Airway Replicas Research Articles

Deposition of graphene nanomaterial aerosols in human upper airways

ABSTRACTGraphene nanomaterials have attracted wide attention in recent years on their application to state-of-the-art technology due to their outstanding physical properties. On the other hand, the nanotoxicity of graphene materials also has rapidly become a serious concern especially in occupational health. Graphene naomaterials inevitably could become airborne in the workplace during manufacturing processes. The inhalation and subsequent deposition of graphene nanomaterial aerosols in the human respiratory tract could potentially result in adverse health effects to exposed workers. Therefore, investigating the deposition of graphene nanomaterial aerosols in the human airways is an indispensable component of an integral approach to graphene occupational health. For this reason, this study carried out a series of airway replica deposition experiments to obtain original experimental data for graphene aerosol airway deposition. In this study, graphene aerosols were generated, size classified, and delivered into human airway replicas (nasal and oral-to-lung airways). The deposition fraction and deposition efficiency of graphene aerosol in the airway replicas were obtained by a novel experimental approach. The experimental results acquired showed that the fractional deposition of graphene aerosols in airway sections studied were all less than 4%, and the deposition efficiency in each airway section was generally lower than 0.03. These results indicate that the majority of the graphene nanomaterial aerosols inhaled into the human respiratory tract could easily penetrate through the head airways as well as the upper part of the tracheobronchial airways and then transit down to the lower lung airways, where undesired biological responses might be induced.

Low re-inhalation of the exhaled flow during normal nasal breathing in a pediatric airway replica

To estimate the fraction of the exhaled airflow that is re-inhaled during normal nasal breathing, experiments were carried out in a water tank with an anatomically accurate respiratory tract model of a 4-year-old child. The velocity of respiratory flow was scaled using similarity laws between air and water. Breath simulation was performed via a computer-controlled piston-cylinder system. Food-dye visualization allows a qualitative analysis of the re-inhaled fraction of this exhaled flow. For the quantitative analysis, neutrally buoyant particles were added to the water medium, and illuminated by the laser which illuminates the whole breathing region of the respiratory model, such that the trajectory and quantity of the re-inhaled particles can be recorded and counted. The experimental results in the pediatric airway replica show that a negligible fraction (<0.06%) of the exhaled airflow is re-inhaled during normal nasal breathing in the absence of the rising thermal plume. The artificial plume generated by a heated aluminium brick at the tank bottom increases the re-inhalation ratio by 4 times under the investigated case (albeit still at a very low value of 0.15%). Our results thus reveal that during normal nasal breathing in the present pediatric subject, the vast majority of human exhaled airflow escapes from the inhalation zone and is not re-inhaled.

Validation of airway resistance models for predicting pressure loss through anatomically realistic conducting airway replicas of adults and children

This work describes in vitro measurement of the total pressure loss at varying flow rate through anatomically realistic conducting airway replicas of 10 children, 4 to 8 years old, and 5 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. (2005. J. Appl. Physiol. 98, 970–980) most accurately predicted central conducting airway resistance for inspiratory flow rates ranging from 15 to 90L/min. Models proposed by Pedley et al. (1970. J. Respir. Physiol. 9, 371–386) and by Katz et al. (2011. J. Biomech. 44, 1137–1143) 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 (60L/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 60L/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.

An idealized branching airway geometry that mimics average aerosol deposition in pediatric central conducting airways

The objective of this work 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 5.2µm 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.

Investigation of the Airflow inside Realistic and Semi-Realistic Replicas of Human Airways

Measurement of velocity in human lungs during breathing cycle is a challenging task for researchers, since the measuring location is accessible only with significant difficulties. A special measuring rig consisting of optically transparent replica of human lungs, breathing simulator, particle generator and Laser-Doppler anemometer was developed and used for investigation of the velocity in specific locations of lungs during simulated breathing cycle. Experiments were performed on two different replicas of human lungs in corresponding measuring points to facilitate the analysis of the influence of the geometry and its simplification on the flow. The analysis of velocity course and turbulence intensity revealed that special attention should be devoted to the modelling of vocal cords position during breathing, as the position of laryngeal jet created by vocal cords significantly influences velocity profiles in trachea. The shapes of velocity courses during expiration proved to be consistent for both replicas; however magnitudes of peak expiratory velocity differ between the corresponding measuring points in both the replicas.

