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Mandibular advancement devices (MADs) are frequently prescribed for obstructive sleep apnea (OSA) patients, but approximately one third of patients experience no therapeutic benefit. Understanding the mechanisms by which MADs prevent pharyngeal collapse may help optimize MAD therapy. This study quantified the relative contributions of changes in airspace cross‐sectional area (CSA) versus changes in velopharyngeal compliance in determining MAD efficacy. Sixteen patients with moderate to severe OSA (mean apnea–hypopnea index of 32 ± 15 events/h) underwent measurements of the velopharyngeal closing pressure (PCLOSE) during drug induced sedated endoscopy (DISE) via stepwise reductions in nasal mask pressure and recording of the intraluminal pressure with a catheter. Airspace CSA was estimated from video endoscopy. Pharyngeal compliance was defined as the slope of the area–pressure relationship of the velopharyngeal airspace. MAD therapy reduced PCLOSE from a median of 0.5 cmH2O pre‐advancement to a median of −2.6 cmH2O post‐advancement (p = 0.0009), increased the minimal CSA at the velopharynx by approximately 20 mm2 (p = 0.0067), but did not have a statistically significant effect on velopharyngeal compliance (p = 0.23). PCLOSE had a strong correlation with CSA but did not correlate with velopharyngeal compliance. Our results suggest that MADs reduce velopharyngeal collapsibility by increasing airway size as opposed to affecting velopharyngeal compliance. This contradicts the speculation of previous literature that the effectiveness of MADs is partially due to a reduction in velopharyngeal compliance resulting from stretching of the soft palate. These findings suggest that quantification of velopharyngeal CSA pre‐ and post‐MAD advancement has potential as a biomarker to predict the success of MAD therapy. [ABSTRACT FROM AUTHOR]

Context: Inhaled nanoparticles can migrate to the brain via the olfactory bulb, as demonstrated in experiments in several animal species. This route of exposure may be the mechanism behind the correlation between air pollution and human neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Objectives: This article aims to (i) estimate the dose of inhaled nanoparticles that deposit in the human olfactory epithelium during nasal breathing at rest and (ii) compare the olfactory dose in humans with our earlier dose estimates for rats. Materials and methods: An anatomically-accurate model of the human nasal cavity was developed based on computed tomography scans. The deposition of 1–100 nm particles in the whole nasal cavity and its olfactory region were estimated via computational fluid dynamics (CFD) simulations. Our CFD methods were validated by comparing our numerical predictions for whole-nose deposition with experimental data and previous CFD studies in the literature. Results: In humans, olfactory dose of inhaled nanoparticles is highest for 1–2 nm particles with ∼1% of inhaled particles depositing in the olfactory region. As particle size grows to 100 nm, olfactory deposition decreases to 0.01% of inhaled particles. Discussion and conclusion: Our results suggest that the percentage of inhaled particles that deposit in the olfactory region is lower in humans than in rats. However, olfactory dose per unit surface area is estimated to be higher in humans in the 1--7 nm size range due to the larger inhalation rate in humans. These dose estimates are important for risk assessment and dose-response studies investigating the neurotoxicity of inhaled nanoparticles. [ABSTRACT FROM PUBLISHER]

Human exposure to hydrogen sulfide (H2S) gas occurs from natural and industrial sources and can result in dose-related neurological, respiratory, and cardiovascular effects. Olfactory neuronal loss in H2S-exposed rats has been used to develop occupational and environmental exposure limits. Using nasal computational fluid dynamics (CFD) models, a correlation was found between wall mass flux and olfactory neuronal loss in rodents, suggesting an influence of airflow patterns on lesion locations that may affect interspecies extrapolation of inhaled dose. Human nasal anatomy varies considerably within a population, potentially affecting airflow patterns and dosimetry of inhaled gases. This study investigates interhuman variability of H2S nasal dosimetry using anatomically accurate CFD models of the nasal passages of five adults and two children generated from magnetic resonance imaging (MRI) or computed tomography (CT) scan data. Using allometrically equivalent breathing rates, steady-state inspiratory airflow and H2S uptake were simulated. Approximate locations of olfactory epithelium were mapped in each model to compare air:tissue flux in the olfactory region among individuals. The fraction of total airflow to the olfactory region ranged from 2% to 16%. Despite this wide range in olfactory airflow, H2S dosimetry in the olfactory region was predicted to be similar among individuals. Differences in the 99th percentile and average flux values were <1.2-fold at inhaled concentrations of 1, 5, and 10 ppm. These preliminary results suggest that differences in nasal anatomy and ventilation among adults and children do not have a significant effect on H2S dosimetry in the olfactory region. [ABSTRACT FROM AUTHOR]

