WYKORZYSTANIE TECHNOLOGII DRUKOWANIA 3D DO MODELOWANIA GÓRNYCH DRÓG ODDECHOWYCH W PEŁNEJ SKALI

The project "Implementation of rapid prototyping for modelling the upper respiratory tract in normal and typical pathologies" investigates the urgent problem of improving the reliability of diagnosis and effectiveness of treatment of disorders of the nasal breathing. Possibilities of modern 3D-printing technology for creation of individual natural anatomical models of the upper respiratory tract and determination of their aerodynamic characteristics are considered. The characteristics of the laminar boundary layer of the air flow in the parietal region of the nasal cavity are investigated under different modes of breathing in normal and with typical disorders of the nasal breathing. The concept of investigation of the aerodynamic indices of the anatomical structures of the respiratory system by the results of test tests of individual full-scale 3D models, obtained by the data of spiral computed tomography, is being developed. Theoretical bases of the method of computer planning of restorative rhinosurgical interventions in patients with chronic diseases of the nasal cavity are grounded, based on the change of the configuration of the anatomical structures of the nasal cavity taking into account the aerodynamic parameters of respiration. Modern distance learning and testing tools are being created to demonstrate the technology developed, to provide theoretical knowledge, practical skills and to solve situational tasks for a wide range of specialists. Development and research of natural patterns of the upper respiratory tract allows for supplementing and expanding the knowledge about the aerodynamic characteristics of the nasal cavity, to make decisions about therapy in a short period of time. Experience of the Laboratory of the Institute for Multiphase Processes (IMP) of the Leibniz Universität Hannover (LUH) in the development and use of rapid prototyping capabilities in biotechnology will provide technical support to the project.Projekt „Wdrożenie szybkiego prototypowania do modelowania górnych dróg oddechowych w normalnych i typowych patologiach” bada pilny problem poprawy wiarygodności diagnozy i skuteczności leczenia zaburzeń oddychania przez nos. Rozważane są możliwości nowoczesnej technologii druku 3D do tworzenia indywidualnych naturalnych modeli anatomicznych górnych dróg oddechowych i określania ich właściwości aerodynamicznych. Charakterystyka laminarnej warstwy granicznej przepływu powietrza w okolicy ciemieniowej jamy nosowej jest badana w różnych trybach oddychania w normalnym i typowym zaburzeniu oddychania przez nos. Opracowywana jest koncepcja badania wskaźników aerodynamicznych struktur anatomicznych układu oddechowego na podstawie wyników testów testowych poszczególnych pełnoskalowych modeli 3D, uzyskanych z danych spiralnej tomografii komputerowej. Podstawy teoretyczne metody komputerowego planowania rekonstrukcyjnych interwencji nosorożców u pacjentów z przewlekłymi chorobami jamy nosowej są oparte na zmianie konfiguracji struktur anatomicznych jamy nosowej z uwzględnieniem parametrów aerodynamicznych oddychania. Tworzone są nowoczesne narzędzia do nauki na odległość i testowania w celu zademonstrowania opracowanej technologii, zapewnienia wiedzy teoretycznej, umiejętności praktycznych i rozwiązywania zadań sytuacyjnych dla szerokiego grona specjalistów. Opracowanie i badanie naturalnych wzorów górnych dróg oddechowych pozwala uzupełnić i poszerzyć wiedzę na temat właściwości aerodynamicznych jamy nosowej w celu podjęcia decyzji o terapii w krótkim okresie czasu. Doświadczenie laboratorium Instytutu Procesów Wielofazowych (IMP) Leibniz Universität Hannover (LUH) w zakresie rozwoju i wykorzystania możliwości szybkiego prototypowania w biotechnologii zapewni wsparcie techniczne dla projektu

Determination of microcharacteristics of air flow in the nasal cavity during breathing

