Internal microdosimetry of alpha-emitting radionuclides.

At the tissue level, energy deposition in cells is determined by the microdistribution of alpha-emitting radionuclides in relation to sensitive target cells. Furthermore, the highly localized energy deposition of alpha particle tracks and the limited range of alpha particles in tissue produce a highly inhomogeneous energy deposition in traversed cell nuclei. Thus, energy deposition in cell nuclei in a given tissue is characterized by the probability of alpha particle hits and, in the case of a hit, by the energy deposited there. In classical microdosimetry, the randomness of energy deposition in cellular sites is described by a stochastic quantity, the specific energy, which approximates the macroscopic dose for a sufficiently large number of energy deposition events. Typical examples of the alpha-emitting radionuclides in internal microdosimetry are radon progeny and plutonium in the lungs, plutonium and americium in bones, and radium in targeted radionuclide therapy. Several microdosimetric approaches have been proposed to relate specific energy distributions to radiobiological effects, such as hit-related concepts, LET and track length-based models, effect-specific interpretations of specific energy distributions, such as the dual radiation action theory or the hit-size effectiveness function, and finally track structure models. Since microdosimetry characterizes only the initial step of energy deposition, microdosimetric concepts are most successful in exposure situations where biological effects are dominated by energy deposition, but not by subsequently operating biological mechanisms. Indeed, the simulation of the combined action of physical and biological factors may eventually require the application of track structure models at the nanometer scale.

The degree of inhomogeneity of the absorbed cell nucleus doses in the bronchial region of the human respiratory tract.

Inhalation of short-lived radon progeny is an important cause of lung cancer. To characterize the absorbed doses in the bronchial region of the airways due to inhaled radon progeny, mostly regional lung deposition models, like the Human Respiratory Tract Model (HRTM) of the International Commission on Radiological Protection, are used. However, in this model the site specificity of radiation burden in the airways due to deposition and fast airway clearance of radon progeny is not described. Therefore, in the present study, the Radact version of the stochastic lung model was used to quantify the cellular radiation dose distribution at airway generation level and to simulate the kinetics of the deposited radon progeny resulting from the moving mucus layer. All simulations were performed assuming an isotope ratio typical for an average dwelling, and breathing mode characteristic of a healthy adult sitting man. The study demonstrates that the cell nuclei receiving high doses are non-uniformly distributed within the bronchial airway generations. The results revealed that the maximum of the radiation burden is at the first few bronchial airway generations of the respiratory tract, where most of the lung carcinomas of former uranium miners were found. Based on the results of the present simulations, it can be stated that regional lung models may not be fully adequate to describe the radiation burden due to radon progeny. A more realistic and precise calculation of the absorbed doses from the decay of radon progeny to the lung requires deposition and clearance to be simulated by realistic models of airway generations.

Stability test of novel combined formulated dry powder inhalation system containing antibiotic: physical characterization and in vitro-in silico lung deposition results.

Objective: The aim was to study the stability of dry powder inhaler (DPI) formulations containing antibiotic with different preparation ways - carrier-based, carrier-free, and novel combined formulation - and thereby to compare their physicochemical and in vitro-in silico aerodynamical properties before and after storage. Presenting a novel combined technology in the field of DPI formulation including the carrier-based and carrier-free methods, it is the most important reason to introduce this stable formulation for the further development of DPIs. Methods: The structure, the residual solvent content, the interparticle interactions, the particle size distribution and the morphology of the samples were studied. The aerodynamic values were determined based on the cascade impactor in vitro lung model. We tested the in silico behavior of the novel combined formulated samples before and during storage. Results: The physical measurements showed that the novel combined formulated sample was the most favorable. It was found that thanks to the formulation technique and the use of magnesium stearate (MgSt) has a beneficial effect on the stability compared with the carrier-based formulation without MgSt and carrier-free formulations. The results of in vitro and in silico lung models were consistent with the physical results, so the highest deposition was found for the novel combined formulated sample during the storage. Conclusions: It can be established that after the storage a novel combined formulated DPI contained amorphous drug to have around 2.5 µm mass median aerodynamic diameter and nearly 50% fine particle fraction predicted high lung deposition in silico also.

Comparison of airway deposition distributions of particles in healthy and diseased workers in an Egyptian industrial site.

