Large-scale CFD simulations of the transitional and turbulent regime for the large human airways during rapid inhalation

The dynamics of unsteady flow in the human large airways during a rapid inhalation were investigated using highly detailed large-scale computational fluid dynamics on a subject-specific geometry. The simulations were performed to resolve all the spatial and temporal scales of the flow, thanks to the use of massive computational resources. A highly parallel finite element code was used, running on two supercomputers, solving the transient incompressible Navier–Stokes equations on unstructured meshes. Given that the finest mesh contained 350 million elements, the study sets a precedent for large-scale simulations of the respiratory system, proposing an analysis strategy for mean flow, fluctuations and wall shear stresses on a rapid and short inhalation (a so-called sniff). The geometry used encompasses the exterior face and the airways from the nasal cavity, through the trachea and up to the third lung bifurcation; it was derived from a contrast-enhanced computed tomography (CT) scan of a 48-year-old male. The transient inflow produces complex flows over a wide range of Reynolds numbers (Re). Thanks to the high fidelity simulations, many features involving the flow transition were observed, with the level of turbulence clearly higher in the throat than in the nose. Spectral analysis revealed turbulent characteristics persisting downstream of the glottis, and were captured even with a medium mesh resolution. However a fine mesh resolution was found necessary in the nasal cavity to observe transitional features. This work indicates the potential of large-scale simulations to further understanding of airway physiological mechanics, which is essential to guide clinical diagnosis; better understanding of the flow also has implications for the design of interventions such as aerosol drug delivery.We acknowledge PRACE for awarding us access to resource FERMI based in Italy at Bologna hosted by Cineca. This work was financially supported by the PRACE project Pra04 693 (2011050693 to the Fourth PRACE regular call). The second author gratefully acknowledges support from project ‘MatComPhys’ under the European Research Executive Agency FP7-PEOPLE-2011- IEF framework. The third author was supported by the Engineering and Physical Sciences Research Council [grant number EP/ M506345/1].Peer ReviewedPostprint (author's final draft

Large-scale CFD and micro-particles simulations in a large human airways under sniff condition and drug delivery application

