Numerical investigation of blood flow and red blood cell rheology: the magnetic field effect.

In this study, the motion and deformation of a red blood cell in a Poiseuille flow through microvessels under the effect of a uniform transverse magnetic field is comprehensively investigated to get a better insight into blood hemorheology. The rheology of the RBC and the surrounding blood flow are examined numerically in two dimensions using a Finite Element Method. It is essential to know that the flow patterns of blood change in the presence of an RBC. The simulation results demonstrate that the magnetic field has significant influence on the flow stream and the behavior of the RBC, including the motion and the cells deformation.

Numerical modeling of particle deposition in a realistic respiratory airway using CFD-DPM and genetic algorithm.

In this study, a realistic model of the respiratory tract obtained from CT medical images was used to solve the flow field and particle motion using the Eulerian-Lagrangian approach to obtain the maximum particle deposition in the bronchial tree for the main purpose of optimizing the performance of drug delivery devices. The effects of different parameters, including particle diameter, particle shape factor, and air velocity, on the airflow field and particle deposition pattern in different zones of the lung were investigated. In addition, a genetic algorithm was employed to obtain the maximum particle deposition in the bronchial tree and the effect of the aforementioned parameters on particle deposition. Reverse flow, vortex formation, and laryngeal jet all affect the airflow structure and particle deposition pattern. The mouth-throat region had the highest deposition fraction at various flow rates. A change in the deposition pattern with an increased deposition fraction in the throat was observed owing to the increased diameter and shape factor of the particles, resulting from the higher inertia and drag force, respectively. The particle deposition analysis showed that three parameters, shape factor, diameter, and velocity, are directly related to particle deposition, and the diameter is the most effective parameter for particle deposition, with an effect of 60% compared to the shape factor and velocity. Finally, the prediction of the genetic algorithm reported a maximum particle deposition in the bronchial tree of 17%, whereas, based on the numerical results, the maximum particle deposition was reported to be 16%. Therefore, there is a 1% difference between the prediction of the genetic algorithm and the numerical results, which indicates the high accuracy of the prediction of the genetic algorithm.

Lung function measurements in preclinical research: What has been done and where is it headed?

Due to the close interaction of lung morphology and functions, repeatable measurements of pulmonary function during longitudinal studies on lung pathophysiology and treatment efficacy have been a great area of interest for lung researchers. Spirometry, as a simple and quick procedure that depends on the maximal inspiration of the patient, is the most common lung function test in clinics that measures lung volumes against time. Similarly, in the preclinical area, plethysmography techniques offer lung functional parameters related to lung volumes. In the past few decades, many innovative techniques have been introduced for in vivo lung function measurements, while each one of these techniques has their own advantages and disadvantages. Before each experiment, depending on the sensitivity of the required pulmonary functional parameters, it should be decided whether an invasive or non-invasive approach is desired. On one hand, invasive techniques offer sensitive and specific readouts related to lung mechanics in anesthetized and tracheotomized animals at endpoints. On the other hand, non-invasive techniques allow repeatable lung function measurements in conscious, free-breathing animals with readouts related to the lung volumes. The biggest disadvantage of these standard techniques for lung function measurements is considering the lung as a single unit and providing only global readouts. However, recent advances in lung imaging modalities such as x-ray computed tomography and magnetic resonance imaging opened new doors toward obtaining both anatomical and functional information from the same scan session, without the requirement for any extra pulmonary functional measurements, in more regional and non-invasive manners. Consequently, a new field of study called pulmonary functional imaging was born which focuses on introducing new techniques for regional quantification of lung function non-invasively using imaging-based techniques. This narrative review provides first an overview of both invasive and non-invasive conventional methods for lung function measurements, mostly focused on small animals for preclinical research, including discussions about their advantages and disadvantages. Then, we focus on those newly developed, non-invasive, imaging-based techniques that can provide either global or regional lung functional readouts at multiple time-points.

Effect of laryngeal jet on dry powder inhaler aerosol deposition: a numerical simulation.

Although pulmonary drug delivery has been deeply investigated, the effect of the laryngeal jet on particle deposition during drug delivery with dry powder inhalers (DPI) has not been evaluated profoundly. In this study, the flow structure and particle deposition pattern of a DPI in two airway models, one with mouth-throat region including the larynx and the other one without it, are numerically investigated. The results revealed that the laryngeal jet has a considerable effect on particle deposition. The presence of laryngeal jet leads to 4-fold and 2-fold higher deposition efficiencies for inlet flow rates of 30 and 90 L/min, respectively.

Numerical and Machine Learning Analysis of the Parameters Affecting the Regionally Delivered Nasal Dose of Nano- and Micro-Sized Aerosolized Drugs.