The objective of this study is the prediction and comparison of airway deposition patterns of an industrial aerosol in healthy workers and workers suffering from silicosis. Mass concentrations and related size distributions of particulate matter were measured in the industrial area of Samalut in Minia, Egypt. A novel stochastic lung deposition model, simulating the symptoms of silicosis by chronic bronchial (Br) obstruction and emphysema in the acinar (Ac) region, was applied to compute mass deposition fractions, deposition density, deposition rate and deposition density rate distributions in healthy and diseased workers. In the case of healthy workers, both mass deposition fractions and deposition rates are highest in the first half of the Ac region of the lung, while the corresponding deposition density and deposition density rate distributions exhibit a maximum in the large Br airways. In the case of diseased lungs, bullous emphysema causes a large deposition peak in the region of the bronchioli respiratorii. Regional mass deposition fractions adopt maximum values in the extrathoracic region, except during mouth breathing for bullous emphysema, where Ac deposition can be the most prominent. In general, lung deposition is significantly higher in diseased than in healthy lungs. Indeed, workers suffering from silicosis receive significantly higher Ac doses than healthy workers exposed to the same aerosol. Thus, this illness may progress faster if a diseased worker remains in a strongly polluted area.

Mutation induction by inhaled radon progeny modeled at the tissue level.

The observable responses of living systems to ionizing radiation depend on the level of biological organization studied. Understanding the relationships between the responses characteristic of the different levels of organization is of crucial importance. The main objective of the present study is to investigate how some cellular effects of radiation manifest at the tissue level by modeling mutation induction due to chronic exposure to inhaled radon progeny. For this purpose, a mathematical model of the bronchial epithelium was elaborated to quantify cell nucleus hits and cell doses. Mutagenesis was modeled considering endogenous as well as radiation-induced DNA damages and cell cycle shortening due to cell inactivation. The model parameters describing the cellular effects of radiation are obtained from experimental data. Cell nucleus hits, cell doses, and mutation induction were computed for the activity hot spots of the large bronchi at different exposures. Results demonstrate that the mutagenic effect of densely ionizing radiation is dominated by cell cycle shortening due to cell inactivation and not by DNA damages. This suggests that radiation burdens of non-progenitor cells play a significant role in mutagenesis in case of protracted exposures to densely ionizing radiation. Mutation rate as a function of dose rate exhibits a convex shape below a threshold. This threshold indicates the exhaustion of the tissue regeneration capacity of local progenitor cells. It is suggested that progenitor cell hyperplasia occurs beyond the threshold dose rate, giving a possible explanation of the inverse dose-rate effect observed in the epidemiology of lung cancer among uranium miners.

Effect of site-specific bronchial radon progeny deposition on the spatial and temporal distributions of cellular responses.

Inhaled short-lived radon progenies may deposit in bronchial airways and interact with the epithelium by the emission of alpha particles. Simulation of the related radiobiological effects requires the knowledge of space and time distributions of alpha particle hits and biological endpoints. Present modelling efforts include simulation of radioaerosol deposition patterns in a central bronchial airway bifurcation, modelling of human bronchial epithelium, generation of alpha particle tracks, and computation of spatio-temporal distributions of cell nucleus hits, cell killing and cell transformation events. Simulation results indicate that the preferential radionuclide deposition at carinal ridges plays an important role in the space and time evolution of the biological events. While multiple hits are generally rare for low cumulative exposures, their probability may be quite high at the carinal ridges of the airway bifurcations. Likewise, cell killing and transformation events also occur with higher probability in this area. In the case of uniform surface activities, successive hits as well as cell killing and transformation events within a restricted area (say 0.5 mm(2)) are well separated in time. However, in the case of realistic inhomogeneous deposition, they occur more frequently within the mean cycle time of cells located at the carinal ridge even at low cumulative doses. The site-specificity of radionuclide deposition impacts not only on direct, but also on non-targeted radiobiological effects due to intercellular communication. Incorporation of present results into mechanistic models of carcinogenesis may provide useful information concerning the dose-effect relationship in the low-dose range.

Quantification of airway deposition of intact and fragmented pollens.

