Detailed flow patterns in the nasal cavity.

The human nasal cavity filters and conditions inspired air while providing olfactory function. Detailed experimental study of nasal airflow patterns has been limited because of the complex geometry of the nasal cavity. In this work, particle image velocimetry was used to determine two-dimensional instantaneous velocity vector fields in parallel planes throughout a model of the nasal cavity that was subjected to a nonoscillatory flow rate of 125 ml/s. The model, which was fabricated from 26 computed tomography scans by using rapid prototyping techniques, is a scaled replica of a human right nasal cavity. The resulting vector plots show that the flow is laminar and regions of highest velocity are in the nasal valve and in the inferior airway. The relatively low flow in the olfactory region appears to protect the olfactory bulb from particulate pollutants. Low flows were also observed in the nasal meatuses, whose primary function has been the subject of debate. Comparison of sequentially recorded data suggests a steady flow.     

Large eddy simulation of the unsteady flow-field in an idealized human mouth-throat configuration

The present study concerns the simulation and analysis of the flow field in the upper human respiratory system in order to gain an improved understanding of the complex flow field with respect to the process affecting drug delivery for medical treatment of the human air system. For this purpose, large eddy simulation (LES) is chosen because of its powerful performance in the transitional range of laminar and turbulent flow fields. The average gas velocity in a constricted tube is compared with experimental data (Ahmed and Giddens, 1983) and numerical data from Reynolds-averaged Navier-Stokes (RANS) equations coupled with low Reynolds number (LRN) κ-ω model (Zhang and Kleinstreuer, 2003) and LRN shear-stress transport κ-ω model (Jayaraju et al., 2007), for model validation. The present study emphasizes on the instantaneous flow field, where the simulations capture different scales of secondary vortices in different flow zones including recirculation zones, the laryngeal jet zone, the mixing zone, and the wall shear layer. It is observed that the laryngeal jet tail breaks up, and the unsteady motion of laryngeal jet is coupled with the unsteady distribution of secondary vortices in the jet boundary. The present results show that it is essential to study the unsteady flow field since it strongly affects the particle flow in the human upper respiratory system associated with drug delivery for medical treatment.     

Optimization of magnetophoretic-guided drug delivery to the olfactory region in a human nose model

Magnetophoretic-guided delivery has been shown to be able to improve the olfactory doses. However, due to the complex nasal structure and quick decay of magnetic intensity, precise control of particle motion in the human nose remains a challenge. In this study, an optimization model was developed for magnetophoretic olfactory delivery systems. The performance of the model was evaluated using a baseline device design in an MRI-based human nose geometry. Three key components of the delivery system were examined, which included the particle release position, the front magnet to minimize nasal valve depositions, and the top magnet to attract particles into the olfactory region. Results show that the magnetophoretic olfactory delivery device can be significantly improved by optimizing the product and operational parameters. The olfactory delivery efficiency was increased by 1.5-fold compared to the baseline design. The top magnet height and strength were shown to be the most influential factor in olfactory delivery, followed by the drug release position and the front magnet strength. The optimization framework developed in this study can be easily adapted for the optimization of intranasal drug delivery to other regions such as paranasal sinuses.     

Numerical modeling of odorant uptake in the rat nasal cavity

An anatomically accurate 3-dimensional numerical model of the right rat nasal cavity was developed and used to compute low, medium, and high flow rate inspiratory and expiratory mucosal odorant uptake (imposed patterning) for 3 odorants with different mucus solubilities. The computed surface mass flux distributions were compared with anatomic receptor gene expression zones identified in the literature. In general, simulations predicted that odorants that were highly soluble in mucus were absorbed dorsally and medially, corresponding roughly to receptors from one of the gene expression zones. Insoluble odorants tended to be absorbed more peripherally in the rat olfactory region corresponding to the other 2 zones. These findings also agreed in general with the electroolfactogram measurements and the voltage-sensitive dye measurements reported in the literature. This numerical approach is the first to predict detailed odorant flux information across the olfactory mucosa in the rat nasal cavity during inspiratory and expiratory flow and to relate it to anatomic olfactory receptor location, physiological function, and biochemical experiment. This numerical technique can allow us to separate the contributions of imposed and inherent patterning mechanisms on the rat olfactory mucosa.     

