrathoracic obstruction, and (3) Ve50/FVC ≥ 1.5 s(-1). We calculated predicted total lung capacity (pTLC) ratio by dividing the donor pTLC by the recipient pTLC. We measured airway luminal areas on thoracic computer tomographic scans. We compared survival in patients with and without the SUPRA pattern. MEASUREMENTS AND MAIN RESULTS: the SUPRA FVL pattern occurred in 56% of the 89 patients who qualified for the analysis. The pTLC ratio of SUPRA and non-SUPRA patients was 1.11 and 0.99, respectively (P = 0.004). A higher pTLC ratio was correlated with increased probability of the SUPRA pattern (P = 0.0072). Airway luminal areas were larger in SUPRA patients (P = 0.009). Survival was better in the SUPRA cohort (P = 0.009). CONCLUSIONS: the SUPRA FVL pattern was frequent in BLT/HLT patients. High expiratory flows in SUPRA patients could result from increased lung elastic recoil or reduced airway resistance, both of which could be caused by the pTLC mismatch. Improved survival in the SUPRA cohort suggests potential therapeutic approaches to improve outcomes in BLT/HLT patients

Mechanical Interactions Between the Upper Airway and the Lungs that Affect the Propensity to Obstructive Sleep Apnea in Health and Chronic Lung Disease

Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive narrowing and collapse of the upper airways during sleep. It is caused by multiple anatomic and nonanatomic factors but end-expiratory lung volume (EELV) is an important factor as increased EELV can stabilize the upper airway via caudal traction forces. EELV is impacted by changes in sleep stages, body position, weight, and chronic lung diseases, and this article reviews the mechanical interactions between the lungs and upper airway that affect the propensity to OSA. In doing so, it highlights the need for additional research in this area

Regional aerosol deposition in the human airways: the SimInhale benchmark case and a critical assessment of in silico methods

Regional deposition effects are important in the pulmonary delivery of drugs intended for the topical treatment of respiratory ailments. They also play a critical role in the systemic delivery of drugs with limited lung bioavailability. In recent years, significant improvements in the quality of pulmonary imaging have taken place, however the resolution of current imaging modalities remains inadequate for quantifying regional deposition. Computational Fluid-Particle Dynamics (CFPD) can fill this gap by providing detailed information about regional deposition in the extrathoracic and conducting airways. It is therefore not surprising that the last 15 years have seen an exponential growth in the application of CFPD methods in this area. Survey of the recent literature however, reveals a wide variability in the range of modelling approaches used and in the assumptions made about important physical processes taking place during aerosol inhalation. The purpose of this work is to provide a concise critical review of the computational approaches used to date, and to present a benchmark case for validation of future studies in the upper airways. In the spirit of providing the wider community with a reference for quality assurance of CFPD studies, in vitro deposition measurements have been conducted in a human-based model of the upper airways, and several groups within MP1404 SimInhale have computed the same case using a variety of simulation and discretization approaches. Here, we report the results of this collaborative effort and provide a critical discussion of the performance of the various simulation methods. The benchmark case, in vitro deposition data and in silico results will be published online and made available to the wider community. Particle image velocimetry measurements of the flow, as well as additional numerical results from the community, will be appended to the online database as they become available in the future

Measurements of Total Aerosol Deposition and Validation of Airway Resistance Models in Anatomically Realistic Intrathoracic Conducting Airway Replicas of Children

One objective of this research was to obtain a correlation that quantitatively predicts micrometer-sized aerosol particle deposition in the upper conducting airways (trachea to generation 3) of children. Experiments were conducted using steady inhalation air flow rates to measure the deposition of monodisperse particles with diameters of 3.5–5.5 micro-meter in replicas of the upper tracheobronchial airways of 11 children aged 2–8 years. The total deposition of particles was measured in each replica using gravimetry. Validation was performed by measuring deposition in five adult replicas and comparing with existing published data. Although there is considerable intersubject variability in our data, the empirical correlation of Chan & Lippmann (1980) was found to predict total deposition reasonably well in all of our adult and child replicas. A second goal of this study was to design an idealized pediatric central conducting airway model that mimics average total particle deposition in the airways of 4-8 year old children. Dimensions of the idealized model were selected based on analytical prediction of deposition in scaled versions of existing adult airway geometries. Validation experiments were then conducted using steady inhalation air flow rate to measure the deposition of monodisperse particles with mass median diameters (MMD) of 3.5, 4.5, 5 and 5.2 micro-meter in the idealized pediatric model. The total deposition of particles was measured using gravimetry. Experimental data confirmed that aerosol deposition in the idealized pediatric central conducting airway geometry was consistent with the average deposition previously measured in 10 realistic airway replicas for children 4-8 years old. Finally, this thesis describes in vitro measurements of the total pressure loss at varying flow rate through anatomically realistic conducting airway replicas of ten children, 4 to 8 years old, and five adults. Experimental results were compared with analytical predictions made using published airway resistance models. For the adult replicas, the model proposed by van Ertbruggen et al. (J. Appl. Physiol. 98:970-980,2005) most accurately predicted central conducting airway resistance for inspiratory flow rates ranging from 15 to 90 L/min. Models proposed by Pedley et al. (J. Respir. Physiol. 9:371-386,1970) and by Katz et al. (J. Biomechanics 44:1137-1143,2011) also provided reasonable estimates, but with a tendency to over predict measured pressure loss for both models. For child replicas, the Pedley and Katz models both provided good estimation of measured pressure loss at flow rates representative of resting tidal breathing, but under predicted measured values at high inspiratory flow rate (60 L/min). The van Ertbruggen model, developed based on flow simulations performed in an adult airway model, tended to under predict measured pressure loss through the child replicas across the range of flow rates studied (2 to 60 L/min). These results are intended to provide guidance for selection of analytical pressure loss models for use in predicting airway resistance and ventilation distribution in adults and children

Delivery of inhalation drugs to children for asthma and other respiratory diseases

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