In vivo experiments have shown that nanoparticles depositing in the rat olfactory region can translocate to the brain via the olfactory nerve. Quantitative predictions of the dose delivered by inhalation to the olfactory region are needed to clarify this route of exposure and to evaluate the dose-response effects of exposure to toxic nanoparticles. Previous in vivo and in vitro studies quantified the percentage of inhaled nanoparticles that deposit in the rat nasal passages, but olfactory dose was not determined. The dose to specific nasal epithelium types is expected to vary with inhalation rate and particle size. The purpose of this investigation, therefore, was to develop estimates of nanoparticle deposition in the nasal and, more specifically, olfactory regions of the rat. A three-dimensional, anatomically accurate, computational fluid dynamics (CFD) model of the rat nasal passages was employed to simulate inhaled airflow and to calculate nasal deposition efficiency. Particle sizes from 1 to 100 nm and airflow rates of 288, 432, and 576 ml/min (1, 1.5, and 2 times the estimated resting minute volume) were simulated. The simulations predicted that olfactory deposition is maximum at 6–9% of inhaled material for 3- to 4-nm particles. The spatial distribution of deposited particles was predicted to change significantly with particle size, with 3-nm particles depositing mostly in the anterior nose, while 30-nm particles were more uniformly distributed throughout the nasal passages. [ABSTRACT FROM AUTHOR]

Certain inhaled chemicals, such as reactive, water-soluble gases, are readily absorbed by the nasal mucosa upon inhalation and may cause damage to the nasal epithelium. Comparisons of the spatial distribution of nasal lesions in laboratory animals exposed to formaldehyde with gas uptake rates predicted by computational models reveal that lesions usually occur in regions of the susceptible epithelium where gas absorption is highest. Since the uptake patterns are influenced by air currents in the nose, interindividual variability in nasal anatomy and ventilation rates due to age, body size, and gender will affect the patterns of gas absorption in humans, potentially putting some age groups at higher risk when exposed to toxic gases. In this study, interhuman variability in the nasal dosimetry of reactive, water-soluble gases was investigated by means of computational fluid dynamics (CFD) models in 5 adults and 2 children, aged 7 and 8 years old. Airflow patterns were investigated for allometrically scaled inhalation rates corresponding to resting breathing. The spatial distribution of uptake at the airway walls was predicted to be nonuniform, with most of the gas being absorbed in the anterior portion of the nasal passages. Under the conditions of these simulations, interhuman variability in dose to the whole nose (mass per time per nasal surface area) due to differences in anatomy and ventilation was predicted to be 1.6-fold among the 7 individuals studied. Children and adults displayed very similar patterns of nasal gas uptake; no significant differences were noted between the two age groups. [ABSTRACT FROM AUTHOR]

Although there is much data available on mammalian long-bone allometry, a theory explaining these data is still lacking. We show that bending and axial compression are the relevant loading modes and elucidate why the elastic similarity model failed to explain the experimental data. Our analysis provides scaling relations connecting bone diameter and length to the axial and transverse components of the force, in good agreement with experimental data. The model also accounts for other important features of long-bone allometry. [ABSTRACT FROM AUTHOR]

