Inhalation dosimetry of nasally inhaled respiratory aerosols in the human respiratory tract with locally remodeled conducting lungs.

Objective: Respiratory diseases are often accompanied by alterations to airway morphology. However, inhalation dosimetry data in remodeled airways are scarce due to the challenges in reconstructing diseased respiratory morphologies. This study aims to study the airway remodeling effects on the inhalation dosimetry of nasally inhaled nanoparticles in a nose-lung geometry that extends to G9 (ninth generation).Materials and methods: Statistical shape modeling was used to develop four diseased lung models with varying levels of bronchiolar dilation/constriction in the left-lower (LL) lobe (i.e. M1-M4). Respiratory airflow and particle deposition were simulated using a low Reynolds number k-ω turbulence model and a Lagrangian tracking approach.Results: Significant discrepancies were observed in the flow partitions between the left and right lungs, as well as between the lower and upper lobes of the left lung, which changed by 10-fold between the most dilated and constricted models.Much lower doses were predicted on the surface of the constricted LL bronchioles G4-G9, as well as into the peripheral airways beyond G9 of the LL lung. However, the LL lobar remodeling had little effect on the dosimetry in the nasopharynx, as well as on the total dosimetry in the nose-lung geometry (up to G9).Conclusion: It is suggested that airway remodeling may pose a higher viral infection risk to the host by redistributing the inhaled viruses to healthy lung lobes. Airway remodeling effects should also be considered in the treatment planning of inhalation therapies, not only because of the dosimetry variation from altered lung morphology but also its evolution as the disease progresses.

A comparison of CFPD, compartment, and uniform distribution models for radiation dosimetry of radionuclides in the lung.

Radioactive aerosols that arise from natural sources and nuclear accidents can be a long-term hazard to human health. Despite the heterogeneous particle deposition in the respiratory tract, uniform aerosol doses have long been assumed in respiratory radiation dosimetry predictions, such as in the compartment and uniform distribution models. It is unclear how these deposition patterns affect internal radiation doses, which are critical in the health assessment of radioactive hazards. This work seeks to quantify the radio-dosimetry sensitivity to initial deposition patterns by comparing computational and compartment/uniform models. A new approach was developed to implement the compartment model into voxel phantoms (e.g. VIP-man) for radiation dosimetry. The calculated radiation fluence, energy deposition density and organ doses were compared to those obtained from coupling computational fluid-particle dynamics (CFPD) with Monte Carlo radiation transport and to those obtained from uniform source distribution approximation. The results show that the source particle distribution within the respiratory system substantially influences the radiation dosimetry distribution. The compartment and uniform models underestimated aerosol deposition in the crania ridge, leading to lower doses in the trachea and surrounding organs. For 0.5 MeV gammas, the CFPD-Monte Carlo N-particle (MCNP) model predicted a tracheal dose twice that of the compartment model and four times the uniform model. For 1 MeV betas, the CFPD-MCNP-predicted tracheal dose is 2.6 times that of the compartment model and 14 times the uniform model. Compared to the compartment/uniform models, the CFPD approach predicted a 50% lower beta dose in the lung but higher beta doses in the heart (six times), liver (four times) and stomach (2.5 times). It is suggested that including compartments for the lung periphery and tracheal carina ridge may improve the dosimetry accuracy of compartment models.

A new approach to estimate ultrafine particle respiratory deposition.

Ultrafine particles (UFPs) in workplaces have been and continue to be an important occupational health concern. The inhalation and the consequent deposition of UFPs in workers' lower airways can lead to many adverse health effects. Therefore, it is vital to study the deposition of UFPs in the human respiratory tract from the viewpoint of occupational health. In this study, a set of physiologically representative human tracheobronchial airway replicas were made using high-resolution 3D printers, and a new approach that was distinct from the traditional methods was developed to apply these airway replicas in estimating UFP respiratory deposition. The results showed that UFP respiratory deposition could be readily and systematically measured by the differential-based approach. The results of this study imply the feasibility of developing a mobile aerosol lung deposition apparatus in the future for on-site workplace UFP respiratory deposition to evaluate the UFP inhalation dosimetry for workers in the real workplaces.

