Tissue-engineered Human Cardiac Models for Quantitative Risk Assessment and Disease ModelingdissertationsDaley, Mark CameroncreatorCoulombe, KareenAdvisorTripathi, AnhubavReaderChoi, Bum-RakReaderHoffman-Kim, DianeReaderFerguson, StephenReaderBrown University. Biology and Medicine: Biomedical Engineeringsponsor2025xxi, 243 p.born digitalThesis (Ph. D.)--Brown University, 2025thesesDrug development is an increasingly expensive process, with the total cost of bringing a novel compound to market now exceeding one billion dollars. This inefficiency is largely due to a disconnect between non-human preclinical models and clinical responses in humans, with traditional preclinical assessment relying on small animals or immortalized cell lines that fail to capture human-specific cardiac physiology. As a result, cardiac toxicity accounts for around 15% of safety-related pre- and post-market withdrawals. Moreover, many cardiac diseases also occur due to non-monogenic mutations which cannot be easily modeled with current approaches, severely limiting drug discovery efforts. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising approach to address these challenges and can act as human- and patient-specific models of the heart. The overall objective of this dissertation was to develop hiPSC-CM-based tissue-engineered approaches to improve preclinical models of cardiac toxicity and disease. Towards this end, we employed a multipronged approach across three distinct contexts of use to exhibit the potential of hiPSC-CMs to serve as fit-for-purpose models throughout the drug discovery pipeline. We first demonstrated that engineered cardiac microtissues accurately predict the proarrhythmic risk of compounds affecting normal cardiac repolarization. We further developed a framework by which to quantify the effects of biological and technical variation on arrhythmia risk assessment, creating an approach for defining both experimental and analytical requirements. We additionally leveraged hiPSC-CMs as a screening platform for identifying cardioprotective cotreatments for preventing anthracycline-induced cardiotoxicity during anticancer therapy. Finally, we developed and integrated a patient-specific hiPSC line into a Wolff-Parkinson-White Syndrome disease model to study atrial fibrillation resulting from a novel genetic mechanism. Overall, this dissertation has advanced the development of fit-for-purpose hiPSC-CM-based models across preclinical drug discovery, providing a foundation for accurate, human-centered models to assist in the development of next-generation compounds.induced pluripotent stem cellscardiovascular diseaseCardiotoxicityDoxorubicin-Induced CardiotoxicityWolff-Parkinson-White syndromearrythmiaRisk assessmentEnglishRPB20250707