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Heart-on-a-chip
a pneumatic system that can impose uniform uniaxial used hiPSC-CMs and collagen to construct the engineered
cyclic strain to the 3D microtissues. cardiac microtissues and studied the effect of mechanical
The substrate stiffness is another mechanical conditions and electrical stimulation on the maturation
stimulus in heart-on-a-chip. In the native myocardial of cardiac tissue . Rasponi et al. developed a biological
[51]
tissues, the mechanical property, for example, stiffness reactor which can provide a uniform electric field and
is spatially non-uniform which has been observed in periodic uniaxial strain to the 3D cardiac microtissues .
[52]
the tissue slices . The stiffness would affect the cells
[48]
in growth, differentiation, gene expression, and protein 2.4. Microsensors
secretion. It has been found that the CMs would have Microsensors are the fourth elements in heart-on-a-chip.
sarcomere in 48 h when cultured on the soft substrate. The function is to monitor the status of cells/microtissues
However, the sarcomere was not observed when cells in heart-on-a-chip. At the early stage, some biochemical
were cultured on the medium stiffness substrate. Studies reagents were used to stain cells to characterize their status
have been conducted to evaluate the effects of 2D and functionalities. The disadvantage is that this method is
substrate stiffness on CMs contraction rate, stress, and destructive to cells, and it is difficult to implement the real-
intracellular calcium concentration. Experimental results time monitoring. In recent years, some researchers have
indicate that the contraction force of CMs in vitro would begun to integrate microsensors in heart-on-a-chip to monitor
change with matrix stiffness in a time-dependent manner. [53]
Bajaj et al. cultured embryonic chicken CMs on PAAm the physiological status of cardiac cells noninvasively .
gels with different stiffness. They have found that the (1) Measurement of contraction force
stiffness of gels affects the beating frequency in 24 h .
[49]
Moreover, the surface morphology of substrate One property of CMs is that it can generate contraction
also affects the behavior of cells. In heart-on-a-chip, the force. The contraction force is an important indicator
microstructure on substrate can regulate the alignment of of CMs status. The contraction of CMs is visible in the
CMs, which is a critical factor influencing the contraction microscope, but it is difficult to quantify the contraction
force. Lewis et al. fabricated a heart-on-a-chip by 3D force by direct observation. The atomic force microscopy
bioprinting. In this chip, they fabricated microgroove (AFM) and traction force microscopy (TFM) are capable
structures on the surface of substrate. The CMs were to quantify the contraction force. However, it may affect
cultured on the substrate surface and cells tend to orient behaviors of the cells . Moreover, the instruments are
[54]
along the grooves. By regulating the alignment of CMs, expensive and complex to operate. Some researchers
the contraction force would be enhanced since cells tend integrated microsensors in heart-on-a-chip to measure
to contract along the same long axis . the contraction force of CMs (see Table 2 for the details).
[12]
Some researchers have simultaneously imposed the One commonly used method is to fabricate an elastic
electrical and mechanical stimuli to cells. Murry et al. found component in heart-on-a-chip. The CMs cultured on the
that if both electrical and mechanical stimuli are imposed, elastic component would cause the visible deformation
the hESC-CMs can mature at a faster pace . Later, they of the component [55-58] . The elastic component could
[50]
Table 2. Microsensors for contraction force measurement in heart-on-a-chip
Mechanism Structures Materials Cells Applications Measured
values
Visible Biowires [62,63,93] POMaC [62] iPSC-CMs [62,63] Cell maturation [57,62] Contraction
deformation Cantilever [59,64] PDMS [59] Rat CMs [59,64] Drug screening force
Micropillars [57] Hydrogel [57,64] HCFs [63] [57,59,62,63] 2.89-5.09 µN [64]
Helical structure [56] Disease model [63] ~40 µN [62]
Contractile stress
~15.4 kPa [59]
~1.7 kPa [57]
Electrical Piezoelectric [69] AlN [69] Rat CMs [12,67,72,74] Drug screening [9,12,67-69] Contraction force
sensors Crack sensor [74] Pt-PDMS [74] iPSC-CMs [68,69] ~107 nN [74]
Piezoresistive [12,67,68] CNTs-PDMS [68] Contractile stress
CB:TPU [12] ~2.34 kPa [68]
7-15 kPa [12]
Structural Cantilever [56] GelMA [66] Rat CMs [66] Drug screening [56,66] crawling speed
color Biological-Crawling Biological soft 20 µm/s [66]
robot [66] robots [66]

60 International Journal of Bioprinting (2021)–Volume 7, Issue 3