Статья посвящена определению степени травматизации слизистой оболочки носовой полости с турбулентным воздушным потоком. Прохождение воздуха через верхний носовой ход обеспечивает доставку молекул одоривертора в чувствительные области обонятельного анализатора. Изучение характеристик воздушного потока в верхнем носовом проходе позволяет определить границы пристеночного ламинарного воздушного подслоя и изучить назальную аэродинамику на микроуровне. Турбулентный поток способствует чрезмерному высушиванию слизистой оболочки носовой полости, что приводит к ее морфологической перестройке к субатрофическому процессу. Было обнаружено, что толщина ламинарного подслоя составляет около 1 мм, поэтому участок слизистой оболочки подвергается сушке с увеличением турбулентности течения в местах сужения носовой полости (обонятельной щели).The aim of the work is to determine the degree of traumatization of the mucous membrane of the nasal cavity by turbulent air flow. It should be noted that it is especially important to determine in the narrowing of the nasal cavity (olf actory gap), where the mucous membrane is subjected to drying with increasing turbulence of the air flow. Achieving this goal will increase the effectiveness of diagnosis and treatment of respiratory and olfactory disorders and will help to identify the pathogenesis of chronic rinological diseases. An important characteristic of nasal breathing is the distribution of air flow rates along the sections of the nasal cavity. When analyzing the existing approaches, it was determined that the main method of studying the aerodynamics of the nasal cavity is rhinomanometry. However, there is not always a clear correlation between anatomical and functional indicators, as well as subjective feelings of the patient and rhinomanometric data. The passage of air through the upper nasal passage ensures the delivery of odorivector molecules to sensitive areas of the olfactory analyzer. The study of the characteristics of the air flow in the upper nasal passage allows us to determine the boundaries of the near-wall laminar air sublayer and to study nasal aerodynamics at the micro level. Turbulent flow contributes to the excessive drying of the mucous membrane of the nasal cavity, leading to its morphological rearrangement towards the subatrophic process. It was found out that the thickness of the laminar layer is of the order of 1 mm, therefore the protuberances of the mucosa are subjected to drying with increasing turbulence of the flow at the sites of narrowing of the nasal cavity (olfactory gap). The prospect of work is the study of the characteristics of the boundary layer in typical pathologies in various respiratory regimes, which will improve the efficiency of diagnosis and treatment of respiratory and olfactory disorders and will help to identify the pathogenesis of chronic rinological diseases

Determination of microcharacteristics of air flow in the nasal cavity during breathing

Статья посвящена определению степени травматизации слизистой оболочки носовой полости с турбулентным воздушным потоком. Прохождение воздуха через верхний носовой ход обеспечивает доставку молекул одоривертора в чувствительные области обонятельного анализатора. Изучение характеристик воздушного потока в верхнем носовом проходе позволяет определить границы пристеночного ламинарного воздушного подслоя и изучить назальную аэродинамику на микроуровне. Турбулентный поток способствует чрезмерному высушиванию слизистой оболочки носовой полости, что приводит к ее морфологической перестройке к субатрофическому процессу. Было обнаружено, что толщина ламинарного подслоя составляет около 1 мм, поэтому участок слизистой оболочки подвергается сушке с увеличением турбулентности течения в местах сужения носовой полости (обонятельной щели).The aim of the work is to determine the degree of traumatization of the mucous membrane of the nasal cavity by turbulent air flow. It should be noted that it is especially important to determine in the narrowing of the nasal cavity (olf actory gap), where the mucous membrane is subjected to drying with increasing turbulence of the air flow. Achieving this goal will increase the effectiveness of diagnosis and treatment of respiratory and olfactory disorders and will help to identify the pathogenesis of chronic rinological diseases. An important characteristic of nasal breathing is the distribution of air flow rates along the sections of the nasal cavity. When analyzing the existing approaches, it was determined that the main method of studying the aerodynamics of the nasal cavity is rhinomanometry. However, there is not always a clear correlation between anatomical and functional indicators, as well as subjective feelings of the patient and rhinomanometric data. The passage of air through the upper nasal passage ensures the delivery of odorivector molecules to sensitive areas of the olfactory analyzer. The study of the characteristics of the air flow in the upper nasal passage allows us to determine the boundaries of the near-wall laminar air sublayer and to study nasal aerodynamics at the micro level. Turbulent flow contributes to the excessive drying of the mucous membrane of the nasal cavity, leading to its morphological rearrangement towards the subatrophic process. It was found out that the thickness of the laminar layer is of the order of 1 mm, therefore the protuberances of the mucosa are subjected to drying with increasing turbulence of the flow at the sites of narrowing of the nasal cavity (olfactory gap). The prospect of work is the study of the characteristics of the boundary layer in typical pathologies in various respiratory regimes, which will improve the efficiency of diagnosis and treatment of respiratory and olfactory disorders and will help to identify the pathogenesis of chronic rinological diseases

Determination of microcharacteristics of air flow in the nasal cavity during breathing

