Julia S. Kimbell

COMPUTATIONAL FLUID DYNAMICS SIMULATIONS OF INSPIRATORY AIRFLOW IN THE HUMAN NOSE AND NASOPHARYNX

Extrapolation of the regional dose of an inhaled xenobiotic from laboratory animals to humans for purposes of assessing human health risk is problematic because of large interspecies differences in nasal respiratory physiology and airway anatomy. There is a need for dosimetry models that can adjust for these differences in the upper respiratory tract. The present work extends previous efforts in this laboratory and elsewhere to simulate nasal airflow profiles numerically in laboratory animals and humans. A three-dimensional, anatomically accurate representation of an adult human nasal cavity and nasopharynx was constructed. The Navier-Stokes and continuity equations for airflow were solved using the finite-element method under steady-state, inspiratory conditions simulating rest and light exercise (steady-state inspiratory flow rates: 15 L/min and 26 L/min, respectively) with the fluid dynamics software package FIDAP. Simulated airflow was streamlined in the main nasal passages and complex in the vestibul...

Particle Deposition in Human Nasal Airway Replicas Manufactured by Different Methods. Part II: Ultrafine Particles

Information on the deposition efficiency of aerosol particles in the nasal airways is used for optimizing the delivery of therapeutic aerosols into the nose and for risk assessment of toxic airborne pollutants inhaled through the nose into the respiratory system. Nasal particle deposition is often studied using plastic replicas of nasal airways. Deposition efficiency in a nasal replica manufactured by stereolithography has not been reported to date. We determined the inertial particle deposition efficiency of two replicas of the same nasal airways manufactured by different stereolithography machines and compared results with deposition efficiencies reported for models manufactured by other techniques from the same magnetic resonance imaging scans. Deposition in the replicas was measured for particles of aerodynamic diameter between 1 and 10 μm and constant inspiratory flow rates ranging from 20–40 Ipm. Deposition efficiency of the replicas increased from nearly 0–100% with increasing particle inertia. For a range of particle inertias, particle deposition in the replica made with higher resolution stereolithography machine was slightly less than in the replica made with a lower resolution stereolithography process. These data showed lower deposition efficiency when compared with other deposition studies in nasal replicas based on the same magnetic resonance imaging data. The differences in deposition efficiency can be attributed in part to differences in methods used to manufacture the replicas. There was little or no difference in deposition due to cutting tool size, some difference due to the use of assembly plates, and some difference due to surface roughness. These associations suggest that inertial nasal particle deposition is significantly influenced by small differences in nasal airways.

Studies of inspiratory airflow patterns in the nasal passages of the F344 rat and rhesus monkey using nasal molds: Relevance to formaldehyde toxicity

For highly water soluble and reactive gases, such as formaldehyde, the reported distribution of nasal lesions in rats and rhesus monkeys following inhalation exposure may be attributable, at least in part, to regional gas uptake patterns that are a consequence of nasal airflow characteristics. Inspiratory nasal airflow was studied at flow rates across the physiologic range using a unidirectional dynamically similar water-dye siphon system in clear acrylic molds of the nasal airways of F344 rats and rhesus monkeys. In both species there were complex and inspiratory flow streams, exhibiting regions of simple laminar, complex secondary (vortices, eddies, swirling), and turbulent flows, with only minor effects of the volumetric flow rates studied on these flow patterns. There was a precise association between points of dye intake at the nostril with complex but generally coherent streaklines throughout the nose, indicating the potential for sensitive dependence of nasal airflow on nostril geometry. On the basis of these studies, a classification for the major airways (meatuses) in the nasal passages of rats and rhesus monkeys was proposed. The spiral shape of the anterior nasal airway of the rat was considered to play an important role in local mixing of inspired airstreams. In the rhesus monkey, the complex geometry of the nasal vestibule contributed to the formation of secondary flows and turbulence in the anterior nose, which represents a potentially important difference between rheusus monkeys and humans. There was a good correlation between routes of flow, regional secondary flows, turbulence, and impaction of airstreams on the airway wall, with the reported distribution of formaldehyde-induced nasal lesions in rats and rhesus monkeys. These studies support the proposal that nasal airflow patterns play an important role in the distribution of lesions induced by formaldehyde.