Numerical study of dynamic glottis and tidal breathing on respiratory sounds in a human upper airway model.

BACKGROUND: Human snores are caused by vibrating anatomical structures in the upper airway. The glottis is a highly variable structure and a critical organ regulating inhaled flows. However, the effects of the glottis motion on airflow and breathing sound are not well understood, while static glottises have been implemented in most previous in silico studies. The objective of this study is to develop a computational acoustic model of human airways with a dynamic glottis and quantify the effects of glottis motion and tidal breathing on airflow and sound generation. METHODS: Large eddy simulation and FW-H models were adopted to compute airflows and respiratory sounds in an image-based mouth-lung model. User-defined functions were developed that governed the glottis kinematics. Varying breathing scenarios (static vs. dynamic glottis; constant vs. sinusoidal inhalations) were simulated to understand the effects of glottis motion and inhalation pattern on sound generation. Pressure distributions were measured in airway casts with different glottal openings for model validation purpose. RESULTS: Significant flow fluctuations were predicted in the upper airways at peak inhalation rates or during glottal constriction. The inhalation speed through the glottis was the predominating factor in the sound generation while the transient effects were less important. For all frequencies considered (20-2500 Hz), the static glottis substantially underestimated the intensity of the generated sounds, which was most pronounced in the range of 100-500 Hz. Adopting an equivalent steady flow rather than a tidal breathing further underestimated the sound intensity. An increase of 25 dB in average was observed for the life condition (sine-dynamic) compared to the idealized condition (constant-rigid) for the broadband frequencies, with the largest increase of approximately 40 dB at the frequency around 250 Hz. CONCLUSION: Results show that a severely narrowing glottis during inhalation, as well as flow fluctuations in the downstream trachea, can generate audible sound levels.

Molecular Binding Contributes to Concentration Dependent Acrolein Deposition in Rat Upper Airways: CFD and Molecular Dynamics Analyses.

Existing in vivo experiments show significantly decreased acrolein uptake in rats with increasing inhaled acrolein concentrations. Considering that high-polarity chemicals are prone to bond with each other, it is hypothesized that molecular binding between acrolein and water will contribute to the experimentally observed deposition decrease by decreasing the effective diffusivity. The objective of this study is to quantify the probability of molecular binding for acrolein, as well as its effects on acrolein deposition, using multiscale simulations. An image-based rat airway geometry was used to predict the transport and deposition of acrolein using the chemical species model. The low Reynolds number turbulence model was used to simulate the airflows. Molecular dynamic (MD) simulations were used to study the molecular binding of acrolein in different media and at different acrolein concentrations. MD results show that significant molecular binding can happen between acrolein and water molecules in human and rat airways. With 72 acrolein embedded in 800 water molecules, about 48% of acrolein compounds contain one hydrogen bond and 10% contain two hydrogen bonds, which agreed favorably with previous MD results. The percentage of hydrogen-bonded acrolein compounds is higher at higher acrolein concentrations or in a medium with higher polarity. Computational dosimetry results show that the size increase caused by the molecular binding reduces the effective diffusivity of acrolein and lowers the chemical deposition onto the airway surfaces. This result is consistent with the experimentally observed deposition decrease at higher concentrations. However, this size increase can only explain part of the concentration-dependent variation of the acrolein uptake and acts as a concurrent mechanism with the uptake-limiting tissue ration rate. Intermolecular interactions and associated variation in diffusivity should be considered in future dosimetry modeling of high-polarity chemicals such as acrolein.

Visualization and Quantification of Nasal and Olfactory Deposition in a Sectional Adult Nasal Airway Cast.