The nasal epithelium is an important target for drug delivery to the nose and secondary organs such as the brain via the olfactory bulb. For both topical and brain delivery, the targeting of specific nasal regions such as the olfactory epithelium (brain) is essential, yet challenging. In this study, a numerical model was developed to predict the regional dose as mass per surface area (for an inhaled mass of 2.5 mg), which is the biologically most relevant dose metric for drug delivery in the respiratory system. The role of aerosol diameter (particle diameter: 1 nm to 30 µm) and inhalation flow rate (4, 15 and 30 L/min) in optimal drug delivery to the vestibule, nasal valve, olfactory and nasopharynx is assessed. To obtain the highest doses in the olfactory region, we suggest aerosols with a diameter of 20 µm and a medium inlet air flow rate of 15 L/min. High deposition on the olfactory epithelium was also observed for nanoparticles below 1 nm, as was high residence time (slow flow rate of 4 L/min), but the very low mass of 1 nm nanoparticles is prohibitive for most therapeutic applications. Moreover, high flow rates (30 L/min) and larger micro-aerosols lead to highest doses in the vestibule and nasal valve regions. On the other hand, the highest drug doses in the nasopharynx are observed for nano-aerosol (1 nm) and fine microparticles (1-20 µm) with a relatively weak dependence on flow rate. Furthermore, using the 45 different inhalation scenarios generated by numerical models, different machine learning models with five-fold cross-validation are trained to predict the delivered dose and avoid partial differential equation solvers for future predictions. Random forest and gradient boosting models resulted in R2 scores of 0.89 and 0.96, respectively. The aerosol diameter and region of interest are the most important features affecting delivered dose, with an approximate importance of 42% and 47%, respectively.

A Multimodal Imaging-Supported Down Syndrome Mouse Model of RSV Infection.

Individuals with Down syndrome (DS) are more prone to develop severe respiratory tract infections. Although a RSV infection has a high clinical impact and severe outcome in individuals with DS, no vaccine nor effective therapeutics are available. Any research into infection pathophysiology or prophylactic and therapeutic antiviral strategies in the specific context of DS would greatly benefit this patient population, but currently such relevant animal models are lacking. This study aimed to develop and characterize the first mouse model of RSV infection in a DS-specific context. Ts65Dn mice and wild type littermates were inoculated with a bioluminescence imaging-enabled recombinant human RSV to longitudinally track viral replication in host cells throughout infection progression. This resulted in an active infection in the upper airways and lungs with similar viral load in Ts65Dn mice and euploid mice. Flow cytometric analysis of leukocytes in lungs and spleen demonstrated immune alterations with lower CD8+ T cells and B-cells in Ts65Dn mice. Overall, our study presents a novel DS-specific mouse model of hRSV infection and shows that potential in using the Ts65Dn preclinical model to study immune-specific responses of RSV in the context of DS and supports the need for models representing the pathological development.

Flow Structure and Particle Deposition Analyses for Optimization of a Pressurized Metered Dose Inhaler (pMDI) in a Model of Tracheobronchial Airway.

Inhalation therapy plays an important role in management or treatment of respiratory diseases such asthma and chronic obstructive pulmonary diseases (COPDs). For decades, pressurized metered dose inhalers (pMDIs) have been the most popular and prescribed drug delivery devices for inhalation therapy. The main objectives of the present computational work are to study flow structure inside a pMDI, as well as transport and deposition of micron-sized particles in a model of human tracheobronchial airways and their dependence on inhalation air flow rate and characteristic pMDI parameters. The upper airway geometry, which includes the extrathoracic region, trachea, and bronchial airways up to the fourth generation in some branches, was constructed based on computed tomography (CT) images of an adult healthy female. Computational fluid dynamics (CFD) simulation was employed using the k-ω model with low-Reynolds number (LRN) corrections to accomplish the objectives. The deposition results of the present study were verified with the in vitro deposition data of our previous investigation on pulmonary drug delivery using a hollow replica of the same airway geometry as used for CFD modeling. It was found that the flow structure inside the pMDI and extrathoracic region strongly depends on inhalation flow rate and geometry of the inhaler. In addition, regional aerosol deposition patterns were investigated at four inhalation flow rates between 30 and 120 L/min and for 60 L/min yielding highest deposition fractions of 24.4% and 3.1% for the extrathoracic region (EX) and the trachea, respectively. It was also revealed that particle deposition was larger in the right branches of the bronchial airways (right lung) than the left branches (left lung) for all of the considered cases. Also, optimization of spray characteristics showed that the optimum values for initial spray velocity, spray cone angle and spray duration were 100 m/s, 10° and 0.1 sec, respectively. Moreover, spray cone angle, more than any other of the investigated pMDI parameters can change the deposition pattern of inhaled particles in the airway model. In conclusion, the present investigation provides a validated CFD model for particle deposition and new insights into the relevance of flow structure for deposition of pMDI-emitted pharmaceutical aerosols in the upper respiratory tract.