Nasal insulin gel as an alternate to parenteral insulin: Formulation,preclinical, and clinical studies

The objective of the present study was to formulate insulin gel for intranasal administration and to evaluate with respect to in vitro release studies and hypoglycemic activity in animal model and healthy human volunteers. The insulin gel was formulated using the combination of carbopol and hydroxypropyl methylcellulose as gelling agent. The in vivo efficacy of insulin gel administered intranasally was assessed by measuring the blood glucose levels and serum insulin levels at specified time intervals in rats and humans. The use of bioadhesive nasal gel containing insulin not only promoted the prolonged contact between the drug and the absorptive sites in the nasal cavity but also facilitated direct absorption of medicament through the nasal mucosa. Absorption of the drug through the nasal mucosa was high in the first 0.5 to 1.5 hours of the study with a sharp decline in blood sugar and rise in insulin values corresponding to that decline in blood sugar. This study further demonstrates that administration of insulin intranasally in gel form is a pleasant and painless alternative to injectable insulin. Published: September 30, 2005.     

The effect of inlet flow profile and nozzle diameter on drug delivery to the maxillary sinus

In this paper, the effect of the turbulence and swirling of the inlet flow and the diameter of the nozzle on the flow characteristics and the particles' transport/deposition patterns in a realistic combination of the nasal cavity (NC) and the maxillary sinus (MS) were examined. A computational fluid dynamics (CFD) model was developed in ANSYS® Fluent using a hybrid Reynolds averaged Navier–Stokes–large-eddy simulation algorithm. For the validation of the CFD model, the pressure distribution in the NC was compared with the experimental data available in the literature. An Eulerian–Lagrangian approach was employed for the prediction of the particle trajectories using a discrete phase model. Different inlet flow conditions were investigated, with turbulence intensities of 0.15 and 0.3, and swirl numbers of 0.6 and 0.9 applied to the inlet flow at a flow rate of 7 L/min. Monodispersed particles with a diameter of 5 µm were released into the nostril for various nozzle diameters. The results demonstrate that the nasal valve plays a key role in nasal resistance, which damps the turbulence and swirl intensities of the inlet flow. Moreover, it was found that the effect of turbulence at the inlet of the NC on drug delivery to the MS is negligible. It was also demonstrated that increasing the flow swirl at the inlet and decreasing the nozzle diameter improves the total particle deposition more than threefold due to the generation of the centrifugal force, which acts on the particles in the nostril and vestibule. The results also suggest that the drug delivery efficiency to the MS can be increased by using a swirling flow with a moderate swirl number of 0.6. It was found that decreasing the nozzle diameter can increase drug delivery to the proximity of the ostium in the middle meatus by more than 45%, which subsequently increases the drug delivery to the MS. The results can help engineers design a nebulizer to improve the efficiency of drug delivery to the maxillary sinuses.

     

Modeling inspiratory and expiratory steady-state velocity fields in the Sprague-Dawley rat nasal cavity

Distribution patterns of odorant molecules in the rat nasal olfactory region depend in large part on the detailed airflow patterns in the nasal cavity, which in turn depend on the anatomical structure. To investigate these flow patterns, we constructed an anatomically accurate finite element model of the right nasal cavity of the Sprague-Dawley rat based on horizontal (anterior-posterior) nasal cast cross sections. By numerically solving the fluid mechanical momentum and continuity equations using the finite element method, we studied the flow distribution and the complete velocity field for both inspiration and expiration throughout the nasal cavity under physiological flow rates of resting breathing and sniffing. Detailed velocity profiles, volumetric flow distributions, and streamline patterns for quasi-steady airflow are presented. S-shaped streamlines passing through the olfactory region are found to be less prevalent during expiratory than inspiratory flow leading to trapping and an increase in odorant molecule retention in the olfactory region during sniffing. The rat nasal velocity calculations will be used to study the distribution of odorant uptake onto the rat olfactory mucosa and compare it with the known anatomic location of some types of rat olfactory receptors.     