PURPOSE: To compare drug deposition in the nose and olfactory region with different nasal devices and administration techniques. A Sar-Gel based colorimetry method will be developed to quantify local deposition rates. METHODS: A sectional nasal airway cast was developed based on an MRI-based nasal airway model to visualize deposition patterns and measure regional dosages. Four nasal spray pumps and four nebulizers were tested with both standard and point-release administration techniques. Delivered dosages were measured using a high-precision scale. The colorimetry correlation for deposited mass was developed via image processing in Matlab and its performance was evaluated through comparison to experimental measurements. RESULTS: Results show that the majority of nasal spray droplets deposited in the anterior nose while only a small fraction (less than 4.6%) reached the olfactory region. For all nebulizers considered, more droplets went beyond the nasal valve, leading to distinct deposition patterns as a function of both the nebulizer type (droplet size and initial speed) and inhalation flow rate. With the point-release administration, up to 9.0% (±1.9%) of administered drugs were delivered to the olfactory region and 15.7 (±2.4%) to the upper nose using Pari Sinus. CONCLUSIONS: Standard nasal devices are inadequate to deliver clinically significant olfactory dosages without excess drug losses in other nasal epitheliums. The Sar-Gel based colorimetry method appears to provide a simple and practical approach to visualize and quantify regional deposition.

Effects of the facial interface on inhalation and deposition of micrometer particles in calm air in a child airway model.

CONTEXT: How the facial interface affects particle inhalability and depositions within the airway is not well understood. Previous studies of inhalation dosimetry are limited to either inhalability or deposition, rather than the two studied in a systematic way. OBJECTIVE: To systematically evaluate the effects of the facial interface on aerosol inhalability, nasal deposition and thoracic dose in a 5-year-old child airway model using a coupled imaging-computational fluid dynamics approach. METHODS: A face-nose-throat model was developed from magnetic resonance imaging scans of a 5-year-old boy. Respiration airflows and particle transport were simulated with the low Reynolds number k-ω turbulence model and the Lagrangian tracking approach. Particles ranging from 1 to 70 µm were considered in a calm air. RESULTS: Retaining the facial interface in the computational model induced substantial variations in flow dynamics, aerosol inhalability and thoracic doses. The nasal and thoracic deposition fractions were much lower with the facial interface due to the low inhalability into downward-facing nostrils and facial deposition losses. For a given inhalation rate of 10 L/min, including the facial interface reduced the thoracic dose by 5% for 2.5-µm particles and by 50% for 10 µm particles in the child model. Considering localized conditions, facial interface substantially increased depositions at the turbinate region and dorsal pharynx. CONCLUSION: This study highlighted the need to include facial interface in future numerical and in vitro studies. Findings of this study have practical implications in the design of aerosol samplers and interpretation of deposition data from studies without facial interfaces.

Assessing Nasal Epithelial Dynamics: Impact of the Natural Nasal Cycle on Intranasal Spray Deposition.

This study investigated the intricate dynamics of intranasal spray deposition within nasal models, considering variations in head orientation and stages of the nasal cycle. Employing controlled delivery conditions, we compared the deposition patterns of saline nasal sprays in models representing congestion (N1), normal (N0), and decongestion (P1, P2) during one nasal cycle. The results highlighted the impact of the nasal cycle on spray distribution, with congestion leading to confined deposition and decongestion allowing for broader dispersion of spray droplets and increased sedimentation towards the posterior turbinate. In particular, the progressive nasal dilation from N1 to P2 decreased the spray deposition in the middle turbinate. The head angle, in conjunction with the nasal cycle, significantly influenced the nasal spray deposition distribution, affecting targeted drug delivery within the nasal cavity. Despite controlled parameters, a notable variance in deposition was observed, emphasizing the complex interplay of gravity, flow shear, nasal cycle, and nasal morphology. The magnitude of variance increased as the head tilt angle increased backward from upright to 22.5° to 45° due to increasing gravity and liquid film destabilization, especially under decongestion conditions (P1, P2). This study's findings underscore the importance of considering both natural physiological variations and head orientation in optimizing intranasal drug delivery.

Sensitivity Analysis and Uncertainty Quantification of Nanoparticle Deposition from Tongue Morphological Variations.