Although pollen is one of the most widespread agents that can cause allergy, its airway transport and deposition is far from being fully explored. The objective of this study was to characterize the airway deposition of pollens and to contribute to the debate related to the increasing number of asthma attacks registered after thunderstorms. For the quantification of the deposition of inhaled pollens in the airways computer simulations were performed. Our results demonstrated that smaller and fragmented pollens may penetrate into the thoracic airways and deposit there, supporting the theory that fragmented pollen particles are responsible for the increasing incidence of asthma attacks following thunderstorms. Pollen deposition results also suggest that children are the most exposed to the allergic effects of pollens. Finally, pollens between 0.5 and 20 µm deposit more efficiently in the lung of asthmatics than in the healthy lung, especially in the bronchial region.

Deposition distribution of the new coronavirus (SARS-CoV-2) in the human airways upon exposure to cough-generated droplets and aerosol particles.

The new coronavirus disease 2019 (COVID-19) has been emerged as a rapidly spreading pandemic. The disease is thought to spread mainly from person-to-person through respiratory droplets produced when an infected person coughs, sneezes, or talks. The pathogen of COVID-19 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It infects the cells binding to the angiotensin-converting enzyme 2 receptor (ACE2) which is expressed by cells throughout the airways as targets for cellular entry. Although the majority of persons infected with SARS-CoV-2 experience symptoms of mild upper respiratory tract infection, in some people infections of the acinar airways result in severe, potentially fatal pneumonia. However, the induction of COVID-19 pneumonia requires that SARS-CoV-2 reaches the acinar airways. While huge efforts have been made to understand the spread of the disease as well as the pathogenesis following cellular entry, much less attention is paid to how SARS-CoV-2 from the environment reach the receptors of the target cells. The aim of the present study is to characterize the deposition distribution of SARS-CoV-2 in the airways upon exposure to cough-generated droplets and aerosol particles. For this purpose, the Stochastic Lung Deposition Model has been applied. Particle size distribution, breathing parameters supposing normal breathing through the nose, and viral loads were taken from the literature. We found that the probability of direct infection of the acinar airways due to inhalation of particles emitted by a bystander cough is very low. As the number of viruses deposited in the extrathoracic airways is about 7 times higher than in the acinar airways, we concluded that in most cases COVID-19 pneumonia must be preceded by SARS-CoV-2 infection of the upper airways. Our results suggest that without the enhancement of viral load in the upper airways, COVID-19 would be much less dangerous. The period between the onset of initial symptoms and the potential clinical deterioration could provide an opportunity for prevention of pneumonia by blocking or significantly reducing the transport of viruses towards the acinar airways. Therefore, even non-specific treatment forms like disinfection of the throat and nasal and oral mucosa may effectively keep the viral load of the upper airways low enough to avoid or prolong the progression of the disease. In addition, using a tissue or cloth in order to absorb droplets and aerosol particles emitted by own coughs of infected patients before re-inhalation is highly recommended even if they are alone in quarantine.

Stochastic aspects of primary cellular consequences of radon inhalation.

In this study, a composite, biophysical mechanism-based microdosimetric model was developed for the assessment of the primary cellular consequences of radon inhalation. Based on the concentration of radio-aerosols in the inhaled air and the duration of exposure, this mathematical approach allows the computation of the distribution of cellular burdens and the resulting distribution of cellular inactivation and oncogenic transformation probabilities within the epithelium of the human central airways. The composite model is composed of three major parts. The first part is a lung-particle interaction model applying computational fluid and particle dynamics (CFPD) methods. The second part is a lung dosimetry model that quantifies the cellular distribution of radiation exposure within the bronchial epithelium. The third part of the composite model is the unit-track-length model, which allows the prediction of the biological outcome of the exposure at the cellular level. Computations were made for different exposure durations for a miner working in a New Mexico uranium mine. The spatial pattern of the exposed cell nuclei along the epithelium, the distributions of single and multiple alpha-particle hits, the distributions of cell nucleus doses, and cell inactivation and cell transformation probabilities as a function of the number of inhalations (length of exposure) were investigated and compared for up to 500 inhalations.

Simulation and minimisation of the airway deposition of airborne bacteria.