As we inhale, the air drawn through our nose undergoes successive accelerations and decelerations as it is turned, split, and recombined before splitting again at the end of the trachea as it enters the bronchi. Fully describing the dynamic behaviour of the airflow and how it transports inhaled particles poses a severe challenge to computational simulations. The dynamics of unsteady flow in the human large airways during a rapid and short inhalation (a so-called sniff) is a perfect example of perhaps the most complex and violent human inhalation inflow. Combining the flow solution with a Lagrangian computation reveals the effects of flow behaviour and airway geometry on the deposition of inhaled microparticles. Highly detailed large-scale computational fluid dynamics allow resolving all the spatial and temporal scales of the flow, thanks to the use of massive computational resources. A highly parallel finite element code running on supercomputers can solve the transient incompressible Navier-Stokes equations on unstructured meshes. Given that the finest mesh contained 350 million elements, the study sets a precedent for large-scale simulations of the respiratory system, proposing an analysis strategy for mean flow, fluctuations, wall shear stresses, energy spectral and particle deposition on a rapid and short inhalation. Then in a second time, we will propose a drug delivery study of nasal sprayed particle from commercial product in a human nasal cavity under different inhalation conditions; sniffing, constant flow rate and breath-hold. Particles were introduced into the flow field with initial spray conditions, including spray cone angle, insertion angle, and initial velocity. Since nasal spray atomizer design determines the particle conditions, fifteen particle size distributions were used,each defined by a log-normal distribution with a different volume mean diameter. This thesis indicates the potential of large-scale simulations to further understanding of airway physiological mechanics, which is essential to guide clinical diagnosis; better understanding of the flow and delivery of therapeutic aerosols, which could be applied to improve diagnosis and treatment.En una inhalación, el aire que atraviesa nuestra cavidad nasal es sometido a una serie de aceleraciones y deceleraciones al producirse un giros, bifurcaciones y recombinarse de nuevo antes de volver a dividirse de nuevo a la altura de la tráquea en la entrada a los bronquios principales. La descripción precisa y acurada del comportamiento dinámico de este fluido así como el transporte de partículas inhalada que entran con el mismo a través de una simulación computacional supone un gran desafío. La dinámica del fluido en las vías respiratorias durante una inhalación rápida y corta (también llamado sniff) es un ejemplo perfecto de lo que sería probablemente la inhalación en el ser humano más compleja y violenta. Combinando la solución del fluido con un modelo lagrangiano revela el comportamiento del flujo y el effecto de la geometría de las vías respiratorias sobre la deposición de micropartículas inhaladas. La dinámica de fluidos computacional a gran escala de alta precisión permite resolver todas las escalas espaciales y temporales gracias al uso de recursos computacionales masivos. Un código de elementos finitos paralelos que se ejecuta en supercomputadoras puede resolver las ecuaciones transitorias e incompresibles de Navier-Stokes. Considerando que la malla más fina contiene 350 millones de elementos, cabe señalar que el presente estudio establece un precedente para simulaciones a gran escala de las vías respiratorias, proponiendo una estrategia de análisis para flujo medio, fluctuaciones, tensiones de corte de pared, espectro de energía y deposición de partículas en el contexto de una inhalación rápida y corta. Una vez realizado el analisis anterior, propondremos un estudio de administración de fármacos con un spray nasal en una cavidad nasal humana bajo diferentes condiciones de inhalación; sniff, caudal constante y respiración sostenida. Las partículas se introdujeron en el fluido con condiciones iniciales de pulverización, incluido el ángulo del cono de pulverización, el ángulo de inserción y la velocidad inicial. El diseño del atomizador del spray nasal determina las condiciones de partículas, entonces se utilizaron quince distribuciones de tamaño de partícula, cada uno definido por una distribución logarítmica normal con una media de volumen diferente. Esta tesis demuestra el potencial de las simulaciones a gran escala para una mejor comprensión de los mecanismos fisiológicos de las vías respiratorias. Gracias a estas herramientas se podrá mejorar el diagnóstico y sus respectivos tratamientos ya que con ellas se profundizará en la comprensión del flujo que recorre las vías aereas así como el transporte de aerosoles terapéuticos

Mechanics of airflow in human inhalation

The mechanics of airflow in the large airways during inspiration affects important physiological functions such as ventilation, olfaction, heat exchange and mass transfer. The behaviour of the airflow is important not only for healthcare applications including diagnosis, intervention planning and assessment, but for inhalation toxicology. This research aims to further the understanding of human nasal physiology through computational modelling. Specifically, the effects of transient inhalation conditions on flow dynamics and transport were characterised and the changes in flow behaviour in response to certain pathologies quantified. The key findings can be summarised as follows: Firstly, the time scales for airflow in the large airways have been identified and the initial flow patterns revealed. Three phases in the temporal behaviour of the flow were identified (flow initiation, quasi-equilibrium and decay). The duration of each phase differs depending on the quantity of interest. Flow in the nose was characterised as transitional, whilst in parts of the descending airways it is turbulent, particularly in the faster moving regions around the jets which may occur in the pharynx, larynx and at the superior end of the trachea. The bulk of the flow is biased to fill only certain regions of the airways, whilst other regions carry little flow, due to features upstream. Analysis of cross-sectional images provided by medical imaging does not necessarily provide a representative view of the area available to the flow. Various scalar species were employed to represent the fate of nanoparticles and gaseous species within the airways. Only species with high diffusion rates exhibited significant absorption at the airway walls. Airway pathologies often cause changes to the geometry of the airway. One such pathology, the goitre, was found to curve the trachea and in some cases cause constriction. Both these geometric changes were found to increase the pressure loss and energy required to drive flow through the trachea. Furthermore, the flow in pathological cases was more disturbed. High resolution simulations have been used to address these topics and the scales simulated have been analysed in terms of the smallest features possible in the flow to determine their fidelity.Open Acces

