Modelling Drug Delivery to the Small Airways: Optimization Using Response Surface Methodology.

AIM: The aim of this in silico study was to investigate the effect of particle size, flow rate, and tidal volume on drug targeting to small airways in patients with mild COPD. METHOD: Design of Experiments (DoE) was used with an in silico whole lung particle deposition model for bolus administration to investigate whether controlling inhalation can improve drug delivery to the small conducting airways. The range of particle aerodynamic diameters studied was 0.4 - 10 µm for flow rates between 100 - 2000 mL/s (i.e., low to very high), and tidal volumes between 40 - 1500 mL. RESULTS: The model accurately predicted the relationship between independent variables and lung deposition, as confirmed by comparison with published experimental data. It was found that large particles (~ 5 µm) require very low flow rate (~ 100 mL/s) and very small tidal volume (~ 110 mL) to target small conducting airways, whereas fine particles (~ 2 µm) achieve drug targeting in the region at a relatively higher flow rate (~ 500 mL/s) and similar tidal volume (~ 110 mL). CONCLUSION: The simulation results indicated that controlling tidal volume and flow rate can achieve targeted delivery to the small airways (i.e., > 50% of emitted dose was predicted to deposit in the small airways), and the optimal parameters depend on the particle size. It is hoped that this finding could provide a means of improving drug targeting to the small conducting airways and improve prognosis in COPD management.

Development of an effective two-equation turbulence modeling approach for simulating aerosol deposition across a range of turbulence levels.

Pharmaceutical aerosol systems present a significant challenge to computational fluid dynamics (CFD) modeling based on the need to capture multiple levels of turbulence, frequent transition between laminar and turbulent flows, anisotropic turbulent particle dispersion, and near-wall particle transport phenomena often within geometrically complex systems over multiple time scales. Two-equation turbulence models, such as the k-ω family of approximations, offer a computationally efficient solution approach, but are known to require the use of near-wall (NW) corrections and eddy interaction model (EIM) modifications for accurate predictions of aerosol deposition. The objective of this study was to develop an efficient and effective two-equation turbulence modeling approach that enables accurate predictions of pharmaceutical aerosol deposition across a range of turbulence levels. Key systems considered were the traditional aerosol deposition benchmark cases of a 90-degree bend (Re=6,000) and a vertical straight section of pipe (Re=10,000), as well as a highly complex case of direct-to-infant (D2I) nose-to-lung pharmaceutical aerosol delivery from an air-jet dry powder inhaler (DPI) including a patient interface and infant nasal geometry through mid-trachea (500

Comparison of microparticle transport and deposition in nasal cavity of three different age groups.

Objective: The nasal cavity effectively captures the particles present in inhaled air, thereby preventing harmful and toxic pollutants from reaching the lungs. This filtering ability of the nasal cavity can be effectively utilized for targeted nasal drug delivery applications. This study aims to understand the particle deposition patterns in three age groups: neonate, infant, and adult.Materials and methods: The CT scans are built using MIMICS 21.0, followed by CATIA V6 to generate a patient-specific airway model. Fluid flow is simulated using ANSYS FLUENT 2021 R2. Spherical monodisperse microparticles ranging from 2 to 60 µm and a density of 1100 kg/m3 are simulated at steady-state and sedentary inspiration conditions.Results: The highest nasal valve depositions for the neonate are 25% for 20 µm, for infants, 10% for 50 µm, 15% for adults, and 15% for 15 µm. At mid nasal region, deposition of 15% for 20 µm is observed for infant and 8% for neonate and adult nasal cavities at a particle size of 10 and 20 µm, respectively. The highest particle deposition at the olfactory region is about 2.7% for the adult nasal cavity for 20 µm, and it is <1% for neonate and infant nasal cavities.Discussion and conclusions: The study of preferred nasal depositions during natural sedentary breathing conditions is utilized to determine the size that allows medication particles to be targeted to specific nose regions.

Oxidative potential associated with reactive oxygen species of size-resolved particles: The important role of the specific sources.

