Heart-on-a-Plate for Modelling of Cardiac Physiology and Drug Screening

The current drug development process is both very slow (15 year average) and costly ($1.5B/drug average). Despite this hefty investment, inefficiencies in the drug screening process routinely result in the withdrawal of drugs from the market due to serious toxicities and adverse cardiovascular effects. Safety screen assessments performed on cell cultures and animal models do not always correlate with clinical risk. Specifically, this entire framework predicts only 75-90% of the effects of a drug in a human patient, resulting in the abandonment of many promising drugs early in development and enabling some cardiotoxic drugs go to market. A potential explanation is that much of the safety and efficacy testing has relied upon animal studies and little information has been gathered from human preparations. The applicability of animal studies is limited by the fundamental cardiovascular differences amid species. Similarly, cardiac ion channel in vitro screens frequently involve non-cardiac cells (Chinese hamster ovary, CHO or human embryonic kidney, HEK) that have been engineered to overexpress an individual target ion channel, most commonly the human ether-a-go-go (hERG) channel (I_Kr current). However, interference with other currents may also contribute to cardiac complications necessitating an assessment protocol that evaluates the effect of a drug on the collective behaviour of cardiac ion channels.

Organ-on-a-chip devices hold a promise to revolutionize the way drugs are discovered and tested when used in conjunction with cardiomyocytes derived from human pluripotent stem cells. Current devices are limited by the presence of non-physiological materials such as glass and drug-absorbing PDMS as well as the necessity for specialized equipment such as vacuum lines and fluid pumps that inherently limit their throughput. An overview of two new technologies, Biowire and AngioChip, that overcome some of the limitations above will be presented. Biowires and AngioChips are situated in an open-concept plate-like platform compatible with current liquid handling practices that involve pipetting or pipetting robots. The use of these technologies in maturation of cardiomyocytes derived from pluripotent stem cells, their perfusion, drug testing and disease modelling will be presented.