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.

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.

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.

Two-way coupling and Kolmogorov scales on inhaler spray plume evolutions from Ventolin, ProAir, and Qvar.

Previous numerical studies of pulmonary drug delivery using metered-dose inhalers (MDIs) often neglected the momentum transfer from droplets to fluid. However, Kolmogorov length scales in MDI flows can be comparable to the droplet sizes in the orifice vicinity, and their interactions can modify the spray behaviors. This study aimed to evaluate the two-way coupling effects on spray plume evolutions compared to one-way coupling. The influences from the mass loading, droplet size, and inhaler type were also examined. Large-eddy simulation and Lagrangian approach were used to simulate the flow and droplet motions. Two-way coupled predictions appeared to provide significantly improved predictions of the aerosol behaviors close to the Ventolin orifice than one-way coupling. Increasing the applied MDI dose mass altered both the fluid and aerosol dynamics, notably bending the spray plume downward when applying a dose ten times larger. The droplet size played a key role in spray dynamics, with the plume being suppressed for 2-µm aerosols and enhanced for 20-µm aerosols. The Kolmogorov length scale ratio dp/η correlated well with the observed difference in spray plumes, with suppressed plumes when dp/η < 0.1 and enhanced plumes when dp/η > 0.1. For the three inhalers considered (Ventolin, ProAir, and Qvar), significant differences were predicted using two-way and one-way coupling despite the level and manifestation of these differences varied. Two-way coupling effects were significant for MDI sprays and should be considered in future numerical studies.

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.

Liquid Film Translocation Significantly Enhances Nasal Spray Delivery to Olfactory Region: A Numerical Simulation Study.

Previous in vivo and ex vivo studies have tested nasal sprays with varying head positions to enhance the olfactory delivery; however, such studies often suffered from a lack of quantitative dosimetry in the target region, which relied on the observer's subjective perception of color changes in the endoscopy images. The objective of this study is to test the feasibility of gravitationally driven droplet translocation numerically to enhance the nasal spray dosages in the olfactory region and quantify the intranasal dose distribution in the regions of interest. A computational nasal spray testing platform was developed that included a nasal spray releasing model, an airflow-droplet transport model, and an Eulerian wall film formation/translocation model. The effects of both device-related and administration-related variables on the initial olfactory deposition were studied, including droplet size, velocity, plume angle, spray release position, and orientation. The liquid film formation and translocation after nasal spray applications were simulated for both a standard and a newly proposed delivery system. Results show that the initial droplet deposition in the olfactory region is highly sensitive to the spray plume angle. For the given nasal cavity with a vertex-to-floor head position, a plume angle of 10° with a device orientation of 45° to the nostril delivered the optimal dose to the olfactory region. Liquid wall film translocation enhanced the olfactory dosage by ninefold, compared to the initial olfactory dose, for both the baseline and optimized delivery systems. The optimized delivery system delivered 6.2% of applied sprays to the olfactory region and significantly reduced drug losses in the vestibule. Rheological properties of spray formulations can be explored to harness further the benefits of liquid film translocation in targeted intranasal deliveries.

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.

Leveraging statistical shape modeling in computational respiratory dynamics: Nanomedicine delivery in remodeled airways.

