UC Berkeley

With highly regulated safety requirements, the average cost of drug development is $2.5B, which has increased by more than 9-fold since 1979. Preclinical studies include both in vitro and in vivo studies in non-human models to determine the efficacy and toxicity of the compound before any administration to people. However, no commonly used platforms accurately predict drug effects on patients, since they do not mimic human physiology. The fourth reason for drug withdrawal from the market in the last 70 years were unexpected side effects on the cardiovascular system, such as toxicity or dysfunction of the heart, associated with life-threatening conditions. Accordingly, the FDA has mandated that all drugs must be screened for the potential to alter ventricular repolarization prior to human studies. There is an urgent need to develop tools to diminish time and costs of the drug development pipeline while getting safer and more efficient cardiotoxicity screening. A big advance for 2D in vitro assays for cardiotoxicity screens was the discovery of human induced pluripotent stem cells (hiPSC) from which cardiomyocytes with patients genetics could be derived. However, one challenge remains : hiPSC-derived cardiomyocytes (CM) show immature metabolic and mechanical properties, questioning their prognostic capabilities. In this thesis, we demonstrated that the combination of 3D culture of hiPSC-CM in microphysiological systems (heart-on-a-chip) with fatty-acid based media, synergized to promote maturation of hiPSC-CM metabolism and electrophysiology. To further improve the maturation of the tissues we screened through different confinement chamber designs and selected for parameters that enhance mechanical, morphological and contractility outcomes of tissues. As the COVID-19 pandemic hit, we saw the opportunity for our matured cardiac system to rapidly predict cardiotoxicity associated with potential therapeutics (hydroxychloroquine combination with azithromycin) in a mock clinical trial experimental design as well as in an acute dose escalation study. The high content system can help clinicians rapidly evaluate safety properties of potential therapeutics in crisis times to hopefully accelerate access of patients to treatment.