The human tongue has highly variable morphology. Its role in regulating respiratory flows and deposition of inhaled aerosols remains unclear. The objective of this study was to quantify the uncertainty of nanoparticle deposition from the variability in tongue shapes and positions and to rank the importance of these morphological factors. Oropharyngeal models with different tongue postures were reconstructed by modifying an existent anatomically accurate upper airway geometry. An LRN k-ω model was applied to solve the multiregime flows, and the Lagrangian tracking approach with near-wall treatment was used to simulate the behavior and fate of inhaled aerosols. Once the database of deposition rates was completed, a surrogate model was trained using Gaussian process regression with polynomial kernels and was validated by comparing its predictions to new CFD simulations. Input sensitivity analysis and output updateability quantification were then performed using the surrogate model. Results show that particle size is the most significant parameter in determining nanoparticle deposition in the upper airway. Among the morphological factors, the shape variations in the central tongue had a higher impact on the total deposition than those in the back tongue and glottal aperture. When considering subregional deposition, mixed sensitivity levels were observed among morphological factors, with the back tongue being the major factor for throat deposition and the central tongue for oral deposition. Interaction effects between flow rate and morphological factors were much higher than the effects from individual parameters and were most significant in the throat (pharyngolaryngeal region). Given input normal variances, the nanoparticle deposition exhibits logarithmical normal distributions, with much lower uncertainty in 100-nm than 2-nm aerosols.

Effects of Nozzle Retraction Elimination on Spray Distribution in Middle-Posterior Turbinate Regions: A Comparative Study.

The standard multi-dose nasal spray pump features an integrated actuator and nozzle, which inevitably causes a retraction of the nozzle tip during application. The retraction stroke is around 5.5 mm and drastically reduces the nozzle's insertion depth, which further affects the initial nasal spray deposition and subsequent translocation, potentially increasing drug wastes and dosimetry variability. To address this issue, we designed a new spray pump that separated the nozzle from the actuator and connected them with a flexible tube, thereby eliminating nozzle retraction during application. The objective of this study is to test the new device's performance in comparison to the conventional nasal pump in terms of spray generation, plume development, and dosimetry distribution. For both devices, the spray droplet size distribution was measured using a laser diffraction particle analyzer. Plume development was recorded with a high-definition camera. Nasal dosimetry was characterized in two transparent nasal cavity casts (normal and decongested) under two breathing conditions (breath-holding and constant inhalation). The nasal formulation was a 0.25% w/v methyl cellulose aqueous solution with a fluorescent dye. For each test case, the temporospatial spray translocation in the nasal cavity was recorded, and the final delivered doses were quantified in five nasal regions. The results indicate minor differences in droplet size distribution between the two devices. The nasal plume from the new device presents a narrower plume angle. The head orientation, the depth at which the nozzle is inserted into the nostril, and the administration angle play crucial roles in determining the initial deposition of nasal sprays as well as the subsequent translocation of the liquid film/droplets. Quantitative measurements of deposition distributions in the nasal models were augmented with visualization recordings to evaluate the delivery enhancements introduced by the new device. With an extension tube, the modified device produced a lower spray output and delivered lower doses in the front, middle, and back turbinate than the conventional nasal pump. However, sprays from the new device were observed to penetrate deeper into the nasal passages, predominantly through the middle-upper meatus. This resulted in consistently enhanced dosing in the middle-upper turbinate regions while at the cost of higher drug loss to the pharynx.

Schlieren imaging and video classification of alphabet pronunciations: exploiting phonetic flows for speech recognition and speech therapy.

Speech is a highly coordinated process that requires precise control over vocal tract morphology/motion to produce intelligible sounds while simultaneously generating unique exhaled flow patterns. The schlieren imaging technique visualizes airflows with subtle density variations. It is hypothesized that speech flows captured by schlieren, when analyzed using a hybrid of convolutional neural network (CNN) and long short-term memory (LSTM) network, can recognize alphabet pronunciations, thus facilitating automatic speech recognition and speech disorder therapy. This study evaluates the feasibility of using a CNN-based video classification network to differentiate speech flows corresponding to the first four alphabets: /A/, /B/, /C/, and /D/. A schlieren optical system was developed, and the speech flows of alphabet pronunciations were recorded for two participants at an acquisition rate of 60 frames per second. A total of 640 video clips, each lasting 1 s, were utilized to train and test a hybrid CNN-LSTM network. Acoustic analyses of the recorded sounds were conducted to understand the phonetic differences among the four alphabets. The hybrid CNN-LSTM network was trained separately on four datasets of varying sizes (i.e., 20, 30, 40, 50 videos per alphabet), all achieving over 95% accuracy in classifying videos of the same participant. However, the network's performance declined when tested on speech flows from a different participant, with accuracy dropping to around 44%, indicating significant inter-participant variability in alphabet pronunciation. Retraining the network with videos from both participants improved accuracy to 93% on the second participant. Analysis of misclassified videos indicated that factors such as low video quality and disproportional head size affected accuracy. These results highlight the potential of CNN-assisted speech recognition and speech therapy using articulation flows, although challenges remain in expanding the alphabet set and participant cohort.

