Cardiovascular disease (CVD) represents the largest cause of natural death, accounting for more than 18 million fatalities each year. CVD due to ischemia accounts for a majority of these fatalities and occurs when an artery supplying blood to the heart muscle is blocked, creating a region of hypoxia. Severe ischemia causes myocardial infarction, leading to tissue death or overall cardiac dysfunction. Bioelectronic recording devices open new avenues for long-term electrophysiology by enabling detection and measurement of signals produced by cardiomyocytes (CMs). Changes in O2 levels in the microcellular environment induce function responses, including shifts in gene expression and changes in resting membrane potential. Electrical measurements that provide the shape and duration of action potentials give information regarding the density, type and metabolic state of ion channels. Current devices are limited by challenges, including immune responses to implanted devices, mechanical mismatch between rigid electronics and tissue, and limited quantities of electrodes. The effects of acute hypoxia on CMs were studied using a 32-channel multielectrode array (MEA), and a bioelectronic heart-on-a-chip model was demonstrated. Contracting CMs fire action potentials which can be measured by extracellular recording elements in close proximity to the cell membrane. These noninvasive, long-term, real-time measurements enable monitoring of electrical synchrony and tissue maturation. To simulate ischemic O2 fluctuations, a microfluidic channel was used to switch between normoxic and hypoxic media. Our MEAs yielded ≥ 85% functional interfaces and were successful in providing multiplexed, continuous recordings. First, the cells beat with a frequency of 3.0 ± 0.5 Hz across n = 8 cultures. Hypoxia (1% O2) was induced for 5 hours, where tachycardia was observed, and the beating frequency increased from 3.2 to 4.2 Hz. A gradual reduction in frequency followed until arrhythmia was reached with longer firing intervals at 4.9 ± 1.5 seconds. The CMs recovered within 30 minutes after introducing normoxic media. The high yield of multiplexed signals from the MEAs enabled monitored beat rates that behaved as expected. This model can be adapted to include 3D tissue constructs or extended to larger, denser arrays. Further studies of CVD through electrophysiology readings can better inform pharmaceutical and therapeutic developments through disease modeling and drug screening applications.

Heart-on-a-chip model with integrated bioelectronics for monitoring cardiac electrophysiology under acute hypoxia

ACS Spring Meeting 2021

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