Two Dimensional Mathematical Study of Flow Dynamics Through Emphysemic Lung

There are various lung diseases, such as chronic obstructive pulmonary disease, asthma, fibrosis, emphysema etc., occurred due to deposition of different shape and size particles. Among them we focused on flow dynamics of viscous air through an emphysemic lung. We considered lung as a porous medium and porosity is a function of tidal volume. Two dimensional generalized equation of momentum is used to study the flow of air and equation of motion is used to study the flow of nanoparticles of elongated shape. Darcy term for flow in porous media and shape factor for nonspherical nanoparticles are used in mathematical model. Finite difference technique is used to solve the governing equation numerically. Various parameters such as inlet Reynolds number, media porosity, Darcy number, breathing rate and particle shape factor are found on flow dynamics. Results demonstrated that during inhalation, breathing stress increases and the deposition of particles is smaller due to the rupture alveoli in an emphysematous lung as compared to healthy lung

Particle deposition in replica healthy and emphysematous alveolar models using computational fluid dynamics

Particle deposition in the pulmonary region of the lung has gained increasing interest in the past years. Of particular interest are nano-sized particles, because they have the potential of crossing the blood-gas barrier and into the capillaries. Many factors contribute to how and where particles deposit, such as lung morphology, breathing conditions, fluid flow characteristics, and alveolar wall movement. These many factors make simulating particle deposition in the alveoli difficult. The experimental in vivo studies have commonly used micron sized particles and there is a lack of data for smaller sized particles. Due to these many factors, deposition in the pulmonary region is not well understood. Furthermore, little attention has been paid to the emphysematous lungs, which have characteristics quite different than the healthy lung. In this work, healthy and emphysematous replica acinus models were created from human lung casts using a 3D reconstruction software package. The models were used for simulating the particle deposition due to diffusion using Fine Particle Model (FPM). The FPM program was validated against an analytical solution using a straight tube, before moving on to predict the deposition in the alveolar models. Two particle sizes, 1 and 3 nm, were used to understand and compare pure diffusion in the lung using concentration contours. Results showed the particle deposition rate (particles/s) to be higher in the emphysemic. However, deposition rate per area (particles/m²s) was found to be higher in the healthy model. The deposition efficiency (% of particles that deposit) of the healthy model was greater than the emphysemic model, consistent with literature. Results were found to be lower than experimental in vivo measurements and whole lung model of local alveolar deposition (particles deposited in alveoli/particles entering alveoli) in comparison to our results in the pulmonary region, showing the importance of including axial diffusion effects. More work must be done experimentally and numerically before an understanding of deposition of particles of this size can be determined

Numerical Modelling of Transport in Complex Porous Media: Metal Foams to the Human Lung

Transport in porous media has many practical applications in science and engineering. This work focuses on the development of numerical methods for analyzing porous media flows and uses two major applications, metal foams and the human lung, to demonstrate the capabilities of the methods. Both of these systems involve complex pore geometries and typically involve porous domains of complex shape. Such geometric complexities make the characterization of the relevant effective properties of the porous medium as well as the solution of the governing equations in conjugate fluid-porous domains challenging. In porous domains, there are typically too many individual pores to consider transport processes directly; instead the governing equations are volume-averaged to obtain a new sets of governing equations describing the conservation laws in a bulk sense. There are, however, unknown pore-level terms remaining in the volume-averaged equations that must be characterized using effective properties that account for the effects of processes at the pore level. Once closed, the volume-averaged equations can be solved numerically, however currently available numerical methods for conjugate domains do not perform well at fluid-porous interfaces when using unstructured grids. In light of the preceding discussion, the goals of this work are: (i) to develop a finite-volume-based numerical method for solving fluid flow and non-equilibrium heat transfer problems in conjugate fluid-porous domains that is compatible with general unstructured grids, (ii) to characterize the relevant flow and thermal properties of an idealized graphite foam, (iii) to determine the permeability of an alveolated duct, which is considered as a representative element of the respiratory region of the human lung, and (iv) to conduct simulations of airflow in the human lung using a novel fluid-porous description of the domain. Results show that the numerical method that has been developed for conjugate fluid-porous systems is able to maintain accuracy on all grid types, flow directions, and flow speeds considered. This work also introduces a comprehensive set of correlations for the effective properties of graphite foam, which will be useful for studying the performance of devices incorporating this new material. In order to model air flow in the lung as a porous medium, the permeability of an alveolated duct is obtained using direct pore-level simulations. Finally, simulations of air flow in the lung are presented which use a novel fluid-porous approach wherein the upper airways are considered as a pure fluid region and the smaller airways and alveoli are considered as a porous domain

Unveiling advanced mechanisms of inhalable drug aerosol dynamics using computational fluid dynamics and discrete element method