Oropharyngeal swallowing hydrodynamics of thin and mildly thick liquids in an anatomically accurate throat-epiglottis model.

Understanding the mechanisms underlying dysphagia is crucial in devising effective, etiology-centered interventions. However, current clinical assessment and treatment of dysphagia are still more symptom-focused due to our limited understanding of the sophisticated symptom-etiology associations causing swallowing disorders. This study aimed to elucidate the mechanisms giving rise to penetration flows into the laryngeal vestibule that results in aspirations with varying symptoms. Methods: Anatomically accurate, transparent throat models were prepared with a 45° down flapped epiglottis to simulate the instant of laryngeal closure during swallowing. Fluid bolus dynamics were visualized with fluorescent dye from lateral, rear, front, and endoscopic directions to capture key hydrodynamic features leading to aspiration. Three influencing factors, fluid consistency, liquid dispensing site, and dispensing speed, were systemically evaluated on their roles in liquid aspirations. Results: Three aspiration mechanisms were identified, with liquid bolus entering the airway through (a) the interarytenoid notch (notch overflow), (b) cuneiform tubercle recesses (recess overflow), and (c) off-edge flow underneath the epiglottis (off-edge capillary flow). Of the three factors considered, liquid viscosity has the most significant impact on aspiration rate, followed by the liquid dispensing site and the dispensing speed. Water had one order of magnitude higher aspiration risks than 1% w/v methyl cellulose solution, a mildly thick liquid. Anterior dispensing had higher chances for aspiration than posterior oropharyngeal dispensing for both liquids and dispensing speeds considered. The effects of dispending speed varied. A lower speed increased aspiration for anterior-dispensed liquids due to increased off-edge capillary flows, while it significantly reduced aspiration for posterior-dispensed liquids due to reduced notch overflows. Visualizing swallowing hydrodynamics from multiple orientations facilitates detailed site-specific inspections of aspiration mechanisms.

Hygroscopic aerosol deposition in the human upper respiratory tract under various thermo-humidity conditions.

The deposition of hygroscopic aerosols is highly complex in nature, which results from a cumulative effect of dynamic particle growth and the real-time size-specific deposition mechanisms. The objective of this study is to evaluate hygroscopic effects on the particle growth, transport, and deposition of nasally inhaled aerosols across a range of 0.2-2.5 µm in an adult image-based nose-throat model. Temperature and relative humidity fields were simulated using the LRN k-ω turbulence model and species transport model under a spectrum of thermo-humidity conditions. Particle growth and transport were simulated using a well validated Lagrangian tracking model coupled with a user-defined hygroscopic growth module. Results of this study indicate that the saturation level and initial particle size are the two major factors that determine the particle growth rate (d/d0), while the effect of inhalation flow rate is found to be not significant. An empirical correlation of condensation growth of nasally inhaled hygroscopic aerosols in adults has been developed based on a variety of thermo-humidity inhalation conditions. Significant elevated nasal depositions of hygroscopic aerosols could be induced by condensation growth for both sub-micrometer and small micrometer particulates. In particular, the deposition of initially 2.5 µm hygroscopic aerosols was observed to be 5-8 times that of inert particles under warm to hot saturated conditions. Results of this study have important implications in exposure assessment in hot humid environments, where much higher risks may be expected compared to normal conditions.

