Biomedical and biophysical limits to mathematical modeling of pulmonary system mechanics: a scoping review on aerosol and drug delivery.

Undoubtedly, the construction of the biomechanical geometry systems with the help of computer tomography (CT) and magnetic resonance imaging (MRI) has made a significant advancement in studying in vitro numerical models as accurately as possible. However, some simplifying assumptions in the computational studies of the respiratory system have caused errors and deviations from the in vivo actual state. The most important of these hypotheses is how to generate volume from the point cloud exported from CT or MRI images, not paying attention to the wall thickness and its effect in computational fluid dynamic method, statistical logic of aerosol trap in software; and most importantly, the viscoelastic effect of respiratory tract wall in living tissue pointed in the fluid-structure interaction method. So that applying the viscoelastic dynamic mesh effect in the form of the moving deforming mesh can be very effective in achieving more appropriate response quality. Also, changing the volume fraction of the pulmonary extracellular matrix constituents leads to changes in elastic modulus (storage modulus) and the viscous modulus (loss modulus) of lung tissue. Therefore, in the biomedical computational methods where the model wall is considered flexible, the viscoelastic properties of the texture must be considered correctly

CFD modelling of air flow and fine powder deposition in the respiratory tract

This project was to investigate and observe characteristics of micro particles suspended in the ambient air or pharmaceutical aerosols with respect to the mechanisms of deposition in human airways under different inspiratory conditions. Such determination includes pattern observations of inspiratory flow-field of the air, particle trajectory during inspiratory conditions and particle deposition. Computational fluid dynamic (CFD) was employed to simulate above problems, aiming to observe flow-field of the inspiratory air and characteristic of flow turbulence in the respiratory tract as well as particle behaviour in the respiratory tract regarding to the particle deposition. In order to do so, three different airway models were employed for the simulations: two realistic airway models introduced by Kitaoka and Weibel airways model. The motion of micro-sized particles between 1~20 μm were simulated under the steady state two inlet-inspiratory conditions – inhalation condition (60 L/min) and breathing condition (18 L/min); to evaluate deposition efficiency. Inertial impaction was dominantly caused high density deposition of particles in upper tracheobronchial region, particularly in regions where daughter airways bifurcate. Results also showed that the velocity in the first bifurcation of airway was higher than the inlet velocity. Back pressures were been observed in lower generations, and high pressures were been observed at every bifurcation regions. The increase of velocity was observed where the fluid directions rapidly changed. Turbulence kinetic energy was the least in main bronchus of respiratory tract and fluctuated from generation to generation. In Kitaoka’s generation 0-7 model, deposition fractions of 2 μm, 6 μm and 10 μm particles were 6.6%, 60.7% and 91.5% respectively under inhalation condition whereas deposition fractions of such particles were 2.9%, 9.0% and 44.9% under breathing condition. In Kitaoka’s generation 0-11 model, deposition fractions of 2 μm, 6 μm and 10 μm particles were 30.9%, 80.1% and 99.8% respectively under inhalation condition whereas deposition fractions of such particles were 16.2%, 24.4% and 62.6% under breathing condition. Furthermore in Weibel’s generation 3-6 model, deposition fractions of 2 μm, 6 μm and 10 μm particles were 9.7%, 38.3% and 97.4% respectively under inhalation condition whereas deposition fractions of such particles were 3.2%, 15.6% and 56.2% under breathing condition

The effect of rapid maxillary expansion on the upper airway’s aerodynamic characteristics