Статья посвящена определению степени травматизации слизистой оболочки носовой полости с турбулентным воздушным потоком. Прохождение воздуха через верхний носовой ход обеспечивает доставку молекул одоривертора в чувствительные области обонятельного анализатора. Изучение характеристик воздушного потока в верхнем носовом проходе позволяет определить границы пристеночного ламинарного воздушного подслоя и изучить назальную аэродинамику на микроуровне. Турбулентный поток способствует чрезмерному высушиванию слизистой оболочки носовой полости, что приводит к ее морфологической перестройке к субатрофическому процессу. Было обнаружено, что толщина ламинарного подслоя составляет около 1 мм, поэтому участок слизистой оболочки подвергается сушке с увеличением турбулентности течения в местах сужения носовой полости (обонятельной щели).The aim of the work is to determine the degree of traumatization of the mucous membrane of the nasal cavity by turbulent air flow. It should be noted that it is especially important to determine in the narrowing of the nasal cavity (olf actory gap), where the mucous membrane is subjected to drying with increasing turbulence of the air flow. Achieving this goal will increase the effectiveness of diagnosis and treatment of respiratory and olfactory disorders and will help to identify the pathogenesis of chronic rinological diseases. An important characteristic of nasal breathing is the distribution of air flow rates along the sections of the nasal cavity. When analyzing the existing approaches, it was determined that the main method of studying the aerodynamics of the nasal cavity is rhinomanometry. However, there is not always a clear correlation between anatomical and functional indicators, as well as subjective feelings of the patient and rhinomanometric data. The passage of air through the upper nasal passage ensures the delivery of odorivector molecules to sensitive areas of the olfactory analyzer. The study of the characteristics of the air flow in the upper nasal passage allows us to determine the boundaries of the near-wall laminar air sublayer and to study nasal aerodynamics at the micro level. Turbulent flow contributes to the excessive drying of the mucous membrane of the nasal cavity, leading to its morphological rearrangement towards the subatrophic process. It was found out that the thickness of the laminar layer is of the order of 1 mm, therefore the protuberances of the mucosa are subjected to drying with increasing turbulence of the flow at the sites of narrowing of the nasal cavity (olfactory gap). The prospect of work is the study of the characteristics of the boundary layer in typical pathologies in various respiratory regimes, which will improve the efficiency of diagnosis and treatment of respiratory and olfactory disorders and will help to identify the pathogenesis of chronic rinological diseases

Visualization of the olfactory slit

Статья посвящена проблеме визуализации обонятельной щели. Изучение процесса восприятия и идентификации пахучих веществ необходимо для многих отраслей жизнедеятельности человека: от парфюмерии и рекламного бизнеса до оборонной промышленности. Обонятельная щель является одной из основных составляющих частей обонятельного анализатора, поэтому визуализация ее внутренних структур представляет собой важную задачу для исследования процесса восприятия запахов. Рассмотрены основные методы визуализации верхних дыхательных путей.Purpose of work is consider possibilities of visualization of the olfactory slit for diagnostics of pathological conditions of the upper respiratory tract. The objectives of the work are the analysis of hardware and imaging techniques structures olfactory analyzer. Traditionally introscopic diagnosis of diseases of the nasal cavity was performed by X-ray. At the present stage, to determine the configuration of the upper respiratory tract is expedient to use X-ray data spiral computed tomography. Visualization of the olfactory slit by digital volume tomography is recommended as the most informative methods in the complex preoperative examination of patients with diseases of the nose and paranasal sinuses, which are planned surgical intervention in the olfactory slit. Imaging Systems of computer tomographs often have modules dimensional (2D), as well as space (3D) processing and display of data. In the 2D module implements the functionality of building multiplanar reconstruction and segmentation of tomographic images on individual anatomical structures. When forming tomographic images reconstructed by means of spiral CT region seems set of elementary volumes - voxels (voxel - volume element), each of which is characterized by the density in Hounsfield units NU. Thus, the presented methods and imaging hardware olfactory slit through which is carried a correct diagnosis of pathological conditions of the upper respiratory tract, in particular the olfactory apparatus. considered methods make it possible to develop algorithms to generate optimal endosurgical access based on process modeling of of surgical interventions and post-operative monitoring of the patients

Microencapsulación de nanopartículas de quitosano para la administración pulmonar de macromoléculas terapéuticas

