This study presents a combined experimental and numerical investigation of fiber transport and deposition in a realistic model of the female respiratory tract, extending to the seventh generation of branching. Numerical simulations were performed using the Euler-Lagrange Euler-Rotation (ELER) method, an efficient alternative to conventional Finite Volume Methods that benefits from explicit formulation and vast scalability, enabling fast parallelization on high-performance clusters. The ELER method was coupled with the Lattice Boltzmann Method (LBM) to simulate fiber dynamics under a realistic inspiratory flow profile. Experimental validation was conducted using an identical physical airway replica. The results demonstrated good agreement between simulations and experiments in the upper airways and trachea, with some discrepancies in the bifurcations, likely owing to the challenges of modeling complex turbulent flow with ELER. This method is more accurate than corresponding effective diameter simulations. Deposition patterns were analyzed as a function of fiber dimensions, revealing higher accuracy of the ELER method for smaller particles and confirming the tendency of higher aspect ratio fibers to penetrate deeper into the lungs. The orientation-dependent deposition mechanism was deployed, underscoring the importance of solving the actual orientations of the fibers. While advancing our understanding of fiber transport in female airways, the findings also reveal limitations in current numerical techniques, particularly in bifurcations. This study emphasizes the distinct behavior of fibrous versus spherical particles, with fibers exhibiting a greater propensity to reach deeper lung regions, which has significant implications for inhalation toxicology and drug delivery.

• Klíčová slova
• Deposition, Euler–Lagrange Euler-rotation, Female airway geometry, Fiber transport, In silico, In vitro, Lattice Boltzmann method,
• MeSH
• aplikace inhalační MeSH
• biologické modely * MeSH
• dýchací soustava * MeSH
• lidé MeSH
• plíce MeSH
• počítačová simulace MeSH
• trachea * fyziologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND OBJECTIVE: Drug inhalation is generally accepted as the preferred administration method for treating respiratory diseases. To achieve effective inhaled drug delivery for an individual, it is necessary to use an interdisciplinary approach that can cope with inter-individual differences. The paper aims to present an individualised pulmonary drug deposition model based on Computational Fluid and Particle Dynamics simulations within a time frame acceptable for clinical use. METHODS: We propose a model that can analyse the inhaled drug delivery efficiency based on the patient's airway geometry as well as breathing pattern, which has the potential to also serve as a tool for a sub-regional diagnosis of respiratory diseases. The particle properties and size distribution are taken for the case of drug inhalation by using nebulisers, as they are independent of the patient's breathing pattern. Finally, the inhaled drug doses that reach the deep airways of different lobe regions of the patient are studied. RESULTS: The numerical accuracy of the proposed model is verified by comparison with experimental results. The difference in total drug deposition fractions between the simulation and experimental results is smaller than 4.44% and 1.43% for flow rates of 60 l/min and 15 l/min, respectively. A case study involving a COVID-19 patient is conducted to illustrate the potential clinical use of the model. The study analyses the drug deposition fractions in relation to the breathing pattern, aerosol size distribution, and different lobe regions. CONCLUSIONS: The entire process of the proposed model can be completed within 48 h, allowing an evaluation of the deposition of the inhaled drug in an individual patient's lung within a time frame acceptable for clinical use. Achieving a 48-hour time window for a single evaluation of patient-specific drug delivery enables the physician to monitor the patient's changing conditions and potentially adjust the drug administration accordingly. Furthermore, we show that the proposed methodology also offers a possibility to be extended to a detection approach for some respiratory diseases.

• Klíčová slova
• Computational fluid and particle dynamics, Drug deposition, Individualised approach, Inhaled drug delivery, Respiratory airway,
• MeSH
• aerosoly MeSH
• aplikace inhalační MeSH
• COVID-19 MeSH
• farmakoterapie COVID-19 MeSH
• hydrodynamika MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• nebulizátory a vaporizátory * MeSH
• plíce metabolismus   diagnostické zobrazování   MeSH
• počítačová simulace * MeSH
• SARS-CoV-2 MeSH
• velikost částic MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aerosoly MeSH