BACKGROUND AND OBJECTIVE: Accurate knowledge of the delivered doses to the diseased site in the respiratory tract is crucial to elicit desired therapeutic outcomes. However, such information is still difficult to obtain due to inaccessibility for measurement or visualization, complex network structure, and challenges in reconstructing lung geometries with disease-invoked airway remodeling. This study presents a novel method to simulate the airway remodeling in a mouth-lung geometry extending to G9. METHODS: Statistical shape modeling was used to extract morphological features from a lung geometry database and four new models (i.e., M1-M4) were generated with parameter-controlled dilated/constricted bronchioles in the left-lower (LL) lung. The variations in airflow and particle deposition due to the airway remodeling were simulated using a well-tested k-ω turbulence model and a Lagrangian tracking approach. RESULTS: Significant variations in flow partitions between the lower and upper lobes of the left lung, as well as between the left and right lungs. The flow partition into the LL lobe varied by 10-fold between the most dilated and constricted models in this study. Significantly lower doses were also predicted on the surface of the constricted LL bronchioles G4-G9, as well as into the peripheral airways beyond G9. However, the total dosimetry in the mouth-lung geometry (up to G9) exhibited low sensitivity to the LL lobar remodeling. Results in this study suggest that the optimal nanomedicine should be 2-10 nm in diameter if targeted at the constricted bronchioles G4-G9 as in topical inhalation therapy but should be larger than 20 nm if targeted at the alveolar region as in systemic therapy. CONCLUSIONS: This study highlights the large dose variability from local airway remodeling and the need to consider these variations in the treatment planning for pneumonia and other obstructive respiratory diseases.

Micrometer aerosol deposition in normal and emphysematous subacinar models.

Emphysema is a chronic respiratory disease characterized by interalveolar septa destruction and enlarged air sacs. How the inhalation dosimetry in the pulmonary acini varies in the time course of emphysema is still unclear. The aim of this study is to numerically evaluate the impact of septal destructions on particle deposition in a pyramid-shape subacinar model that is composed of 496 alveoli. Four emphysematous models were generated by progressively removing the inter-alveolar septa from the normal geometry. Spatial distribution and temporal evolution of particle deposition were quantified in expanding/contracting subacinar models on both total and regional basis using a well-validated discrete-phase Lagrangian model. Airflow fields in the subacinar cavities are sensitive to the septal raptures, with regular, radial streamlines in the proximal alveoli in the normal geometry in contrast to unsymmetrical and recirculating flows in the emphysematous subacini. Intensified collateral ventilation and significantly increased doses in the outer wall and base are observed in disease than heath. The deposition rate of small particles (1-1.5 µm) is more sensitive to the level of septal rapture than large particles (2.5-3 µm). Unexpectedly, more particles per unit area deposit on the outer wall and at the base of the subacinus than on the inner septal walls. The subacinus-averaged doses increase with progressing septal destructions, suggesting an escalating risk factor to the acinar health at the late stages of emphysema.

Effects of mask-wearing on the inhalability and deposition of airborne SARS-CoV-2 aerosols in human upper airway.

Even though face masks are well accepted as tools useful in reducing COVID-19 transmissions, their effectiveness in reducing viral loads in the respiratory tract is unclear. Wearing a mask will significantly alter the airflow and particle dynamics near the face, which can change the inhalability of ambient particles. The objective of this study is to investigate the effects of wearing a surgical mask on inspiratory airflow and dosimetry of airborne, virus-laden aerosols on the face and in the respiratory tract. A computational model was developed that comprised a pleated surgical mask, a face model, and an image-based upper airway geometry. The viral load in the nose was particularly examined with and without a mask. Results show that when breathing without a mask, air enters the mouth and nose through specific paths. When wearing a mask, however, air enters the mouth and nose through the entire surface of the mask at lower speeds, which favors the inhalation of ambient aerosols into the nose. With a 65% filtration efficiency (FE) typical for a three-layer surgical mask, wearing a mask reduces dosimetry for all micrometer particles except those of size 1 µm-3 µm, for which equivalent dosimetry with and without a mask in the upper airway was predicted. Wearing a mask reduces particle penetration into the lungs, regardless of the FE of the mask. The results also show that mask-wearing protects the upper airway (particularly the nose and larynx) best from particles larger than 10 µm while protecting the lungs best from particles smaller than 10 µm.

Extracting signature responses from respiratory flows: Low-dimensional analyses on Direct Numerical Simulation-predicted wakes of a flapping uvula.