Strategies and Devices for Improving Respiratory Drug Delivery to Infants and Children with Cystic Fibrosis

Cystic Fibrosis (CF) is a degenerative disease, which causes thickening of the airway surface liquid and reduced mucociliary clearance, which provides an ideal habitat for bacterial infections. Early treatment of CF in children can prevent chronic infection, improve quality of life, and increase life expectancy. The most predominant bacteria found in CF-diseased lungs is Pseudomonas aeruginosa (Pa), which can be treated with inhaled tobramycin. Excipient enhanced growth (EEG) powder formulations are well suited for administering tobramycin to children, as the EEG approach provides minimal upper airway loss and targeted drug delivery. This method uses an initially small aerosol for high extrathroacic transmission, and includes hygroscopic excipients within the formulation that absorb moisture from the humid airways and increase lung retention of the aerosol. The overarching goal of this work was to develop delivery systems and strategies for improving respiratory drug delivery to children with CF, which was based on insights from computational fluid dynamics (CFD) simulations and in vitro models. The studies presented in this dissertation have three distinct and sequential phases: (i) CFD methods development; (ii) respiratory device design and optimization; and (iii) complete-airway modeling for aerosol delivery strategy development. The methods development phase produced meshing and solution guidelines that were computationally-efficient, accurate, and validated based on in vitro data. Results showed that the two-equation k-ω model, with near-wall corrections, was capable of matching experimental data across a range of Reynolds numbers and particle sizes that are specific to respiratory drug delivery. The guidelines also provided comparable accuracy to the more complex Large Eddy Simulation (LES) model, while providing multiple order-of-magnitude savings in computational time. The device optimization phase developed a highly efficient delivery system for tobramycin administration to pediatric CF patients. Correlations were developed, based on flow field quantities, that were predictive of aerosolization performance and depositional loss. Successful a priori validation with experimental testing highlighted the predictive capabilities of the correlations and CFD model accuracy. The best-case delivery system demonstrated an aerosol size of approximately 1.5 µm and expected lung dose of greater than 75% of loaded dose, which is a marked improvement compared to commercial devices. The delivery strategy development phase identified optimal EEG aerosol properties that better unify drug surface concentration. These studies present numerical models of a tobramycin EEG powder formulation for the first time, and provide the first instance of a complete-airway CFD model evaluating pediatric CF lungs. Results show that EEG aerosols are capable of delivering the drug above the minimum inhibitory concentration in all airway regions, reducing regional dose variability, and targeting the lower airways where infection is more predominant. In conclusion, results from this dissertation demonstrate: (i) accurate and efficient CFD models of respiratory drug delivery; (ii) optimized designs for respiratory delivery systems; and (iii) optimal delivery strategies for inhaled tobramycin to pediatric patients with CF

Subject-variability effects on micron particle deposition in human nasal cavities