Oxidative potential (OP) is a predictor of particulate matter (PM) toxicity. Size-resolved PM and its components that influence OP values can be generated from several sources. However, There is little research have attempted to determine the PM toxicity generated from specific sources. This paper studied the OP characterization and reactive oxygen species (ROS) formation of particles from specific sources and their effects on human health. OP associated with ROS of size-resolved particles was analyzed by using dithiothreitol (DTT) method and electron paramagnetic resonance (EPR) spectroscopy technology. And OP and ROS deposition of specific source PM were calculated for health through the Multi-path particle deposition (MPPD) model. The results evidenced that the highest water-soluble OP (OPws) from traffic sources (OPm: 104.50 nmol min-1·ug-1; OPv: 160.15 nmol min-1·m-3) and the lowest from ocean sources (OPm: 22.25 nmol⋅min-1⋅ug-1; OPv: 54.16 nmol min-1·m-3). The OPws allocation in PM from different sources all have a unimodal pattern range from 0.4 to 3.2 µm. ROS (·OH) displayed the uniform trend as PM OPws, indicating that PM< 3.2 is the major contributor to adverse health impacts for size-resolved PM because of its enhanced oxidative activity compared with PM> 3.2. Furthermore, this study predicted the DTT consumption of PM were assigned to different components. Most DTT losses are attributed to the transition metals. For specific sources, transition metals dominates DTT losses, accounting for 38%-80% of DTT losses from different sources, followed by Hulis-C, accounting for 1%-10%. MPPD model calculates that over 66% of pulmonary DTT loss comes by PM< 3.2, and over 71% of pulmonary ROS generation from PM< 3.2. Among these sources of pollution, traffic emissions are the primary contributors to reactive oxygen species (ROS) in environmental particulate matter (PM). Therefore, emphasis should be placed on controlling traffic emissions, especially in coastal areas.

An experimental study on lung deposition of inhaled 2 µm particles in relation to lung characteristics and deposition models.

BACKGROUND: The understanding of inhaled particle respiratory tract deposition is a key link to understand the health effects of particles or the efficiency for medical drug delivery via the lung. However, there are few experimental data on particle respiratory tract deposition, and the existing data deviates considerably when comparing results for particles > 1 µm. METHODS: We designed an experimental set-up to measure deposition in the respiratory tract for particles > 1 µm, more specifically 2.3 µm, with careful consideration to minimise foreseen errors. We measured the deposition in seventeen healthy adults (21-68 years). The measurements were performed at tidal breathing, during three consecutive 5-minute periods while logging breathing patterns. Pulmonary function tests were performed, including the new airspace dimension assessment (AiDA) method measuring distal lung airspace radius (rAiDA). The lung characteristics and breathing variables were used in statistical models to investigate to what extent they can explain individual variations in measured deposited particle fraction. The measured particle deposition was compared to values predicted with whole lung models. Model calculations were made for each subject using measured variables as input (e.g., breathing pattern and functional residual capacity). RESULTS: The measured fractional deposition for 2.3 µm particles was 0.60 ± 0.14, which is significantly higher than predicted by any of the models tested, ranging from 0.37 ± 0.08 to 0.53 ± 0.09. The multiple-path particle dosimetry (MPPD) model most closely predicted the measured deposition when using the new PNNL lung model. The individual variability in measured particle deposition was best explained by breathing pattern and distal airspace radius (rAiDA) at half inflation from AiDA. All models underestimated inter-subject variability even though the individual breathing pattern and functional residual capacity for each participant was used in the model. CONCLUSIONS: Whole lung models need to be tuned and improved to predict the respiratory tract particle deposition of micron-sized particles, and to capture individual variations - a variation that is known to be higher for aged and diseased lungs. Further, the results support the hypothesis that the AiDA method measures dimensions in the peripheral lung and that rAiDA, as measured by the AiDA, can be used to better understand the individual variation in the dose to healthy and diseased lungs.

In Vitro and In Silico Investigations on Drug Delivery in the Mouth-Throat Models with Handihaler®.