Nasal drug delivery

The nasal cavity has for more than three decades been widely explored as a potential alternative route to oral or parenteral administration for systemically active drugs. The nasal route has shown remarkable advantages that include a rapid and high systemic availability, avoidance of first pass metabolism by the liver, and the possibility of targeting drugs directly from the nasal cavity to the brain [1, 2]. Considerable knowhow and data have been accumulated over the years from investigational work carried out by various excellent research groups in academia and industry. New nasal delivery carriers and emerging technologies have been used for product design and efficient clinical translation to nasal medicines. The nasal route for systemic administration is attractive in many therapeutic areas where a rapid onset of action is required, e.g., pain, erectile dysfunction, frigidity, migraine, seizures, insomnia, panic attacks, Parkinson rigidity, hot flushes, emesis, Alzheimer or MS attacks, and cardiovascular events. An increasing number of small molecules are being marketed as nasal products such as Zomig® (zolmitriptan), Imitrex® (sumatriptan), and Stadol NS (butorphanol tartrate) for migraine treatment, Aerodiol® (estradiol hemihydrate) for menopausal syndrome treatment, PecFent® and Instanyl® (fentanyl) for severe pain treatment, and Nicorette® (nicotine) for smoking cessation [3]. With this growing number of applications, the US market of intranasal drug products is expected to reach US

Septal deviation and nasal resistance: an investigation using virtual surgery and computational fluid dynamics.

5.2 billion by 2017 [4]. It is noteworthy that most of the marketed products are based on molecules sufficiently lipophilic to enable therapeutic levels of the drug to reach the systemic circulation, thus requiring no nasal absorption enhancers. Despite the obvious advantages of intranasal drug delivery, the nasal cavity presents a number of limitations for drug absorption, including low intrinsic permeability for some drugs, such as hydrophilic molecules, peptides, proteins, and nucleotides, rapid mucociliary clearance, and enzymatic degradation [1, 2]. In order to achieve efficient and safe intranasal drug products, a number of strategies for overcoming nasal delivery barriers can be applied. In the design of a nasal product, three main cooperative entities should be taken in consideration: the drug, the delivery carrier, and the administration device. The factors to be considered in the design and development of an efficient nasal product, related to these three components, are schematically presented as a three-lobe fleur-de-lys in Fig. 1. Several important morphological and physiological constraints on nasal drug delivery including limited volume of administration requiring high drug potency or mucosal enzymatic drug degradation should be kept in mind when formulating new nasal products. Also, the key properties required from drug candidates for development of successful intranasal products would be potency, lipophilicity, and water solubility. The nasal delivery of hydrophilic or high molecular weight drugs would be in need of a nasal absorption promoter in order for the drug to be transported across the nasal membrane in sufficient quantity for therapeutic use. Innovative strategy approaches to design efficient nasal delivery systems for specific drugs are currently in various stages of research and development. These include new nasal enhanced delivery technologies, design of carriers that impede drug degradation by mucosal enzymes, modulation E. Touitou (*) Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel e-mail: touitou@cc.huji.ac.il

Correlation of regional formaldehyde flux predictions with the distribution of formaldehyde-induced squamous metaplasia in F344 rat nasal passages.

BACKGROUND Septal deviation is an extremely common anatomic variation in healthy adults. However, there are no standard criteria to determine when a deviated septum is clinically relevant. Presently, selection of patients for septoplasty is based on mostly clinical examination, which is prone to observer bias and may lead to unsuccessful treatment. The objective of this article is twofold. First, we investigate whether the location of a septal deviation within the nasal passages affects nasal resistance. Second, we test whether computer simulations are consistent with rhinomanometry studies in predicting that anterior septal deviations increase nasal resistance more than posterior deviations. METHODS A three-dimensional computational model of a healthy nose was created from computed tomography scans. Geometry-deforming software was used to produce models with septal deviations. Computational fluid dynamics techniques were used to simulate nasal airflow and compute nasal resistance. RESULTS Our results revealed that the posterior nasal cavity can accommodate significant septal deviations without a substantial increase in airway resistance. In contrast, a deviation in the nasal valve region more than doubled nasal resistance. These findings are in good agreement with the rhinomanometry literature and with the observation that patients with anterior septal deviations benefit the most from septoplasty. CONCLUSION In the model, anterior septal deviations increased nasal resistance more than posterior deviations. This suggests, in agreement with the literature, that other causes of nasal obstruction (dysfunction of the nasal valve, allergy, etc.) should be carefully considered in patients with posterior septal deviations because such deviations may not affect nasal resistance. This study illustrates how computational modeling and virtual manipulation of the nasal geometry are useful to investigate nasal physiology.Background Septal deviation is an extremely common anatomic variation in healthy adults. However, there are no standard criteria to determine when a deviated septum is clinically relevant. Presently, selection of patients for septoplasty is based on mostly clinical examination, which is prone to observer bias and may lead to unsuccessful treatment. The objective of this article is twofold. First, we investigate whether the location of a septal deviation within the nasal passages affects nasal resistance. Second, we test whether computer simulations are consistent with rhinomanometry studies in predicting that anterior septal deviations increase nasal resistance more than posterior deviations. Methods A three-dimensional computational model of a healthy nose was created from computed tomography scans. Geometry-deforming software was used to produce models with septal deviations. Computational fluid dynamics techniques were used to simulate nasal airflow and compute nasal resistance. Results Our results revealed that the posterior nasal cavity can accommodate significant septal deviations without a substantial increase in airway resistance. In contrast, a deviation in the nasal valve region more than doubled nasal resistance. These findings are in good agreement with the rhinomanometry literature and with the observation that patients with anterior septal deviations benefit the most from septoplasty. Conclusions In the model, anterior septal deviations increased nasal resistance more than posterior deviations. This suggests, in agreement with the literature, that other causes of nasal obstruction (dysfunction of the nasal valve, allergy, etc.) should be carefully considered in patients with posterior septal deviations because such deviations may not affect nasal resistance. This study illustrates how computational modeling and virtual manipulation of the nasal geometry are useful to investigate nasal physiology.