Estimation of carbon nanotubes deposition in a human respiratory tract replica

Investigation of the deposition of airborne carbon nanotubes (CNTs) in the human respiratory tract is essential from the occupational health perspective. Due to the dimension of CNTs, it is very difficult to apply traditional deposition experimental methods to CNTs for conducting a deposition study using human airway replicas. In this research, an innovative experimental approach was adopted to estimate the deposition of CNTs in the human respiratory tract. Two types of CNT materials were used as the challenge CNT materials. The deposition experiments were carried out by delivering size classified CNT aerosols into a human airway replica (from the oral cavity down to part of the 4th lung generation). The CNT deposition fractions and efficiencies in the airways were estimated based on the air flow rates, as well as the CNT concentrations measured in associated lung airways. Experimental results acquired showed that CNT deposition fractions in different sections of the airway replica were all smaller than 5%. The CNT deposition efficiency in the tracheobronchial airways was generally less than 0.1. This result implies that the CNTs inhaled into the human respiratory tract could easily penetrate through the upper airways and transit down to the lower airways to cause potential health effects.

Carbon nanotubes size classification, characterization and nasal airway deposition

Workers and researchers in the carbon nanotubes (CNT)-related industries and laboratories might be exposed to CNT aerosols while generating and handling CNT materials. From the viewpoint of occupational health, it is essential to study the deposition of CNT aerosol in the human respiratory tract to investigate the potential adverse health effects. In this study, a human nasal airway replica and two types of CNT materials were employed to conduct CNT nasal airway deposition studies. The two CNT materials were aerosolized by a nebulizer-based wet generation method, with size classified by three designated classification diameters (51, 101 and 215 nm), and then characterized individually in terms of their morphology and aerodynamic diameter. The nasal deposition experiments were carried out by delivering the size classified CNTs into the nasal airway replica in three different inspiratory flow rates. From the characterization study, it showed that the morphology of the size classified CNTs could be in a variety of complex shapes with their physical dimension much larger than their classification diameter. In addition, it was found that the aerodynamic diameters of the classified CNTs were slightly smaller than their classification diameter. The nasal deposition data acquired in this study showed that the deposition efficiency of CNTs in the nasal airway were generally less than 0.1, which implies that the majority of the CNTs inhaled into the nose could easily penetrate through the entire nasal airway and transit further down to the lower airways, possibly causing adverse health effects.

Deposition of Particles in Human Mouth-Throat Replicas and a USP Induction Port.

Oral inhalation is the common route of drug delivery to pulmonary airways. In general, deposition in the oropharyngeal airways from a drug-delivery device makes up a substantial portion of the emitted dose, which affects the dose delivered to the lung. Studies with airway replicas made from cadaver or magnetic resonance imaging scans show that for micrometer-sized particles, impaction is the dominant deposition mechanism. Several deposition studies in oropharyngeal replicas found that the deposition efficiency can be correlated with the mouth inlet velocity and inlet mouthpiece diameter. Other studies show that the deposition efficiency is best correlated with the mean diameter of internal geometry and the mean velocity based on the mean diameter. We investigated the mouth inlet diameter, as well as internal airway dimensions and their influence on oropharyngeal deposition based on experimental data from this study. Several human oropharyngeal replicas with different mouth inlet diameters and the USP induction port were used. We found that the aerosol deposition increased with decreasing mouth inlet diameter. Several mathematical expressions were tried to correlate the deposition efficiency with the Stokes number calculated based on (1) mouth inlet diameter and inlet velocity, (2) mean diameter of internal geometry and mean velocity, (3) mouth inlet velocity and mean diameter, and (4) mouth inlet velocity and minimum diameter in the oropharyngeal replica. The best correlation was obtained in case 4. This correlation could explain the intra-subject variation when deposition was found to vary with mouth inlet diameter, such as in some aerosol drug-delivery devices. It could also explain the intersubject variability in oropharyngeal deposition when human volunteers with different airway geometries and mouth openings were studied.

Pediatric in vitro and in silico models of deposition via oral and nasal inhalation.

