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Yang, et al.
are also available for MEA. Offenhäusser et al. proposed observed the beating cycle of CM. By changing the distance
a graphene-based MEA microsensors and monitored the between two adjacent microchambers, they confirmed
extracellular action potential of CMs . The MEA can the clustering effect of CMs. Another feature of CMs
[75]
detect local action potentials with high spatial resolution is contraction, and the contraction force is an important
and high sensitivity, but failed to measure the contractility indicator of cell physiological state. Varghese et al.
of CMs. Some researchers combined the MEA and fabricated a heart-on-a-chip, and studied the influence of
interdigital electrode (IDE) together to measure the electrical stimulation on the contraction force of CMs .
[81]
action potential, contraction force, beating rate, and other Some researchers fabricated heart-on-a-chip with the
parameters (Figure 3Di) . The MEA is an electrically biowire structures. Two flexible wires fabricated from a
[76]
stable, high-throughput, and non-invasive microsensor poly(octamethylene maleate (anhydride) citrate) (POMaC)
for recording the electrophysiology of CMs. polymer are secured with adhesive glue. The chip was
Sometimes, the microtissues in heart-on-a-chip are used to study the response of immature CMs to electrical
in 3D and thus 3D electrodes are required to measure stimulation. It was found that electrical stimulation
the electrophysiological signals in the microtissues. could increase the microstructure of myofibrils, increase
To date, various 3D nanoelectrode structures have the electrical conduction, and change the properties of
been developed, including nanotubes, nanopillars, and electrophysiology and calcium ion transients. The human
mushroom-shaped electrodes . Lieber et al. fabricated circulatory system is composed of the heart and a complex
[77]
a nanoscale field-effect transistor device which shows a network of blood vessels. Blood pressure is an important
high sensitivity in water and acid/alkali solution. They issue of blood circulation, and it can be studied by heart-on-
modified the transistor surface with phospholipid bilayers a-chip. Sethu et al. designed a chip which can accurately
and implemented the real-time monitoring of intracellular simulate the hemodynamic stress, and they found the
[82]
potentials of single cell (Figure 3Dii) . Abbott et al. stress can promote the maturation of CMs . Wu et al.
[77]
fabricated nanoscale intracellular electrodes and realized developed a heart-on-a-chip to simulate the circulation
[83]
a high-fidelity electrophysiological image for neonatal system . The chip includes four pump units representing
rat cardiomyocytes . Some researchers used 3D plasma the four heart chambers, and the pressure is controllable to
[78]
nanoelectrodes to record the electrical activities inside and study its influence on the cells (Figure 4A).
outside the cells for a long term. Lieber et al. introduced 3.2 Disease modeling
a 3D nanoelectrode array that mimics the tissue scaffold.
The device can simultaneously map the action potential Disease modeling is an important step in analyzing
in three dimensions in real time. This heart-on-a-chip disease mechanisms and developing drugs for
with 3D nanoelectrode array can realize the monitoring treatments . Coronary heart disease refers to the
[84]
of electrophysiological activity in the process of culture stenosis or blockage of the vascular lumen caused by
and development . coronary atherosclerosis. Coronary heart disease may
[79]
lead to the myocardial infarction in the later stage. For
3. Biomedical applications of heart-on-a-chip a better understanding of the coronary heart disease and
for exploring effective treatments, Wang et al. designed a
Heart-on-a-chip has found various applications, including heart-on-a-chip in which the oxygen was well controlled
physiology study, disease modeling, and drug screening. to study the myocardial damage caused by hypoxia
Compared with the traditional techniques, heart-on-a- (Figure 4B) . Liu et al. fabricated the heart-on-a-chip
[85]
chip can better mimic the cellular microenvironment and to model the non-uniform oxygen distribution. The model
promotes the maturation of microtissues. In addition, can mimic the blockage of coronary arteries and study the
heart-on-a-chip enables the real-time monitoring of the electrophysiological response of myocardial hypoxia .
[86]
status of cells/microtissues. In this section, we discuss For CMs, the activity of Ca channels would affect the
2+
the applications of heart-on-a-chip in physiology study, contraction. Elvassore et al. designed a heart-on-a-chip
disease modeling, and drug screening. and found that the hypoxia would induce the reversible
[87]
2+
3.1. Physiology study change of Ca concentration in CMs .
Cardiac fibrosis could form a large number of
With the assistance of heart-on-a-chip, we can enhance fibrosis scar tissue, and lead to heart failure. Heart-on-a-
our understanding in the physiological characteristics of chip can be used to simulate the cardiac fibrosis model by
heart. One feature of CMs is that they can rhythmically controlling the number of fibroblasts and the concentration
beat and are responsive to external stimuli such as force of collagen in the engineered microtissues. Experimental
and electricity. Yasuda et al. used agarose material and results showed that increasing the fibroblast density can
fabricated a heart-on-a-chip with microchamber array . reduce the contraction force . Some researchers used 3D
[80]
[12]
They cultured single CM in each microchamber, and hydrogel microtissues to model the cardiac fibroblasts .
[88]
International Journal of Bioprinting (2021)–Volume 7, Issue 3 63