Toward transmembrane potential estimation from in vitro multi-electrode field potentials using mathematical modeling

Boulakia, Muriel; Raphel, Fabien; Gerbeau, Jean-Frédéric; Zitoun, Philippe

doi:10.1016/j.vascn.2015.08.038

Cited by 3 publications

(1 citation statement)

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“…With this study, we want to show that mathematical modeling and numerical simulation can contribute to a better understanding of the MEA measurements. Some preliminary simulations of the FP were recently presented [10], [11], [12] and the modeling of drug effects, side effects and interactions was addressed in several works [13], [14], [15]. But to the best of our knowledge, the present article is the first in silico study of drug effects on the FP.…”

Section: Introductionmentioning

confidence: 97%

Parameters Estimation approach for the MEA/hiPSC-CM asaays

Bouyssier

Zemzemi

2017

Computing in Cardiology Conference (CinC)

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We propose a mathematical approach for the analysis of drugs effects on the electrical activity of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) based on multi-electrode array (MEA) experiments. Our goal is to produce an in silico tool able to simulate drugs action in MEA/hiPSC-CM assays and to fit the drug model parameters to the experimental data. The electrical activity of the stem cells at the ion-channel level is modeled using the Paci et al. (2013) transmembrane potential model. We use the bidomain model in order to describe the propagation of the electrical wave in the stem cells preparation. The field potential (FP) measured by the MEA is modeled by the extracellular potential of the bidomain equations. First, we propose a strategy allowing to generate FPs in good agreement with the experimental data. Second, we introduce a drug/ion channels interaction based on a pore block model. Results show that the model reflects properly the main effects of the drug on the FP. In order to estimate the parameters of the drug model, we define a cost function minimizing the gap between the model and the observed FPs. We use an optimization algorithm based on a gradient descent method where the cost function gradient is computed using an adjoint approach. We generated field potential for the five drugs with fixed gold standard IC50 and drug dose values. Then, supposing that one of the gold standard parameters is not known and adding 10% gaussian noise, the algorithm is able to estimate this parameter with more than 95% of accuracy. This approach could also be used in the future to optimize drug doses in order to achieve desired therapeutic effects.

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Section: Introductionmentioning

confidence: 97%

Parameters Estimation approach for the MEA/hiPSC-CM asaays

Bouyssier

Zemzemi

2017

Computing in Cardiology Conference (CinC)

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Comprehensive in vitro Proarrhythmia Assay (C i PA): Pending issues for successful validation and implementation

Cavero¹,

Guillon

Ballet

et al. 2016

Journal of Pharmacological and Toxicological Methods

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In order to advance the CiPA paradigm from the current testing and validation stages to a research and regulatory drug development strategy, systematic guidance by CiPA stakeholders is necessary to expedite solutions to pending and newly arising issues. Once a study protocol is proved to yield robust and reproducible results within and across laboratories, it can be implemented as qualified regulatory procedure.

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