Capsule-based dry powder inhalers (DPIs) are widely used to treat chronic obstructive pulmonary disease (COPD) by delivering active pharmaceutical ingredients (APIs) via inhalation into human respiratory systems. Previous research has shown that the actuation flow rate, aerodynamic particle size distribution (APSD), and particle shape of lactose carriers are factors that can influence the particle deposition patterns in human respiratory systems. Understanding the dynamics of APIs transport in DPIs and airways can provide significant value for the design optimization of DPIs and particle shapes to enhance the delivery of APIs to the designated lung sites, i.e., small airways. Thus, it is necessary to investigate how to modulate the above-mentioned factors to increase the delivery efficacy to small airways and enhance the therapeutic effect to treat COPD. Compared with in vitro and in vivo methods, computational fluid-particle dynamics (CFPD) models allow researchers to study the transport dynamics of inhalable therapeutic dry powders in both DPI and human respiratory systems. However, existing CFPD models neglect particle-particle interactions, and most existing airway models lack peripheral lung airway and neglect the airway deformation kinematics. Such deficiencies can lead to inaccurate predictions of particle transport and deposition. This study developed a one-way coupled computational fluid dynamics (CFD) and discrete element method (DEM) model to simulate the particle-particle and particle-device interactions, and the transport of API-carrier dry powder mixtures with different shapes of carriers in a DPI flow channel. The influence of actuation flow rate (30 to 90 L/min) and particle shape (aspect ratio equals 1, 5, and 10) on lactose carrier dynamics in a representative DPI, i.e., SpirivaTM HandihalerTM, has been investigated. Subsequently, an elastic truncated whole-lung model has also been developed to predict particle transport and deposition from mouth to alveoli, with disease-specific airway deformation kinematics. Numerical results indicate that 90 L/min actuation flow rate generates the highest delivery efficiency of Handihaler, as approximately 26% API reaches the deep lung region. The elastic truncated whole-lung modeling results show that noticeable differences of predictions between static and elastic lung models can be found, which demonstrates the necessity to model airway deformation kinematics in virtual lung models

Estratégias de formulação com vista à melhoria dos resultados terapêuticos na doença pulmonar obstrutiva crónica: desafios e oportunidades

A doença pulmonar obstrutiva crónica (DPOC) é uma doença do foro pulmonar que é caracterizada por sintomas respiratórios persistentes, como a dispneia e a tosse, e uma limitação contínua do fluxo de ar. O fumo de tabaco é considerado o principal fator de risco, mas alguns fatores do indivíduo também exercem um papel importante no desenvolvimento desta patologia. Atualmente, o tratamento existente foca-se no alívio da sintomatologia através da administração de broncodilatadores de longa duração e, quando necessário e adequado, corticosteróides inaláveis. A via pulmonar continua a ser a via preferencial para o tratamento desta doença, pelo facto de permitir uma administração localizada e oferecer várias vantagens, como um início de ação mais rápido e efeitos adversos reduzidos. Porém, o pulmão é um órgão muito complexo, pelo que também existem alguns desafios na utilização desta via. Apesar de ser uma das doenças crónicas mais comuns, a DPOC continua a ser um grande problema de saúde pública, apresentando morbilidade e mortalidade crescentes. Estes dados provam que as terapêuticas convencionais nem sempre são suficientes para controlar a doença, pelo que existe uma necessidade crescente de encontrar alternativas que permitam melhorar os resultados terapêuticos. Várias estratégias de formulação têm surgido ao longo dos últimos anos para tentar colmatar os obstáculos que impedem o sucesso terapêutico nos doentes com DPOC. Neste sentido, a nanotecnologia, as terapêuticas com RNA, e outras estratégias, têm-se mostrado cada vez mais prevalentes e têm vindo a ganhar peso a nível de investigação, com o intuito de explorar as oportunidades que cada uma delas pode oferecer, bem como os desafios que terão de ser solucionados na eventualidade da sua implementação. Neste contexto, o objetivo desta dissertação consiste em explorar algumas das estratégias de formulação que estão atualmente em investigação e que apresentam resultados promissores no tratamento da DPOC, juntamente com as oportunidades e os desafios a elas associados.Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by persistent respiratory symptoms, like dyspnea and cough, and a continuous airflow limitation. Cigarette smoke is considered the main risk factor, but some factors of the individual also play an important role in the development of this disease. At present, the existing treatment focuses on relieving symptoms through the administration of longacting bronchodilators and, when deemed necessary and appropriate, inhaled corticosteroids. The pulmonary route continues to be preferential for the treatment of this disease, as it allows a localized delivery and offers several advantages, such as a faster onset of action and reduced side effects. However, the lungs are a very complex organ, so there are some challenges in using this route. Despite being one of the most common chronic diseases, COPD continues to be a major public health problem, with growing morbidity and mortality. This data proves that conventional therapies are not always sufficient to control the disease, so there is a rising need to find alternatives to help improve therapeutic results. Several formulation strategies have emerged over the last few years to try to overcome the obstacles that prevent therapeutic success in COPD patients. In this sense, nanotechnology, RNA therapies, and other strategies, have become increasingly prevalent and gather popularity in the research field, with the intent of studying the opportunities each has to offer, as well as the challenges that will need to be resolved in the event of their implementation. In this context, the purpose of this dissertation is to explore some of the formulation strategies that are currently under investigation and show promising results in the treatment of COPD, along with the associated opportunities and challenges

