Reflective lens-free imaging on high-density silicon microelectrode arrays for monitoring and evaluation of in vitro cardiac contractility.

Thomas Pauwelyn,Lakyn Mayo,Stefan Janssens,Liesbet Lagae,Xuan Zheng,Veerle Reumers,Andy Lambrechts,Dries Braeken,Richard Stahl

doi:10.1364/boe.9.001827

Thomas Pauwelyn, Lakyn Mayo + Show 7 more

Open Access

https://doi.org/10.1364/boe.9.001827

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Abstract

The high rate of drug attrition caused by cardiotoxicity is a major challenge for drug development. Here, we developed a reflective lens-free imaging (RLFI) approach to non-invasively record in vitro cell deformation in cardiac monolayers with high temporal (169 fps) and non-reconstructed spatial resolution (352 µm) over a field-of-view of maximally 57 mm2. The method is compatible with opaque surfaces and silicon-based devices. Further, we demonstrated that the system can detect the impairment of both contractility and fast excitation waves in cardiac monolayers. Additionally, the RLFI device was implemented on a CMOS-based microelectrode array to retrieve multi-parametric information of cardiac cells, thereby offering more in-depth analysis of drug-induced (cardiomyopathic) effects for preclinical cardiotoxicity screening applications.

Highlights

Monitoring of the contractility of cardiac cells in vitro is crucial for the preclinical assessment of drug-induced cardiotoxicity, which accounts for up to 45% of market withdrawal [1]
To evaluate the performance of the digital in-line holography reflective lens-free imaging (RLFI) system, we first imaged neonatal rat ventricular cardiomyocytes in glass wells glued onto SiO2 wafers
Seeded primary rat ventricular cardiomyocytes were imaged over a FOV of 57 mm2 (Fig. 2(b)), where the interference patterns created by individual cardiac cells are detected

Summary

Introduction

Monitoring of the contractility of cardiac cells in vitro is crucial for the preclinical assessment of drug-induced cardiotoxicity, which accounts for up to 45% of market withdrawal [1]. Planar patch clamp is part of the standard electrophysiological toolbox for the determination of in vitro cardiotoxicity [5] These systems can register intracellular action potentials of dissociated cells [6], the method is invasive and only short measurements are feasible. CMOS-based MEAs greatly enhance the throughput, spatial resolution and quality of these measurements compared to more simple glass-based MEAs [7,11,12,13,14]. Another approach involves measuring the fluorescence of cardiac cells genetically altered to produce voltage sensitive dyes, but fluorescence is susceptible to photobleaching and phototoxicity [15]

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