Liposomal carrier systems have emerged as a promising technology for pulmonary drug delivery. This study focuses on two selected liposomal systems, namely, dipalmitoylphosphatidylcholine stabilized by phosphatidic acid and cholesterol (DPPC-PA-Chol) and dipalmitoylphosphatidylcholine stabilized by polyethylene glycol and cholesterol (DPPC-PEG-Chol). First, the research investigates the stability of these liposomal systems during the atomization process using different kinds of nebulizers (air-jet, vibrating mesh, and ultrasonic). The study further explores the aerodynamic particle size distribution of the aerosol generated by the nebulizers. The nebulizer that demonstrated optimal stability and particle size was selected for more detailed investigation, including Andersen cascade impactor measurements, an assessment of the influence of flow rate and breathing profiles on aerosol particle size, and an in vitro deposition study on a realistic replica of the upper airways. The most suitable combination of a nebulizer and liposomal system was DPPC-PA-Chol nebulized by a Pari LC Sprint Star in terms of stability and particle size. The influence of the inspiration flow rate on the particle size was not very strong but was not negligible either (decrease of Dv50 by 1.34 μm with the flow rate increase from 8 to 60 L/min). A similar effect was observed for realistic transient inhalation. According to the in vitro deposition measurement, approximately 90% and 70% of the aerosol penetrated downstream of the trachea using the stationary flow rate and the realistic breathing profile, respectively. These data provide an image of the potential applicability of liposomal carrier systems for nebulizer therapy. Regional lung drug deposition is patient-specific; therefore, deposition results might vary for different airway geometries. However, deposition measurement with realistic boundary conditions (airway geometry, breathing profile) brings a more realistic image of the drug delivery by the selected technology. Our results show how much data from cascade impactor testing or estimates from the fine fraction concept differ from those of a more realistic case.

• Klíčová slova
• aerosol, deposition, inhalation, liposome, nebulizer, particle size, pulmonary drug delivery,
• MeSH
• 1,2-dipalmitoylfosfatidylcholin MeSH
• aerosoly MeSH
• aplikace inhalační MeSH
• bronchodilatancia * MeSH
• cholesterol MeSH
• design vybavení MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• liposomy MeSH
• nebulizátory a vaporizátory MeSH
• trachea * MeSH
• velikost částic MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1,2-dipalmitoylfosfatidylcholin MeSH
• aerosoly MeSH
• bronchodilatancia * MeSH
• cholesterol MeSH
• liposomy MeSH

The numerical simulation of inhaled aerosols in medical research starts to play a crucial role in understanding local deposition within the respiratory tract, a feat often unattainable experimentally. Research on children is particularly challenging due to the limited availability of in vivo data and the inherent morphological intricacies. CFD solvers based on Finite Volume Methods (FVM) have been widely employed to solve the flow field in such studies. Recently, Lattice Boltzmann Methods (LBM), a mesoscopic approach, have gained prominence, especially for their scalability on High-Performance Computers. This study endeavours to compare the effectiveness of LBM and FVM in simulating particulate flows within a child's respiratory tract, supporting research related to particle deposition and medication delivery using LBM. Considering a 5-year-old child's airway model at a steady inspiratory flow, the results are compared with in vitro experiments. Notably, both LBM and FVM exhibit favourable agreement with experimental data for the mean velocity field and the turbulence intensity. For particle deposition, both numerical methods yield comparable results, aligning well with in vitro experiments across a particle size range of 0.1-20 µm. Discrepancies are identified in the upper airways and trachea, indicating a lower deposition fraction than in the experiment. Nonetheless, both LBM and FVM offer invaluable insights into particle behaviour for different sizes, which are not easily achievable experimentally. In terms of practical implications, the findings of this study hold significance for respiratory medicine and drug delivery systems - potential health impacts, targeted drug delivery strategies or optimisation of respiratory therapies.

• Klíčová slova
• Child airways, Finite Volume Method, In vitro measurement, Lattice Boltzmann Method, Particle deposition,
• MeSH
• aerosoly MeSH
• hydrodynamika * MeSH
• lidé MeSH
• počítačová simulace MeSH
• předškolní dítě MeSH
• trachea * anatomie a histologie   MeSH
• velikost částic MeSH
• Check Tag
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aerosoly MeSH

In this study, novel Trojan particles were engineered for direct delivery of doxorubicin (DOX) and miR-34a as model drugs to the lungs to raise local drug concentration, decrease pulmonary clearance, increase lung drug deposition, reduce systemic side effects, and overcome multi-drug resistance. For this purpose, targeted polyelectrolyte nanoparticles (tPENs) developed with layer-by-layer polymers (i.e., chitosan, dextran sulfate, and mannose-g-polyethyleneimine) were spray dried into a multiple-excipient (i.e., chitosan, leucine, and mannitol). The resulting nanoparticles were first characterized in terms of size, morphology, in vitro DOX release, cellular internalization, and in vitro cytotoxicity. tPENs showed comparable cellular uptake levels to PENs in A549 cells and no significant cytotoxicity on their metabolic activity. Co-loaded DOX/miR-34a showed a greater cytotoxicity effect than DOX-loaded tPENs and free drugs, which was confirmed by Actin staining. Thereafter, nano-in-microparticles were studied through size, morphology, aerosolization efficiency, residual moisture content, and in vitro DOX release. It was demonstrated that tPENs were successfully incorporated into microspheres with adequate emitted dose and fine particle fraction but low mass median aerodynamic diameter for deposition into the deep lung. The dry powder formulations also demonstrated a sustained DOX release at both pH values of 6.8 and 7.4.

