Book Description

Drug development cost over the years has increased while the number of approved drugs annually has declined, mainly due to high attrition rates in clinical trials. To lower the burden of the cost of drug development, there is an urgent need for more predictive human tissue models to determine drug efficacy and safety as early as possible. Although animal models have contributed immensely, both to the development of new drugs and our understanding of physiology or disease, frequent discordances between animal and human studies have been found. Despite significant development in computational and in vitro biology, standard culture platforms (e.g., cell lines grown in 2D culture in a dish) offer limited control over the culture environment and often fail to recapitulate the complexity of in vivo biology. Biomimetic modeling of human tissues aims to bridges the gap between 2D in vitro culture and animal models by approximating the complex molecular, structural, and functional phenotypes of native tissues. In this context, microphysiological systems or organotypic models have attracted substantial interest in recent times owing to their potential in providing key insights into physiological and pathological processes. These innovative devices could serve as powerful platforms at multiple stages of the drug discovery and development processes to accelerate pre-clinical testing. Tubular structures in vivo are ubiquitous, being present in mammary ducts, blood vessels, and the intestine among other organs. In this dissertation, a set of microphysiological systems developed to study and improve the modeling of disease processes in tubular organs, including cancer progression, metastasis, and gastrointestinal infections, are presented. A method established to generate arrays of tubular tissues enabling robust and complex multi-tissue interactions for increased throughput studies is described. Also presented is an organotypic model used to mimic cancer-vascular interactions involved in extravasation, a process in cancer metastasis that involves cancer cells exiting the vascular system. Finally, a more complex microphysiological system developed to elucidate human immune cell response during parasitic infection of the intestinal tract is described. Together, these microphysiological systems extend our ability to study and develop new therapies that target microenvironmental factors contributing to the progression of diseases involving tubular organs.