Generation and Culture of Cardiac Microtissues in a Microfluidic Chip with a Reversible Open Top Enables Electrical Pacing, Dynamic Drug Dosing and Endothelial Cell Co-Culture

Abstract

Cardiovascular disease morbidity has increased worldwide in recent years while drug development has been affected by failures in clinical trials and lack of physiologically relevant models. Organs-on-chips and human pluripotent stem cell technologies aid to overcome some of the limitations in cardiac in vitro models. Here, a bi-compartmental, monolithic heart-on-chip device that facilitates porous membrane integration in a single fabrication step is presented. Moreover, the device includes open-top compartments that allow facile co-culture of human pluripotent stem cell-derived cardiomyocytes and human adult cardiac fibroblast into geometrically defined cardiac microtissues. The device can be reversibly closed with a glass seal or a lid with fully customized 3D-printed pyrolytic carbon electrodes allowing electrical stimulation of cardiac microtissues. A subjacent microfluidic channel allowed localized and dynamic drug administration to the cardiac microtissues, as demonstrated by a chronotropic response to isoprenaline. Moreover, the microfluidic channel could also be populated with human induced pluripotent stem-derived endothelial cells allowing co-culture of heterotypic cardiac cells in one device. Overall, this study demonstrates a unique heart-on-chip model that systematically integrates the structure and electromechanical microenvironment of cardiac tissues in a device that enables active perfusion and dynamic drug dosing. Advances in the engineering of human heart-on-chip models represent an important step towards making organ-on-a-chip technology a routine aspect of preclinical cardiac drug development.

Emerging technologies for cardiac tissue engineering and artificial hearts

“…Firstly, the viability maintenance and electromechanical integration of seeding cells with host cells after implantation remain to be explored. In this regard, organs‐on‐chips could be utilized as ideal research platforms to investigate the factors or mechanisms determining these processes, 91,92 thus proving guidance for safe and effective transplantation of engineered tissues.…”