This work aimed to evaluate the relative inhalation parameters that affect the deposition of inhaled aerosols, including mouth-throat morphology, airflow rate, and initial condition of emitted particles. In vitro experiments were conducted using the US Pharmacopeia (USP) throat and a realistic mouth-throat (RMT) with Handihaler®. Then, in silico study of the gas-solid flow was performed by computational fluid dynamics and discrete phase method. Results indicated that aerosol deposition in RMT was higher compared to that in USP throat at an airflow rate of 30 L/min, with 33.16 ± 7.84% and 21.11 ± 7.1% lung deposition in USP throat and RMT models, respectively, which showed a better correlation with in vivo data from the literature. Increasing airflow rate resulted in better drug aerosolization, while the fine particle dose trend ascended before declining, with the peak value obtained at a flow rate of 40 L/min. Overall, the effect of geometrical variation was more significant. Additionally, in silico results demonstrated clearly that the initial conditions of the emitted particles from inhalers affected the subsequent deposition. Larger momentum possessed by the central aerosol jet entering the mouth directly led to stronger impaction, which resulted in the deposition in the front region of mouth-throat models. This study is beneficial to develop an in silico method to understand the underlying mechanisms of in vivo mouth-throat deposition.

Particulate PCDD/F size distribution and potential deposition in respiratory system from a hazardous waste thermal treatment process.

The particulate polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) of various sizes produced from the waste incinerators might have different toxicities, deposition characteristics, and potential health effects in the respiratory system, and their total toxicity equivalent (TEQ) concentration has been strictly regulated in recent years. There is a knowledge gap on the effects of air pollution control devices on particle size distributions (PSDs) of PCDD/Fs and their TEQ deposition. A hazardous waste thermal treatment plant equipped with an advanced scrubber, a cyclone demister, and activated carbon adsorption coupled with a baghouse filtration was investigated in this study. An 8-stage impactor was used to collect the particle distribution of PM10 and bounded PCDD/Fs from the gas stream at four sampling points located before and after each control unit. A "TEQDE" index is defined for the toxicity deposition of PM10-PCDD/F in the respiratory system. The advanced scrubbers significantly reduced the PM10-PCDD/F levels, especially for those with sizes ≥0.6 and ≤ 0.4 µm. Additionally, the cyclone also showed a better performance than the general dry gas treatment but had an efficiency drop with 1.5-4 µm particles. The PM10-PCDD/F loads in the final adsorption-filtration unit were eased and effectively removed the PM10-PCDD/Fs to sizes ≤0.5 or≥1.5 µm. The total TEQDE was 0.00052 ng WHO-TEQ Nm-3 and had a peak level of 0.000157 ng WHO-TEQ Nm-3 at 1.2 µm. PSDs were more sensitive to the PSDs of PM mass at high PM levels but strongly correlated with the PSDs of "PM10-PCDD/Fs/PM10" at low PM10 loads. Consequently, the advanced control system could effectively remove the PM10-PCDD/Fs and might extend the adsorption-filtration lifetime. However, the PM10-PCDD/Fs ≤ 0.4 µm had a higher TEQ deposition rate and should be further considered in emissions and ambient air quality evaluations.

Modelled lung deposition and retention of welding fume particles in occupational scenarios: a comparison to doses used in vitro.

Translating particle dose from in vitro systems to relevant human exposure remains a major challenge for the use of in vitro studies in assessing occupational hazard and risk of particle exposure. This study aimed to model the lung deposition and retention of welding fume particles following occupational scenarios and subsequently compare the lung doses to those used in vitro. We reviewed published welding fume concentrations and size distributions to identify input values simulating real-life exposure scenarios in the multiple path particle dosimetry (MPPD) model. The majority of the particles were reported to be below 0.1 µm and mass concentrations ranged between 0.05 and 45 mg/m3. Following 6-h exposure to 5 mg/m3 with a count median diameter of 50 nm, the tracheobronchial lung dose (0.89 µg/cm2) was found to exceed the in vitro cytotoxic cell dose (0.125 µg/cm2) previously assessed by us in human bronchial epithelial cells (HBEC-3kt). However, the tracheobronchial retention decreased rapidly when no exposure occurred, in contrast to the alveolar retention which builds-up over time and exceeded the in vitro cytotoxic cell dose after 1.5 working week. After 1 year, the tracheobronchial and alveolar retention was estimated to be 1.15 and 2.85 µg/cm2, respectively. Exposure to low-end aerosol concentrations resulted in alveolar retention comparable to cytotoxic in vitro dose in HBEC-3kt after 15-20 years of welding. This study demonstrates the potential of combining real-life exposure data with particle deposition modelling to improve the understanding of in vitro concentrations in the context of human occupational exposure.