Delivery of Agarose-aided Sprays to the Posterior Nose for Mucosa Immunization and Short-term Protection against Infectious Respiratory Diseases.

AIM: The study aimed to deliver sprays to the posterior nose for mucosa immunization or short-term protection. BACKGROUND: Respiratory infectious diseases often enter the human body through the nose. Sars-Cov-2 virus preferentially binds to the ACE2-rich tissue cells in the nasopharynx (NP). Delivering medications to the nose, especially to the NP region, provides either a short-term protective/therapeutic layer or long-term mucosa immunization. Hydrogel-aided medications can assist film formation, prolong film life, and control drug release. However, conventional nasal sprays have failed to dispense mediations to the posterior nose, with most sprays lost in the nasal valve and front turbinate. OBJECTIVE: The objective of the study was to develop a practical delivery system targeting the posterior nose and quantify the dosimetry distribution of agarose-saline solutions in the nasal cavity. METHOD: The solution viscosities with various hydrogel concentrations (0.1-1%) were measured at different temperatures. Dripping tests on a vertical plate were conducted to understand the hydrogel concentration effects on the liquid film stability and mobility. Transparent nasal airway models were used to visualize the nasal spray deposition and liquid film translocation. RESULT: Spray dosimetry with different hydrogel concentrations and inhalation flow rates was quantified on a total and regional basis. The solution viscosity increased with decreasing temperature, particularly in the range of 60-40 oC. The liquid viscosity, nasal spray atomization, and liquid film mobility were highly sensitive to the hydrogel concentration. Liquid film translocations significantly enhanced delivered doses to the caudal turbinate and nasopharynx when the sprays were administered at 60 oC under an inhalation flow rate of 11 L/min with hydrogel concentrations no more than 0.5%. On the other hand, sprays with 1% hydrogel or administered at 40 oC would significantly compromise the delivered doses to the posterior nose. CONCLUSION: Delivering sufficient doses of hydrogel sprays to the posterior nose is feasible by leveraging the post-administration liquid film translocation.

Nasal anatomy and sniffing in respiration and olfaction of wild and domestic animals.

Animals have been widely utilized as surrogate models for humans in exposure testing, infectious disease experiments, and immunology studies. However, respiratory diseases affect both humans and animals. These disorders can spontaneously affect wild and domestic animals, impacting their quality and quantity of life. The origin of such responses can primarily be traced back to the pathogens deposited in the respiratory tract. There is a lack of understanding of the transport and deposition of respirable particulate matter (bio-aerosols or viruses) in either wild or domestic animals. Moreover, local dosimetry is more relevant than the total or regionally averaged doses in assessing exposure risks or therapeutic outcomes. An accurate prediction of the total and local dosimetry is the crucial first step to quantifying the dose-response relationship, which in turn necessitates detailed knowledge of animals' respiratory tract and flow/aerosol dynamics within it. In this review, we examined the nasal anatomy and physiology (i.e., structure-function relationship) of different animals, including the dog, rat, rabbit, deer, rhombus monkey, cat, and other domestic and wild animals. Special attention was paid to the similarities and differences in the vestibular, respiratory, and olfactory regions among different species. The ventilation airflow and behaviors of inhaled aerosols were described as pertinent to the animals' mechanisms for ventilation modulation and olfaction enhancement. In particular, sniffing, a breathing maneuver that animals often practice enhancing olfaction, was examined in detail in different animals. Animal models used in COVID-19 research were discussed. The advances and challenges of using numerical modeling in place of animal studies were discussed. The application of this technique in animals is relevant for bidirectional improvements in animal and human health.

Visualization and Estimation of Nasal Spray Delivery to Olfactory Mucosa in an Image-Based Transparent Nasal Model.