• Klíčová slova
• Chitosan, Nano-in-microparticles, Pulmonary delivery, Small molecules, miRNAs,
• Publikační typ
• časopisecké články MeSH

This contribution is focused on the preparation of a liposomal drug delivery system of erlotinib resisting the nebulization process that could be used for local treatment of non-small-cell lung cancer. Liposomes with different compositions were formulated to reveal their influence on the encapsulation efficiency of erlotinib. An encapsulation efficiency higher than 98 % was achieved for all vesicles containing phosphatidic acid (d ≈ 100 nm, ζ = - 43 mV) even in the presence of polyethylene glycol (d ≈ 150 nm, ζ = - 17 mV) which decreased this value in all other formulas. The three most promising formulations were nebulized by two air-jet and two vibrating mesh nebulizers, and the aerosol deposition in lungs was calculated by tools of computational fluid and particle mechanics. According to the numerical simulations and measurements of liposomal stability, air-jet nebulizers generated larger portion of the aerosol able to penetrate deeper into the lungs, but the delivery is likely to be more efficient when the formulation is administered by Aerogen Solo vibrating mesh nebulizer because of a higher portion of intact vesicles after the nebulization. The leakage of encapsulated drug from liposomes nebulized by this nebulizer was lower than 2 % for all chosen vesicles.

• Klíčová slova
• Aerodynamic particle size, Encapsulation, Liposome, Nebulization, Non-small-cell lung cancer, Numerical simulations,
• MeSH
• aplikace inhalační MeSH
• bronchodilatancia MeSH
• erlotinib MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• liposomy MeSH
• nádory plic * MeSH
• nebulizátory a vaporizátory MeSH
• nemalobuněčný karcinom plic * MeSH
• plíce MeSH
• respirační aerosoly a kapénky MeSH
• velikost částic MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bronchodilatancia MeSH
• erlotinib MeSH
• liposomy MeSH

In this study, three different molecules (cholesterol, phosphatidic acid, and polyethylene glycol) were used for the stabilization of liposomes during the nebulization process. The purpose of this article is to answer the question of whether the change in the composition of liposomes affected the parameters of generated aerosol and whether the nebulization process affected observed properties of liposomes. Firstly, liposomes with different composition were prepared and their properties were checked by dynamic and electrophoretic light scattering. The membrane properties were measured by fluorescence spectroscopy - especially generalized polarization (Laurdan) and anisotropy (Diphenylhexatriene). The same characteristic of liposomes was measured after the nebulization by vibrating mesh nebulizer. Cholesterol was capable of liposome stabilization because of increased membrane fluidity. The membrane properties of the outer and inner parts were not influenced by the nebulization process. Electrostatic stabilization was successful for the lowest concentration of phosphatidic acid, but after the nebulization process the hydration of the membrane outer part was changed. Higher amount of PEG needs to be added for successful steric stabilization. The nebulization process of the two lowest concentrations of PEG slightly influenced immobilized water and the rigidity of inner part of the membrane (especially around the phase transition temperature).

• Klíčová slova
• Cholesterol, Fluorescence spectroscopy, Liposome, Nebulization, Phosphatidic acid, Polyethylene glycol,
• MeSH
• aerosoly MeSH
• chirurgické síťky * MeSH
• liposomy * MeSH
• nebulizátory a vaporizátory MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aerosoly MeSH
• liposomy * MeSH