Application of Physiological Computational Fluid Dynamics Models to Predict Interspecies Nasal Dosimetry of Inhaled Acrolein

Squamous epithelium lines the nasal vestibule of the rat, rhesus monkey, and human. Respiratory, transitional, and olfactory epithelia line most areas posterior to the nasal vestibule. Inhaled formaldehyde gas induces squamous metaplasia posterior to the nasal vestibule and does not induce lesions in the nasal vestibule in rats and rhesus monkeys, indicating that squamous epithelium is resistant to irritant effects of formaldehyde and that squamous metaplasia may be an adaptive response. If squamous metaplasia is determined by formaldehyde dosimetry rather than by tissue-specific factors, squamous epithelium may be protective by absorbing less formaldehyde than other epithelial types. In a previous study, a three-dimensional, anatomically accurate computational fluid dynamics (CFD) model of the anterior F344 rat nasal passages was used to simulate inspiratory airflow and inhaled formaldehyde transport. The present study consisted of two related parts. First, the rat CFD model was used to test the hypothesis that the distribution of formaldehyde-induced squamous metaplasia is related to the location of high-flux regions posterior to squamous epithelium. Regional formaldehyde flux into nonsquamous epithelium predicted by the CFD model correlated with regional incidence of formaldehyde-induced squamous metaplasia on the airway perimeter of one cross-sectional level of the noses of F344 rats exposed to 10 and 15 ppm formaldehyde gas for 6 months. Formaldehyde flux into nonsquamous epithelium was estimated to vary by an order of magnitude depending on the degree of formaldehyde absorption by squamous epithelium. These results indicate that the degree to which squamous epithelium absorbs formaldehyde strongly affects the rate and extent of the progression of squamous metaplasia with continued exposure to formaldehyde. In the second part of this study, the CFD model was used to predict squamous metaplasia progression. Data needs for verification of this model prediction are considered. These results indicate that information on the permeability of squamous epithelium in rats, monkeys, and humans is important for accurate prediction of uptake in regions posterior to the nasal vestibule.

Toward personalized nasal surgery using computational fluid dynamics.

Acrolein is a highly soluble and reactive aldehyde and is a potent upper-respiratory-tract irritant. Acrolein-induced nasal lesions in rodents include olfactory epithelial atrophy and inflammation, epithelial hyperplasia, and squamous metaplasia of the respiratory epithelium. Nasal uptake of inhaled acrolein in rats is moderate to high, and depends on inspiratory flow rate, exposure duration, and concentration. In this study, anatomically accurate three-dimensional computational fluid dynamics (CFD) models were used to simulate steady-state inspiratory airflow and to quantitatively predict acrolein tissue dose in rat and human nasal passages. A multilayered epithelial structure was included in the CFD models to incorporate clearance of inhaled acrolein by diffusion, blood flow, and first-order and saturable metabolic pathways. Kinetic parameters for these pathways were initially estimated by fitting a pharmacokinetic model with a similar epithelial structure to time-averaged acrolein nasal extraction data and were then further adjusted using the CFD model. Predicted air:tissue flux from the rat nasal CFD model compared well with the distribution of acrolein-induced nasal lesions from a subchronic acrolein inhalation study. These correlations were used to estimate a tissue dose-based no-observed-adverse-effect level (NOAEL) for inhaled acrolein. A human nasal CFD model was used to extrapolate effects in laboratory animals to human exposure conditions on the basis of localized tissue dose and tissue responses. Assuming that equivalent tissue dose will induce similar effects across species, a NOAEL human equivalent concentration for inhaled acrolein was estimated to be 8 ppb.

