Advancements in acoustic drug delivery for paranasal sinuses: A comprehensive review.

Chronic rhinosinusitis (CRS) impacts patients' quality of life and healthcare costs. Traditional methods of drug delivery, such as nasal sprays and irrigation, have limited effectiveness. Acoustic Drug Delivery (ADD) using a nebulizer offers targeted delivery of drug to the sinuses, which may improve the treatment of CRS. This review examines the influence of aerosol particle characteristics, aero-acoustic parameters, inlet flow conditions, and acoustic waves on sinus drug delivery. Key findings reveal that smaller particles improve the ADD efficiency, whereas larger sizes or increased density impair it. The oscillation amplitude of the air plug in the ostium is crucial for the ADD efficiency. Introducing acoustic waves at the NC-sinus system's resonance frequency improves aerosol deposition within sinuses. Future research should address advanced models, optimizing particle characteristics, investigating novel acoustic waveforms, incorporating patient-specific anatomy, and evaluating long-term safety and efficacy. Tackling these challenges, ADD could offer more effective and targeted treatments for sinus-related conditions such as CRS.

Numerical and Machine Learning Analysis of the Parameters Affecting the Regionally Delivered Nasal Dose of Nano- and Micro-Sized Aerosolized Drugs.

The nasal epithelium is an important target for drug delivery to the nose and secondary organs such as the brain via the olfactory bulb. For both topical and brain delivery, the targeting of specific nasal regions such as the olfactory epithelium (brain) is essential, yet challenging. In this study, a numerical model was developed to predict the regional dose as mass per surface area (for an inhaled mass of 2.5 mg), which is the biologically most relevant dose metric for drug delivery in the respiratory system. The role of aerosol diameter (particle diameter: 1 nm to 30 µm) and inhalation flow rate (4, 15 and 30 L/min) in optimal drug delivery to the vestibule, nasal valve, olfactory and nasopharynx is assessed. To obtain the highest doses in the olfactory region, we suggest aerosols with a diameter of 20 µm and a medium inlet air flow rate of 15 L/min. High deposition on the olfactory epithelium was also observed for nanoparticles below 1 nm, as was high residence time (slow flow rate of 4 L/min), but the very low mass of 1 nm nanoparticles is prohibitive for most therapeutic applications. Moreover, high flow rates (30 L/min) and larger micro-aerosols lead to highest doses in the vestibule and nasal valve regions. On the other hand, the highest drug doses in the nasopharynx are observed for nano-aerosol (1 nm) and fine microparticles (1-20 µm) with a relatively weak dependence on flow rate. Furthermore, using the 45 different inhalation scenarios generated by numerical models, different machine learning models with five-fold cross-validation are trained to predict the delivered dose and avoid partial differential equation solvers for future predictions. Random forest and gradient boosting models resulted in R2 scores of 0.89 and 0.96, respectively. The aerosol diameter and region of interest are the most important features affecting delivered dose, with an approximate importance of 42% and 47%, respectively.

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

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

How severe acute respiratory syndrome coronavirus-2 aerosol propagates through the age-specific upper airways.

The recent outbreak of the COVID-19 causes significant respirational health problems, including high mortality rates worldwide. The deadly corona virus-containing aerosol enters the atmospheric air through sneezing, exhalation, or talking, assembling with the particulate matter, and subsequently transferring to the respiratory system. This recent outbreak illustrates that the severe acute respiratory syndrome (SARS) coronavirus-2 is deadlier for aged people than for other age groups. It is evident that the airway diameter reduces with age, and an accurate understanding of SARS aerosol transport through different elderly people's airways could potentially help the overall respiratory health assessment, which is currently lacking in the literature. This first-ever study investigates SARS COVID-2 aerosol transport in age-specific airway systems. A highly asymmetric age-specific airway model and fluent solver (ANSYS 19.2) are used for the investigation. The computational fluid dynamics measurement predicts higher SARS COVID-2 aerosol concentration in the airway wall for older adults than for younger people. The numerical study reports that the smaller SARS coronavirus-2 aerosol deposition rate in the right lung is higher than that in the left lung, and the opposite scenario occurs for the larger SARS coronavirus-2 aerosol rate. The numerical results show a fluctuating trend of pressure at different generations of the age-specific model. The findings of this study would improve the knowledge of SARS coronavirus-2 aerosol transportation to the upper airways which would thus ameliorate the targeted aerosol drug delivery system.

Effect of swirling flow and particle-release pattern on drug delivery to human tracheobronchial airways.

