@misc {43010,
	title = {Estimating active tension in cardiac micromuscles},
	howpublished = {World Congress on Biomechanics (WCB), Taipei, Taiwan (Virtual)},
	year = {2022},
	type = {Contributed},
	abstract = {Introduction:Microphysiological systems (MPSs) provide a well-defined environment for the formation and monitoring of cardiac micromuscles, and provide a powerful platform for both disease and drug development studies. Such devices can replicate key features of the heart{\textquoteright}s electromechanical behavior, giving a detailed in vitro testbed for investigating cardiac function, both biomechanics and electrophysiology. In an MPS, quantities like displacement and velocity can be identified based on optical measurements of the tissues during contraction [1]. While useful for evaluating relative changes in muscle twitch, it remains difficult to quantify and characterize the underlying active tension that causesdisplacement during contraction.Methods:In this work, we applied an inverse modeling approach to estimate the active tension generated during contraction, as well as the fiber directions in a cardiac micromuscle. Cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSC-CMs) were loaded into MPSs and self-assembled into a uniaxial beating microtissue. High-speed microscopic videos were recorded over several contractions and changes in displacement were calculated. Finally, we used a computational mechanical model in combination with an optimization algorithm, similar to the one used in [2], to find the active tension and fiber directions likely to cause the tissue displacement.Results:Using the displacement recorded for a single chip (Fig 1A), the active strain (Fig 1C), varying over time and space, and the fiber direction (Fig 1D), varying over space, can be estimated. The model, depending on these two variables, was able to closely reproduce (Fig 1B) the displacement given as input. The corresponding mean active tension for this specific experiment at peak contraction value is given by 0.059 {\textpm} 0.043 (active strain) and the corresponding fiber direction angle 3.3{\textdegree} {\textpm} 25.8{\textdegree}.Discussion:Through our framework we can identify regions of active contraction, and fiber direction alignment, both known to be important metrics from a physiological perspective. We can also quantify the active tension generated. This approach can be used to quantify differences and changes in a range of experiments where mechanical properties are critical metrics, including but not limited to screening of drugs that alter contractility, and tissue structural development in different maturation protocols.References:[1] Huebsch, N et al. Metabolically-Driven Maturation of hiPSC-Cell Derived Cardiac Chip. Biorxiv (preprint). 2020. https://doi.org/10.1101/485169.[2] Finsberg, H. et al: Estimating cardiac contraction through high resolution data assimilation of a personalized mechanical model. Journal of Computational Science. 2018;24:85{\textendash}90. https://doi.org/10.1016/j.jocs.2017.07.013},
	doi = {  10.5281/zenodo.6844384},
	url = {https://zenodo.org/record/6844384$\#$.Y6wym37MJFQ},
	author = {Telle, {\r A}shild and Charrez, B{\'e}r{\'e}nice and Charwat, Verena and Finsberg, Henrik and Kevin E. {Healy} and Wall, Samuel}
}
@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}}
}
@article {27952,
	title = {Heart Muscle Microphysiological System for Cardiac Liability Prediction of Repurposed COVID-19 Therapeutics},
	journal = {Frontiers in Pharmacology},
	volume = {12},
	year = {2021},
	pages = {684252},
	publisher = {Frontiers Media SA},
	doi = {10.3389/fphar.2021.684252},
	url = {doi.org/10.3389/fphar.2021.684252},
	author = {Charrez, B{\'e}r{\'e}nice and Charwat, Verena and Siemons, Brian and Goswami, Ishan and Sakolish, Courtney and Luo, Yu-Syuan and Finsberg, Henrik and Andrew G {Edwards} and Miller, Evan and Rusyn, Ivan and Healy, Kevin}
}
@article {27951,
	title = {In vitro safety {\textquotedblleft}clinical trial{\textquotedblright} of the cardiac liability of drug polytherapy},
	journal = {Clinical and Translational Science},
	volume = {14},
	year = {2021},
	month = {03/2021},
	pages = {1155-1165},
	publisher = {Wiley Online Library},
	doi = {https://doi.org/10.1111/cts.13038},
	url = {https://ascpt.onlinelibrary.wiley.com/doi/full/10.1111/cts.13038},
	author = {Charrez, B{\'e}r{\'e}nice and Charwat, Verena and Siemons, Brian and Finsberg, Henrik and Miller, Evan and Andrew G {Edwards} and Kevin E. {Healy}}
}
@article {27079,
	title = {Improved computational identification of drug response using optical measurements of human stem cell derived cardiomyocytes in microphysiological systems},
	journal = {Frontiers in Pharmacology},
	volume = {10},
	number = {1648},
	year = {2020},
	month = {02/2020},
	publisher = {Frontiers},