Dry powder inhaler aerosol deposition in a model of tracheobronchial airways: Validating CFD predictions with in vitro data.

Effective drug delivery into the lungs plays an important role in management of pulmonary diseases that affect millions all around the world. The main objective of this investigation is to study airflow structure, as well as transport and deposition of micron-size particles at different inhalation flow rates in a realistic model of human tracheobronchial airways. The airway model was developed based on computed tomography (CT) images of a healthy 48-years-old female, which includes extrathoracic, trachea, and bronchial airways up to fourth generations. Computational fluid dynamics (CFD) simulations were performed to predict transport and deposition of inhaled particles and the results were compared to our previous in vitro experiments. Airflow structure was studied through velocity contours and streamlines in the extrathoracic region, where the onset of turbulence, reverse flow and subsequently vortex formation, and laryngeal jet are found to be critical phenomenons in the formation of airflow and deposition patterns. The deposition data was presented by deposition efficiency (DE) and deposition fraction (DF) against impaction parameter and Stokes number. At all of the inhalation flow rates, highest values of deposition fractions were devoted to the mouth-throat (MT), tracheobronchial tree (TB), and trachea (Tra), respectively (At 60 L/min: MT = 6.7%, TB = 5.3%, Tra = 1.9%). The numerical deposition data showed a good agreement with the experimental deposition data in most of the airway regions (e.g. less than 10% difference between the deposition fractions in the tracheobronchial region). Enhancing inhalation flow rate in all of the airway regions led to an uptrend in deposition rate due to the increase of particles inertia and turbulence level. In addition, the increase of particle deposition with enhancing inhalation flow rate in all of the sections including extrathoracic, trachea, and tracheobronchial tree suggesting that inertial impaction is the dominant deposition mechanism due to the increase of inertial force. In conclusion, the validated CFD model provided an opportunity to cover the limitations of our previous experimental investigation on aerosol deposition of commercial inhalers and became an efficient method for further studies.

Development of human respiratory airway models: A review.

Pulmonary drug delivery has gained great interest as an important subject of research over the past decades given the lung diseases which are affecting millions of people suffer from these diseases. Drug delivery into the respiratory system is influenced by many anatomical and physiological factors such as lung morphometry, breathing patterns, fluid dynamics, particle properties, etc. The respiratory airway structure is one of these parameters which greatly influences the deposition pattern of inhaled drug particles. There have been a wide variety of major morphometric studies, conducted using cadavers to increase an understanding of the respiratory airway anatomy and provide important information for developing realistic airway models. Casting as one of the first methods, was utilized for morphometric studies providing a hollow model for in vitro investigations. The above-mentioned morphometric data were utilized to describe the first idealized airway model as a simple symmetric description of the branching airways, later followed by more realistic asymmetric models. However, even these asymmetric airway models were not good enough to reflect the anatomical complexities of the human respiratory airway and contained several major limitations which made them inefficient. Further attempts alongside with the progress of technology led to introduction of the stochastic and image-based models which provided more realistic and efficient tools for numerical and experimental investigations. The main objective of this study is to provide a comprehensive review about the development of different perspectives of the respiratory airway modeling over the past decades. The following sections will present useful information about anatomy of the human respiratory tract, and different viewpoints of the respiratory airway modeling, including their historical routes, strengths, and deficiencies.

Experimental investigation of aerosol deposition through a realistic respiratory airway replica: An evaluation for MDI and DPI performance.

PURPOSE: In the present work, a comparison between MDI and DPI for evaluating performance of the devices were carried out by experimentally investigating the deposition parameters through a realistic airway replica. METHODS: Computed tomography (CT) images of the respiratory airway of a healthy subject were used to develop the realistic model. The airway replica was included extrathoracic, trachea, and tracheobronchial tree up to fourth generations which was fabricated by rapid prototyping. Afterward, in vitro experiments were performed to validate the airway model by comparing the total deposition (G0 to G3) of present replica with available data in the literature. Drug deposition (Salbutamol) in the model was measured by determining concentration of the segments sample by High Performance Liquid Chromatography (HPLC) assay. RESULTS: Deposition parameters were used for investigating the deposition patterns of the inhaled particles. Results showed that inertial impaction is the dominant mechanism in the most regions of the replica. It was found that the MDI delivered more drug to the tracheobronchial tree compared to the DPI for three different flow rate. CONCLUSION: The developed realistic respiratory airways model provided an opportunity to more accurately evaluate the performance of drug delivery devices and studying mechanisms of the drug deposition.