The present study aims to investigate the effect of swirling flow on particle deposition in a realistic human airway. A computational fluid dynamic (CFD) model was utilized for the simulation of oral inhalation and particle transport patterns, considering the k-ω turbulence model. Lagrangian particle tracking was used to track the particles' trajectories. A normal breathing condition (30 L/min) was applied, and two-micron particles were injected into the mouth, considering swirling flow to the oral inhalation airflow. Different cases were considered for releasing the particles, which evaluated the impacts of various parameters on the deposition efficiency (DE), including the swirl intensity, injection location and pattern of the particle. The work's novelty is applying several injection locations and diameters simultaneously. The results show that the swirling flow enhances the particle deposition efficiency (20-40%) versus no-swirl flow, especially in the mouth. However, releasing particles inside the mouth, or injecting them randomly with a smaller injection diameter (dinj) reduced DE in swirling flow condition, about 50 to 80%. Injecting particles inside the mouth can decrease DE by about 20%, and releasing particles with smaller dinj leads to 50% less DE in swirling flow. In conclusion, it is indicated that the airflow condition is an important parameter for a reliable drug delivery, and it is more beneficial to keep the inflow uniform and avoid swirling flow.

Acoustic drug delivery to the maxillary sinus.

Acoustic drug delivery (ADD) is an innovative method for drug delivery to the nose and paranasal sinuses and can be used to treat chronic rhinosinusitis (CRS). The underlying mechanism of ADD is based on the oscillatory exchange of air between the nasal cavity (NC) and the maxillary sinus (MS) through the ostium, which assists with the transfer of the drug particles from the NC to the sinuses. This study aims to examine the efficacy of ADD for drug delivery to the MS using an acoustic wave applied to nebulised aerosols entering the nostril. Here, the effect of acoustic frequency, amplitude, and nebulisation flowrate on the efficiency of ADD to the MS is investigated experimentally. A computational fluid dynamics model was also developed to understand the deposition and transport patterns of the aerosols. The results showed that superimposing an acoustic frequency of 328 Hz, which is the resonance frequency of the selected 3D printed model of the NC-MS combination, on the nebulised aerosols could improve the efficiency of the drug delivery to the MS by 75-fold compared with non-acoustic drug delivery case (p < 0.0001). The experimental data also shows that an increase in the amplitude of excitation, increases the concentration of aerosol deposition in the MS significantly; however, it reaches to a plateau at a sound pressure level of 120 dB re 20 µPa.

Acoustically-driven drug delivery to maxillary sinuses: Aero-acoustic analysis.

This paper investigates the effect of aero-acoustic parameters on the efficiency of acoustically-driven drug delivery (ADD) to human maxillary sinus (MS). To be more specific, the effect of the frequency, amplitude at the acoustic excitation, and the inlet mean flow rate on the efficiency of ADD to the MS is studied. Direct computational aero-acoustics, using a validated computational fluid dynamics (CFD) model, has been utilised to carry out the parametric study. The transport pattern of the particles (drugs) in the presence of an external acoustic field has been investigated through the discrete phase model. Extensive computational simulations have revealed that the most important parameter in acoustically-driven drug delivery to the MS is the amplitude of the oscillation of the air plug in the ostium, which is largest when the combination of nasal cavity and MS is at resonance. Also, it has been found that the amplitude of the inlet acoustic wave has a direct correlation with the efficiency of the drug delivery to the MS. Moreover, the inlet mean airflow rate adversely affects the efficiency of the drug delivery to the MS. The results of this study suggest that applying an external acoustic field after distributing the drug particles with no mean flow results in a better drug delivery than in the presence of an inlet mean flow.

Development of human respiratory airway models: A review.

Pulmonary drug delivery has gained great interest as an important subject of research over the past decades given the lung diseases which are affecting millions of people suffer from these diseases. Drug delivery into the respiratory system is influenced by many anatomical and physiological factors such as lung morphometry, breathing patterns, fluid dynamics, particle properties, etc. The respiratory airway structure is one of these parameters which greatly influences the deposition pattern of inhaled drug particles. There have been a wide variety of major morphometric studies, conducted using cadavers to increase an understanding of the respiratory airway anatomy and provide important information for developing realistic airway models. Casting as one of the first methods, was utilized for morphometric studies providing a hollow model for in vitro investigations. The above-mentioned morphometric data were utilized to describe the first idealized airway model as a simple symmetric description of the branching airways, later followed by more realistic asymmetric models. However, even these asymmetric airway models were not good enough to reflect the anatomical complexities of the human respiratory airway and contained several major limitations which made them inefficient. Further attempts alongside with the progress of technology led to introduction of the stochastic and image-based models which provided more realistic and efficient tools for numerical and experimental investigations. The main objective of this study is to provide a comprehensive review about the development of different perspectives of the respiratory airway modeling over the past decades. The following sections will present useful information about anatomy of the human respiratory tract, and different viewpoints of the respiratory airway modeling, including their historical routes, strengths, and deficiencies.

