@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}}
}
@article {27659,
	title = {Identifying drug response by combining measurements of the membrane potential, the cytosolic calcium concentration, and the extracellular potential in microphysiological systems},
	journal = {Frontiers in Pharmacology},
	volume = {11},
	year = {2021},
	pages = {569489},
	publisher = {Frontiers},
	abstract = {Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) offer a new means to study and understand the human cardiac action potential, and can give key insight into how compounds may interact with important molecular pathways to destabilize the electrical function of the heart. Important features of the action potential can be readily measured using standard experimental techniques, such as the use of voltage sensitive dyes and fluorescent genetic reporters to estimate transmembrane potentials and cytosolic calcium concentrations. Using previously introduced computational procedures, such measurements can be used to estimate the current density of major ion channels present in hiPSC-CMs, and how compounds may alter their behavior. However, due to the limitations of optical recordings, resolving the sodium current remains difficult from these data. Here we show that if these optical measurements are complemented with observations of the extracellular potential using multi electrode arrays (MEAs), we can accurately estimate the current density of the sodium channels. This inversion of the sodium current relies on observation of the conduction velocity which turns out to be straightforwardly computed using measurements of extracellular waves across the electrodes. The combined data including the membrane potential, the cytosolic calcium concentration and the extracellular potential further opens up for the possibility of accurately estimating the effect of novel drugs applied to hiPSC-CMs.},
	doi = {doi: 10.3389/fphar.2020.569489},
	url = {https://www.frontiersin.org/articles/10.3389/fphar.2020.569489/full},
	author = {Karoline Horgmo {J{\ae}ger} and Charwat, Verena and Wall, Samuel and Kevin E. {Healy} and Tveito, Aslak}
}
@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 {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}
}
@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}
}
@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}}
}