Controlled pulmonary drug delivery systems employing non-spherical particles as drug carriers attract considerable attention nowadays. Such anisotropic morphologies may travel deeper into the lung airways, thus enabling the efficient accumulation of therapeutic compounds at the point of interest and subsequently their sustained release. This study focuses on the fabrication of electrospun superparamagnetic polymer-based biodegradable microrods consisting of poly(l-lactide) (PLLA), polyethylene oxide (PEO) and oleic acid-coated magnetite nanoparticles (OA·Fe3O4). The production of magnetite-free (0% wt. OA·Fe3O4) and magnetite-loaded (50% and 70% wt. Fe3O4) microrods was realized upon subjecting the as-prepared electrospun fibers to UV irradiation, followed by sonication. Moreover, drug-loaded microrods were fabricated incorporating methyl 4-hydroxybenzoate (MHB) as a model pharmaceutical compound and the drug release profile from both, the drug-loaded membranes and the corresponding microrods was investigated in aqueous media. In addition, the magnetic properties of the produced materials were exploited for remote induction of hyperthermia under AC magnetic field, while the possibility to reduce transport losses and enhance the targeted delivery to lower airways by manipulation of the airborne microrods by DC magnetic field was also demonstrated.

• Klíčová slova
• Biodegradable microrods, Electrospinning, Human airways, Lungs, Magnetic field, Magnetic hyperthermia, Pulmonary drug delivery, Superparamagnetic fibers,
• MeSH
• lékové transportní systémy MeSH
• magnetické jevy MeSH
• magnetické nanočástice * MeSH
• magnetismus MeSH
• plíce MeSH
• vytápění * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• magnetické nanočástice * MeSH

The inhalation route has a substantial influence on the fate of inhaled particles. An outbreak of infectious diseases such as COVID-19, influenza or tuberculosis depends on the site of deposition of the inhaled pathogens. But the knowledge of respiratory deposition is important also for occupational safety or targeted delivery of inhaled pharmaceuticals. Simulations utilizing computational fluid dynamics are becoming available to a wide spectrum of users and they can undoubtedly bring detailed predictions of regional deposition of particles. However, if those simulations are to be trusted, they must be validated by experimental data. This article presents simulations and experiments performed on a geometry of airways which is available to other users and thus those results can be used for intercomparison between different research groups. In particular, three hypotheses were tested. First: Oral breathing and combined breathing are equivalent in terms of particle deposition in TB airways, as the pressure resistance of the nasal cavity is so high that the inhaled aerosol flows mostly through the oral cavity in both cases. Second: The influence of the inhalation route (nasal, oral or combined) on the regional distribution of the deposited particles downstream of the trachea is negligible. Third: Simulations can accurately and credibly predict deposition hotspots. The maximum spatial resolution of predicted deposition achievable by current methods was searched for. The simulations were performed using large-eddy simulation, the flow measurements were done by laser Doppler anemometry and the deposition has been measured by positron emission tomography in a realistic replica of human airways. Limitations and sources of uncertainties of the experimental methods were identified. The results confirmed that the high-pressure resistance of the nasal cavity leads to practically identical velocity profiles, even above the glottis for the mouth, and combined mouth and nose breathing. The distribution of deposited particles downstream of the trachea was not influenced by the inhalation route. The carina of the first bifurcation was not among the main deposition hotspots regardless of the inhalation route or flow rate. On the other hand, the deposition hotspots were identified by both CFD and experiments in the second bifurcation in both lungs, and to a lesser extent also in both the third bifurcations in the left lung.

• Klíčová slova
• Airways, Computational fluid mechanics, Deposition hotspots, Flow, Laser Doppler anemometry, Lungs, Numerical simulations, Particle deposition, Positron emission tomography,
• Publikační typ
• časopisecké články MeSH

Medical aerosols are key elements of current chronic obstructive pulmonary disease (COPD) therapy. Therapeutic effects are conditioned by the delivery of the right amount of medication to the right place within the airways, that is, to the drug receptors. Deposition of the inhaled drugs is sensitive to the breathing pattern of the patients which is also connected with the patient's disease severity. The objective of this work was to measure the realistic inhalation profiles of mild, moderate, and severe COPD patients, simulate the deposition patterns of Symbicort® Turbuhaler® dry powder drug and compare them to similar patterns of healthy control subjects. For this purpose, a stochastic airway deposition model has been applied. Our results revealed that the amount of drug depositing within the lungs correlated with the degree of disease severity. While drug deposition fraction in the lungs of mild COPD patients compared with that of healthy subjects (28% versus 31%), lung deposition fraction characteristic of severe COPD patients was lower by a factor of almost two (about 17%). Deposition fraction of moderate COPD patients was in-between (23%). This implies that for the same inhaler dosage severe COPD patients receive a significantly lower lung dose, although, they would need more.

• Klíčová slova
• aerosol drug deposition, dry powder inhalers, inhalation profile measurements,
• Publikační typ
• časopisecké články MeSH