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Yang, et al.
With the improvement of resolution, some cells are favorable since the purpose of heart-on-a-chip
researchers used 3D bioprinting to fabricate microfluidic is to study heart disease of human beings. Unfortunately,
chips . In 3D bioprinting, the microfluidic chip is it is difficult to obtain human cells directly. To date, the
[18]
fabricated in a layer-by-layer manner. The major frequently used cells in heart-on-a-chip are animal’s
advantage of 3D bioprinting is that it is an integrated primary cells and/or commercial cell lines. The animal
fabrication method, and enables 3D complex structures. cells are different from human cells in term of species.
Using 3D bioprinting, the microfluidic chip can be One possible solution to the dilemma is the use of
fabricated in one-step. The assembling errors in chip induced pluripotent stem cells (iPSCs) which offer an
assembly can be avoided . To date, various microfluidic almost unlimited source of cells . As a novel technique,
[19]
[21]
chips have been fabricated with high definition and high deriving CMs from iPSCs are still unsatisfying as the
quality. cells are usually phenotypically immature. Improving the
maturity of CMs is the challenging part of developing
2.2. Microtissues heart-on-a-chip.
The second component of heart-on-a-chip is the
microtissues. According to the dimension, microtissue (2) Fabrication of microtissues
can be divided into 2D microtissue and 3D microtissue. As aforementioned, microtissues can be divided into 2D
Based on the cells in microtissue, it can be divided into and 3D types. In 2D microtissues, cells are cultured in a
single type of cells and co-culture of multiple types of planner layer. Patterning cells are an important task for 2D
cells (see Table 1 for the details). Both dimension and cell microtissues fabrication . Micro-contact printing is the
[22]
types have significant influence on cell shape, alignment, most frequently used technique for cell patterning [23,24] . In
expression of structural protein, and sarcomere length this method, the pattern of liquid biomaterials is realized
and beating. on the surface of a substrate through conformal contact
with the soft mold (Figure 2A) . The area with liquid
[25]
(1) Cells in heart-on-a-chip biomaterial (e.g. fibronectin and hyaluronic acid) is
Cell type and source are the key parameters that may adhesive to living cells. Thus, cells proliferate on these
affect the performance of heart-on-a-chip. The adult patterning areas only. Gabriele et al. dipped fibronectin

heart is mainly composed of cardiomycytes (CMs), with PDMS mold and then transferred to the substrate .
[26]
human cardiac fibroblasts (hCFs), endothelial cells, and Due to the good biocompatibility of fibronectin, cells
others, which can perform different functions to make tend to adhere and grow on the area with fibronectin. In
the heart work. Although CMs only account for ~33% of this manner, they obtained 2D microtissues with well-
the total number of cells, they account for ~75% of the controlled shape.
heart volume . CMs are responsible for heart beating The tissues in vivo are usually in 3D morphology.
[20]
and considered as the most important cells. Thus, CMs It has been found that the 2D and 3D microtissues are
are usually adopted in heart-on-a-chip. Usually, human different in protein expression and drug response. To

Table 1. Some representative microtissues in heart-on-a-chip
Features Fabrication methods Cells Materials Functionalities
Pa t t e rne d Soft lithography [22,27] HUVECs [22] PAAm [22] To study the influence of
microtissues Microcontact printing [22-25] Rat CMs [24,25,28] Collagen [24] stiffness on cell morphology [22]
Electrospinning [44] Fibroblasts [24] GelMA [28] To promote the attachment,
3D bioprinting [28] MeTro [25] spreading, alignment, and
intercellular
communication [24,25,28]
Vascularized 3D bioprinting [30,34,100] HUVECs [30,34,98] Alginate [30] To align cardiomyocytes
microtissues Photocuring [32] iPSC-CMs [30] GelMA [30,98] that can contract
Lithography [34] Rat CMs [32] PEGDA , synchronously [30,32]
[98]
hydroxybutyl chitosan
(HBC) [34]
Microtissues 3D bioprinting [31,33] NIH/3T3 , C2C12 [33] GelMA [31,33] Biomimetic heterogeneous
[33]
with multiple iPSC-CMs [29,31] Alginate [31] tissues [31,33]
cells Endothelial cells [29] Gelatin, Fibrinogen [29] Multiple-organs-on-a-chip [29]

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