Evaluation of the Polyhedral Mesh Style for Predicting Aerosol Deposition in Representative Models of the Conducting Airways.

A critical factor affecting the accuracy of Computational Fluid Dynamic (CFD) simulations and the time required to conduct them is construction of the computational mesh. This study aimed to evaluate the relatively new polyhedral mesh style for simulating aerosol deposition in the upper conducting airways compared with established meshing techniques and experimental data. Hexahedral and polyhedral mesh solutions were compared in two benchmark geometries: 1) a 90°-bend with flow characteristics similar to the extrathoracic airways of an adolescent child, and 2) a double bifurcation representing bifurcations B3-B5 in an adult. Both 4-block and 5-block hexahedral meshes were used in the 90°-bend to capture the potential of fully-structured hexahedral meshes. In the 90°-bend, polyhedral elements matched polydisperse in vitro deposition data with 20% relative error (RE; averaged across the particle sizes considered), which is an improvement on the accuracy of the 4-block hexahedral mesh (35% RE) and is similar to the accuracy of the 5-block hexahedral mesh (19% RE). In the double bifurcation, deposition fraction relative differences evaluated between polyhedral and hexahedral meshes ranged from 0.3% to 28.6% for the different particle sizes assessed, which is an order of magnitude improvement compared with previous studies that considered hexahedral vs. hybrid tetrahedral-prism meshes for the same flow field. Solution convergence time with polyhedral elements was found to be 50% to 140% higher than with hexahedral meshes of comparable size. While application dependent, the increase in simulation time observed with polyhedral meshes will likely be outweighed by the ease and convenience of polyhedral mesh construction. It was concluded that the polyhedral mesh style, with sufficient resolution especially near the walls, is an excellent alternative to the highly regarded hexahedral mesh style for predicting upper airway aerosol transport and deposition and provides a powerful new tool in the assessment of respiratory aerosol dosimetry.

Fluorescent reconstitution on deposition of PM2.5 in lung and extrapulmonary organs.

The deposition of PM2.5 (fine particulate matter in air with diameter smaller than 2.5 µm) in lungs is harmful to human health. However, real-time observation on the deposition of particles in the acinar area of the lung is still a challenge in experiments. Here, a fluorescent imaging method is developed to visualize the deposition process with a high temporal and spatial resolution. The observations reveal that the deposition pattern is nonuniform, and the maximum deposition rate in the acinar area differs significantly from the prediction of the widely used average deposition model. The method is also used to find single particles in the kidney and liver, though such particles are commonly believed to be too large to enter the extrapulmonary organs.

Role of diesel exhaust particles in the induction of allergic asthma to low doses of soybean.

INTRODUCTION: Exposure to environmental pollutants such as diesel exhaust particles (DEP) increases the risk of asthma and asthma exacerbation. However, the exact mechanisms inducing asthma to low doses of allergens remain poorly understood. The present study aimed to analyse the immunomodulatory effect of the inhalation of DEP in a mouse model exposed to non-asthmagenic doses of soybean hull extract (SHE). MATERIAL AND METHODS: BALB/c ByJ mice were randomly divided into four experimental groups. Two groups received nasal instillations of saline and the other two groups received 3 mg ml-1 SHE during 5 days per week for 3 weeks. One group in each pair also received 150 µg of DEP in the same instillations 3 days per week. SHE-specific IgE levels, oxidative stress, leukocyte pattern and optical projection tomography (OPT) imaging studies were assessed. RESULTS: Inhalation of SHE and/or DEP increased levels of H2O2 in BAL, while coexposure to SHE and DEP increased SHE-specific IgE levels in serum. Inhalation of SHE alone increased eosinophils, B cells, total and resident monocytes and decreased levels of NK cells, while inhalation of DEP increased neutrophils and decreased total monocytes. Regarding dendritic cells (DC), the inhalation of SHE and/or DEP increased the total population, while the inhalation of SHE alone increased Th2-related DCs (CD11b + Ly6C-) and decreased tolerogenic DCs (CD11b-Ly6C-). However, coexposure to SHE and DEP increased oxidative stress-sensitive DCs (CD11b-Ly6C+) and decreased Th1-related DCs (CD11b + Ly6C+). As regards macrophages, inhalation of SHE and DEP decreased total and alveolar populations. DEP deposition in lung tissue did not differ between groups. CONCLUSION: Coexposure to DEP activates the asthmatic response to low doses of soy by triggering the immune response and oxidative stress.