Uvula-induced snoring and associated obstructive sleep apnea is a complex phenomenon characterized by vibrating structures and highly transient vortex dynamics. This study aimed to extract signature features of uvula wake flows of different pathological origins and develop a linear reduced-order surrogate model for flow control. Six airway models were developed with two uvula kinematics and three pharynx constriction levels. A direct numerical simulation (DNS) flow solver based on the immersed boundary method was utilized to resolve the wake flows induced by the flapping uvula. Key spatial and temporal responses of the flow to uvula kinematics and pharynx constriction were investigated using continuous wavelet transform (CWT), proper orthogonal decomposition (POD), and dynamic mode decomposition (DMD). Results showed highly complex patterns in flow topologies. CWT analysis revealed multiscale correlations in both time and space between the flapping uvular and wake flows. POD analysis successfully separated the flows among the six models by projecting the datasets in the vector space spanned by the first three eigenmodes. Perceivable differences were also captured in the time evolution of the DMD modes among the six models. A linear reduced-order surrogate model was constructed from the predominant eigenmodes obtained from the DMD analysis and predicted vortex patterns from this surrogate model agreed well with the corresponding DNS simulations. The computational and analytical platform presented in this study could bring a variety of applications in breathing-related disorders and beyond. The computational efficiency of surrogate modeling makes it well suited for flow control, forecasting, and uncertainty analyses.

Alveolar size effects on nanoparticle deposition in rhythmically expanding-contracting terminal alveolar models.

Significant differences in alveolar size exist in humans of different ages, gender, health, and among different species. The effects of alveolar sizes, as well as the accompanying breathing frequencies, on regional and local dosimetry of inhaled nanoparticles have not been sufficiently studied. Despite a well-accepted qualitative understanding of the advection-diffusion-sedimentation mechanism in the acinar region, a quantitative picture of the interactions among these factors remains inchoate. The objective of this study is to quantify the effects of alveolar size on the regional and local deposition of inhaled nanoparticles in alveolar models of varying complexities and to understand the dynamic interactions among different deposition mechanisms. Three different models were considered that retained 1, 4, and 45 alveoli, respectively. For each model, the baseline geometry was scaled by », ½, 2, 4, and 8 times by volume. Temporal evolution and spatial distribution of particle deposition were tracked using a discrete-phase Lagrangian model. Lower retentions of inhaled nanoparticles were observed in the larger alveoli under the same respiration frequency, while similar retentions were found among different geometrical scales if breathing frequencies allometrically matched the alveolar size. Dimensional analysis reveals a manifold deposition mechanism with tantamount contributions from advection, diffusion, and gravitational sedimentation, each of which can become dominant depending on the location in the alveoli. Results of this study indicate that empirical correlations obtained from one sub-population cannot be directly applied to others, nor can they be simply scaled as a function of the alveolar size or respiration frequency due to the regime-transiting deposition mechanism that is both localized and dynamic.

Nasal dilation effects on olfactory deposition in unilateral and bi-directional deliveries: In vitro tests and numerical modeling.

The human nose can expand either actively or passively to increase airflow. Nasal dilation may alter drug delivery efficiencies in the nasal airway or olfactory region. However, the dosage enhancement from nasal dilations has not been quantified. The mechanisms underlying the dilation-induced deposition variation are also not clear. This study aims to quantify the nasal dilation effects on drug delivery in the nasal airway and olfactory region using in vitro tests and numerical analysis. Two variants of an existing normal nasal airway model were developed with different levels of airway dilation. Airway dimensions were quantified in terms of hydraulic diameter, cross-sectional area, and surface area to volume ratio. Sectional nose casts were prepared using a 3-D printer for visualizing deposition patterns and quantifying delivered dosages. A well-validated computational fluid-particle dynamics (CFPD) model was utilized to understand the underlying mechanisms in the unilateral and bi-directional deliveries. In vitro tests show that nasal dilation lowered the total dosage in the nose but increased the dosage to the olfactory region in both the unilateral and bi-directional deliveries. Compared to the normal nose with unilateral delivery, nasal dilation enhanced the olfactory deposition by a factor of 2.2, while nasal dilatation with the bi-directional delivery increased by a factor of 4. Complementary numerical analyses revealed the growth of a recirculation zone in the middle meatus of dilated noses, which induced lower pressure and increased ventilation to the upper nose. In bi-directional deliveries, a significantly higher fraction of airflow was ventilated to the upper airway in the outflow side of the nose and contributed to the elevated olfactory dosage. Nasal dilation in combination with the bi-directional delivery is recommended over the conventional unilateral method for olfactory targeting.