Respiratory tract deposition models provide a useful method for optimizing the design and administration of inhaled pharmaceutical aerosols, and can be useful for estimating exposure risks to inhaled particulate matter. As aerosol must first pass through the extrathoracic region prior to reaching the lungs, deposition in this region plays an important role in both cases. Compared to adults, much less extrathoracic deposition data are available with pediatric subjects. Recently, progress in magnetic resonance imaging and computed tomography scans to develop pediatric extrathoracic airway replicas has facilitated addressing this issue. Indeed, the use of realistic replicas for benchtop inhaler testing is now relatively common during the development and in vitro evaluation of pediatric respiratory drug delivery devices. Recently, in vitro empirical modeling studies using a moderate number of these realistic replicas have related airway geometry, particle size, fluid properties, and flow rate to extrathoracic deposition. Idealized geometries provide a standardized platform for inhaler testing and exposure risk assessment and have been designed to mimic average in vitro deposition in infants and children by replicating representative average geometrical dimensions. In silico mathematical models have used morphometric data and aerosol physics to illustrate the relative importance of different deposition mechanisms on respiratory tract deposition. Computational fluid dynamics simulations allow for the quantification of local deposition patterns and an in-depth examination of aerosol behavior in the respiratory tract. Recent studies have used both in vitro and in silico deposition measurements in realistic pediatric airway geometries to some success. This article reviews the current understanding of pediatric in vitro and in silico deposition modeling via oral and nasal inhalation.

Measurements of total aerosol deposition in intrathoracic conducting airway replicas of children

The 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 3.5–5.5μm 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 also measuring deposition in five adult replicas and the Alberta Idealized Throat 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.

Nasal versus oral aerosol delivery to the “lungs” in infants and toddlers

The oral route has been considered superior to the nasal route for aerosol delivery to the lower respiratory tract (LRT) in adults and children. However, there are no data comparing aerosol delivery via the oral and nasal routes in infants. The aim of this study was to compare nasal and oral delivery of aerosol in anatomically correct replicas of infants' faces containing both nasal and oral upper airways. Three CT-derived upper respiratory tract ("URT") replicas representing infants/toddlers aged 5, 14 and 20 months were studied and aerosol delivery to the "lower respiratory tract" (LRT) by either the oral or nasal route for each of the replicas was measured at the "tracheal" opening. A radio-labeled (99mDTPA) normal saline solution aerosol was generated by a soft-mist inhaler (SMIRespimat® Boehringer Ingelheim, Germany) and aerosol was delivered via a valved holding chamber (Respichamber® TMI, London, Canada) and an air-tight mask (Unomedical, Inc., McAllen, TX). A breath simulator was connected to the replicas and an absolute filter at the "tracheal" opening captured the aerosol representing "LRT" dose. Age-appropriate mask dimensions and breathing patterns were employed for each of the airway replicas. Two different tidal volumes (Vt ) were used for comparing the nasal versus oral routes. Nasal delivery to the LRT exceeded that of oral delivery in the 5- and 14-month models and was equivalent in the 20-month model. Differences between nasal and oral delivery diminished with "age"/size. Similar findings were observed with lower and higher tidal volumes (Vt ). Nasal breathing for aerosol delivery to the "LRT" is similar to, or more efficient than, mouth breathing in infant/toddler models, contrary to what is observed in older children and adults. Pediatr Pulmonol. 2015; 50:276-283. © 2014 Wiley Periodicals, Inc.

Thoracic Fraction of Inhaled Fiber Aerosol

Size-selective sampling is a health-related method to collect airborne particles based on penetration of inhaled particles into different regions of the human respiratory tract; thus, it is the most relevant sampling method to correlate health risks with occupational exposure. The current practice of sampling asbestos and other fibers is not a size-selective method. The thoracic size fraction, defined as the portion of inhaled particles that can penetrate through the larynx, has been suggested as the most relevant size-selective sampling method for fiber aerosol. The thoracic fraction is based on 1-deposition of inhaled spherical particles in the human extrathoracic airways for mouth breathing and corrected for the particle inhalability. There is no comparable information for fiber aerosols; therefore, there is no technical basis to ascertain whether the current thoracic fraction definition is suitable for fiber aerosols. No human data are available from controlled experiments of inhaled fiber aerosols for the obvious reason that most fiber materials are potentially hazardous when inhaled. Our approach was to measure penetration of fiber aerosol in realistic human oropharyngeal airway replicas and to compare that with data from spherical particles. We showed that realistic human oral airway replicas (including the oral cavity, pharynx, and larynx regions) provided useful spherical and fiber particle deposition in the human head airway. These data could be used to test the thoracic fraction curves. The spherical penetration is in agreement with human in vivo data used to establish the thoracic fraction curve. Fiber penetrations through the larynx of two human oral airway replicas were higher than those for spherical particles for the same aerodynamic diameter using the same replicas. The thoracic curve as defined for spherical particles, therefore, may not include some fibers that could penetrate to the thoracic region.