Experimental study of physiological pulsatile flow past valve prostheses in a model of human aorta--I. Caged ball valves

Pulsatile flow development past a caged ball valve in a model human aorta was studied using laser Doppler anemometry. Velocity profiles measured in the ascending aorta and in the mid-arch region were strongly influenced by the geometry of the valve at the root of the aorta. Velocity profiles distal to the valve were asymmetric with jet-like flow in the peripheral region having larger velocity magnitudes towards the left lateral wall. In early diastole, a streamwise vortex motion was observed throughout the model aorta with fluid moving towards the downstream direction along the left lateral wall and reversed flow along the right lateral wall. With the caged ball valve at the root of the aorta, no reversed flow was observed along the inner wall of curvature in the mid-arch region.     

Hydrolysis of leucine enkephalin in the nasal cavity of the rat--a possible factor in the low bioavailability of nasally administered peptides

In order to investigate the utility of intranasal administration of peptides for systemic medication, the nasal absorption of the model peptide, leucine enkephalin (Tyr-Gly-Gly-Phe-Leu), was studied in the rat. At a concentration of 60 micrograms/ml in Ringer's buffer the pentapeptide was found to undergo, extensive hydrolysis in the nasal cavity. The hydrolysis rather than the polarity of the pentapeptide appears responsible for limiting the nasal absorption of this model compound. In the presence of dipeptides, the hydrolysis of leucine enkephalin was significantly inhibited. These results suggest that the nasal administration of peptides may become an important route for drug administration provided that the peptidases in the nasal mucosa can be transiently inhibited via coadministration of pharmacologically inactive peptidase substrates.     

A numerical study of muco-ciliary transport under the condition of diseased cilia

Structural and functional disorders of pulmonary cilia may result from genetic disorders and acquired insults. A two-dimensional numerical model based on the immersed boundary method coupled with the projection method is used to study the flow physics of muco-ciliary transport of the human respiratory tract under various abnormalities of cilia. The effects of the cilia beat pattern (CBP), ciliary length, immotile cilia, beating amplitude and uncoordinated beating of cilia are investigated. As expected, the mucus velocity decreases as the beating amplitude reduces. The windscreen wiper motion and rigid planar motion, which are two abnormal CBPs owing to genetic disorders, greatly reduce or almost stop the mucus transport. If the ciliary length varies from its standard length, the mucus velocity would decrease. The mucus velocity decreases rather linearly if the number of uniformly distributed immotile cilia increases. The numerical results show that the mucus velocity would be further reduced marginally when the uniformly distributed immotile cilia are rearranged as a cluster of immotile cilia. Furthermore, if half of the cilia are immotile and uniformly distributed and motile cilia beat at reduced amplitude, the incoordination between the active motile cilia would not significantly affect the mucus velocity.     

Effect of intranasal arginine vasopressin on human headache

Arginine vasopressin (AVP), a nonapeptide hormone of posterior pituitary, reaches the central nervous system from systemic blood circulation with a difficulty because of the blood–brain barrier (BBB). The interest has been expressed in the use of the nasal route for delivery of AVP to the brain directly, exploiting the olfactory pathway. Our previous study has demonstrated that AVP in the brain rather than the spinal cord and blood circulation plays an important role in rat pain modulation. For understanding the role of AVP on pain modulation in human, the communication tried to investigate the effect of intranasal AVP on human headache. The results showed that (1) AVP concentration in both plasma and cerebrospinal fluid (CSF) increased significantly in headache patients, who related with the headache level; (2) there was a positive relationship between plasma and CSF AVP concentration in headache patients; and (3) intranasal AVP could relieve the human headache in a dose-dependent manner. The data suggested that intranasal AVP, which was delivered to the brain through olfactory region, could treat human headache and AVP might be a potential drug of pain relief by intranasal administration.     

