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Predicting structural damage to the heart using spontaneously beating 3D cardiac microtissues

Electrophysiology is an important component in understanding cardiotoxicity, but it may not present the whole picture. The US FDA has been examining new approaches to in vitro cardiotoxicity assessment with the Comprehensive in vitro Cardiotoxicity Assay (CiPA) initiative to explore cardiac risk beyond the hERG channel, which is currently the only in vitro assay required by the regulatory authorities for identifying cardiotoxic liability of new pharmaceuticals. Multielectrode Array- (MEA) based platforms such as eCiphr®Cardio are being evaluated under the CiPA initiative for effects on ion channels, however, new research in the applicability of three-dimensional (3D) cardiac microtissues is showing promise in understanding mechanistic liabilities that contribute to structural damage to the heart.

A tri-culture approach consisting of human iPS cell derived cardiomyocytes, cardiac endothelial cells and cardiac fibroblasts, has been implemented at Cyprotex to create 3D cardiac microtissues which mimic the cellular composition of myocytes and non-myocyte cells within the heart. The cells even spontaneously beat like a heart as shown in the video below.

Confocal high content screening (HCS) allows parameters such as mitochondrial disruption and calcium dyshomeostasis, which are indicative of cardiac cell health, to be measured simultaneously within 3D cellular structures. These images demonstrate the resolution possible using 3D confocal HCS.

RGB-cardiac-movie Hoechst-new-cardiac-movie Projections-of-3D-test Projections-of-3D-test-colour-2 Projections-of-Phalloidin-colour

Our research has demonstrated that the Cyprotex’s cardiac tri-culture model is highly predictive for identifying structural cardiotoxins. This research was recently presented at SOT by Cyprotex’s Chief Scientific Officer, Dr Clive Dilworth, and the data can be viewed on our website