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Yang, et al.
provides a platform for high-resolution printing of It was found that electrical stimulation results in a well-
microtissues. organized sarcomere structure and upregulates the heart-
Besides 3D bioprinting, some other methods have specific gene expression . Nieto et al. fabricated a chip
[40]
been employed to fabricate 3D cardiac microtissues. and stimulated the H9C2 cells by depositing an aluminum
Fenech et al. used photolithography to fabricate the film on soda lime glass with physical vapor deposition
network of blood vessels with microvessel diameter (PVD) method . Recently, 3D bioprinting has been used
[41]
ranging from 5 µm to 120 µm . The microvessel to fabricate electrodes in heart-on-a-chip. Lin et al. 3D
[34]
caters to the needs of the large-scale cardiac tissues by printed the microprobes with the conductive polymer poly
providing nutrition and discharging waste. Bartholoma (3,4-ethylenediox-ythiophene): polystyrene sulfonate
et al. have fabricated a scaffold-free functional cardiac (PEDOT: PSS) . Adly et al. fabricated microelectrode
[42]
spheroids which can perform spontaneous beating and arrays (MEAs) with a high resolution by ink-jet printing.
synchronous contraction . Since the fabrication process In this method, the conductive material was deposited the
[35]
is simple, the cardiac spheroids have been widely used in substrate which was composed of PDMS, agarose, and
drug screening. gelatin .
[43]
In natural myocardial tissues, CMs show
2.3. Microactuators synchronous contraction through intercellular electrical
The third component of heart-on-a-chip is the communication, resulting in a strong contraction
microactuators, which are used to impose external stimuli force. It has been found that it can promote electrical
to cells/microtissues. In the native tissues, cells are communication and maturation of myocardial tissues
subjected to various chemical, mechanical, and electrical by adding conductive materials, for example, carbon
cues, which significantly affect the cell behaviors. In nanotubes (CNTs), to cell culture scaffolds. The
heart-on-a-chip, the main function of microactuator directional conduction of CNTs can regulate the alignment
is to stimulate the cells/microtissues to promote their of CMs and improve their beating and contractility. Some
maturation. In this section, we discuss the fabrication of researchers have fabricated CNTs or silk scaffolds by
microactuators for electrical and mechanical stimulation. electrospinning and found that the materials can improve
the maturity of CMs .
[44]
(1) Electrical stimulation microactuators
It is known that CMs are responsive to electrophysiological (2) Mechanical stimulation microactuators
stimulation. Electrical stimulation can increase the In addition to the electrical stimulation, mechanical
percentage of cells that beat spontaneously and assist in stimulation also plays an important role in heart. It has
cell synchronization and calcium processing. In a heart- been found that the external mechanical forces can affect
on-a-chip, electrical stimulation is usually performed the alignment, phenotype, calcium concentration, and
[45]
through electrodes that are in contact with cells . contractile properties of CMs . In this section, we mainly
[36]
A variety of materials have been applied to fabricate discuss two types of mechanical stimuli, mechanical
electrical actuators in heart-on-a-chip, including copper, stress, and mechanical properties of substrate.
graphite, titanium, silver, platinum, and alloys . As a A variety of devices have been developed to
[37]
commonly used electrode, graphite has good machining impose mechanical stress to CMs with the purpose to
performance, and is wear-resistant and low-cost. Margari mimic the physiological functions of heart. We would
et al. fabricated an engineered heart-on-a-chip which introduce two types of mechanical stress microactuators,
includes graphite electrodes and gold electrodes . The the electromagnetic microactuators, and pneumatic
[38]
hPSC-CMs were cultured on the electrodes and the CMs microactuators. Electromagnetic microactuators are
became mature after 14 days. Platinum and titanium widely used due to its stability and high sensitivity. Li
electrodes are also used in heart-on-a-chip. Zhang et al. et al. fabricated a device to impose mechanical stress to
fabricated a 3D cylindrical platinum electrode, which can cells. In their experiments, the magnetic particles were
electrically stimulate the cells for a few weeks . The mixed to the cell-laden hydrogels. The electromagnetic
[39]
advantage of using platinum and titanium is that they microactuators were placed at the ends of hydrogel
have high corrosion resistance. structures. In this manner, the non-contact electromagnetic
Some metal electrodes may cause toxic reaction force can be applied to the cells . The force is well
[46]
in the culture, and the electrodes may degrade due to controlled in magnitude, frequency, and duration by
the electrochemical reaction with the culture medium. the electromagnetic microactuators. This method was
An alternative solution is the indium tin oxide (ITO) successful in promoting the maturation of CMs. As to
film, which has good conductivity, optical transparency, the pneumatic actuators, Rasponi et al. have developed
stability, and non-toxicity. Kang et al. used ITO to a heart-on-a-chip that can mimic the mechanical
electrically stimulate neonatal rat ventricular myocytes. microenvironment of native CMs . The chip includes
[47]
International Journal of Bioprinting (2021)–Volume 7, Issue 3 59