Heterogeneity in lobar and near-acini deposition of inhaled aerosol in the mouse lung.

Laboratory animals are often used to derive health risk from environmental exposure or to assess the therapeutic effect of a drug delivered by inhaled therapy. Knowledge of the in-situ distribution of deposited particles on airway and alveolar surfaces is essential in any assessment of these effects. A unique database including both high-resolution lung anatomy and deposition data in four strains of laboratory mice have been recently made publicly available to the research community (https://doi.org/10.25820/9arg-9w56). Using these data, we investigated the effect of particle size on the distribution of deposited particles at the lobar and near-acini level. Analysis was performed on a total of 33 mice where 3, 16 and 14 animals were exposed to 0.5µm, 1µm and 2µm particles, respectively. Ratio of normalized deposition to normalized volume was calculated for each lobe (DV lobe ). At the near-acini level, the skew and standard deviation of the frequency distribution of particle deposition were calculated. Significant deviation above 1 was found for DV ratio in the cranial lobe (DV Cranial ). DV Middle , DV Caudal and DV Accessory were all significantly <1 and lower than DV left (p<0.01). At the near-acini level, skew and standard deviation were positively correlated with particle size and the presence of hot spots (high deposition) were mainly found in the apical region of the lung. These results highlight the uneven distribution of deposited particles in the mouse lung. Thus, depending on the lung sample location, individual analysis to determine overall deposition may either underestimate or overestimate total lung burden, at least for micron-sized particles.

Regional deposition of the allergens and micro-aerosols in the healthy human nasal airways.

The nasal cavity is the inlet to the human respiratory system and is responsible for the olfactory sensation, filtering pollutant particulate matter, and humidifying the air. Many research studies have been performed to numerically predict allergens, contaminants, and/or drug particle deposition in the human nasal cavity; however, the majority of these investigations studied only one or a small number of nasal passages. In the present study, a series of Computed Tomography (CT) scan images of the nasal cavities from ten healthy subjects were collected and used to reconstruct accurate 3D models. All models were divided into twelve anatomical regions in order to study the transport and deposition features of different regions of the nasal cavity with specific functions. The flow field and micro-particle transport equations were solved, and the total and regional particle deposition fractions were evaluated for the rest and low activity breathing conditions. The results show that there are large variations among different subjects. The standard deviation of the total deposition fraction in the nasal cavities was the highest for 5 × 10 4

Advances and limitations in the determination and assessment of gunshot residue in the environment.

Gunshot residue (GSR) stemming from the discharge of firearms has been essential to advancements in the field of forensic science however the human and environmental health impacts from GSR are far less researched. GSR represents a multifaceted concern: it contains a complex mixture of inorganic and organic components and produces airborne particles with variable sizes, depositions, and fates. Herein we evaluate studies in the literature examining GSR collection, deposition, composition, environmental contamination, and potential remediation techniques within the last two decades (2000 - 2020). Throughout we reflect upon key findings and weaknesses in relation to environmental characterization of GSR and associated firearm contaminants. Research focused on techniques to analyze both inorganic and organic GSR simultaneously has begun, but requires additional effort. A vast majority of the available environmental characterization literature focuses on soil contamination at outdoor firing ranges for a select number of elements (Cu, Pb, Sb) with comparisons between ranges or at different collection distances and depths. There is limited ability for between study comparisons due to collection and analysis differences as well as a lack of background soil sampling. Notably, these studies lack direct quantification of the contribution of contaminants from GSR as well as analysis of organic compounds. Currently, there is a need for air monitoring to determine the composition, deposition, and fate of GSR, particularly in outdoor settings. This review summarizes the collection, characterization, and environmental studies related to GSR and highlights areas of research needed to establish the environmental health impacts.