[ES] El objetivo de esta tesis doctoral ha sido el diseño de sistemas microparticulares capaces de actuar como vehículos de nanopartículas de quitosano, obtenidas por gelificación iónica, y de complejos de lípidos y nanopartículas de quitosano hacía el pulmón, con el fin de conseguir una absorción pulmonar de la macromolécula terapéutica asociada a las nanopartículas. Para ello, se ha seleccionado como excipiente el manitol y como procedimiento de microencapsulación la técnica de atomización, optimizando las condiciones de este proceso para obtener microsferas con propiedades morfológicas y aerodinámicas adecuadas para su administración por vía pulmonar. Para la preparación de los sistemas complejos de lípidos y nanopartículas de quitosano, se han elegido dos lípidos endógenos del pulmón, la dipalmitoilfosfatidilcolina (DPPC) y el dimiristoilfosfatidilglicerol (DMPG), con carga neutra y negativa, respectivamente, y se ha comprobado que el recubrimiento lipídico de las nanopartículas es más eficaz cuando ambos fosfolípidos están presentes en la formulación. El análisis estructural de las microsferas conteniendo nanopartículas, ha demostrado que éstas se distribuyen uniformemente en la matriz de manitol. Utilizando la insulina y la albúmina bovina marcada con isotiocianato de fluoresceína (FITC-BSA) como modelos, se ha evidenciado el potencial de ambos sistemas para asociar péptidos y proteínas. Además, se ha observado que el proceso de atomización no produce ningún efecto negativo sobre las propiedades de los sistemas encapsulados, ni en el perfil de liberación de la insulina a partir de los mismos. Los estudios realizados con las microsferas conteniendo nanopartículas en dos líneas celulares del epitelio respiratorio (Calu-3 y A549), han demostrado la biocompatibilidad del sistema, evidenciando además fenómenos de mucoadhesión. Por otro lado, estudios preliminares in vivo realizados con este mismo sistema, tras la administración intratraqueal a ratas, han demostrado que las microsferas alcanzan el espacio alveolar, siendo más eficaces en la reducción de los niveles de glucosa que la disolución de insulina con una dosis equivalente. En definitiva, el conjunto de los resultados obtenidos en este trabajo experimental pone de manifiesto el interés de estos sistemas como vehículos para la administración pulmonar de péptidos y proteínas terapéuticos.[EN] The goal of this thesis was the design of microparticulate systems which act as vehicles of chitosan nanoparticles and complexes formed between nanoparticles, produced by ionic gelation, and lipids, to the lung, in order to achieve a pulmonary absorption of the therapeutic macromolecule associated to the nanoparticles. To do so, manitol and spray-drying were selected as excipient and microencapsulation technique, respectively, and the process parameters were optimized to obtain microspheres with such morphological and aerodynamic properties, that allowed their lung delivery. To prepare the lipid/nanoparticles complexes, we chose two endogenous lipids of the lung, dipalmitoylphophatidylcholine (DPPC) and dimyristoylphosphatidylglycerol (DMPG), with neutral and negative charge, respectively. It was demonstrated that the lipidic coating of the nanoparticles was more efficient when both phospholipids were present in the formulation. The structural analysis of microspheres containing nanoparticles showed that nanoparticles are homogeneously distributed in the mannitol microspheres. Using insulin and fluorescein isothiocyanate albumin (FITC-BSA) as models, the potential of both drug delivery systems to associate peptides and proteins was elicited. Moreover, it was observed that the spray-drying process does not induce any negative effect neither on the characteristics of the microencapsulated systems, nor on the insulin release profile. Studies performed with microspheres containing nanoparticles, in two respiratory epithelial cell lines (Calu-3 and A549), revealed the system biocompatibility, evidencing also mucoadhesion properties. Furthermore, preliminary in vivo studies performed with this system, upon intratracheal administration to rats, demonstrated that microspheres reach the alveolar region, providing significantly better hypoglycemic effect as compared to a an insulin solution of similar dose. As a whole, results obtained from this experimental work evidenced the interest of these systems as vehicles for the pulmonary administration of therapeutic macromolecules

Particle depositions in multi stage liquid impinger as simplified lung model using computational fluid dynamic