Validated computer simulations of the airflow and particle dynamics in human nasal cavities are important for local, segmental and total deposition predictions of both inhaled toxic and therapeutic particles. Considering three, quite different subject-specific nasal airway configurations, micron-particle transport and deposition for low-to-medium flow rates have been analyzed. Of special interest was the olfactory region from which deposited drugs could readily migrate to the central nervous system for effective treatment. A secondary objective was the development of a new dimensionless group with which total particle deposition efficiency curves are very similar for all airway models, i.e., greatly reducing the impact of intersubject variability. Assuming dilute particle suspensions with inhalation flow rates ranging from 7.5 to 20 L/min, the airflow and particle-trajectory equations were solved in parallel with the in-house, multi-purpose Alya program at the Barcelona Supercomputing Center. The geometrically complex nasal airways generated intriguing airflow fields where the three subject models exhibit among them both similar as well as diverse flow structures and wall shear stress distributions, all related to the coupled particle transport and deposition. Nevertheless, with the new Stokes-Reynolds-number group, , the total deposition-efficiency curves for all three subjects and flow rates almost collapsed to a single function. However, local particle deposition efficiencies differed significantly for the three subjects when using particle diameters = 2, 10, and . Only one of the three subject-specific olfactory regions received, at relatively high values of the inertial parameter , some inhaled microspheres. Clearly, for drug delivery to the brain via the olfactory region, a new method of directional inhalation of nanoparticles would have to be implemented.The authors acknowledge Dr. Rick Corley and colleagues at Pacific Northwest National Laboratory for providing the subject B nasal surface geometry and Dr. Edgar Matida and Dr. Matthew Johnson at Carleton University for providing the subject C nasal surface geometryPeer ReviewedPostprint (published version

Aerosol generation and entrainment model for cough simulations

The airborne transmission of diseases is of great concern to the public health community. The possible spread of infectious disease by aerosols is of particular concern among health-care workers and emergency responders, who face a much greater risk of exposure to these hazards than does the general public. Some diseases, such as influenza, spread by dissemination and inhalation of aerosols of small droplet nuclei that are generated by coughing and remain airborne for an extended time. For that reason a better understanding of the generation of aerosols is important. Therefore, the main objective of this study is to investigate the flow dynamics and the aerosol generation during coughing. This research aims to develop a fairly simple yet an accurate model for the flow simulation in the upper respiratory tract, mainly in the larynx, and the number and size distribution of the aerosols generated during coughing.;In order to provide a more complete analysis tool, a secondary objective is to develop a simple reduced order model for the purpose of simulating the air flow and particle dynamics in the larynx. To this end a pseudo two-dimensional model (PTM) has been developed and run for several cases including, sinusoidal laminar and low Reynolds number flow cases including breathing and coughing. The comparison of the PTM model results with FLUENT has shown that the PTM model is capable of producing accurate results within a fraction of execution time needed for the multi-dimensional FLUENT\u27s model.;The aerosol generation and entrainment model (AGEM) is integrated into this validated one-dimensional model. This is done by utilizing a one dimensional turbulent kinetic energy equation. AGEM is then employed to calculate the aerosol formations during a cough, which is simulated by the one dimensional flow solver. The final size distribution of the aerosol droplets is calculated and these findings are compared with laboratory measurements. It is shown that, with appropriate model coefficients, it is possible to obtain size distribution of aerosols that is consistent with the experimental findings. A parametric study by variation of physical properties of the mucus has also been carried out. The results show some interesting trend with changing surface tension and varying cough signals.;This study may be considered as a step towards a more complete understanding of aerosol generation mechanisms by coughing, which in turn lead to airborne transmission of diseases. The simulation tools developed should serve the scientist to do more parametric studies in a fairly quick manner and investigate the aerosol dispersion in the confined areas as well as studying particle deposition patterns within the upper respiratory track

CFD simulation of the airflow through the human respiratory tract

This study compares the effect of extra-thoracic airways (ETA) on the flow field through the lower airways by carrying out simulations of the airflow through the human respiratory tract. Three geometries, consisting of the ETA, CT-derived lower airway, and a combination of the two were utilized in simulations that were performed for transient breathing in addition to constant inspiration/expiration. Physiologically-appropriate regional ventilation for two different flow rates was induced at the distal boundaries by imposing appropriate lobar specific flow rates. Two breathing rates were considered, i.e., 7.5 and 15 breaths per minute with a tidal volume of 0.5 liter. For comparison, the flow rates for constant inspiration/expiration were selected to be identical to the peak flow rates during the transient breathing. Significant differences indicate that simulations that utilize constant inspiration or expiration may not be appropriate for gaining insight into the flow patterns through the human airways