The impact of geometrical parameters on acoustically driven drug delivery to maxillary sinuses.

Acoustically driven nebulized drug delivery (acoustic aerosol delivery) is the most efficient noninvasive technique for drug delivery to maxillary sinuses (MS). This method is based on the oscillation of the air plug inside the ostium to transport drug particles from the nasal cavity (NC) to the MS. The larger the wavelength of the air plug oscillation in the ostium, the greater the penetration of drug particles to the MS. However, using this technique, the maximum drug delivery efficiency achieved to date is 5%, which means 95% of the aerosolized drugs do not enter the MS and are wasted. Since the largest amplitude of the air plug oscillation occurs at its resonance frequency, to achieve an improved MS drug delivery efficiency, it is important to determine the resonance frequency of the nose-sinus combination accurately. This paper aims to investigate the impact of geometrical parameters on the resonance frequency of the nose-sinus model. Both experimental and computational acoustic models, along with the theoretical analysis, were conducted to determine the resonance frequency of an idealized nose-sinus model. The computational modeling was carried out using computational fluid dynamics (CFD) and finite element analysis (FEA), whereas in the analytical solution, the mathematical relationships developed for a conventional Helmholtz resonator were employed. A series of experiments were also conducted to measure the resonance frequency of a realistic NC-MS combination. The results demonstrated a good agreement between the experimental and CFD modeling, while the FEA and theoretical analysis showed a significant deviation from the experimental data. Also, it was shown that the resonance frequency of the idealized nose-sinus model increases by up to twofold with increasing the ostium diameter from 3 to 9 mm; however, it has an inverse relationship with the ostium length and sinus volume. It was also reported that the resonance frequency of the nose-sinus model is independent of the NC width and MS shape.

CFD simulation of aerosol delivery to a human lung via surface acoustic wave nebulization.

Administration of drug in the form of particles through inhalation is generally preferable in the treatment of respiratory disorders. Conventional inhalation therapy devices such as inhalers and nebulizers, nevertheless, suffer from low delivery efficiencies, wherein only a small fraction of the inhaled drug reaches the lower respiratory tract. This is primarily because these devices are not able to produce a sufficiently fine drug mist that has aerodynamic diameters on the order of a few microns. This study employs computational fluid dynamics to investigate the transport and deposition of the drug particles produced by a new aerosolization technique driven by surface acoustic waves (SAWs) into an in silico lung model geometrically reconstructed using computed tomography scanning. The particles generated by the SAW are released in different locations in a spacer chamber attached to a lung model extending from the mouth to the 6th generation of the lung bronchial tree. An Eulerian approach is used to solve the Navier-Stokes equations that govern the airflow within the respiratory tract, and a Lagrangian approach is adopted to track the particles, which are assumed to be spherical and inert. Due to the complexity of the lung geometry, the airflow patterns vary as it penetrates deeper into the lung. High inertia particles tend to deposit at locations where the geometry experiences a significant reduction in cross section. Our findings, nevertheless, show that the injection location can influence the delivery efficiency: Injection points close to the spacer centerline result in deeper penetration into the lung. Additionally, we found that the ratio of drug particles entering the right lung is significantly higher than the left lung, independent of the injection location. This is in good agreement with this fact that the most of airflow enters to the right lobes.

Magnetic drug targeting through a realistic model of human tracheobronchial airways using computational fluid and particle dynamics.

Magnetic drug targeting (MDT) is a local drug delivery system which aims to concentrate a pharmacological agent at its site of action in order to minimize undesired side effects due to systemic distribution in the organism. Using magnetic drug particles under the influence of an external magnetic field, the drug particles are navigated toward the target region. Herein, computational fluid dynamics was used to simulate the air flow and magnetic particle deposition in a realistic human airway geometry obtained by CT scan images. Using discrete phase modeling and one-way coupling of particle-fluid phases, a Lagrangian approach for particle tracking in the presence of an external non-uniform magnetic field was applied. Polystyrene (PMS40) particles were utilized as the magnetic drug carrier. A parametric study was conducted, and the influence of particle diameter, magnetic source position, magnetic field strength and inhalation condition on the particle transport pattern and deposition efficiency (DE) was reported. Overall, the results show considerable promise of MDT in deposition enhancement at the target region (i.e., left lung). However, the positive effect of increasing particle size on DE enhancement was evident at smaller magnetic field strengths (Mn [Formula: see text] 1.5 T), whereas, at higher applied magnetic field strengths, increasing particle size has a inverse effect on DE. This implies that for efficient MTD in the human respiratory system, an optimal combination of magnetic drug career characteristics and magnetic field strength has to be achieved.