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Yang, et al.
chip. Compared with the 2D microtissues, the heart-on- An important challenge for heart-on-a-chip is to
a-chip with 3D microtissues is complex in structure and better mimic the microenvironment of native cells . The
[94]
thus, the throughput is lower. However, the advantage challenges include addressing the issues pertaining to cell
is that the functionalities are close to native tissues and alignment, multiple cells co-culture and external stimuli
the maturation is improved. Nakayama et al. fabricated a which are key factors to improve cell maturation and
heart-on-a-chip with 3D microtissues using 3D bioprinter. functionalities. They can be implemented by fabricating
The cell spheroids were printed on the micropillar array, micro-patterned substrate, complex 3D scaffold, and
and the contraction force of the 3D microtissues was vascularized tissues. It is still challenging to fabricate these
evaluated by measuring the micropillar deformation. The structures. Perhaps, 3D bioprinting is a possible solution
platform can be used for drug screening by adding drugs which has shown a great potential in biofabrication. To
into the device and observing the response afterward. date, 3D bioprinting has enabled cell alignment, co-culture
Chen et al. fabricated the 3D microtissues using 3D of multiple cells, and vascularized myocardial tissue.
bioprinting, and monitored the concentration of calcium. Nevertheless, precise regulation of cell microenvironment
They found that the isopropylnoradrenaline can affect the (especially the spatial-temporal anisotropic
calcium concentration . Zhao et al. designed a heart- microenvironment) still needs further exploration.
[28]
on-a-chip with biowire structures, which can be used for There are considerable research on the microsensors
drug screening and gene expression testing. This chip can in heart-on-a-chip . However, the accuracy and
[53]
record the contraction force and calcium concentration sensitivity are still unsatisfying. PDMS as an elastic
in real-time . Paker et al. fabricated a heart-on-a-chip material is widely used in microsensors to measure
[93]
with 24 MTFs and each MTF can detect the contraction conTFM. The modulus of PDMS is still high and thus
force and beating frequency of cardiomyocytes. Using the deformation caused by CMs is relatively small. For
this heart-on-a-chip, they tested the influence of 12 drugs the microsensors based on optical method, it is complex
(e.g. Isradipine, Nicardipine, Clofilium, and Flecainide) to measure the contraction force. The strain microsensors
and demonstrated the application of this chip in drug can read out the contraction force directly, but the
screening (Figure 4C) . Wan et al. fabricated a heart-on- stability, linearity, and accuracy of the microsensors
[72]
a-chip with 3D microtissues and used it for cardiotoxicity are not satisfying . With the advances of wearable
[7]
studies of drugs (antibiotics, antidiabetic drugs, and and flexible electronics, more microsensors have been
anticancer drugs). Compared with the 2D model, the 3D invented. These microsensors could be used in heart-on-
microtissues performed better in drug screening. The a-chip, and monitor the status of cells.
results by 3D microtissues are consistent with clinical As a promising technique, 3D bioprinting has shown
observations . a great potential in fabricating highly integrated heart-on-
[5]
a-chip in one step . Using 3D bioprinting, it becomes
[95]
4. Summary and outlook possible to fabricate the microfluidic chip, microtissues,
In this paper, we review the recent advances of heart- microactuators, and microsensors on the same platform. On
on-a-chip, including the history, structures, fabrication the basis of 3D bioprinting, some researchers developed 4D
[96]
methods, and the biomedical applications. Collectively, we bioprinting method . In 4D bioprinting, smart materials
propose that a highly integrated heart-on-a-chip includes were used and the printed objects can change their shapes
four elements: Microfluidic chip, cells/microtissues, or functionalities with time. This technique can be used
microactuators, and microsensors. The microfluidic chip to fabricate microactuators and impose mechanical stress
and microtissues are necessary for a heart-on-a-chip. to cells. For 3D/4D bioprinting, there are still challenges,
The microactuators can be used to impose electrical and/ such as on how to improve the resolution and develop novel
or mechanical stimuli to cells. The microsensors are materials with good printability and mechanical properties.
designed to monitor the performance of cells in heart-on- Another challenge for heart-on-a-chip is the
a-chip. Various methods have been proposed to fabricate commercialization. To ensure the physiological state of
heart-on-a-chip. We shed light on the 3D bioprinting the cardiac cells, the storage and transportation should
which is a promising technique and can enable the one- be considered which are necessary for the off-the-shelf
step fabrication of heart-on-a-chip. 3D bioprinting has use. One possible solution is to use the vitrifying method
greatly improved the complexity, functionality, and which is commonly used in reproductive medicine . The
[97]
efficiency of heart-on-a-chip. Heart-on-a-chip has found chip together with the microtissues is frozen under a low
broad applications in biomedical engineering, including temperature, and the physiological activity of the cells is
physiology study, disease modeling, and drug screening. paused. When it is ready to be used, the heart-on-a-chip
At present, the development and applications of heart- is rewarmed to activate physiological activity of the cells.
on-a-chip are still in its early stage, and facing some Such vitrifying process necessitates strict demands for
challenges. the design and materials of heart-on-a-chip.

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