Micro-electrode channel guide (µECG) technology: an online method for continuous electrical recording in a human beating heart-on-chip

Roberta Visone,Daniela Cruz-Moreira,Alberto Redaelli,Paola Occhetta,Enrico Pesenti,Marco Rasponi,Matteo Moretti,Stefano Piazza,Giovanni S Ugolini,Simona Marzorati

doi:10.1088/1758-5090/abe4c4

Abstract

Cardiac toxicity still represents a common adverse outcome causing drug attrition and post-marketing withdrawal. The development of relevant in vitro models resembling the human heart recently opened the path towards a more accurate detection of drug-induced human cardiac toxicity early in the drug development process. Organs-on-chip have been proposed as promising tools to recapitulate in vitro the key aspects of the in vivo cardiac physiology and to provide a means to directly analyze functional readouts. In this scenario, a new device capable of continuous monitoring of electrophysiological signals from functional in vitro human hearts-on-chip is here presented. The development of cardiac microtissues was achieved through a recently published method to control the mechanical environment, while the introduction of a technology consisting in micro-electrode coaxial guides allowed to conduct direct and non-destructive electrophysiology studies. The generated human cardiac microtissues exhibited synchronous spontaneous beating, as demonstrated by multi-point and continuous acquisition of cardiac field potential, and expression of relevant genes encoding for cardiac ion-channels. A proof-of-concept pharmacological validation on three drugs proved the proposed model to potentially be a powerful tool to evaluate functional cardiac toxicity.

Highlights

Cardiac toxicity represents one of the most recurrent adverse reactions in later stages of the drug discovery pipeline (DDP) [1] and the first cause of drug withdrawal during post-marketing surveillance [2]
The micro-electrode coaxial guides technology To provide a means for the precise positioning of 3D micro-electrodes within microfluidic platforms, a dead-end microchannel geometry was designed as a guiding track for the insertion of 3D wire-shaped probes (figure 1(a))
To validate μECG concept, we designed a microfluidic platform consisting of a single coaxial guide to assess its compatibility with the recording of 3D microtissues electrical activity (figure 1(b))

Summary

Introduction

Cardiac toxicity represents one of the most recurrent adverse reactions in later stages of the drug discovery pipeline (DDP) [1] and the first cause of drug withdrawal during post-marketing surveillance [2]. The development of relevant in vitro models resembling the human heart represents a urgent need to improve cardiotoxicity prediction in the early pre-clinical phases of DDP and, in turn, to plan safer clinical studies. In this context, the introduction of human induced pluripotent stem cell-derived cardiomyocytes (h-iPSC-CMs) brought significant advantages in the field allowing human-based investigations of drug-related risks [4], especially when used in combination with technological tools allowing for direct recording of electrophysiological activity (e.g. multielectrode array (MEA)) [5, 6]. Organs-on-chip (OoC) technology has been proposed as promising approach to recapitulate in vitro the key aspects of the in vivo cardiac physiology with an unprecedented level of accuracy [17], owing to their superior ability to apply controlled biochemical and biophysical stimuli (i.e. mechanical [18] and/or electrical) [15, 19, 20]

Methods

Results

Discussion

Conclusion