Background The effect of rapid maxillary expansion (RME) on the upper airway (UA) has been studied earlier but without a consistent conclusion. This study aims to evaluate the outcome of RME on the UA function in terms of aerodynamic characteristics by applying a computational fluid dynamics (CFD) simulation. Methods This retrospective cohort study consists of seventeen cases with two consecutive CBCT scans obtained before (T0) and after (T1) RME. Patients were divided into two groups with respect to patency of the nasopharyngeal airway as expressed in the adenoidal nasopharyngeal ratio (AN): group 1 was comprised of patients with an AN ratio < 0.6 and group 2 encompassing those with an AN ratio ≥ 0.6. CFD simulation at inspiration and expiration were performed based on the three-dimensional (3D) models of the UA segmented from the CBCT images. The aerodynamic characteristics in terms of pressure drop (ΔP), maximum midsagittal velocity (Vms), and maximum wall shear stress (Pws) were compared by paired t-test and Wilcoxon test according to the normality test at T0 and T1. Results The aerodynamic characteristics in UA revealed no statistically significant difference after RME. The maximum Vms (m/s) decreased from 2.79 to 2.28 at expiration after RME (P = 0.057). Conclusion The aerodynamic characteristics were not significantly changed after RME. Further CFD studies with more cases are warranted.publishedVersio

Physiologically based modelling of nanoparticle biodistribution and biokinetics

To predict the toxicity of nanoparticles (1-100 nm), it is crucial to understand their biokinetics i.e. how they are taken up, distributed, dissolved and removed from the body. Such information can be gained from biodistribution studies in animals. However, to make predictions for other types of nanoparticles, exposure conditions and species, including humans, extrapolations from such studies are required. Use of models, such as physiologically based pharmacokinetic (PBPK) models, makes extrapolations feasible, given that the models are sufficiently validated. In this thesis, a conceptual nanospecific PBPK model for intravenous administration to rats was developed and applied to different types of inert nanoparticles using experimental data from recent scientific publications (Papers I and II). The model represents systemic distribution and serves as a foundation for expansion to other species and other exposure routes (inhalation, dermal, oral). The PBPK simulations suggest that the model is able to describe the biokinetics of different types of inert nanoparticles given intravenously despite large differences in properties and exposure conditions. Our model is the first to include separate compartments for phagocytic cells and saturable phagocytosis. The simulations show that (1) phagocytosis needs to be incorporated in nano PBPK models, (2) the dose has a clear impact on biokinetics, but (3) further refinements are needed to better reflect processes such as agglomeration, corona formation and dissolution. The model was slightly modified to describe the biodistribution and biokinetics of nanoceria of different sizes and administered via other routes (Paper III). While the model could well predict the biokinetics after intravenous dosing, the predictions of inhalation, instillation and ingestion data were poor. The poor agreement may be partly due to low absorption via these routes, resulting in low nanoceria levels in tissues and organs, often close to or below the detection limit, in tissues. However, low absorption is hardly the only explanation, as the experimentally observed concentration time courses of nanoceria in tissues suggest that the biokinetics depend not only on the nanoparticle properties (size, coating) but also on the exposure conditions (dose, exposure route). The PBPK model was further developed to account for the complexity of inhalation exposure to nanoparticles (Paper IV). The modified model includes regional particle deposition in the respiratory tract, mucociliary clearance and phagocytosis in the lungs, olfactory uptake, and transport into the systemic circulation by alveolar wall translocation. The PBPK model described the biodistribution well and again suggested phagocytosis to be very important. The PBPK simulations were performed assuming that the nanoparticles are inert, i.e. do not dissolve or degrade in the body. However, when modelling the experimental data it seemed that the biokinetics might be better explained by introducing dissolution in the PBPK model. A related problem is that most experimental studies of metal nanoparticles use elemental analysis such as inductively coupled plasma mass spectrometry (ICP-MS). Such analyses do not discriminate between different forms of metal and therefore obscures the biokinetics. To test if gold nanoparticles dissolve in biological media, we developed an in vitro method to characterize dissolution of gold nanoparticles in contact with cell medium, macrophages and lipopolysaccharide (LPS)-triggered macrophages, simulating a disease state (Paper V). We demonstrated that gold nanoparticles are dissolved by cell medium and macrophages and even more so by LPS-triggered macrophages. The dissolution rate was higher for 5 nm than for 50 nm gold particles

COVID-19 Infection: Implications for Perioperative and Critical Care Physicians.

