In silico modelling of multi‐electrode arrays for enhancing cardiac drug testing on hiPSC‐CM heterogeneous tissues

Figures

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  Figure 1. Schematic representation of the MEA device A, detailed representation of the experimental setup. The top row depicts two pictures of the device, showing the interaction with the culture of cells (on the left) and the position of the six independent culture chambers, separated by a macrolon ring (photo on the right). The bottom row depicts a schematic diagram of the MEA chip (on the left): inside each well, in between the marked two bars exiting from the circle in the middle of the MEA, there is a field of nine electrodes with an internal reference electrode (see the zoomed view on the right). B, geometry used in the MEA model simulations. The domain contains 3 × 3 evenly spaced electrodes, and the propagating wave is initiated by a group of spontaneously firing cells in the lower left corner of the domain.

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  Figure 2. Heterogenous tissue configuration Random position of AL and VL cells inside the MEA well when considering 30% of AL hiPSC‐CMs. In the bottom left corner, a group of spontaneously beating VL cells is imposed in this configuration. If the percentage of AL hiPSC‐CMs is >50, then a group of spontaneously beating AL cells has to be imposed.

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  Figure 3. Phenotype‐specific ionic models Tissue heterogeneity is described using two different ionic models: the Paci2020 model for VL hiPSC‐CMs and the Botti2024 model for AL hiPSC‐CMs. They simulate both the spontaneous firing activity (used for the automatic corner, solid lines in the upper panel) and the response to a given stimulus (used in the rest of the domain, dashed lines in the upper panel). Ionic currents that underlie the differences between the AL and VL hiPSC‐CMs are shown in the other panels. Notably, the primary distinction is the presence of atrial‐specific IKur and IKCa currents in the AL hiPSC‐CMs. For the sake of clarity, only currents in spontaneously firing hiPSC‐CMs are shown, allowing for better visualization of non‐overlapping traces. Unless otherwise specified, units of ionic current are expressed as [pA/pF].

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  Figure 4. Activation time maps Activation time isochrones computed by solving the MEA model when considering homogeneous VL or AL tissue, or mixed configurations of phenotype‐specific hiPSC‐CMs in the well. The colour bar indicates the range of values represented by the displayed equipotential lines.

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  Figure 5. Local conduction speed maps The local conduction speed vector field was computed at each point, considering either homogeneous VL or AL tissue, as well as a mixed configuration of phenotype‐specific hiPSC‐CMs within the well. To enhance clarity, 20% of the vector field arrows are displayed.

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  Figure 6. Repolarization time maps Isochrones of repolarization time were computed using the MEA model for various heterogeneous configurations of phenotype‐specific hiPSC‐CMs within the well. The colour scale indicates the range of repolarization times along the equipotential lines. Isochrones illustrate the irregular patterns in highly heterogeneous tissues, while the colour gradient emphasizes the prolonged recovery times for AL tissues returning to the resting state.

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  Figure 7. APD time maps Isochrones of APD were computed using the MEA model for various heterogeneous configurations of phenotype‐specific hiPSC‐CMs within the well. The colour scale indicates the range of APDs along the equipotential lines. Isochrones illustrate the irregular patterns in highly heterogeneous tissues.

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  Figure 8. Heterogeneity effect on the average conduction velocity; AP and FP in the nine electrodes A, MEA domain with nine electrodes and transmembrane potential v about 30 ms after stimulation. B and D, AP and the FP waveforms at the nine electrodes placed as in A; Simulations WEre performed considering 30% AL hiPSC‐CMs in the MEA platform. C, increasing average conduction velocity for increasing percentage of AL hiPSC‐CMs in the MEA well. This relationship highlights how cellular composition directly influences electrical coupling efficiency and conduction properties.

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  Figure 9. Ionic model comparison for healthy and BrS1‐ or BrS2‐affected VL hiPSC‐CMs Simulated AP of a healthy VL hiPSC‐CM (solid black line) alongside a modified model that incorporates changes to replicate the single‐cell effects characteristic of diseased hiPSC‐CMs (dashed lines). Red dashed lines refer to BrS1 modelling, while Green dashed lines refer to BrS2 modelling. The modifications of activation and inactivation curves (bottom panels) lead to modified ionic currents (bottom‐up approach). Thus, ionic currents reflect altered ionic dynamics associated with the diseased state, highlighting differences in AP morphology (upper panel).

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  Figure 10. Electrical activity in the selected electrode AP v (left panel) and FP U (right panel), recorded by one electrode when considering hiPSC‐CM tissue in control conditions (black line) and when considering both the BrS1 and BrS2 changes affecting the VL ionic model (red and green lines, respectively). Note that the AP in the left panel is not equivalent to the single‐cell dynamics shown in Fig. 9.

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  Figure 11. Local conduction speed map comparison Comparison of the local conduction speed vector field of the healthy tissue (Control, left panel) and the tissue affected by BrS1 (right panel). In both cases, the simulations were performed considering 30% of AL hiPSC‐CMs inside the well. To enhance clarity, only 20% of the vector field arrows are displayed. The colour scale shows both the local and global reduction of the BrS1 conduction velocity.

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  Figure 12. Mexiletine effect A, control (dashed line) and drug effects (continuous line) on v (top) and ICaL current (bottom) for phenotype‐specific ionic models (Paci2020 VL dynamics on the left, Botti2024 AL dynamics on the right). B, experimental data from Millard et al. (2018); and C, simulated results: black lines correspond to control conditions, blue lines to mexiletine effect. D, experimental data from Millard et al. (2018). Left: experimental FP waveforms (black line corresponds to control conditions, blue line corresponds to mexiletine effect). Right: percentage of change for different drug concentrations of the following biomarkers: beat period (BP), FP duration (FPD), FPD measurements rate‐corrected (FPDc) using the Fridericia correction (Fridericia, 2003) and spike amplitude (AMP).