Respiratory infections represent one of the most important bioaerosol-associated health effects. Bacteria are infectious micro-organisms that may, after inhalation, cause specific respiratory diseases. Although a large number of inhalable pathogenic bacteria have been identified and the related respiratory symptoms are well known, their airway transport and deposition are still not fully explored. The objective of this work was to characterise the deposition of inhaled bacteria in different regions of the lung and to find the optimum breathing modes, which ensure the minimum chance of a bacterial infection in a given environment. For this purpose a stochastic computer lung model has been applied. In order to find the breathing pattern that yields the lowest deposited fraction of the inhaled particles, multiple simulations were carried out with several combinations of tidal volumes ranging from 400 to 2000 ml, and breathing cycles ranging from 2 to 10 s. Particle aerodynamic diameters varied between 1 and 20 mum, and simulations were performed for both nose and mouth breathing conditions. Present computations demonstrated that regional (extrathoracic, tracheobronchial, acinar), lobar, and generation number-specific deposition distributions of the inhaled particles are highly sensitive to their aerodynamic diameter and to the breathing parameters. According to our results, mouth breathing with short breathing periods, no breath hold, and low tidal volumes minimises the total respiratory system deposition. On the other hand, lung (bronchial and acinar) deposition can be minimised by a breathing mode characterised by short breathing cycles through the nose with long breath holds after exhalations and high tidal volumes.

Modelling of cell deaths and cell transformations of inhaled radon in homes and mines based on a biophysical and microdosimetric model.

PURPOSE: In this study a biophysical mechanism-based microdosimetric model was applied to predict the biological effects of inhaled radon progenies in homes and in uranium mines. MATERIALS AND METHODS: The radon daughter concentrations of more than 2000 homes were averaged in case of home exposure and the New Mexico uranium mine data were used in case of exposure in mines. The complex microdosimetric model applied in this work was developed by combining a computational fluid and particle dynamics (CFPD) lung model with a lung dosimetry model that quantify the local distribution of radiation burden and the Unit-Track-Length Model, which characterizes the biological outcome of the exposure. RESULTS: Our results show that the inhomogeneity of radon daughter deposition is stronger in the case of mines. Consequently, the numbers of cells which receive multiple hits and the maxima of radiation burdens are significantly higher in mines. In contrast to this, the distributions and maximum values of cell transformation probabilities are very similar in the two cases. CONCLUSIONS: If the same amounts of inhaled progenies are considered then primary cellular consequences are very similar in case of homes and mines, however, the local maxima of radiation burden are higher in mines.

Three-dimensional model for aerosol transport and deposition in expanding and contracting alveoli.

Particle transport and deposition within a model alveolus, represented by a rhythmically expanding and contracting hemisphere, was modeled by a three-dimensional analytical model for the time-dependent air velocity field as a superposition of uniform and radial flow components, satisfying both the mass and momentum conservation equations. Trajectories of particles entrained in the airflow were calculated by a numerical particle trajectory code to compute simultaneously deposition by inertial impaction, gravitational sedimentation, Brownian diffusion, and interception. Five different orientations of the orifice of the alveolus relative to the direction of gravity were selected. Deposition was calculated for particles from 1 nm to 10 microm, for 3 breathing conditions, and for 5 different entrance times relative to the onset of inspiration. For the analyzed cases, the spatial orientation of the orifice of an alveolus has practically no effect on deposition for particles below about 0.1 microm, where deposition is dominated by Brownian motion. Above about 1 microm, where deposition is governed primarily by gravitational settling, deposition can vary from 0 to 100%, depending on the spatial orientation, while deposition of particles 0.1-1 microm falls between these two extreme cases. Due to the isotropic nature of Brownian motion, deposition of the 10-nm particles is practically uniform for all spatial orientations. However, for larger particles, deposition can be quite inhomogeneous, consistent with the direction of gravity. While nearly all particles are exhaled during the successive expiration phase, there are a few cases where particles still leave the alveolus even after many breathing cycles.

Quantification of particle deposition in asymmetrical tracheobronchial model geometry.

The primary objective of this study was to quantify the local inspiratory and expiratory aerosol deposition in a highly asymmetric five-generation tracheobronchial tree. User-enhanced commercial codes and self-developed software was used to compute the air velocity field as well as particle deposition distributions for a large size range of inhalable particles. The numerical model was validated by comparison of our results with experimental flow measurements and particle deposition data available in the open literature. Our simulations show highly localised deposition patterns for all particle sizes, but mainly for the larger particles. As expected, deposition efficiencies and deposition fractions proved to be very sensitive to the particle size. The deposition density in the hot spots can be hundreds and even thousand times higher than the mean deposition density. Present results can be of interest to researchers involved in the assessment of adverse health effects of inhaled aerosols or optimising the drug aerosol delivery into the lung.

