Development and applications of in-vitro and in-silico models of the cardiovascular system to study the effects of mechanical circulatory support.

Cardiovascular diseases (CVDs) are the leading cause of mortality globally. With ongoing interest in CVDs treatment, preclinical models for drug/therapeutic development that allow for fast iterative research are needed. Owing to the inherent complexity of the cardiovascular system, current in-vitro models of the cardiovascular system fail to replicate many of the physiological aspects of the cardiovascular system. In this dissertation, the main concern is with heart failure (HF). In advanced HF, patients may receive Left Ventricular Assist Devices (LVADs) as a bridge to transplant or destination therapy. However, LVADs have many limitations, including inability to adapt to varying tissue demand conditions, risk of ventricular suction, and diminished arterial pulsatility. To address these issues, this dissertation aims to use and develop computer, cellular, and tissue models of the cardiovascular system. 1) Use an in-silico model of the cardiovascular system to develop a novel control algorithm for LVADs. The control system was rigorously tested and showed adequate perfusion during rest and exercise, protect against ventricular suction under reduced heart preload, and augment arterial pulsatility through pulse modulation without requiring sensor implantation or model-based estimations. 2) While pulsatility augmentation was feasible through the developed control algorithm, the pulse waveform that could normalize the vascular phenotype is unknown. To address this, an endothelial cell-smooth muscle cell microfluidic coculture model was developed to recreate the physiological mechanical stimulants in the vascular wall. The results demonstrated different effects of pulsatile shear stress and stretch on endothelial cells and may indicate that a pulse pressure of at least 30 mmHg is needed to maintain normal endothelial morphology. 3) In order to study the effects of mechanical unloading on the native ventricle, a novel cardiac tissue culture model (CTCM) was developed. CTCM provided physiological electromechanical and humoral stimulation with 25% preload stretch and thyroid and glucocorticoid treatment maintained the cardiac phenotype for 12 days. The device was thoroughly characterized and tested. Results demonstrated improved viability, energy utilization, fibrotic remodeling, and structural integrity compared to available culture systems. The system was also used to reproduce ventricular volume-overload and the results demonstrated hypertrophic and fibrotic remodeling, typical of volume-overload pathology

Toxicological profile for uranium

"A Toxicological Profile for Uranium, Draft for Public Comment was released in May 2011. This edition supersedes any previously released draft or final profile." - p iiiChemical manager(s)/author(s): Sam Keith, Obaid Faroon, Nickolette Roney, Franco Scinicariello, Sharon Wilbur, ATSDR, Division of Toxicology and Human Health Sciences, Atlanta, GA; Lisa Ingerman, Fernando Llados, Daneil Plewak, David Wohlers, Gary Diamond, SRC, Inc., North Syracuse, NY.201