A vast majority of heart attacks occur due to rapid progression of plaque buildup in the coronary arteries that supply blood to the heart muscles. The diseased arteries can be treated with drugs delivered locally to vulnerable plaques—ones that may rupture and release emboli, resulting in the formation of thrombus, or blood clot that can cause blockage of the arterial lumen. In designing these local drug delivery devices, important issues regarding drug distribution and targeting need to be addressed to ensure device design optimization as physiological forces can cause the local concentration to be very different from mean drug tissue concentration estimated from in vitro experiments and animal studies. Therefore, the main objective of this work was to develop a computational tool-set to support the design of a catheter-based local drug delivery system that uses nanoparticles as drug carriers by simulating drug transport and quantifying local drug distribution in coronary artery walls. Toward this end, a three dimensional mathematical model of coupled transport of drug and drug-encapsulated nanoparticles was developed and solved numerically by applying finite element based isogeometric analysis that uses NURBS-based techniques to describe the artery wall geometry. To gain insight into the parametric sensitivity of drug distribution, a study of the effect of Damkohler number and Peclet number was carried out. The tool was then applied to a three-dimensional idealized multilayered model of the coronary artery wall under healthy and diseased condition. Preliminary results indicated that use of realistic geometry is essential in creating physiological flow features and transport forces necessary for developing catheter-based drug delivery design procedures. Hence, simulations were run on a patient-specific coronary artery wall segment with a typical atherosclerotic plaque characterized by a lipid pool encased by a thin fibrous cap. Results show that plaque heterogeneity and artery wall inhomogeneity have a considerable effect on drug distribution. The computational tool-set developed was able to successfully capture trends observed in local drug delivery by incorporating a multitude of relevant physiological phenomena, and thus demonstrated its potential utility in optimizing drug design parameters including delivery location, nanoparticle surface properties and drug release rate. / text

A hybrid surface/subsurface flow and transport model is developed that blends distributed parameter models with simpler lumped parameter models. The hybrid model solves the channel flow and saturated groundwater flow domains in continuous time using fully distributed physically-based formulations. This system is supplemented with the overland flow and unsaturated groundwater flow that uses lumped parameter descriptions in discrete time. In the proposed model, a one-dimensional channel flow model is dynamically coupled with a two-dimensional vertically-averaged groundwater flow model along the river bed. As an alternative to the commonly applied iterative solution technique, a so-called simultaneous solution procedure is developed to provide a better understanding to the coupled flow problem. This new methodology is based on the principle of solving the two flow domains within a single matrix structure in a simultaneous manner. In addition to the flow model, a coupled contaminant transport model is also developed to simulate the migration of contaminants between surface and subsurface domains. The contaminant transport model dynamically couples a one-dimensional channel transport model with a two-dimensional vertically-averaged groundwater transport model. The coupling is performed at the river bed interface via advective and dispersive transport mechanisms. A modified extension of the proposed simultaneous solution procedure is also implemented to solve the coupled contaminant transport problem. The dynamic coupling provides the much needed understanding for the continuity of contaminants in strongly interacting surface/subsurface systems such as a river and an unconfined aquifer. The coupled flow and transport models are applied to the lower Altamaha watershed in southern Georgia. The flow model is used to perform simulations of hydrologic and hydraulic conditions along the river and in the dynamically linked surfacial aquifer. The model predicted the flood patterns including the magnitude of peaks and their arrival times with accuracy. Under the given flow conditions, the transport model is then implemented to test alternative contaminant transport patterns both in the river and within the aquifer. It has been found that the channel network would serve as a conduit for rapid transport of contaminants within the aquifer to large distances in small time frames.