Transport and deposition of hygroscopic particles in asthmatic subjects with and without airway narrowing.

This study numerically investigates the effect of hygroscopicity on transport and deposition of particles in severe asthmatic lungs with distinct airway structures. The study human subjects were selected from two imaging-based severe asthmatic clusters with one characterized by non-constricted airways and the other by constricted airways in the lower left lobe (LLL). We compared the deposition fractions of sodium chloride (NaCl) particles with a range of aerodynamic diameters (1-8 µm) in cluster archetypes under conditions with and without hygroscopic growth. The temperature and water vapor distributions in the airways were simulated with an airway wall boundary condition that accounts for variable temperature and water vapor evaporation at the interface between the lumen and the airway surface liquid layer. On average, the deposition fraction increased by about 6% due to hygroscopic particle growth in the cluster subjects with constricted airways, while it increased by only about 0.5% in those with non-constricted airways. The effect of particle growth was most significant for particles with an initial diameter of 2 µm in the cluster subjects with constricted airways. The effect diminished with increasing particle size, especially for particles with an initial diameter larger than 4 µm. This suggests the necessity to differentiate asthmatic subjects by cluster in engineering the aerosol size for tailored treatment. Specifically, the treatment of severe asthmatic subjects who have constricted airways with inhalation aerosols may need submicron-sized hygroscopic particles to compensate for particle growth, if one targets for delivering to the peripheral region. These results could potentially inform the choice of particle size for inhalational drug delivery in a cluster-specific manner.

The effect of oral and nasal breathing on the deposition of inhaled particles in upper and tracheobronchial airways.

The inhalation route has a substantial influence on the fate of inhaled particles. An outbreak of infectious diseases such as COVID-19, influenza or tuberculosis depends on the site of deposition of the inhaled pathogens. But the knowledge of respiratory deposition is important also for occupational safety or targeted delivery of inhaled pharmaceuticals. Simulations utilizing computational fluid dynamics are becoming available to a wide spectrum of users and they can undoubtedly bring detailed predictions of regional deposition of particles. However, if those simulations are to be trusted, they must be validated by experimental data. This article presents simulations and experiments performed on a geometry of airways which is available to other users and thus those results can be used for intercomparison between different research groups. In particular, three hypotheses were tested. First: Oral breathing and combined breathing are equivalent in terms of particle deposition in TB airways, as the pressure resistance of the nasal cavity is so high that the inhaled aerosol flows mostly through the oral cavity in both cases. Second: The influence of the inhalation route (nasal, oral or combined) on the regional distribution of the deposited particles downstream of the trachea is negligible. Third: Simulations can accurately and credibly predict deposition hotspots. The maximum spatial resolution of predicted deposition achievable by current methods was searched for. The simulations were performed using large-eddy simulation, the flow measurements were done by laser Doppler anemometry and the deposition has been measured by positron emission tomography in a realistic replica of human airways. Limitations and sources of uncertainties of the experimental methods were identified. The results confirmed that the high-pressure resistance of the nasal cavity leads to practically identical velocity profiles, even above the glottis for the mouth, and combined mouth and nose breathing. The distribution of deposited particles downstream of the trachea was not influenced by the inhalation route. The carina of the first bifurcation was not among the main deposition hotspots regardless of the inhalation route or flow rate. On the other hand, the deposition hotspots were identified by both CFD and experiments in the second bifurcation in both lungs, and to a lesser extent also in both the third bifurcations in the left lung.

A numerical study of the effect of breathing mode and exposure conditions on the particle inhalation and deposition.

OBJECTIVE: The exposure to airborne particles are of great concern in public health. The present study was aimed to clarify the effects of the breathing mode (nasal and oral inhalation) and exposure conditions on particle inhalation and deposition in human airway. METHODS: A scanned upper airway embedded body model in an extended computational domain was constructed to perform numerical investigation into the inhalation and deposition of airborne particles. RESULTS: It was clarified that the inhalation of sub-micro and micro particles was of high efficiency and insensitive to the breathing mode, while super microparticles were much less inhalable, in particular under the nasal intake. Moreover, the relative variation of environmental wind speed and direction could significantly reshape the breathing zone as well as modify the critical inhalable area at far upstream. In addition, the breathing mode was found to be affective on the regional deposition of the microparticles, and increasing the proportion of nasal inhalation flowrate slightly enhanced the total deposition in the upper airway model. CONCLUSION: The breathing mode and exposure conditions significantly influence the particle inhalability and deposition pattern in human airway, which should be considered in the evaluation of health risk associated with airborne particle exposure.