Objectives: Approximately 25% of Americans suffer from laryngopharyngeal reflux (LPR), a disease for which no effective medical therapy exists. Pepsin is a predominant source of damage during LPR and a key therapeutic target. Fosamprenavir (FOS) inhibits pepsin and prevents damage in an LPR mouse model. Inhaled FOS protects at a lower dose than oral; however, the safety of inhaled FOS is unknown and there are no inhalers for laryngopharyngeal delivery. A pre‐Good Lab Practice (GLP) study of inhaled FOS was performed to assess safety and computational fluid dynamics (CFD) modeling used to predict the optimal particle size for a laryngopharyngeal dry powder inhaler (DPI). Methods: Aerosolized FOS, amprenavir (APR), or air (control) were provided 5 days/week for 4 weeks (n = 6) in an LPR mouse model. Organs (nasal cavity, larynx, esophagus, trachea, lung, liver, heart, and kidney) were assessed by a pathologist and bronchoalveolar lavage cytokines and plasma cardiotoxicity markers were assessed by Luminex assay. CFD simulations were conducted in a model of a healthy 49‐year‐old female. Results: No significant increase was observed in histologic lesions, cytokines, or cardiotoxicity markers in FOS or APR groups relative to the control. CFD predicted that laryngopharyngeal deposition was maximized with aerodynamic diameters of 8.1–11.5 μm for inhalation rates of 30–60 L/min. Conclusions: A 4‐week pre‐GLP study supports the safety of inhaled FOS. A formal GLP assessment is underway to support a phase I clinical trial of an FOS DPI for LPR. Level of Evidence: NA. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis is a common disease worldwide, and the frequently prescribed nasal sprays do not sufficiently deliver the topical medications to the target sites so that the final treatment in severe cases is surgery. Therefore, there is a huge demand to improve drug delivery devices that could target the maxillary sinuses more effectively. In the present study, different particle diameters and device pulsation flow rates, mainly used in pulsating aerosol delivery devices such as the PARI SINUS®, are considered to evaluate optimal maxillary sinus deposition efficiency (DE). Numerical simulations of the particle-laden flow using a large eddy simulation with a local dynamic k-equation sub-grid scale model are performed in a patient-specific nasal cavity. By increasing the pulsation flow rate from 4 l/min to 15 l/min, nasal DE increases from 37% to 68%. Similarly, by increasing the particle size from 1 µm to 5 µm, nasal DE increases from 34% to 43% for a pulsation flow rate of 4 l/min. Moreover, normalized velocity, vorticities, and particle deposition pattern in different regions of the main nasal cavity and maxillary sinuses are visualized and quantified. Due to the nosepiece placement in the right nostril, more particles penetrate into the right maxillary sinus than into the left maxillary sinus despite the maxillary ostium being larger in the left cavity. Lower pulsation flow rates such as 4 l/min improve the DE in the left maxillary sinus. The use of 3 µm particles enhances the DE in the right maxillary sinus as well as the overall total maxillary drug delivery. [ABSTRACT FROM AUTHOR]

Topical intra-nasal sprays are amongst the most commonly prescribed therapeutic options for sinonasal diseases in humans. However, inconsistency and ambiguity in instructions show a lack of definitive knowledge on best spray use techniques. In this study, we have identified a new usage strategy for nasal sprays available over-the-counter, that registers an average 8-fold improvement in topical delivery of drugs at diseased sites, when compared to prevalent spray techniques. The protocol involves re-orienting the spray axis to harness inertial motion of particulates and has been developed using computational fluid dynamics simulations of respiratory airflow and droplet transport in medical imaging-based digital models. Simulated dose in representative models is validated through in vitro spray measurements in 3D-printed anatomic replicas using the gamma scintigraphy technique. This work breaks new ground in proposing an alternative user-friendly strategy that can significantly enhance topical delivery inside human nose. While these findings can eventually translate into personalized spray usage instructions and hence merit a change in nasal standard-of-care, this study also demonstrates how relatively simple engineering analysis tools can revolutionize everyday healthcare. Finally, with respiratory mucosa as the initial coronavirus infection site, our findings are relevant to intra-nasal vaccines that are in-development, to mitigate the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Computational fluid dynamics (CFD) allows quantitative assessment of transport phenomena in the human nasal cavity, including heat exchange, moisture transport, odorant uptake in the olfactory cleft, and regional delivery of pharmaceutical aerosols. The first step when applying CFD to investigate nasal airflow is to create a 3-dimensional reconstruction of the nasal anatomy from computed tomography (CT) scans or magnetic resonance images (MRI). However, a method to identify the exact location of the air-tissue boundary from CT scans or MRI is currently lacking. This introduces some uncertainty in the nasal cavity geometry. The radiodensity threshold for segmentation of the nasal airways has received little attention in the CFD literature. The goal of this study is to quantify how uncertainty in the segmentation threshold impacts CFD simulations of transport phenomena in the human nasal cavity. Three patients with nasal airway obstruction were included in the analysis. Pre-surgery CT scans were obtained after mucosal decongestion with oxymetazoline. For each patient, the nasal anatomy was reconstructed using three different thresholds in Hounsfield units (-800HU, -550HU, and -300HU). Our results demonstrate that some CFD variables (pressure drop, flowrate, airflow resistance) and anatomic variables (airspace cross-sectional area and volume) are strongly dependent on the segmentation threshold, while other CFD variables (intranasal flow distribution, surface area) are less sensitive to the segmentation threshold. These findings suggest that identification of an optimal threshold for segmentation of the nasal airway from CT scans will be important for good agreement between in vivo measurements and patient-specific CFD simulations of transport phenomena in the nasal cavity, particularly for processes sensitive to the transnasal pressure drop. We recommend that future CFD studies should always report the segmentation threshold used to reconstruct the nasal anatomy. [ABSTRACT FROM AUTHOR]