Inhaled medication is typically used to treat obstructive pulmonary disease and systemic diseases. The effectiveness of pulmonary drug delivery depends on the amount of drug deposited beyond the oropharyngeal region, the place where the deposition and the uniform distribution occurred. In this study, the performance of multistage liquid impinger (MSLI) simplified model which imitates the physiological lung in delivering the drug was analyzed. In order to achieve this main aim, the airflow patterns and particle depositions efficiency were evaluated in MSLI simplified model using computational fluid dynamic of COMSOL® software. The particle deposition efficiency is studied by varying flowrates (30.0 L/min, 60.0 L/min and 100.0 L/min) and particle sizes (0.1, 1.0, 3.0, 5.0, 10.0 pm) of salbutamol sulphate (density 20.0 kg/m3). The highest particle deposition occurred at flowrate 100.0 L/min and particle size of 1.0 pm as the deposition yield was 15.55% compared to flowrate 60 L/min and 30 L/min which were 10.50% and 3.09% respectively. Previous studies claimed that higher inhalation flowrate generated dispersion forces for sufficient inhalation flowrate thus enhanced higher deposition efficiency. The paired-samples T-test shows there were significant different (t= -15.400, df= 4, p <0.05) in the performance of particle depositions in MSLI simplified model with different flow rates (60.0 L/min and 100.0 L/min). Thus, the efficient fine particle deposition was significantly contributed by higher flowrate. This study also revealed that particle size ranges from 1.0 to 3.0 pm was the most suitable for inhalation treatment. Smaller particle size less than 1.0 pm was not suitable as it tended to exhale before it deposit of while larger particle (more than 5.0 pm) was not suitable for inhaled drug. In conclusion, vigorous air flow pattern promotes higher particle deposition. For efficient fine particle depositions, it is important to consider not only the particle size distribution, but also the flowrate as vital aerosol transportation agent. Statistical analysis, two-way ANOVA indicated that there was a statistically significant interaction between the effect of flowrate and particle size on particle deposition efficiency, F (8, 30)=5.857, p=0.00

Synthesis of pH responsive carriers for pulmonary drug delivery of anti-tuberculosis therapeutics: mesoporous silica nanoparticles and gelatin nanoparticles

Pulmonary drug delivery has historically been used as a route for delivery of therapeutics for respiratory disease management. However, while there are many advantages, there are also some serious limitations, arising mostly from the physical aspects of the inhaler devices. This is more profound when the devices are the driving force for controlling particle size generation, which results in non-uniform particles that end up being swallowed/wasted/expelled. One promising solution to overcome this limitation is to pre-formulate nano/microscale particles with a high degree of manufacturing control. Nanomedicine has advanced such that there are already several nanoparticle formulations commercially available. In the case of tuberculosis treatment, there is an opportunity not only to examine the use of nanoparticles for inhalation therapy, but to take advantage of the fact that the physiochemical environment of diseased tissue is significantly different to health lung tissue (lower pH and increased enzyme concentrations). We formulated two series of nanoparticles, whose design included moieties that could respond to pH and enzymes. To address variability, a Box-Behnken statistical approach was followed to construct mesoporous silica nanoparticles. These “hard nanoparticles” can entrap both lipophilic and hydrophilic drugs and were coated with a pH-sensitive hydrazone linker. It was observed that pH, calcination temperature and ratio of water to silica source played the greatest role, not only in controlling the physicochemical properties of the nanoparticles but also the drug release rate. A second series of nanoparticles were synthesized based on gelatin. This was done partly to add support the comparison of hard (inorganic silica) versus soft, organic particles, but also to enable enzymatic degradation and drug release. Again, diseased lung tissue expresses increased concentrations of gelatinase enzymes that could be used to stimulate drug release at the site of the disease. In addition, it was observed that the non-ionic surfactant C12E10 could interact with the protein via hydrophobic interactions thus affecting the gelatin folding. The folding states affected crosslinking with the pH responsive linker, which in turn affected the rate of drug release. To support the synthetic work, we sought to develop a unique 3D lung model directly from MRI data of tuberculosis infected lungs. This would not only permit the evaluation of our nanoparticles but could be used as a proxy for in-vivo studies in future to predict lung deposition in diseased lung. Thus, this study shows that it is possible to synthesize pH and enzyme sensitive nanoparticles for pulmonary drug delivery in the treatment and management of pulmonary tuberculosis. These particles could be loaded with either hydrophobic or hydrophilic drugs and their distribution in the airway modelled using an in-silico 3D model based on real data. Further development and verification of these results should improve treatment for pulmonary diseases and conditions such as tuberculosis. This is especially urgent in the face of multi-drug resistance and poor side effects profiles for current treatment

Particulate distribution and relationship to endotoxin in poultry production operations