Novel dry powder inhaler formulation containing antibiotic using combined technology to improve aerodynamic properties.

Dry Powder Inhaler (DPI) could offer a propellant-free, easy-to-use powder form ensuring better stability than liquid dosage forms. Therefore the development of traditional carrier-based and carrier-free new generation systems is a determinative factor in the field of DPI formulation. The purpose of our research work was to combine these two systems, utilizing their beneficial properties to produce a novel pulmonary drug delivery system containing ciprofloxacin hydrochloride (CIP). Co-spray drying, surface smoothing and the preparation of an interactive physical mixture were applied as the technological procedures of sample preparation. The carrier-based and carrier-free formulations, as well as the developed novel product were compared to each other. Structural investigations were made by X-ray powder diffraction and micrometric properties (habit, bulk density) were determined. Particle interactions were also evaluated to investigate surface free energy, cohesive-adhesive forces, and spreading coefficient. In vitro aerodynamic properties (mass median aerodynamic diameter), fine particle fraction (FPF) and emitted dose of DPIs were measured using Andersen Cascade Impactor. A novel in silico Stochastic Lung Model was also used to quantify the amount of particles deposited at the target area. The novel-formulated composition presented amorphous spherical particles with an average size of about 2 µm. The in vitro aerodynamic investigations showed a variance in FPF as a function of formulation method (carrier-based: 24%, carrier-free: 54% and applying the novel combination method: 63%). The in silico deposition results were in line with the in vitro measurements and yielded increased lung doses for the sample prepared by the combined technology. This novel DPI formulation provides an opportunity for a more effective therapy with deeper deposition of CIP.

Size distribution, pulmonary deposition and chemical composition of Hungarian biosoluble glass fibers.

Compared to spherical particles, inhaled fibers may cause enhanced adverse health effects because of their specific shape, thus acting as so-called physical carcinogens. The chemical composition of fibers plays a determining role on the durability and hence may play a potential role in related health effects due to their toxic components. The physical properties, that is, length, diameter, and size distribution, and the chemical composition of fiberglass materials sampled at a Hungarian glass wool factory were investigated. The morphology of the particles was studied by optical microscopy and scanning electron microscopy (SEM), while for the chemical analysis instrumental neutron activation analysis (INAA) and SEM combined with energy-dispersive x-ray analysis (EDX) were used. Deposition fractions of the fibers in different regions of the lung and in the whole human respiratory system were computed by a stochastic lung deposition model for different flow rates and equivalent diameters, using experimentally determined size distributions.

Effect of inhomogeneous activity distributions and airway geometry on cellular doses in radon lung dosimetry.

The human tracheobronchial system has a very complex structure including cylindrical airway ducts connected by airway bifurcation units. The deposition of the inhaled aerosols within the airways exhibits a very inhomogeneous pattern. The formation of deposition hot spots near the carinal ridge has been confirmed by experimental and computational fluid and particle dynamics (CFPD) methods. In spite of these observations, current radon lung dosimetry models apply infinitely long cylinders as models of the airway system and assume uniform deposition of the inhaled radon progenies along the airway walls. The aim of this study is to investigate the effect of airway geometry and non-uniform activity distributions within bronchial bifurcations on cellular dose distributions. In order to answer these questions, the nuclear doses of the bronchial epithelium were calculated in three different irradiation situations. (1) First, CFPD methods were applied to calculate the distribution of the deposited alpha-emitting nuclides in a numerically constructed idealised airway bifurcation. (2) Second, the deposited radionuclides were randomly distributed along the surface of the above-mentioned geometry. (3) Finally, calculations were made in cylindrical geometries corresponding to the parent and daughter branches of the bifurcation geometry assuming random nuclide activity distribution. In all three models, the same 218Po and 214Po surface activities per tissue volumes were assumed. Two conclusions can be drawn from this analysis: (i) average nuclear doses are very similar in all three cases (minor differences can be attributed to differences in the linear energy transfer (LET) spectra) and (ii) dose distributions are significantly different in all three cases, with the highest doses at the carinal ridge in case 3.