Alveolar size effects on nanoparticle deposition in rhythmically expanding-contracting terminal alveolar models

Significant differences in alveolar size exist in humans of different ages, gender, health, and among different species. The effects of alveolar sizes, as well as the accompanying breathing frequencies, on regional and local dosimetry of inhaled nanoparticles have not been sufficiently studied. Despite a well-accepted qualitative understanding of the advection-diffusion-sedimentation mechanism in the acinar region, a quantitative picture of the interactions among these factors remains inchoate. The objective of this study is to quantify the effects of alveolar size on the regional and local deposition of inhaled nanoparticles in alveolar models of varying complexities and to understand the dynamic interactions among different deposition mechanisms. Three different models were considered that retained 1, 4, and 45 alveoli, respectively. For each model, the baseline geometry was scaled by (1/4), (1/2), 2, 4, and 8 times by volume. Temporal evolution and spatial distribution of particle deposition were tracked using a discrete-phase Lagrangian model. Lower retentions of inhaled nanoparticles were observed in the larger alveoli under the same respiration frequency, while similar retentions were found among different geometrical scales if breathing frequencies allometrically matched the alveolar size. Dimensional analysis reveals a manifold deposition mechanism with tantamount contributions from advection, diffusion, and gravitational sedimentation, each of which can become dominant depending on the location in the alveoli. Results of this study indicate that empirical correlations obtained from one sub-population cannot be directly applied to others, nor can they be simply scaled as a function of the alveolar size or respiration frequency due to the regime-transiting deposition mechanism that is both localized and dynamic

Dichotomic role of NAADP/two-pore channel 2/Ca2+ signaling in regulating neural differentiation of mouse embryonic stem cells

Poster Presentation - Stem Cells and Pluripotency: abstract no. 1866The mobilization of intracellular Ca2+stores is involved in diverse cellular functions, including cell proliferation and differentiation. At least three endogenous Ca2+mobilizing messengers have been identified, including inositol trisphosphate (IP3), cyclic adenosine diphosphoribose (cADPR), and nicotinic adenine acid dinucleotide phosphate (NAADP). Similar to IP3, NAADP can mobilize calcium release in a wide variety of cell types and species, from plants to animals. Moreover, it has been previously shown that NAADP but not IP3-mediated Ca2+increases can potently induce neuronal differentiation in PC12 cells. Recently, two pore channels (TPCs) have been identified as a novel family of NAADP-gated calcium release channels in endolysosome. Therefore, it is of great interest to examine the role of TPC2 in the neural differentiation of mouse ES cells. We found that the expression of TPC2 is markedly decreased during the initial ES cell entry into neural progenitors, and the levels of TPC2 gradually rebound during the late stages of neurogenesis. Correspondingly, perturbing the NAADP signaling by TPC2 knockdown accelerates mouse ES cell differentiation into neural progenitors but inhibits these neural progenitors from committing to the final neural lineage. Interestingly, TPC2 knockdown has no effect on the differentiation of astrocytes and oligodendrocytes of mouse ES cells. Overexpression of TPC2, on the other hand, inhibits mouse ES cell from entering the neural lineage. Taken together, our data indicate that the NAADP/TPC2-mediated Ca2+signaling pathway plays a temporal and dichotomic role in modulating the neural lineage entry of ES cells; in that NAADP signaling antagonizes ES cell entry to early neural progenitors, but promotes late neural differentiation.postprin

Embryonic Stem Cells

Embryonic stem cells are one of the key building blocks of the emerging multidisciplinary field of regenerative medicine, and discoveries and new technology related to embryonic stem cells are being made at an ever increasing rate. This book provides a snapshot of some of the research occurring across a wide range of areas related to embryonic stem cells, including new methods, tools and technologies; new understandings about the molecular biology and pluripotency of these cells; as well as new uses for and sources of embryonic stem cells. The book will serve as a valuable resource for engineers, scientists, and clinicians as well as students in a wide range of disciplines