Background: Nose-to-brain (N2B) drug delivery offers unique advantages over intravenous methods; however, the delivery efficiency to the olfactory region using conventional nasal devices and protocols is low. This study proposes a new strategy to effectively deliver high doses to the olfactory region while minimizing dose variability and drug losses in other regions of the nasal cavity. Materials and Methods: The effects of delivery variables on the dosimetry of nasal sprays were systematically evaluated in a 3D-printed anatomical model that was generated from a magnetic resonance image of the nasal airway. The nasal model comprised four parts for regional dose quantification. A transparent nasal cast and fluorescent imaging were used for visualization, enabling detailed examination of the transient liquid film translocation, real-time feedback on input effect, and prompt adjustment to delivery variables, which included the head position, nozzle angle, applied dose, inhalation flow, and solution viscosity. Results: The results showed that the conventional vertex-to-floor head position was not optimal for olfactory delivery. Instead, a head position tilting 45-60° backward from the supine position gave a higher olfactory deposition and lower variability. A two-dose application (250 mg) was necessary to mobilize the liquid film that often accumulated in the front nose following the first dose administration. The presence of an inhalation flow reduced the olfactory deposition and redistributed the sprays to the middle meatus. The recommended olfactory delivery variables include a head position ranging 45-60°, a nozzle angle ranging 5-10°, two doses, and no inhalation flow. With these variables, an olfactory deposition fraction of 22.7 ± 3.7% was achieved in this study, with insignificant discrepancies in olfactory delivery between the right and left nasal passages. Conclusions: It is feasible to deliver clinically significant doses of nasal sprays to the olfactory region by leveraging an optimized combination of delivery variables.

Optimized gravity-driven intranasal drop administration delivers significant doses to the ostiomeatal complex and maxillary sinus.

Chronic and allergic rhinosinusitis impacts approximately 12% of the global population. Challenges in rhinosinusitis treatment include paranasal sinus inaccessibility and variability in delivery efficiency among individuals. This study addresses these challenges of drug delivery by developing a high-efficiency, low-variability protocol for nasal drop delivery to the ostiomeatal complex (OMC) and maxillary sinus. Patient-specific nasal casts were dissected to reveal the configurations of conchae and meatus, providing insights into anatomical features amendable for sinus delivery. Fluorescent dye-enhanced videos visualized the dynamic liquid translocation in transparent nasal casts, allowing real-time assessment and quick adjustment to delivery parameters. Dosimetry to the OMC and maxillary sinus were quantified as drop count and mass using a precision scale. Key delivery factors, including the device type, formulation, and head-chin orientation, were systematically investigated in a cohort of ten nasal casts. Results show that both the squeeze bottle and soft-mist nasal pump yielded notably low doses to the OMC with high variability, and no dose from these two devices was detected within the maxillary sinuses. In contrast, the proposed approach, which included a curved nozzle surpassing the nasal valve and leveraged gravity-driven liquid translocation along the lateral nasal wall, delivered significant doses to the OMC and maxillary sinus. Iterative experimentations identified the optimal head tilt to be 40° and chin tilt to be° from the lateral recumbent position. Statistical analyses established the drop count required for effective OMC/sinus delivery. The proposed delivery protocol holds the potential to enhance chronic rhinosinusitis treatment outcomes with low variability. The dual role of nasal anatomy in posing challenges and offering opportunities highlights the need for future investigations using diverse formulations in a larger cohort of nasal models. Optimized gravity-driven intranasal drop administration delivers significant doses to the ostiomeatal complex and maxillary sinus.

A Supine Position and Dual-Dose Applications Enhance Spray Dosing to the Posterior Nose: Paving the Way for Mucosal Immunization.

Delivering vaccines to the posterior nose has been proposed to induce mucosal immunization. However, conventional nasal devices often fail to deliver sufficient doses to the posterior nose. This study aimed to develop a new delivery protocol that can effectively deliver sprays to the caudal turbinate and nasopharynx. High-speed imaging was used to characterize the nasal spray plumes. Three-dimensional-printed transparent nasal casts were used to visualize the spray deposition within the nasal airway, as well as the subsequent liquid film formation and translocation. Influencing variables considered included the device type, delivery mode, release angle, flow rate, head position, and dose number. Apparent liquid film translocation was observed in the nasal cavity. To deliver sprays to the posterior nose, the optimal release angle was found to be 40° for unidirectional delivery and 30° for bidirectional delivery. The flow shear was the key factor that mobilized the liquid film. Both the flow shear and the head position were important in determining the translocation distance. A supine position and dual-dose application significantly improved delivery to the nasopharynx, i.e., 31% vs. 0% with an upright position and one-dose application. It is feasible to effectively deliver medications to the posterior nose by leveraging liquid film translocation for mucosal immunization.