Healthcare systems worldwide are responding to Coronavirus Disease 2019 (COVID-19), an emerging infectious syndrome caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus. Patients with COVID-19 can progress from asymptomatic or mild illness to hypoxemic respiratory failure or multisystem organ failure, necessitating intubation and intensive care management. Healthcare providers, and particularly anesthesiologists, are at the frontline of this epidemic, and they need to be aware of the best available evidence to guide therapeutic management of patients with COVID-19 and to keep themselves safe while doing so. Here, the authors review COVID-19 pathogenesis, presentation, diagnosis, and potential therapeutics, with a focus on management of COVID-19-associated respiratory failure. The authors draw on literature from other viral epidemics, treatment of acute respiratory distress syndrome, and recent publications on COVID-19, as well as guidelines from major health organizations. This review provides a comprehensive summary of the evidence currently available to guide management of critically ill patients with COVID-19

Formulation Strategies to Enhance Nose-to-Brain Delivery of Drugs

Delivery of drugs via the intranasal olfactory route is a non-invasive and practical method of bypassing the blood-brain barrier (BBB). However, targeted delivery and retention of drugs to the olfactory region is a significant challenge due to the geometrical complexity of the nasal cavity and mucociliary clearance. Formulating drugs into particulate-carriers, specifically, carriers with mucoadhesive properties can potentially overcome this challenge by enabling targeted deposition and retention of the drug onto the olfactory epithelium for subsequent nose-to-brain transport. Recent modeling data indicates that particles around 10 μm in size show maximum deposition in the olfactory region, the target site for nose-to-brain drug absorption. Therefore, the primary objectives of this thesis was to develop and characterize 10 μm-sized mucoadhesive microparticles for selective drug deposition in the olfactory region and enhanced nose-to-brain delivery. Furthermore, recently several drug delivery devices that aim to target drug formulations to the olfactory region in the nasal cavity are making their way to the market. Therefore, the second objective of this thesis was to explore if the formulative approach of making particles to a specific size and combining it with a targeting device could augment olfactory targeting and further enhance nose to brain delivery of therapeutic molecules. Consequently, the effect of particle size combined with a bi-directional delivery technique on the olfactory deposition of microparticles in the human nasal cavity was investigated. A naturally occurring mucoadhesive polymer, tamarind seed polysaccharide (TSP), was spray-dried with model drugs, FITC-Dextrans of molecular weight (MW) 3 to 40 kDa. The spray-drying process was optimized by the Box-Behnken experimental design to produce particles with 10 µm size. In-vitro and ex-vivo characterization demonstrated mucoadhesive potential and successful drug loading of TSP-microparticles. Particles of 10 µm in size demonstrated higher olfactory deposition compared to 2 µm sized particles in a 3D-human nasal replica, at standard inhalation airflow rate. The nose to-brain delivery efficiency of the mucoadhesive TSP-microparticles was tested in-vivo in a rodent model. An anti-epileptic drug (AED) phenytoin was loaded into TSP-microparticles and administered intranasally to rats with an insufflator. The analysis of phenytoin concentrations in the rat brain revealed a three-fold greater direct transport of phenytoin with the TSP microparticles compared to the intranasal solution at the end of 60 min. The results from this study demonstrated the potential of TSP-microparticles to improve direct transport of drugs to the brain by enhancing the nasal residence time of phenytoin due to mucoadhesion. In-silico computational fluid and particle dynamics (CFPD) techniques were utilized to identify the variability in olfactory deposition of microparticles between three human subjects with the inhalational delivery technique. Three normal human nasal cavities reconstructed using computerized tomography (CT)-scans were used to study the deposition of particles. The results identified that particles around 10 µm have consistently high deposition in the olfactory regions of three human subjects without any significant inter subject variability. CFPD techniques were also used to study the effect of particle size in combination with a novel bi-directional delivery technique (used in the ‘OPTINOSE®’ targeting device) on the deposition of particles in the human nasal cavities. The deposition of particles in the olfactory region was found to be a function of particle size. The bi-directional delivery technique demonstrated significantly higher deposition of particles in the olfactory region compared to standard inhalation. The results identified a particle size range of 14 to 18 µm can significantly enhance the olfactory deposition of particles when administered with bi-directional delivery technique without any inter-subject variability. In summary, this thesis demonstrated that formulation strategies can augment olfactory deposition and enhance nose-to-brain delivery of therapeutic molecules. This thesis integrated data from in-vitro, in-vivo and in silico studies to refine and optimize a size tailored mucoadhesive microparticle delivery system that has promising potential in the nose to brain drug delivery