Proton fluxes through plasma membranes are essential for regulating intracellular and extracellular pH and mediating co-transport of metabolites and ions. Although conventional electrical measurements are highly sensitive and precise for proton current detection, they provide limited specificity and spatial information. My thesis focuses on developing optical approaches to visualize proton fluxes from ion channels and transporters. It has been demonstrated that channel-mediated acid extrusion causes proton depletion at the inner surface of the plasma membrane. Yet, proton dynamics at the extracellular microenvironment are still unclear. In Chapter II, we developed an optical approach to directly measure pH change in this nanodomain by covalently attaching small-molecule, fluorescent proton sensors to the cell’s glycocalyx using glyco-engineering and copper free ‘click’ chemistry. The extracellularly facing sensors enable real-time detection of proton accumulation and depletion at the plasma membrane, providing an indirect readout of channel and transporter activity that correlated with whole-cell proton current. Moreover, the proton wavefront emanating from one cell was readily visible as it crossed over nearby cells. The transport of monocarboxylates, such as lactate and pyruvate is critical for energy metabolism and is mainly mediated by proton-coupled monocarboxylate transporters (MCT1-MCT4). Although pH electrodes and intracellular fluorescent pH sensors have been widely used for measuring the transport of proton-coupled MCTs, they are unable to monitor the subcellular activities and may underestimate the transport rate due to cell’s volume and intracellular buffering. In Chapter III, we used the Chapter II approach to visualize proton-coupled transport by MCT1-transfected HEK293T cells and observed proton depletion followed by a recovery upon extracellular perfusion of L-lactate or pyruvate. In addition, we identified a putative MCT, CG11665/Hrm that is essential for autophagy during cell death in Drosophila. The results demonstrate that Hrm is a bona fide proton-coupled monocarboxylate transporter that transports pyruvate faster than lactate. Although the approach developed in Chapter II enables visualization of proton fluxes from ion channels and transporters, it’s not applicable in some cell types which cannot incorporate unnatural sialic acid precursors into their glycocalyx, such as INS-1 cells and cardiomyocytes. To address this, in Chapter IV we developed a pH-sensitive, fluorescent WGA conjugate, WGA-pHRho that binds to endogenous glycocalyx. Compared to the results in Chapter II and III, cell surface-attached WGA-pHRho has similar fluorescent signals in response to proton fluxes from proton channel Hv1, omega mutant Shaker-IR R362H and MCT1. With WGA-pHRho, we were able to label the plasma membrane of INS-cells and cardiomyocytes and visualized the transport activity of MCT1 in these cells. Taken together, these findings provide news insights into proton dynamics at the extracellular environment and provide new optical tools to visualize proton fluxes from ion channels and transporters. Moreover, the modularity of the approaches makes them adaptable to study any transport events at the plasma membrane in cells, tissues, and organisms.

Soil freezing/thawing is of importance in the transport of water, heat and solute, with coupled effects. Due to complexity in soil freezing/thawing, uncertainty could be influential in both experimentation and simulation work in frozen soils. Solute and water in frozen soil could reduce the freezing point, resulting in uncertainty in simulation water, heat and solute processes as well as in estimation of frozen soil evaporation. High salinity and groundwater level could result in high soil evaporation during wintertime. Seasonal courses in energy and water balance on surface have shown to be influential to soil water and heat dynamics, as well as in salt accumulation during wintertime. Water and solute accumulated during freezing period resulted in high evaporation during thawing period and enhanced surface salinization. Diurnal changes in surface energy partitioning resulted in significant cycle of freezing/thawing as well as in evaporation/condensation in surface layer, which could in turn affect atmosphere. Uncertainties in experiments and simulations were detectable in investigation of seasonally frozen soils with limited methods and simplified representations of reality in two agricultural fields in northern China. Soil water and solute contents have shown to be more uncertain than soil temperatures in both measurements and simulations. The combination of experiments with process-based model (CoupModel) has proven to be useful in understanding freezing/thawing processes and in identification of uncertainty, when Monte-Carlo based methods were used for evaluation of simulations. Correlations between parameters and model performance indices needed to be taken into account carefully in calibration of the process-based model. Parameters related to soil hydraulic processes and surface energy processes were more sensitive when using different datasets for calibration. In using multiple model performance indicators for multi-objective evaluation, the trade-offs between them have shown to be a source of uncertainty in calibration. More proper representations of the reality in model (e.g., soil hydraulic and thermal properties) and more detailed measurements (e.g., soil liquid water content and solute concentration) as input would be efficient in reducing uncertainty. Relationships between groundwater, soil and climate change would be of high interest for better understanding of cold regions water and energy balance. / 土壤冻融过程对于水热及溶质的运移具有十分重要的影响，并对于寒旱区水文过程的研究有着深远意义。