Functional nasal morphology of chimaerid fishes

Holocephalans (chimaeras) are a group of marine fishes comprising three families: the Callorhinchidae (callorhinchid fishes), the Rhinochimaeridae (rhinochimaerid fishes) and the Chimaeridae (chimaerid fishes). We have used X‐ray microcomputed tomography and magnetic resonance imaging to characterise in detail the nasal anatomy of three species of chimaerid fishes: Chimaera monstrosa, C. phantasma and Hydrolagus colliei. We have shown that the nasal chamber of these three species is linked to the external environment by an incurrent channel and to the oral cavity by an excurrent channel via an oral groove. A protrusion of variable morphology is present on the medial wall of the incurrent channel in all three species, but is absent in members of the two other holocephalan families that we inspected. A third nasal channel, the lateral channel, functionally connects the incurrent nostril to the oral cavity, by‐passing the nasal chamber. From anatomical reconstructions, we have proposed a model for the circulation of water, and therefore the transport of odorant, in the chimaerid nasal region. In this model, water could flow through the nasal region via the nasal chamber or the lateral channel. In either case, the direction of flow could be reversed. Circulation through the entire nasal region is likely to be driven primarily by the respiratory pump. We have identified several anatomical features that may segregate, distribute, facilitate and regulate flow in the nasal region and have considered the consequences of flow reversal. The non‐sensory cilia lining the olfactory sensory channels appear to be mucus‐propelling, suggesting that these cilia have a common protective role in cartilaginous fishes (sharks, rays and chimaeras). The nasal region of chimaerid fishes shows at least two adaptations to a benthic lifestyle, and suggests good olfactory sensitivity, with secondary folding enhancing the hypothetical flat sensory surface area by up to 70%. J. Morphol. 274:987–1009, 2013. © 2013 Wiley Periodicals, Inc.     

Pulmonary drug delivery and retention: A computational study to identify plausible parameters based on a coupled airway-mucus flow model

Pulmonary drug delivery systems rely on inhalation of drug-laden aerosols produced from aerosol generators such as inhalers, nebulizers etc. On deposition, the drug molecules diffuse in the mucus layer and are also subjected to mucociliary advection which transports the drugs away from the initial deposition site. The availability of the drug at a particular region of the lung is, thus, determined by a balance between these two phenomena. A mathematical analysis of drug deposition and retention in the lungs is developed through a coupled mathematical model of aerosol transport in air as well as drug molecule transport in the mucus layer. The mathematical model is solved computationally to identify suitable conditions for the transport of drug-laden aerosols to the deep lungs. This study identifies the conditions conducive for delivering drugs to the deep lungs which is crucial for achieving systemic drug delivery. The effect of different parameters on drug retention is also characterized for various regions of the lungs, which is important in determining the availability of the inhaled drugs at a target location. Our analysis confirms that drug delivery efficacy remains highest for aerosols in the size range of 1-5 μm. Moreover, it is observed that amount of drugs deposited in the deep lung increases by a factor of 2 when the breathing time period is doubled, with respect to normal breathing, suggesting breath control as a means to increase the efficacy of drug delivery to the deep lung. A higher efficacy also reduces the drug load required to be inhaled to produce the same health effects and hence, can help in minimizing the side effects of a drug.     

Atrophic rhinitis: a CFD study of air conditioning in the nasal cavity.