	abstract = {Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) hold great potential for drug screening applications. However, their usefulness is limited by the relative immaturity of the cells{\textquoteright} electrophysiological properties as compared to native cardiomyocytes in the adult human heart. In this work, we extend and improve on methodology to address this limitation, building on previously introduced computational procedures which predict drug effects for adult cells based on changes in optical measurements of action potentials and calcium\&nbsp;transients made in stem cell derived cardiac microtissues. This methodology quantifies ion channel changes through the inversion of data into a mathematical model, and maps this response to an adult phenotype through the assumption of functional invariance of fundamental intracellular and membrane channels during maturation.\&nbsp;Here we utilize an updated action potential model to represent both hiPSC-CMs and adult cardiomyocytes, apply an IC50-based\&nbsp;model of dose-dependent drug effects, and introduce a continuation-based optimization algorithm for analysis of dose escalation measurements using five drugs with known effects. The improved methodology can identify drug induced changes more efficiently, and quantitate important metrics such as IC50 in line with published values. Consequently, the updated methodology is a step towards employing computational procedures to elucidate drug effects in adult cardiomyocytes for new drugs using stem cell-derived experimental tissues.\&nbsp;},
	doi = {10.3389/fphar.2019.01648},
	author = {Karoline Horgmo {J{\ae}ger} and Charwat, Verena and Charrez, B{\'e}r{\'e}nice and Finsberg, Henrik and Maleckar, Molly and Wall, Samuel and Kevin E. {Healy} and Tveito, Aslak}
}
@article {27665,
	title = {In Vitro Safety {\textquotedblleft}Clinical Trial{\textquotedblright} of the Cardiac Liability of Hydroxychloroquine and Azithromycin as COVID19 Polytherapy},
	journal = {Clinical Pharmacology \& Therapeutics},
	year = {2020},
	publisher = { Wiley},
	author = {Charrez, B{\'e}r{\'e}nice and Charwat, Verena and Siemons, Brian and Finsberg, Henrik and Miller, Evan and Andrew G {Edwards} and Kevin E. {Healy}}
}
@misc {27104,
	title = {Finite element modeling of cardiac tissue in heart-on-a-chip systems},
	howpublished = {Washington DC, USA},
	year = {2019},
	abstract = {Heart-on-a-chip devices can be used to control and monitor the cellular microenvironment of human cardiac microtissue, showing great potential as powerful cardiotoxicity screening platforms. Human induced pluripotent stem cell derived cardiomyocytes are combined with microfluidic technology to derive a tissue mimicking adult human ventricular dimensions, physiology and uniaxial beating properties, which can be used for pharmalogical studies and disease modeling [3]. Within such microphysiological systems, indicators of cardiac function, such as electrophysiology (action potential, calcium transient) and beating physiology (beat rate, contraction velocity) can be readily measured using image analysis techniques [2]. However, important mechanical properties such as myocyte contractility, tissue stress and tissue stiffness, cannot easily be revealed using current techniques. We thuspropose a numerical model simulating the dynamic mechanics of the microtissue.For our model we combined previously published models for cardiac electrochemical and mechanical properties, embedded with a geometrical representation of the tissue chamber, to quantify the passive and active properties of the system. We used a zero-dimensional point model of cardiac myofilaments developed by Rice et. al. [4] to calculate the force generated by single myocytes. This was coupled with a three-dimensional continuum model for myocardial mechanics given by Guccione et. al [1]. Together this gave a set of non-linear partial differential equations describing the stress and deformation, which we set up to find an equilibrium solution and calculate the resulting Cauchy stress. We imposed appropriate boundary conditions and solve the system using FEniCS {\textendash} both the framework for spatially dependent nonlinear boundary value problems, and for time-dependent initial value problems {\textendash} and evaluated the system using data provided from experimental pharmacology studies.Our results provide a quantification of the Cauchy stress developed through active myocardial contraction through the domain, and relative changes under differing simulated conditions. We compared these results with experimental measurements of contraction forces, using the same points for measurements. In this dual analysis we observed a comparable relative increase in Cauchy stress and microscopic measurements of contraction force, respectively, correlated with increasing drug doses. This combined in silico / in vitro system give us a platform for the quantification of internal mechanical properties, providing a framework for understanding the physiology complexity of microorgan tissues. Such a system can give new insight in cardiac mechanics in itself, and might also be important for further development of appropriate mathematical models.},
	author = {Telle, {\r A}shild and Charrez, B{\'e}r{\'e}nice and Kevin E. {Healy} and Tveito, Aslak and Wall, Samuel}
}
@misc {27105,
	title = {A numerical model of mechanical properties of cardiac tissue in heart-on-a-chip devices},
	year = {2019},
	address = {Norwegian meeting on PDEs, Trondheim, Norway},
	author = {Telle, {\r A}shild and Charrez, B{\'e}r{\'e}nice and Kevin E. {Healy} and Tveito, Aslak and Wall, Samuel}
}
@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}}
}