Count- and mass-based dosimetry of MDI spray droplets with polydisperse and monodisperse size distributions.

Most previous numerical studies of inhalation drug delivery used monodisperse aerosols or quantified deposition as the ratio of deposited particle number over the total number of released particles (i.e., count-based). These practices are reasonable when the aerosols have a sufficiently narrow size range. However, spray droplets from metered-dose inhalers (MDIs) are often polydisperse with a wide size range, so using monodisperse aerosols and/or count-based deposition quantification may lead to significant errors. The objective of this study was to develop a mass-based dosimetry method and evaluate its performance in lung delivery in a mouth-lung (G9) geometry with an albuterol-CFC inhaler. The conventional practices (monodisperse and polydisperse-count-based) were also simulated for comparison purposes. The MDI actuation in the open space was studied using both high-speed imaging and LES-Lagrangian simulations. Experimentally measured spray velocities and size distribution were implemented in the computational model as boundary conditions. Good agreement was achieved between recorded and simulated spray plume evolution spatially and temporally. The polydisperse-mass-based predictions of MDI doses compared favorably with the measurements in all three regions considered (device, mouth-throat, and lung). Significant errors in MDI regional deposition were predicted using the monodisperse and count-based methods. The new polydisperse-mass-based method also predicted local deposition hot spots that were one order of magnitude higher in intensity than the two conventional methods. The results of this study highlighted that a presentative polydisperse size distribution and appropriate deposition quantification method should be applied to reliably predict the MDI drug delivery in the human respiratory tract.

Lower Inspiratory Breathing Depth Enhances Pulmonary Delivery Efficiency of ProAir Sprays.

Effective pulmonary drug delivery using a metered-dose inhaler (MDI) requires a match between the MDI sprays, the patient's breathing, and respiratory physiology. Different inhalers generate aerosols with distinct aerosol sizes and speeds, which require specific breathing coordination to achieve optimized delivery efficiency. Inability to perform the instructed breathing maneuver is one of the frequently reported issues during MDI applications; however, their effects on MDI dosimetry are unclear. The objective of this study is to systemically evaluate the effects of breathing depths on regional deposition in the respiratory tract using a ProAir-HFA inhaler. An integrated inhaler mouth-throat-lung geometry model was developed that extends to the ninth bifurcation (G9). Large-eddy simulation (LES) was used to compute the airflow dynamics due to concurrent inhalation and orifice flows. The discrete-phase Lagrangian model was used to track droplet motions. Experimental measurements of ProAir spray droplet sizes and speeds were used as initial and boundary conditions to develop the computational model for ProAir-pulmonary drug delivery. The time-varying spray plume from a ProAir-HFA inhaler into the open air was visualized using a high-speed imaging system and was further used to validate the computational model. The inhalation dosimetry of ProAir spray droplets in the respiratory tract was compared among five breathing depths on a regional, sub-regional, and local basis. The results show remarkable differences in airflow dynamics within the MDI mouthpiece and the droplet deposition distribution in the oral cavity. The inhalation depth had a positive relationship with the deposition in the mouth and a negative relationship with the deposition in the five lobes beyond G9 (small airways). The highest delivery efficiency to small airways was highest at 15 L/min and declined with an increasing inhalation depth. The drug loss inside the MDI was maximal at 45-60 L/min. Comparisons to previous experimental and numerical studies revealed a high dosimetry sensitivity to the inhaler type and patient breathing condition. Considering the appropriate inhalation waveform, spray actuation time, and spray properties (size and velocity) is essential to accurately predict inhalation dosimetry from MDIs. The results highlight the importance of personalized inhalation therapy to match the patient's breathing patterns for optimal delivery efficiencies. Further complimentary in vitro or in vivo experiments are needed to validate the enhanced pulmonary delivery at 15 L/min.