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Item Modeling and simulation applications with potential impact in drug development and patient care(2014) Li, Claire; Bies, Robert R.; Foroud, Tatiana; Li, Lang; Renbarger, Jamie L.Model-based drug development has become an essential element to potentially make drug development more productive by assessing the data using mathematical and statistical approaches to construct and utilize models to increase the understanding of the drug and disease. The modeling and simulation approach not only quantifies the exposure-response relationship, and the level of variability, but also identifies the potential contributors to the variability. I hypothesized that the modeling and simulation approach can: 1) leverage our understanding of pharmacokinetic-pharmacodynamic (PK-PD) relationship from pre-clinical system to human; 2) quantitatively capture the drug impact on patients; 3) evaluate clinical trial designs; and 4) identify potential contributors to drug toxicity and efficacy. The major findings for these studies included: 1) a translational PK modeling approach that predicted clozapine and norclozapine central nervous system exposures in humans relating these exposures to receptor binding kinetics at multiple receptors; 2) a population pharmacokinetic analysis of a study of sertraline in depressed elderly patients with Alzheimer’s disease that identified site specific differences in drug exposure contributing to the overall variability in sertraline exposure; 3) the utility of a longitudinal tumor dynamic model developed by the Food and Drug Administration for predicting survival in non-small cell lung cancer patients, including an exploration of the limitations of this approach; 4) a Monte Carlo clinical trial simulation approach that was used to evaluate a pre-defined oncology trial with a sparse drug concentration sampling schedule with the aim to quantify how well individual drug exposures, random variability, and the food effects of abiraterone and nilotinib were determined under these conditions; 5) a time to event analysis that facilitated the identification of candidate genes including polymorphisms associated with vincristine-induced neuropathy from several association analyses in childhood acute lymphoblastic leukemia (ALL) patients; and 6) a LASSO penalized regression model that predicted vincristine-induced neuropathy and relapse in ALL patients and provided the basis for a risk assessment of the population. Overall, results from this dissertation provide an improved understanding of treatment effect in patients with an assessment of PK/PD combined and with a risk evaluation of drug toxicity and efficacy.Item Modeling and simulation of interstitial fluid flow around an osteocyte in a lacuno-canalicular network(AIP, 2022-04-01) Zhu (祝罗丁), Luoding; Barber, Jared; Zigon , Robert; Na (나성수), Sungsoo; Yokota (横田博樹), Hiroki; Mathematical Sciences, School of ScienceExperiments have shown that external mechanical loading plays an important role in bone development and remodeling. In fact, recent research has provided evidence that osteocytes can sense such loading and respond by releasing biochemical signals (mechanotransduction, MT) that initiate bone degradation or growth. Many aspects on MT remain unclear, especially at the cellular level. Because of the extreme hardness of the bone matrix and complexity of the microenvironment that an osteocyte lives in, in vivo studies are difficult; in contrast, modeling and simulation are viable approaches. Although many computational studies have been carried out, the complex geometry that can involve 60+ irregular canaliculi is often simplified to a select few straight tubes or channels. In addition, the pericellular matrix (PCM) is usually not considered. To better understand the effects of these frequently neglected aspects, we use the lattice Boltzmann equations to model the fluid flow over an osteocyte in a lacuno-canalicular network in two dimensions. We focus on the influences of the number/geometry of the canaliculi and the effects of the PCM on the fluid wall shear stress (WSS) and normal stress (WNS) on an osteocyte surface. We consider 16, 32, and 64 canaliculi using one randomly generated geometry for each of the 16 and 32 canaliculi cases and three geometries for the 64 canaliculi case. We also consider 0%, 5%, 10%, 20%, and 40% pericellular matrix density. Numerical results on the WSS and WNS distributions and on the velocity field are visualized, compared, and analyzed. Our major results are as follows: (1) the fluid flow generates significantly greater force on the surface of the osteocyte if the model includes the pericellular matrix (PCM); (2) in the absence of PCM, the average magnitudes of the stresses on the osteocyte surface are not significantly altered by the number and geometry of the canaliculi despite some quantitative influence of the latter on overall variation and distribution of those stresses; and (3) the dimensionless stress (stress after non-dimensionalization) on the osteocyte surface scales approximately as the reciprocal of the Reynolds number and increasing PCM density in the canaliculi reduces the range of Reynolds number values for which the scaling law holds.Item Smoothed Particle Hydrodynamics Modeling of Thermal Barrier Coating Removal Process Using Abrasive Water Jet Technique(ASME, 2022-09) Zhang, Jian; Yang, Xuehui; Sagar, Sugrim; Dube, Tejesh; Koo, Dan Daehyun; Kim, Bong-Gu; Jung, Yeon-Gil; Zhang, Jing; Mechanical and Energy Engineering, School of Engineering and TechnologyIn this work, a new smoothed particle hydrodynamics (SPH)-based model is developed to simulate the removal process of thermal barrier coatings (TBCs) using the abrasive water jet (AWJ) technique. The effects of water jet abrasive particle concentration, incident angle, and impacting time on the fracture behavior of the TBCs are investigated. The Johnson–Holmquist plasticity damage model (JH-2 model) is used for the TBC material, and abrasive particles are included in the water jet model. The results show that the simulated impact hole profiles are in good agreement with the experimental observation in the literature. Both the width and depth of the impact pit holes increase with impacting time. The deepest points in the pit hole shift gradually to the right when a 30-deg water jet incident angle is used because the water jet comes from the right side, which is more effective in removing the coatings on the right side. A higher concentration of abrasive particles increases both the width and depth, which is consistent with the experimental data. The depths of the impact pit holes increase with the water jet incident angle, while the width of the impact holes decreases with the increase in the water jet incident angle. The water jet incident angle dependence can be attributed to the vertical velocity components. The erosion rate increases with the incidence angle, which shows a good agreement with the analytical model. As the water jet incident angle increases, more vertical velocity component contributes to the kinetic energy which is responsible for the erosion process.