3D in vitro Human Stem Cell-derived Cardiovascular Tissue Model and Microfluidic Platform for Targeted Preclinical Drug Screening

项目简介:

PROJECT ABSTRACT: Cardiovascular Diseases (CVDs) are difficult to study and treat with pharmacological interventions due to the need for personalized medicine regimens, limited availability of human myocardium samples, and the difficulty associated with culturing primary cardiomyocytes in vitro for preclinical drug testing. In vivo animal studies are currently used to screen novel CVD therapeutics but are inefficient due to the associated high cost and advanced technical skill level. Incorporating human induced pluripotent stem cell (hiPSC) derived cardiovascular cells into relevant microfluidic devices provides a controlled, reproducible, and patient-specific (targeted) platform to study in vitro the complex process of CVD progression along with the cellular response to biochemical and biophysical changes in their microenvironments. Current in vitro cardiovascular tissue models incorporate cells from different sources and have not yet demonstrated a functional integration of cardiomyocytes with capillary-like networks composed of endothelial cells. Furthermore, microfluidic devices used with these models predominantly rely on external pumps to move fluid through the system. My long-term goals are to develop a patient-specific cardiovascular tissue model and autonomous-flow microfluidic culture platform to: 1) assess the effects of pharmaceutical drug exposure on human myocardium in vitro and 2) conduct fundamental studies of real-time cardiomyocyte-endothelial cell-extracellular matrix interaction for cardiomyopathy, atrial fibrillation, and atherosclerosis. The central hypothesis is that combining hiPSC derived 3D cardiovascular tissue with an autonomous-flow microfluidic device will create a patient-specific, physiologically relevant model that facilitates in vitro study of functional human myocardium. The primary impact of this work is development of a targeted, single source cardiovascular tissue model that will contribute to more effective drug discovery by reflecting human response to therapeutics and help reduce the use of costly animal models. This work also contributes to expanding the genetic diversity in preclinical drug testing studies so results are more representative of the general population.