(338h) Microvasculature-on-a-Chip for Studying Endothelial Cell Pathophysiology

Almost all drugs recently developed in animal models to treat inflammatory disease have failed in clinical trials. There is therefore a critical need for rapid screening of anti-inflammatory drugs before they are tested in expensive and time-consuming animal models and human trials. We have developed a novel microfluidic based assay platform incorporating 3D dynamic cell culture and circulation/vasculature on a chip for understanding inflammatory response and rapid screening of therapeutics. In this presentation, the design and development of this vascularized biomimetic microfluidic system will be presented and the application of this unique platform for studying the role of innate immunity in blood-brain barrier (BBB) breakdown during sepsis, functional changes of endothelial cells in tumor microenvironment, and transport of antibody conjugated drug carriers across physiological barrier will be discussed. Our studies have allowed us to delineate a number of basic mechanisms of the inflammatory response with a focus on the more complex human conditions rather than relying on mouse models to study human inflammatory disease. This has allowed us to develop and screen a novel therapy for treatment of sepsis taking into account the significant differences between human and murine neutrophil-endothelial interactions in response to cytokine activation. This novel system will advance our understanding of the impact of endothelial cell phenotype and signaling events that regulate endothelial and neutrophil activation and will lead to the development of other enabling technologies for basic science and applied studies of other systems in the body that may be difficult to study in animal models.