USE OF COMPUTATIONAL FLUID DYNAMICS MODELS FOR DOSIMETRY OF INHALED GASES IN THE NASAL PASSAGES

OBJECTIVE To evaluate whether virtual surgery performed on 3-dimensional (3D) nasal airway models can predict postsurgical, biophysical parameters obtained by computational fluid dynamics (CFD). METHODS Presurgery and postsurgery computed tomographic scans of a patient undergoing septoplasty and right inferior turbinate reduction (ITR) were used to generate 3D models of the nasal airway. Prior to obtaining the postsurgery scan, the presurgery model was digitally altered to generate 3 virtual surgery models: (1) right ITR only, (2) septoplasty only, and (3) septoplasty with right ITR. The results of the virtual surgery CFD analyses were compared with postsurgical CFD outcome measures including nasal resistance, unilateral airflow allocation, and regional airflow distribution. RESULTS Postsurgery CFD analysis and all virtual surgery models predicted similar reductions in overall nasal resistance, as well as more balanced airflow distribution between sides, primarily in the middle region, when compared with the presurgery state. In contrast, virtual ITR alone produced little change in either nasal resistance or regional airflow allocation. CONCLUSIONS We present an innovative approach for assessing functional outcomes of nasal surgery using CFD techniques. This preliminary study suggests that virtual nasal surgery has the potential to be a predictive tool that will enable surgeons to perform personalized nasal surgery using computer simulation techniques. Further investigation involving correlation of patient-reported measures with CFD outcome measures in multiple individuals is under way.

Multi-material 3D Models for Temporal Bone Surgical Simulation.

Computational fluid dynamics (CFD) models of the nasal passages of a rat, monkey, and human are being used (1) to determine important factors affecting nasal uptake, (2) to make interspecies dosimetric comparisons, (3) to provide detailed anatomical information for the rat, monkey, and human nasal passages, and (4) to provide estimates of regional air-phase mass transport coefficients (a measure of the resistance to gas transport from inhaled air to airway walls) in the nasal passages of all three species. For many inhaled materials, lesion location in the nose follows patterns that are both site and species specific. For reactive, water-soluble (Category 1) gases, regional uptake can be a major factor in determining lesion location. Since direct measurement of airflow and uptake is experimentally difficult, CFD models are used here to predict uptake patterns quantitatively in three-dimensional reconstructions of the F344 rat, rhesus monkey, and human nasal passages. In formaldehyde uptake simulations, absorption processes were assumed to be as rapid as possible, and regional flux (transport rate) of inhaled formaldehyde to airway walls was calculated for rats, primates, and humans. For uptake of gases like vinyl acetate and acrylic acid vapors, physiologically based pharmacokinetic uptake models incorporating anatomical and physical information from the CFD models were developed to estimate nasal tissue dose in animals and humans. The use of biologically based models in risk assessment makes sources of uncertainty explicit and, in doing so, allows quantification of uncertainty through sensitivity analyses. Limited resources can then be focused on reduction of important sources of uncertainty to make risk estimates more accurate.Computational fluid dynamics (CFD) models of the nasal passages of a rat, monkey, and human are being used (1) to determine important factors affecting nasal uptake, (2) to make interspecies dosimetric comparisons, (3) to provide detailed anatomical information for the rat, monkey, and human nasal passages, and (4) to provide estimates of regional air-phase mass transport coefficients (a measure of the resistance to gas transport from inhaled air to airway walls) in the nasal passages of all three species. For many inhaled materials, lesion location in the nose follows patterns that are both site and species specific. For reactive, water-soluble (Category 1) gases, regional uptake can be a major factor in determining lesion location. Since direct measurement of airflow and uptake is experimentally difficult, CFD models are used here to predict uptake patterns quantitatively in three-dimensional reconstructions of the F344 rat, rhesus monkey, and human nasal passages. In formaldehyde uptake simulations, absorption processes were assumed to be as rapid as possible, and regional flux (transport rate) of inhaled formaldehyde to airway walls was calculated for rats, primates, and humans. For uptake of gases like vinyl acetate and acrylic acid vapors, physiologically based pharmacokinetic uptake models incorporating anatomical and physical information from the CFD models were developed to estimate nasal tissue dose in animals and humans. The use of biologically based models in risk assessment makes sources of uncertainty explicit and, in doing so, allows quantification of uncertainty through sensitivity analyses. Limited resources can then be focused on reduction of important sources of uncertainty to make risk estimates more accurate.