Significance of breath-hold time in dry powder aerosol drug therapy of COPD patients.

Aerosol drugs are effectively used to treat chronic respiratory diseases. The efficiency of the therapy depends also on the amount and distribution of drug deposited within the airways. The objective of this study is to apply numerical techniques to analyse the effect of the duration of breath-hold after the inhalation of six different commercialized dry powder drugs on their lung deposition. For this purpose a computational airway deposition model has been adapted and validated to the special case of therapeutic aerosols. Our results show that lung dose of the studied drugs can be enhanced by 11.3%-26.5% with a 5s breath-hold and by 20.7%-53% with a 25s breath-hold compared to the no-breath-hold case. Although this later duration may not be achieved by COPD patients, present results clearly show the importance of holding the breath as long as possible. Current computations also revealed that there is a strong positive correlation between the enhancement of lung dose as a result of breath-hold and the amount of fine particles in the drugs. Present tendencies aiming at producing drug particles of smaller and smaller sizes will lead to the further enhancement of the importance of producing a sufficiently long breath-hold time after the drug inhalation. In addition, higher lung deposition will be possible by the more correct use of inhalation devices, more precise and detailed patient information materials and personalized drug choice and therapy.

Aerodynamic properties and in silico deposition of meloxicam potassium incorporated in a carrier-free DPI pulmonary system.

Dry powder inhalers (DPIs) have been among the fastest developing inhaler forms in the past decades. Researches are focusing on the formulation of carrier-free powders to obtain a higher deep-lung deposition and hereby to increase the effectiveness of the medicine. The aim of our study was to prepare a carrier-free dry powder formulation of meloxicam potassium (MP), a novel salt form of meloxicam, using a one-step co-spray drying technology. Different types of excipients were used to modify the crystal structure and to increase aerosolization efficacy. Micrometric properties and the crystal structure were characterized. Aerodynamic properties were tested in vitro using an Andersen Cascade Impactor. A new in silico Stochastic Lung Model was also applied to quantify the amount of particles deposited at the target area. The results have shown that formulated DPI samples are fulfilling the requirements of effective pulmonary drug delivery: they include spherical particles with low density and 1-5µm size distribution. The in silico deposition results correspond with the in vitro measurements and demonstrate that the engineered microcomposites reach a high lung deposition. MP offers a novel opportunity for a well-controlled DPI formulation prepared by a solution-based co-spray drying method.

Experimental and computational study of the effect of breath-actuated mechanism built in the NEXThaler® dry powder inhaler.

The breath-actuated mechanism (BAM) is a mechanical unit included in NEXThaler® with the role of delaying the emission of the drug until the inhalation flow rate of the patient is sufficiently high to detach the drug particles from their carriers. The main objective of this work was to analyse the effect of the presence of BAM on the size distribution of the emitted drug and its airway deposition efficiency and distribution. Study of the hygroscopic growth of the emitted drug particles and its effect on the deposition was another goal of this study. Size distributions of Foster® NEXThaler® drug particles emitted by dry powder inhalers with and without BAM have been measured by a Next Generation Impactor. Three characteristic inhalation profiles of asthmatic patients (low, moderate and high flow rates) were used for both experimental and modelling purposes. Particle hygroscopic growth was determined by a new method, where experimental measurements are combined with simulations. Upper airway and lung deposition fractions were computed assuming 5s and 10s breath-hold times. By the inclusion of BAM the fine particle fraction of the steroid component increased from 24 to 30% to 47-51%, while that of bronchodilator from 25-34% to 52-55%. The predicted upper airway steroid and bronchodilator doses decreased from about 60% to 35-40% due to BAM. At the same time, predicted lung doses increased from about 20%-35% (steroid) and from 22% to 38% (bronchodilator) for the moderate flow profile and from about 25% to 40% (steroid) and from 29% to 47% (bronchodilator) for the high inhalation flow profile. Although BDP and FF upper airway doses decreased by a factor of about two when BAM was present, lung doses of both components were about the same in the BAM and no-BAM configurations at the weakest flow profile. However, lung dose increased by 2-3% even for this profile when hygroscopic growth was taken into account. In conclusion, the NEXThaler® BAM mechanism is a unique feature enabling high emitted fine particle fraction and enhanced drug delivery to the lungs.