Atrophic rhinitis is a chronic disease of the nasal mucosa. The disease is characterized by abnormally wide nasal cavities, and its main symptoms are dryness, crusting, atrophy, fetor, and a paradoxical sensation of nasal congestion. The etiology of the disease remains unknown. Here, we propose that excessive evaporation of the mucous layer is the basis for the relentless nature of this disease. Airflow and water and heat transport were simulated using computational fluid dynamics (CFD) techniques. The nasal geometry of an atrophic rhinitis patient was acquired from computed tomography scans before and after a procedure to narrow the nasal cavity. Simulations of air conditioning in the atrophic nose were compared with similar computations performed within the nasal geometries of four healthy humans. The excessively wide cavity of the patient generated abnormal flow patterns, which led to abnormal patterns of water fluxes across the wall. Geometrically, the atrophic nose had a much lower surface area than the healthy nasal passages, which increased water fluxes per unit area. Nevertheless, the simulations indicated that the atrophic nose did not condition inspired air as effectively as the healthy geometries. These simulations of water transport in the nasal cavity are consistent with the hypothesis that excessive evaporation of mucus plays a key role in the pathophysiology of atrophic rhinitis. We conclude that the main goals of a surgery to treat atrophic rhinitis should be 1) to restore the original surface area of the nose, 2) to restore the physiological airflow distribution, and 3) to create symmetric cavities.     

Computational model of particle deposition in the nasal cavity under steady and dynamic flow

A computational model for flow and particle deposition in a three-dimensional representation of the human nasal cavity is developed. Simulations of steady state and dynamic airflow during inhalation are performed at flow rates of 9–60 l/min. Depositions for particles of size 0.5–20 μm are determined and compared with experimental and simulation results from the literature in terms of deposition efficiencies. The nasal model is validated by comparison with experimental and simulation results from the literature for particle deposition under steady-state flow. The distribution of deposited particles in the nasal cavity is presented in terms of an axial deposition distribution as well as a bivariate axial deposition and particle size distribution. Simulations of dynamic airflow and particle deposition during an inhalation cycle are performed for different nasal cavity outlet pressure variations and different particle injections. The total particle deposition efficiency under dynamic flow is found to depend strongly on the dynamics of airflow as well as the type of particle injection.     

Numerical modelling of nanoparticle deposition in the nasal cavity and the tracheobronchial airway

Recent advances in nanotechnology have seen the manufacture of engineered nanoparticles for many commercial and medical applications such as targeted drug delivery and gene therapy. Transport of nanoparticles is mainly attributed to the Brownian force which increases as the nanoparticle decreases to 1 nm. This paper first verifies a Lagrangian Brownian model found in the commercial computational fluid dynamics software Fluent before applying the model to the nasal cavity and the tracheobronchial (TB) airway tree with a focus on drug delivery. The average radial dispersion of the nanoparticles was 9x greater for the user-defined function model over the Fluent in-built model. Deposition in the nasal cavity was high for very small nanoparticles. The particle diameter range in which the deposition drops from 80 to 18% is between 1 and 10 nm. From 10 to 150 nm, however, there is only a small change in the deposition curve from 18 to 15%. A similar deposition curve profile was found for the TB airway.     

Induction of olfactory mucosal and liver metabolism of lidocaine by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Formulation of drugs for administration via the nasal cavity is becoming increasingly common. It is of potential clinical relevance to determine whether intranasal drug administration itself, or exposure to other xenobiotics, can modulate the levels and/or activity of nasal mucosal metabolic enzymes, thereby affecting the metabolism and disposition of the drug. In these studies, we examined changes in several of the major metabolic enzymes in nasal epithelial tissues upon exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), as well as the impact of these changes on the metabolism of a model intranasally administered drug, lidocaine. Results of these studies show that TCDD can induce multiple metabolic enzymes in the olfactory mucosa and that the pattern of induction in the olfactory mucosa does not necessarily parallel that which occurs in the liver. Further, increases in enzyme levels noted by Western blot analysis were associated with increased activities of several nasal mucosal enzymes as well as with enhanced conversion of lidocaine to its major metabolite, monoethyl glycine xylidide (MEGX). These results demonstrate that environmental exposures can influence the levels and activity of nasal mucosal enzymes and impact the pharmacology of drugs administered via the nasal route.     

