@article {43086,
	title = {Validating the Arrhythmogenic Potential of High-, Intermediate-, and Low-Risk Drugs in a Human-Induced Pluripotent Stem Cell-Derived Cardiac Microphysiological System},
	journal = {ACS Pharmacology \& Translational Science},
	volume = {5},
	year = {2022},
	pages = {652{\textendash}667},
	publisher = {American Chemical Society},
	abstract = {Evaluation of arrhythmogenic drugs is required by regulatory agencies before any new compound can obtain market approval. Despite rigorous review, cardiac disorders remain the second most common cause for safety-related market withdrawal. On the other hand, false-positive preclinical findings prohibit potentially beneficial candidates from moving forward in the development pipeline. Complex\&nbsp;in vitro\&nbsp;models using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CM) have been identified as a useful tool that allows for rapid and cost-efficient screening of proarrhythmic drug risk. Currently available hiPSC-CM models employ simple two-dimensional (2D) culture formats with limited structural and functional relevance to the human heart muscle. Here, we present the use of our 3D cardiac microphysiological system (MPS), composed of a hiPSC-derived heart micromuscle, as a platform for arrhythmia risk assessment. We employed two different hiPSC lines and tested seven drugs with known ion channel effects and known clinical risk: dofetilide and bepridil (high risk); amiodarone and terfenadine (intermediate risk); and nifedipine, mexiletine, and lidocaine (low risk). The cardiac MPS successfully predicted drug cardiotoxicity risks based on changes in action potential duration, beat waveform (i.e., shape), and occurrence of proarrhythmic events of healthy patient hiPSC lines in the absence of risk cofactors. We showcase examples where the cardiac MPS outperformed existing hiPSC-CM 2D models.},
	doi = {https://doi.org/10.1021/acsptsci.2c00088},
	url = {https://pubs.acs.org/doi/abs/10.1021/acsptsci.2c00088},
	author = {Charwat, Verena and Charrez, B{\'e}r{\'e}nice and Brian A. {Siemons} and Finsberg, Henrik and Karoline Horgmo {J{\ae}ger} and Andrew G {Edwards} and Huebsch, Nathaniel and Wall, Samuel and Miller, Evan and Tveito, Aslak and Kevin E. {Healy}}
}
@misc {26385,
	title = {In Silico - Augmented Cardiac Microphysiological Systems for Evaluating Cardiac Drug Effects},
	year = {2018},
	address = {BMES Conference, Atlanta, USA},
	author = {Wall, Samuel and Karoline Horgmo {J{\ae}ger} and Huebsch, Nathaniel and Charrez, B{\'e}r{\'e}nice and Healy, Kevin and Tveito, Aslak}
}
@misc {26386,
	title = {In Silico - Augmented Cardiac Microphysiological Systems for Evaluating Cardiac Drug Effects},
	year = {2018},
	address = {Keystone Organ on Chip Symposium, Montana, USA},
	author = {Wall, Samuel and Karoline Horgmo {J{\ae}ger} and Huebsch, Nathaniel and Charrez, B{\'e}r{\'e}nice and Healy, Kevin and Tveito, Aslak}
}
@misc {26383,
	title = {In Silico Modeling of Cardiac Microphysiological  Systems for Evaluating Drug Side Effects},
	howpublished = {Heart By Numbers Conference, Berlin, Germany},
	year = {2018},
	author = {Wall, Samuel and Tveito, Aslak and Karoline Horgmo {J{\ae}ger} and Andrew G {Edwards} and Healy, Kevin and Huebsch, Nathaniel and Charrez, B{\'e}r{\'e}nice}
}
@article {26238,
	title = {Inversion and computational maturation of drug response using human stem cell derived cardiomyocytes in microphysiological systems},
	journal = {Nature Scientific Reports },
	volume = {8},
	number = {17626},
	year = {2018},
	month = {12/2018},
	publisher = {Springer Nature},
	abstract = {While cardiomyocytes differentiated from human induced pluripotent stems cells (hiPSCs) hold great promise for drug screening, the electrophysiological properties of these cells can be variable and immature, producing results that are significantly different from their human adult counterparts. Here, we describe a computational framework to address this limitation, and show how in silico methods, applied to measurements on immature cardiomyocytes, can be used to both identify drug action and to predict its effect in mature cells. Our synthetic and experimental results indicate that optically obtained waveforms of voltage and calcium from microphysiological systems can be inverted into information on drug ion channel blockage, and then, through assuming functional invariance of proteins during maturation, this data can be used to predict drug induced changes in mature ventricular cells. Together, this pipeline of measurements and computational analysis could significantly improve the ability of hiPSC derived cardiomycocytes to predict dangerous drug side effects.},
	doi = {10.1038/s41598-018-35858-7},
	url = {https://doi.org/10.1038/s41598-018-35858-7},
	author = {Tveito, Aslak and Karoline Horgmo {J{\ae}ger} and Huebsch, Nathaniel and Charrez, B{\'e}r{\'e}nice and Andrew G {Edwards} and Wall, Samuel and Kevin E. {Healy}}
}