Computational investigation of dust mite allergens in a realistic human nasal cavity.

Aim: Inhaled allergens from house dust mite (HDM) are a major source of allergic disease such as allergic rhinitis and asthma. It has been a challenge to properly evaluate health risks caused by HDM related allergens including mite bodies, eggs and fecal pellets. This paper presents a numerical study on particle deposition of dust mite allergens in a human nasal cavity. Materials and methods: A realistic nasal cavity model was reconstructed from CT scans and a Computational Fluid Dynamics analysis of steady airflow was simulated. The discrete phase model was used to trace particle trajectories of three dust mite related particles. Results: The flow and particle model were validated by comparing with nasal resistance measurement and previous literature respectively. Aerodynamic characteristics and deposition of dust mite allergens in the nasal cavity were analyzed under different breathing conditions including rest and exercising conditions. Conclusions: The numerical results revealed the roles of different nasal cavity regions in filtering various types of dust mite allergens with consideration of breathing conditions.

Detailed deposition analysis of inertial and diffusive particles in a rat nasal passage.

Rats have been widely used as surrogates for evaluating the health effects of inhaled airborne particulate matter. To provide a thorough understanding of particle transport and deposition mechanisms in the rat nasal airway, this article presents a computational fluid dynamics (CFD) study of particle exposure in a realistic rat nasal passage under a resting flow condition. Particles covering a diameter range from 1 nm to 4 µm were passively released in front of the rat's breathing zone, and the Lagrangian particle tracking approach was used to calculate individual particle trajectories. Detailed particle deposition analysis shows the deposition of inertial particles >2 µm is high in the rat nasal vestibule and more than 70% of all inhaled inertial particles were trapped in this region. While for diffusive nanoparticles, the vestibule filtration effect is reduced, only less than 60% of inhaled nanoparticles were blocked by the anterior nasal structures. The particle exposure in the olfactory region only shows notable deposition for diffusive nanoparticles, which peaks at 9.4% for 5 nm particles. Despite the olfactory deposition remains at a low level, the ratio between the olfactory and the main passage is kept around 30-40% for 10-800 nm particles, which indicates a particle-size-independent distribution pattern in the main nasal passage and olfactory. This study provides a deep understanding of particles deposition features in a rat nasal passage, and the research findings can aid toxicologist in inter-species exposure-response extrapolation study.

Numerical Comparison of Nasal Aerosol Administration Systems for Efficient Nose-to-Brain Drug Delivery.

PURPOSE: Nose-to-brain drug administration along the olfactory and trigeminal nerve pathways offers an alternative route for the treatment of central nervous system (CNS) disorders. The characterization of particle deposition remains difficult to achieve in experiments. Alternative numerical approach is applied to identify suitable aerosol particle size with maximized inhaled doses. METHODS: This study numerically compared the drug delivery efficiency in a realistic human nasal cavity between two aerosol drug administration systems targeting the olfactory region: the aerosol mask system and the breath-powered bi-directional system. Steady inhalation and exhalation flow rates were applied to both delivery systems. The discrete phase particle tracking method was employed to capture the aerosol drug transport and deposition behaviours in the nasal cavity. Both overall and regional deposition characteristics were analysed in detail. RESULTS: The results demonstrated the breath-powered drug delivery approach can produce superior olfactory deposition with peaking olfactory deposition fractions for diffusive 1 nm particles and inertial 10 µm. While for particles in the range of 10 nm to 2 µm, no significant olfactory deposition can be found, indicating the therapeutic agents should avoid this size range when targeting the olfactory deposition. CONCLUSIONS: The breath-powered bi-directional aerosol delivery approach shows better drug delivery performance globally and locally, and improved drug administration doses can be achieved in targeted olfactory region.