This thesis dissertation assessed workers who work in poultry barns and their occupational environment in relation to the type of bird housing in which they were exposed (cage-housed birds (CH) or floor-housed birds (FH)) and examined the environmental variables including dust and endotoxin and potential relationships to respiratory symptoms of workers. A cross sectional study was undertaken to assess the environmental exposure levels and respiratory health effects of workers who worked in CH and FH poultry operations. The respiratory results suggested an asthma-like syndrome in these workers. Workers who worked in CH facilities reported greater current and chronic respiratory symptoms and significantly greater current and chronic phlegm as compared to workers from FH facilities. Workers from CH poultry facilities were exposed to greater endotoxin load than workers from FH facilities, but workers from FH operations were exposed to greater levels of total dust. It was found that endotoxin load (EU/mg) was a significant predictor of chronic phlegm for all poultry workers.The effects on dust and endotoxin measurements when utilizing a Marple impactor with greased or ungreased impaction surfaces when sampling in an agricultural environment were unknown, and the potential for effects was tested. There were no significant differences in the aerosol mass median aerodynamic diameters between the greased and ungreased Marple impactors. Endotoxin analysis results appeared to be influenced by impaction grease particularly when very low amounts of endotoxin were present. Size fractioning the dust and endotoxin using Marple impactors in CH and FH poultry operations showed that endotoxin load (EU/mg) was significantly higher in the respirable fraction of area samples in CH poultry operations as compared to FH operations. There were no differences in endotoxin load in the non-respirable size fractions for area samples between CH and FH operations. FH poultry operations had significantly greater dust mass and dust concentration in both respirable and non-respirable fractions for FH operations. There was significantly greater endotoxin load (EU/mg) in the 3.5-6.0 micron size fraction for the CH poultry operations as compared to the FH operations

Strategies and Devices for Improving Respiratory Drug Delivery to Infants and Children with Cystic Fibrosis

Cystic Fibrosis (CF) is a degenerative disease, which causes thickening of the airway surface liquid and reduced mucociliary clearance, which provides an ideal habitat for bacterial infections. Early treatment of CF in children can prevent chronic infection, improve quality of life, and increase life expectancy. The most predominant bacteria found in CF-diseased lungs is Pseudomonas aeruginosa (Pa), which can be treated with inhaled tobramycin. Excipient enhanced growth (EEG) powder formulations are well suited for administering tobramycin to children, as the EEG approach provides minimal upper airway loss and targeted drug delivery. This method uses an initially small aerosol for high extrathroacic transmission, and includes hygroscopic excipients within the formulation that absorb moisture from the humid airways and increase lung retention of the aerosol. The overarching goal of this work was to develop delivery systems and strategies for improving respiratory drug delivery to children with CF, which was based on insights from computational fluid dynamics (CFD) simulations and in vitro models. The studies presented in this dissertation have three distinct and sequential phases: (i) CFD methods development; (ii) respiratory device design and optimization; and (iii) complete-airway modeling for aerosol delivery strategy development. The methods development phase produced meshing and solution guidelines that were computationally-efficient, accurate, and validated based on in vitro data. Results showed that the two-equation k-ω model, with near-wall corrections, was capable of matching experimental data across a range of Reynolds numbers and particle sizes that are specific to respiratory drug delivery. The guidelines also provided comparable accuracy to the more complex Large Eddy Simulation (LES) model, while providing multiple order-of-magnitude savings in computational time. The device optimization phase developed a highly efficient delivery system for tobramycin administration to pediatric CF patients. Correlations were developed, based on flow field quantities, that were predictive of aerosolization performance and depositional loss. Successful a priori validation with experimental testing highlighted the predictive capabilities of the correlations and CFD model accuracy. The best-case delivery system demonstrated an aerosol size of approximately 1.5 µm and expected lung dose of greater than 75% of loaded dose, which is a marked improvement compared to commercial devices. The delivery strategy development phase identified optimal EEG aerosol properties that better unify drug surface concentration. These studies present numerical models of a tobramycin EEG powder formulation for the first time, and provide the first instance of a complete-airway CFD model evaluating pediatric CF lungs. Results show that EEG aerosols are capable of delivering the drug above the minimum inhibitory concentration in all airway regions, reducing regional dose variability, and targeting the lower airways where infection is more predominant. In conclusion, results from this dissertation demonstrate: (i) accurate and efficient CFD models of respiratory drug delivery; (ii) optimized designs for respiratory delivery systems; and (iii) optimal delivery strategies for inhaled tobramycin to pediatric patients with CF