UC Irvine

One of the pressing concerns in translational and clinical research is the development of accurate model systems that allow scientists to recapitulate the native tissue and organ systems vulnerable to disease. Barring direct human experimentation, one of the great challenges of translational research is drawing parallels between a human condition and an appropriate and available model. To address this conundrum, researchers have painstakingly developed a wide range of animal models and creative uses of cell culture to attempt to draw closer comparisons to that of actual human organ systems. While this variety of model options narrows the gap between a human condition and what is observable in a laboratory setting, unfortunately discrepancies remain. The primary objective of the work presented here is to develop novel technologies that enable an accurate representation of a specific target organ system and to apply said technology to study the pathogenesis of two human diseases centered on immune dysregulation, namely COVID-19 and early-stage cardiovascular disease. The advent of microphysiological systems enables the high-throughput study of self-contained, human derived, three-dimensional tissue samples in vitro to provide a range of organ models that can be curated to address specific questions in the study of human diseases. This work focuses on the utilization of two distinct vascular microphysiological systems to study two of the most urgent public health concerns in both the United States and globally. Both COVID-19 and the beginning of cardiovascular disease, atherogenesis, are driven by immune dysregulation and subsequent damage to the vascular system. The two platforms utilized in this work, the vascularized micro-organ and the single channel arteriole, are based off the same principal concept of loading a population of stromal cells and endothelial cells into a polydimethylsiloxane chamber and allowing the resultant vascular tissue to develop under flow conditions. The use of the vascularized micro-organ has allowed us to study both the immediate and downstream inflammatory effects of SARS-CoV-2 infection on a human vascular system while the development of the higher shear single channel arteriole provides insight into the cell-to-cell interactions that initiate the first stage of cardiovascular disease.