An In vitro Study on the Deposition of Micrometer-Sized Particles in the Extrathoracic Airways of Adults During Tidal Oral Breathing

Deposition of particles in the aerodynamic diameter range of 0.5-6.7 μm was measured in nine replicas of the extrathoracic airways of adults with four sinusoidal patterns and oral breathing. The four chosen breathing patterns are typical of those occurring during natural resting breathing and during nebulization therapy. Additionally, deposition of micrometer-sized particles in the "Alberta Idealized Adult Throat," which was previously found useful in simulating the average deposition of particles during inhalation of constant flow rates, was measured during inhalation of the four sinusoidal patterns in this study. To reduce intersubject scatter in developing predictive correlations, the non-dimensional Reynolds (Re) and Stokes (Stk) numbers are used with the square root of the average cross sectional area of the oral airways as the characteristic diameter being found to reduce intersubject variability to the highest extent. Our best fit to the deposition data is given by η = [1 - 1/(1.51 x 10(5)(Stk(3.03)Re(0.25)) + 1)] x 100. Moreover, the "Alberta Idealized Adult Throat" is found to mimic average deposition, given in past in vivo studies, in the upper airways of adults during natural tidal breathing.

In vitro deposition of micrometer-sized particles in the extrathoracic airways of children during tidal oral breathing

Nine oral airway replicas of children 6–14 years old were used for measuring deposition of 0.5–6.3μm diameter particles during inhalation of four representative (sinusoidal) breathing patterns typical of those observed during the use of nebulizers by children. For a given particle size and inhalation flow rate, deposition in the present child replicas is higher than in adults and is not well predicted by adult correlations, even when age-related scaling factors are applied. However, by using subject-specific geometrical dimensions of the airway replicas, dimensionless correlations that predict deposition of micrometer-sized particles in children's oral airways during tidal breathing are presented. Such best fitting correlation gives deposition efficiency η2=[1−1/(4.99(stkR2.41e−0.17)+1)]×100, where Re and Stk are Reynolds and Stokes numbers with length scale given by V/As where V is airway volume and As is airway surface area.

Deposition of inhaled micrometer-sized particles in oropharyngeal airway replicas of children at constant flow rates

This study is aimed at quantifying the deposition of micrometer-sized aerosols in realistic oropharyngeal airway replicas of children 6–14 years old, as well as minimizing interindividual scatter in correlations that fit this data. To perform this study, computed tomography (CT) images of nine children were taken during inhalation at a constant flow rate delivered by an AKITA® inhalation system. After segmenting the oral airways from the CT scan images, rapid prototyping technology was employed to fabricate plastic replicas of the airways. Deposition was then measured by comparing the number concentration of jojoba oil particles, generated by a six-jet Collison atomizer, passing through the replica vs. a blank line with no replica attached. The number concentration and the size of particles in 6 size ranges in the aerodynamic size range of 0.5–5.3μm associated with the impactor stage cutpoints were measured using an electrical low pressure impactor (ELPI). Five medium to high constant breathing flow rates, ranging from 30 to 150L/min, were generated using two vacuum pumps in series. Prior to testing the children's replicas, our deposition measurements were validated using a well-characterized and commercially-available geometry, the Alberta Idealized Throat. The replicas were re-scanned with CT to ensure a high quality fabrication and to measure their dimensions. These dimensions were used to establish a non-dimensional correlation, consisting of Stokes and Reynolds numbers, to reduce the scatter in deposition. Our proposed correlation may be useful for the prediction of deposition of micrometer-sized particles in the oropharyngeal airways of children during inhalation at moderate to high constant flow rates, typical of that seen during the use of pharmaceutical aerosol inhalers.

Research of transport and deposition of aerosol in human airway replica

Growing concern about knowledge of aerosol transport in human lungs is caused by great potential of use of inhaled pharmaceuticals. Second substantial motive for the research is an effort to minimize adverse effects of particular matter emitted by traffic and industry on human health. We created model geometry of human lungs to 7th generation of branching. This model geometry was used for fabrication of two physical models. The first one is made from thin walled transparent silicone and it allows a measurement of velocity and size of aerosol particles by Phase Doppler Anemometry (PDA). The second one is fabricated by stereolithographic method and it is designed for aerosol deposition measurements. We provided a series of measurements of aerosol transport in the transparent model and we ascertained remarkable phenomena linked with lung flow. The results are presented in brief. To gather how this phenomena affects aerosol deposition in human lungs we used the second model and we developed a technique for deposition fraction and deposition efficiency assessment.