Parallel Lagrangian particle transport : application to respiratory system airways

This thesis is focused on particle transport in the context of high computing performance (HPC) in its widest range, from the numerical modeling to the physics involved, including its parallelization and post-process. The main goal is to obtain a general framework that enables understanding all the requirements and characteristics of particle transport using the Lagrangian frame of reference. Although the idea is to provide a suitable model for any engineering application that involves particle transport simulation, this thesis uses the respiratory system framework. This means that all the simulations are focused on this topic, including the benchmarks for testing, verifying and optimizing the results. Other applications, such as combustion, ocean residuals, or automotive, have also been simulated by other researchers using the same numerical model proposed here. However, they have not been included here in the interest of allowing the project to advance in a specific direction, and facilitate the structure and comprehension of this work. Human airways and respiratory system simulations are of special interest for medical purposes. Indeed, human airways can be significantly different in every individual. This complicates the study of drug delivery efficiency, deposition of polluted particles, etc., using classic in-vivo or in-vitro techniques. In other words, flow and deposition results may vary depending on the geometry of the patient and simulations allow customized studies using specific geometries. With the help of the new computational techniques, in the near future it may be possible to optimize nasal drugs delivery, surgery or other medical studies for each individual patient though a more personalized medicine. In summary, this thesis prioritizes numerical modeling, wide usability, performance, parallelization, and the study of the physics that affects particle transport. In addition, the simulation of the respiratory system should carry out interesting biological and medical results. However, the interpretation of these results will be only done from a pure numerical point of view.Aquesta tesi se centra en el transport de partícules dins el context de la computació d'alt rendiment (HPC), en el seu ventall més ampli; des del model numèric fins a la física involucrada, incloent-hi la part de paral·lelització del codi i de post-procés. L'objectiu principal és obtenir un esquema general que permeti entendre tant els requeriments com les característiques del transport de partícules fent servir el marc de referència Lagrangià. Encara que la idea sigui definir un model capaç¸ de simular qualsevol aplicació en el camp de l'enginyeria que involucri el transport de partícules, aquesta tesi utilitza el sistema respiratori com a temàtica de referència. Això significa que totes les simulacions estan emmarcades en aquest camp d'estudi, incloent-hi els tests de referència, verificacions i optimitzacions de resultats. L'estudi d'altres aplicacions, com ara la combustió, els residus oceànics, l'automoció o l'aeronàutica també han estat dutes a terme per altres investigadors utilitzant el mateix model numèric proposat aquí. Tot i així, aquests resultats no han estat inclosos en aquesta tesi per simplificar-la i avançar en una sola direcció; facilitant així l'estructura i millor comprensió d'aquest treball. Pel que fa al sistema respiratori humà i les seves simulacions, tenen especial interès per a propòsits mèdics. Particularment, la geometria dels conductes respiratoris pot variar de manera considerable en cada persona. Això complica l'estudi en aspectes com el subministrament de medicaments o la deposició de partícules contaminants, per exemple, utilitzant les tècniques clàssiques de laboratori (in-vivo o in-vitro). En altres paraules, tant el flux com la deposició poden canviar en funció de la geometria del pacient i aquí és on les simulacions permeten estudis adaptats a geometries concretes. Gràcies a les noves tècniques de computació, en un futur proper és probable que puguem optimitzar el subministrament de medicaments per via nasal, la cirurgia o altres estudis mèdics per a cada pacient mitjançant una medicina més personalitzada. En resum, aquesta tesi prioritza el model numèric, l'amplitud d'usos, el rendiment, la paral·lelització i l'estudi de la física que afecta directament a les partícules. A més, el fet de basar les nostres simulacions en el sistema respiratori dota aquesta tesi d'un interès biològic i mèdic pel que fa als resultats