The epithelial sodium channel (ENaC) is activated upon endoproteolytic cleavage of specific segments in the extracellular domains of the α- and γ-subunits. Cleavage is accomplished by intracellular proteases prior to membrane insertion and by surface-expressed or extracellular soluble proteases once ENaC resides at the cell surface. These cleavage events are partially regulated by intracellular signaling through an unknown allosteric mechanism. Here, using a combination of computational and experimental techniques, we show that the intracellular N terminus of γ-ENaC undergoes secondary structural transitions upon interaction with phosphoinositides. From ab initio folding simulations of the N termini in the presence and absence of phosphatidylinositol 4,5-bisphosphate (PIP2), we found that PIP2 increases α-helical propensity in the N terminus of γ-ENaC. Electrophysiology and mutation experiments revealed that a highly conserved cluster of lysines in the γ-ENaC N terminus regulates accessibility of extracellular cleavage sites in γ-ENaC. We also show that conditions that decrease PIP2 or enhance ubiquitination sharply limit access of the γ-ENaC extracellular domain to proteases. Further, the efficiency of allosteric control of ENaC proteolysis is dependent on Tyr370 in γ-ENaC. Our findings provide an allosteric mechanism for ENaC activation regulated by the N termini and sheds light on a potential general mechanism of channel and receptor activation. [ABSTRACT FROM AUTHOR]

Age-related changes in gross and microscopic structure of the nasal cavity may alter local tissue susceptibility as well as the dose of inhaled toxicant delivered to susceptible sites. This article describes a novel method for the use of magnetic resonance imaging, 3-dimensional airway modeling, and morphometric techniques to characterize the distribution and magnitude of ozone-induced nasal injury in infant monkeys. Using this method, we generated age-specific, 3-dimensional, epithelial maps of the nasal airways of infant Rhesus macaques. The principal nasal lesions observed in this primate model of ozone-induced nasal toxicology were neutrophilic rhinitis, along with necrosis and exfoliation of the epithelium lining the anterior maxilloturbinate. These lesions, induced by acute or cyclic (episodic) exposures, were examined by light microscopy, quantified by morphometric techniques, and mapped on 3-dimensional models of the nasal airways. Here, we describe the histopathologic, imaging, and computational biology methods developed to precisely characterize, localize, quantify, and map these nasal lesions. By combining these techniques, the location and severity of the nasal epithelial injury were correlated with epithelial type, nasal airway geometry, and local biochemical and molecular changes on an individual animal basis. These correlations are critical for accurate predictive modeling of exposure-dose-response relationships in the nasal airways, and subsequent extrapolation of nasal findings in animals to humans for determining risk. [ABSTRACT FROM AUTHOR]

The classical Starling Resistor model has been the paradigm of airway collapse in obstructive sleep apnea (OSA) for the last 30 years. Its theoretical framework is grounded on the wave‐speed flow limitation (WSFL) theory. Recent observations of negative effort dependence in OSA patients violate the predictions of the WSFL theory. Fluid‐structure interaction (FSI) simulations are emerging as a technique to quantify how the biomechanical properties of the upper airway determine the shape of the pressure‐flow curve. This study aimed to test two predictions of the WSFL theory, namely (1) the pressure profile upstream from the choke point becomes independent of downstream pressure during flow limitation and (2) the maximum flowrate in a collapsible tube is VImax=A3/2(ρdA/dP)−1/2, where ρ is air density and A and P are the cross‐sectional area and pressure at the choke point respectively. FSI simulations were performed in a model of the human upper airway with a collapsible pharynx whose wall thickness varied from 2 to 8 mm and modulus of elasticity ranged from 2 to 30 kPa. Experimental measurements in an airway replica with a silicone pharynx validated the numerical methods. Good agreement was found between our FSI simulations and the WSFL theory. Other key findings include: (1) the pressure‐flow curve is independent of breathing effort (downstream pressure vs. time profile); (2) the shape of the pressure‐flow curve reflects the airway biomechanical properties, so that VImax is a surrogate measure of pharyngeal compliance. [ABSTRACT FROM AUTHOR]