In Vivo–In VitroCorrelations: Predicting Pulmonary Drug Deposition from Pharmaceutical Aerosols

In order to answer the question "what research remains to be done?" we review the current state of the art in pharmaceutical aerosol deposition modeling and explore possible in vivo- in vitro correlations (IVIVC) linking drug deposition in the human lung to predictions made using in vitro physical airway models and in silico computer models. The use of physical replicas of portions of the respiratory tract is considered, alongside the advantages and disadvantages of the different imaging methods used to obtain their dimensions. The use of airway replicas to determine drug deposition in vitro is discussed and compared with the predictions from different empirical curve fits to long-standing in vivo deposition data for monodisperse aerosols. The use of improved computational models and three-dimensional computational fluid dynamics (CFD) to predict aerosol deposition within the respiratory tract is examined. CFD's ability to predict both drug deposition from pharmaceutical aerosol sprays and powder behavior in dry powder inhalers is examined; both were highlighted as important areas for future research. Although the authors note the abilities of current in vitro and in silico methods to predict in vivo data, a number of limitations remain. These include our present inability to either image or replicate all but the most proximal airways in sufficient spatial and temporal detail to allow full capture of the fluid and aerosol mechanics in these regions. In addition, the highly complex microscale behavior of aerosols within inhalers and the respiratory tract places extreme computational demands on in silico methods. When the complexity of variations in respiratory tract geometry is associated with additional factors such as breathing pattern, age, disease state, postural position, and patient-device interaction are all considered, it is clear that further research is required before the prediction of all aspects of inhaled pharmaceutical aerosol deposition is possible.

Deposition of Inhaled Ultrafine Aerosols in Replicas of Nasal Airways of Infants

Experimentally measured deposition of ultrafine particles, ranging from 13–100 nm in diameter, in nasal airway replicas of ten infants aged 3–18 months is presented. The replicas included the face, nostrils, and nasal airways including the upper trachea. A differential mobility analyzer (DMA) and a condensation particle counter (CPC) were used to quantify the nasal deposition by comparing the number of polydisperse sodium chloride particles, generated by evaporation from a Collison atomizer, at the inlet and outlet of the replicas. Particles were individually classified in size by DMA and subsequently were counted one size bin at a time by CPC upstream and downstream of each replica. Since in vivo data is not available for infants to compare to, we validated our experimental procedure instead by comparing deposition in nasal airway replicas of six adults with in vivo measurements reported in literature. In the infant replicas, tidal inhalation was simulated at two physiologically compatible flow rates and...

Deposition of micrometer-sized aerosol particles in infant nasal airway replicas

In vitro measurements of particle filtration were made for nasal geometries of 11 infants aged 3–18 months. The geometries were obtained from computed tomography (CT) scans of seven males and four female infants and replicas were built using rapid prototyping. Particles ranging in aerodynamic diameter from 0.8 to 5.3 μ m were passed through these replicas with simulated tidal breathing. Filtration was determined from particle counts upstream and downstream of the models using an electrical low pressure impactor (ELPI). Mathematical fits were constructed to predict the measured deposition based on the relevant parameters. The fractional deposition, η , is found to depend on the Reynolds number of the flow ( Re ), the particle Stokes number ( Stk ), and an airway dimension D defined as airway volume divided by airway surface area. This dependence is well captured by the formula η = 1 - ( 2.164 * 10 5 / ( 2.164 * 10 5 + ( Re 1.118 Stk 1.057 ( D / D avg ) - 2.840 ) ) ) 0.8510 . Here, D avg is the average value of the dimension D for the group studied and is equal to 1.20 mm. Re and Stk also use the dimension D as the length scale in their definitions.

Modeling airflow and particle transport/deposition in pulmonary airways

A review of research papers is presented, pertinent to computer modeling of airflow as well as nano- and micron-size particle deposition in pulmonary airway replicas. The key modeling steps are outlined, including construction of suitable airway geometries, mathematical description of the air-particle transport phenomena and computer simulation of micron and nanoparticle depositions. Specifically, diffusion-dominated nanomaterial deposits on airway surfaces much more uniformly than micron particles of the same material. This may imply different toxicity effects. Due to impaction and secondary flows, micron particles tend to accumulate around the carinal ridges and to form "hot spots", i.e., locally high concentrations which may lead to tumor developments. Inhaled particles in the size range of 20nm< or =dp< or =3microm may readily reach the deeper lung region. Concerning inhaled therapeutic particles, optimal parameters for mechanical drug-aerosol targeting of predetermined lung areas can be computed, given representative pulmonary airways.