@article {42717,
	title = {Metabolically driven maturation of human-induced-pluripotent-stem-cell-derived cardiac microtissues on microfluidic chips},
	journal = {Nature Biomedical Engineering},
	volume = {6},
	year = {2022},
	month = {Jan-04-2022},
	pages = {372 - 388},
	publisher = {Nature Publishing Group},
	address = {London, UK},
	doi = {10.1038/s41551-022-00884-4},
	url = {https://www.nature.com/articles/s41551-022-00884-4https://www.nature.com/articles/s41551-022-00884-4.pdfhttps://www.nature.com/articles/s41551-022-00884-4.pdfhttps://www.nature.com/articles/s41551-022-00884-4},
	author = {Huebsch, Nathaniel and Charrez, Berenice and Neiman, Gabriel and Siemons, Brian and Steven C. {Boggess} and Wall, Samuel and Charwat, Verena and Karoline Horgmo {J{\ae}ger} and Cleres, David and Telle, {\r A}shild and Felipe T. {Lee-Montiel} and Nicholas C. {Jeffreys} and Deveshwar, Nikhil and Andrew G {Edwards} and Serrano, Jonathan and Snuderl, Matija and Stahl, Andreas and Tveito, Aslak and Evan W. {Miller} and Kevin E. {Healy}}
}
@misc {27103,
	title = {A Numerical Model of Heart -on -a-Chip Systems  {\textendash} A Tool for Cardiotoxicity Screening},
	howpublished = {Melbourne, Australia},
	year = {2019},
	abstract = {Organ-on-a-chip devices can be used to control and monitor the cellular microenvironment of human microtissues, providing a promising platform for disease and drug development studies. Here we describe a heart-on-a-chip system combining human induced pluripotent stem cell derived cardiomyocytes with microfluidic technology as a cardiotoxicity screening platform (Mathur et al. Sci. Rep. 2015). Within this microphysiological system, image tracking techniques can be used to monitor important indicators of cardiac function, such as contraction velocity, beat rate, and prevalence (Huebsch et al. Tissue Eng. C. 2015). However, mechanical contraction properties such as force and stress are harder to capture. This motivates the need for a numerical model simulating the mechanical behavior of the microtissue, to predict and help monitor the effect of drugs and mutations on the contractility of the tissue. In this study we propose a model for cardiac tissue applied to a geometric representation of the chip system to predict contraction forces and strain. We are using a zero-dimensional point model of cardiac myofilaments developed by Rice et. al. (Biophysical Journal 2008) to calculate the force generated by single myocytes, embedded within a continuum model for the mechanics of ventricular myocardium given by Guccione et. al (ASME 1991). Combined, this give us a system of partial differential equations, which we solve using the finite element method over a given three-dimensional mesh. The parameters in the model are optimized using data from real heart-on-a-chip devices. We evaluated the system for pharmacology studies (as of now, negative and positive inotropes respectively flecainide and isoproterenol) using experimentally measured calcium amplitude transients to predict resulting Cauchy stresses at increasing drug doses. Combining our numerical model for mechanical simulation with experimental heart-on-a-chip data produced comparable dose response results. We observed similar trends for measurements of internal forces of the tissue under isometric conditions. This combined in silico / in vitro analysis system provides the possibility of a robust technique for understanding the physiological complexity of micro-organ function in vitro, facilitating contraction force assessment for drug screening and disease modeling in heart-on-a-chip systems.\&nbsp;},
	author = {Telle, {\r A}shild and Charrez, Berenice and Kevin E. {Healy} and Tveito, Aslak and Wall, Samuel}
}
@article {Huebsch485169,
	title = {Metabolically-Driven Maturation of hiPSC-Cell Derived Heart-on-a-Chip},
	journal = {{bioRxiv},
	year = {2018},
	publisher = {Cold Spring Harbor Laboratory},
	abstract = {Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) are a promising in vitro tool for drug development and disease modeling, but their immature electrophysiology limits their diagnostic utility. Tissue engineering approaches involving aligned and 3D culture enhance hiPSC-CM maturation but are insufficient to induce electrophysiological maturation. We hypothesized that recapitulating post-natal switching of the heart{\textquoteright}s primary adenosine triphosphate source from glycolysis to fatty acid oxidation could enhance maturation of hiPSC-CM. We combined hiPSC-CM with microfabrication to create 3D cardiac microphysiological systems (MPS) that enhanced immediate microtissue alignment and tissue specific extracellular matrix production. Using Robust Experimental design, we identified a maturation media that allowed the cardiac MPS to correctly assess false positive and negative drug response. Finally, we employed mathematical modeling and gene expression data to explain the observed changes in electrophysiology and pharmacology of MPS exposed to maturation media. In contrast, the same media had no effects on 2D hiPSC-CM monolayers. These results suggest that systematic combination of biophysical stimuli and metabolic cues can enhance the electrophysiological maturation of hiPSC-derived cardiomyocytes.},
	doi = {10.1101/485169},
	url = {https://www.biorxiv.org/content/early/2018/12/10/485169},
	author = {Huebsch, Nathaniel and Charrez, Berenice and Siemons, Brian and Steven C. {Boggess} and Wall, Samuel and Charwat, Verena and Jaeger, Karoline and Felipe Lee T. {Montiel} and Nicholas C. {Jeffreys} and Deveshwar, Nikhil and Andrew G {Edwards} and Serrano, Jonathan and Snuderl, Matija and Stahl, Andreas and Tveito, Aslak and Evan W. {Miller} and Kevin E. {Healy}}
}