Molecular Communications in Viral Infections Research: Modelling, Experimental Data and Future Directions

Hundreds of millions of people worldwide are affected by viral infections each year, and yet, several of them neither have vaccines nor effective treatment during and post-infection. This challenge has been highlighted by the COVID-19 pandemic, showing how viruses can quickly spread and impact society as a whole. Novel interdisciplinary techniques must emerge to provide forward-looking strategies to combat viral infections, as well as possible future pandemics. In the past decade, an interdisciplinary area involving bioengineering, nanotechnology and information and communication technology (ICT) has been developed, known as Molecular Communications. This new emerging area uses elements of classical communication systems to molecular signalling and communication found inside and outside biological systems, characterizing the signalling processes between cells and viruses. In this paper, we provide an extensive and detailed discussion on how molecular communications can be integrated into the viral infectious diseases research, and how possible treatment and vaccines can be developed considering molecules as information carriers. We provide a literature review on molecular communications models for viral infection (intra-body and extra-body), a deep analysis on their effects on immune response, how experimental can be used by the molecular communications community, as well as open issues and future directions

Airway Microbiome in Chronic Lung Disease

Chronic lung disease is one of the main causes of morbidity and mortality worldwide. The recent discovery of the lung microbiome has transformed our understanding of the pathophysiology of respiratory infections and chronic lung disease. In the presented PhD thesis, the hypothesis that the composition of the whole microbial community rather than individual pathogens, is critical in the pathogenesis of chronic lung disease has been investigated. The airway microbiome was studied in a spectrum of chronic lung diseases: non-cystic fibrosis bronchiectasis, chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD) in adult survivors of extremely preterm birth and early pulmonary changes in people living with HIV (PLW-HIV) using culture independent approaches: next generation sequencing and quantitative polymerase chain reactions (qPCR). In all forms of the chronic lung diseases studied, a characteristic pattern of bacterial dysbiosis was identified. This was characterised by a significant decline in the bacterial community biodiversity and a shift in the bacterial community composition away from phylum Bacteroidetes; particularly genus Prevotella whose relative abundance was correlated with an important lung function parameter: FEV1% predicted. In PLW-HIV, some potential respiratory pathogens and gut bacteria were enriched in the airway microbiome which may place this population at higher risk to respiratory morbidities and pneumonia. Chronic lung disease is a sector employing extensive antibiotic prescription practices either to treat acute exacerbations, or as prophylaxis therapy. Substantial scientific evidence currently supports the clinical usefulness of macrolide prophylaxis therapy in managing chronic respiratory conditions. In this thesis, I investigated the effect of antibiotics on the homeostasis of the bacterial communities in the airways and how it contributed to the of antimicrobial resistance (AMR) among microbiota. The airway was found to harbour a rich source of AMR determinants and resistant microbiota. The AMR determinants were more related to the antibiotics used as rescue packs for prompt initiation of self-treatment of exacerbations. Antibiotic prophylaxis therapy was associated with lower total bacterial load and suppressed recognised pathogenic bacteria in the airways with minimal effect on the homeostasis of the respiratory microbiota. The airway bacterial community was resilient towards the disturbances caused by antibiotics use. No definite directional shift in the microbiome compositions associated with prophylactic antibiotics was identified at the group level