在冻土中，溶质的存在导致冰点降低，改变土壤冻融规律，进而影响冻融土壤水热运移。冻融土壤地表水分及能量平衡的季节性变化规律对土壤水热运移及盐分的积累影响较大。同时，土壤冻融的水热平衡日变化规律对表层土壤水热过程影响较为强烈，并进而影响地表的气象变化。试验研究表明，高溶质含量及浅埋深地下水条件为地表的蒸发提供了便利条件，因为高溶质含量土壤冰点降低，同一负温条件下的液态含水量增大，为蒸发提供了可利用水分；而浅埋深地下水对冻融期水盐的表聚提供的方便，进而有助于融化期地表水分的大量蒸发及下层土层水分的大量向上补给。例如，当地下水初始埋深设置在1.5 m时，对于初始含盐量分别为0.2%，0.4% 和0.6% g/g的冻融试验组，冻融期累积蒸发量分别为51.0，96.6和114.0 mm。同样的增加趋势在其它初始地下水埋深设置试验组里也被验证，且初始地下水埋深越浅，累积蒸发量也越大。对于利用有限的试验数据及简化的数值模型对冻融土壤水热及溶质研究，由于试验及模型的不确定性，会造成结果的不确定性。而通过利用不确定性分析的方法将试验结果与数值模型结合起来可以较好地理解土壤冻融过程及处理不确定性，并进而为改进试验方法及完善数值模型提供参考。模型不确定分析结果表明，模型参数之间，及参数与模型模拟效果评价因子之间存在较强的相关性，会造成模拟结果的不确定性。而不同模拟方法的结果对比表明，在进行冻融土壤水热及溶质模拟时，建立更为完善的考虑更为详细的过程的数值模型可以提高模型的模拟效率，减小模拟结果的不确定性。同时，试验数据的不确定性也显示出了对模拟结果的显著影响。精确的试验数据及更为科学的试验方法有助于减少模拟结果的不确定性。在减少模拟结果的不确定性上也有重要作用。同时，由于寒区水文过程的复杂性及在气候变化过程中的重要性，有必要进一步开展寒区地下水，土壤水热盐与气候变化关系的研究，以便于制定更为合理的寒区水资源管理策略。 / Frysning och tining är av betydelse för kopplade flöden av vatten, värme och lösta ämnen i mark. Komplexiteten i sambanden mellan lösta ämnen, ofruset vatten och fryspunkten skapar en osäkerhet vid simuleringar av processer för både vatten, värme och lösta ämnen i marken samt för avdunstningen från markytan. Årtidsberoende mönster i energi- och vattenbalansen för markytan påverkar värme- och vattendynamiken i marken samt ackumulering av salter under vintern. Dygnsvariationer i energibalansens uppdelning vid markytan ger upphov till frysning/tining samt avdunstning och kondensation i ytliga lager som har återkopplingar också till tillstånden i atmosfärens ytskikt. Osäkerheter i både experiment och i simuleringar spårades i undersökningar av säsongstyrd frysning av mark i två provincer av norra Kina. Begräningar i metodik och förenklingar av naturens komplexitet kunde klargöras. Kombinationen av experiment och processbaserad modellering med CoupModel var lyckosam för föreståelsen av frysning/tining och kunde klargöra osäkerhet med hjälp av Monte Carlo teknik. Korrelation mellan parametrar och prestanda hos modellen var en viktig del av kalibreringsproceduren. En förbättrad processbeskrivning av marken och minskad parameterosäkerhet kan erhållas om också mer detaljerade mätningar inbegrips i framtida studier. Sambanden mellan grundvatten, mark och klimatförändringar är av största intresse för en bättre kunna beskriva kalla regioners vatten- och energibalanser. / <p>QC 20160329</p>

Cette thèse apporte des éléments sur la compréhension de la gestion de l'eau et de ses effets sur les performances électriques d'une PEMFC au moyen de modélisations multi-échelle des transferts. Une analyse du transport couplé de charges et de matière dans les pores de la membrane est proposée. La présence d'eau liquide est prise en compte dans les GDL (écoulements diphasiques) et les couches actives (noyage). Le couplage de ces modèles à une description des transferts de matière le long des canaux d’alimentation permet de mettre en évidence une répartition non-uniforme des concentrations en eau, des flux et donc de la densité de courant. Les résultats numériques sont comparés à des données expérimentales (coefficient de partage de l'eau et performance électrique locale) obtenues au laboratoire sur deux piles. Ceci permet de valider les modèles de fonctionnement du cœur de pile et d'alimenter la réflexion sur la connaissance et la modélisation des transferts d'eau dans le cœur de pile / This works contributes to the understanding of water management of polymer electrolyte membrane fuel cell and of its links with the electrical performances. More specifically, the manuscript deals with the multi-scale modelling of transport phenomena. An analysis of coupled mass and charge transfer in the pores of a polymer membrane is presented. The presence of liquid water is considered in the GDL (two-phase flow) and in the active layers (flooding). The description of these phenomena is associated with that of gas depletion along the bipolar plate channels. This allows to emphasize the non-uniformity of water concentration, of the fluxes and as a consequence, of current density. The numerical results are compared with experimental data (water transport coefficient, local electrical performances) measured on two different fuel cells. This comparison validates at least partially the numerical models and provides further information for the analysis of water management within PEMFC