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.

Understanding the mechanisms underlying pulsating aerosol delivery to the maxillary sinus: In vitro tests and computational simulations.

BACKGROUND: Pulsating aerosol delivery has been demonstrated in depositing medications into paranasal sinuses. However, its mechanisms are not fully understood. Influences of the nasal anatomy and sound frequency on intrasinus delivery are not yet clear. OBJECTIVES: This study aimed to gain a better understanding of the mechanisms for enhanced intrasinus delivery with pulsating sound. Specifically, effects of the pulsation frequency, ostium size, and sinus shape on the intrasinus dosage and resonance frequency would be examined. METHODS AND MATERIALS: Both experiments and computational modeling were conducted to understand the pulsating aerosol delivery in both idealized (two-bottle) and realistic nose-sinus models. A computational model of intrasinus pulsation delivery was developed using COMSOL and was cross-validated with both experimental and theoretical results. RESULTS: In contrast to previous studies, seemingly erratic relations between the intrasinus dosage and ostium diameter were observed in experiments, which suggested a more complicated particle transport mechanism. Improved agreement was achieved when grouping the ostium size and sinus volume into the resonance frequency, and therefore, validated the hypothesis that intrasinus deposition strongly depends on the resonance frequency. Extensive computational simulations revealed that the deposition was highest at the resonance frequency and decreased gradually at off-resonance frequencies. The resonance frequency depended on the ostium and sinus morphology, but was independent of the nasal cavity. CONCLUSION: Results of this study verified the hypothesis of resonance being the mechanism for enhanced particle deposition in the maxillary sinus. A better knowledge of the relationship between sinus dosages, pulsating frequency, and nasal morphometry is essential for improving the design of intrasinus delivery devices.

Simulation study of electric-guided delivery of 0.4µm monodisperse and polydisperse aerosols to the ostiomeatal complex.

Despite the high prevalence of rhinosinusitis, current inhalation therapy shows limited efficacy due to extremely low drug delivery efficiency to the paranasal sinuses. Novel intranasal delivery systems are needed to enhance targeted delivery to the sinus with therapeutic dosages. An optimization framework for intranasal drug delivery was developed to target polydisperse charged aerosols to the ostiomeatal complex (OMC) with electric guidance. The delivery efficiency of a group of charged aerosols recently reported in the literature was numerically assessed and optimized in an anatomically accurate nose-sinus model. Key design variables included particle charge number, particle size and distribution, electrode strength, and inhalation velocity. Both monodisperse and polydisperse aerosol profiles were considered. Results showed that the OMC delivery efficiency was highly sensitive to the applied electric field and electrostatic charges carried by the particles. Through the synthesis of electric-guidance and point drug release, focused deposition with significantly enhanced dosage in the OMC can be achieved. For 0.4 µm charged aerosols, an OMC delivery efficiency of 51.6% was predicted for monodisperse aerosols and 34.4% for polydisperse aerosols. This difference suggested that the aerosol profile exerted a notable effect on intranasal deliveries. Sensitivity analysis indicated that the OMC deposition fraction was highly sensitive to the charge and size of particles and was less sensitive to the inhalation velocity considered in this study. Experimental studies are needed to validate the numerically optimized designs. Further studies are warranted to investigate the targeted OMC delivery with both electric and acoustics controls, the latter of which has the potential to further deliver the drug particles into the sinus cavity.

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.