Numerical modelling of nanoparticle deposition in the nasal cavity and the tracheobronchial airway

Recent advances in nanotechnology have seen the manufacture of engineered nanoparticles for many commercial and medical applications such as targeted drug delivery and gene therapy. Transport of nanoparticles is mainly attributed to the Brownian force which increases as the nanoparticle decreases to 1 nm. This paper first verifies a Lagrangian Brownian model found in the commercial computational fluid dynamics software Fluent before applying the model to the nasal cavity and the tracheobronchial (TB) airway tree with a focus on drug delivery. The average radial dispersion of the nanoparticles was 9x greater for the user-defined function model over the Fluent in-built model. Deposition in the nasal cavity was high for very small nanoparticles. The particle diameter range in which the deposition drops from 80 to 18% is between 1 and 10 nm. From 10 to 150 nm, however, there is only a small change in the deposition curve from 18 to 15%. A similar deposition curve profile was found for the TB airway.     

Numerical Simulation of Airway Dimension Effects on Airflow Patterns and Odorant Deposition Patterns in the Rat Nasal Cavity

The sense of smell is largely dependent on the airflow and odorant transport in the nasal cavity, which in turn depends on the anatomical structure of the nose. In order to evaluate the effect of airway dimension on rat nasal airflow patterns and odorant deposition patterns, we constructed two 3-dimensional, anatomically accurate models of the left nasal cavity of a Sprague-Dawley rat: one was based on high-resolution MRI images with relatively narrow airways and the other was based on artificially-widening airways of the MRI images by referencing the section images with relatively wide airways. Airflow and odorant transport, in the two models, were determined using the method of computational fluid dynamics with finite volume method. The results demonstrated that an increase of 34 µm in nasal airway dimension significantly decreased the average velocity in the whole nasal cavity by about 10% and in the olfactory region by about 12% and increased the volumetric flow into the olfactory region by about 3%. Odorant deposition was affected to a larger extent, especially in the olfactory region, where the maximum odorant deposition difference reached one order of magnitude. The results suggest that a more accurate nasal cavity model is necessary in order to more precisely study the olfactory function of the nose when using the rat.     

Characteristics of Nasal-Associated Lymphoid Tissue (NALT) and Nasal Absorption Capacity in Chicken

As the main mucosal immune inductive site of nasal cavity, nasal-associated lymphoid tissue (NALT) plays an important role in both antigen recognition and immune activation after intranasal immunization. However, the efficiency of intranasal vaccines is commonly restricted by the insufficient intake of antigen by the nasal mucosa, resulting from the nasal mucosal barrier and the nasal mucociliary clearance. The distribution of NALT and the characteristic of nasal cavity have already been described in humans and many laboratory rodents, while data about poultry are scarce. For this purpose, histological sections of the chicken nasal cavities were used to examine the anatomical structure and histological characteristics of nasal cavity. Besides, the absorptive capacity of chicken nasal mucosa was also studied using the materials with different particle size. Results showed that the NALT of chicken was located on the bottom of nasal septum and both sides of choanal cleft, which mainly consisted of second lymphoid follicle. A large number of lymphocytes were distributed under the mucosal epithelium of inferior nasal meatus. In addition, there were also diffuse lymphoid tissues located under the epithelium of the concha nasalis media and the walls of nasal cavity. The results of absorption experiment showed that the chicken nasal mucosa was capable to absorb trypan blue, OVA, and fluorescent latex particles. Inactivated avian influenza virus (IAIV) could be taken up by chicken nasal mucosa except for the stratified squamous epithelium sites located on the forepart of nasal cavity. The intake of IAIV by NALT was greater than that of the nasal mucosa covering on non-lymphoid tissue, which could be further enhanced after intranasal inoculation combined with sodium cholate or CpG DNA. The study on NALT and nasal absorptive capacity will be benefit for further understanding of immune mechanisms after nasal vaccination and development of nasal vaccines for poultry.