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Yang, et al.
consuming investigations, high cost, and low efficiency. 2. The structures of heart-on-a-chip
Moreover, there are ethical issues to consider when
conducting research. In recent years, Society for the By reviewing the existing literature, we propose that a
highly integrated heart-on-a-chip includes four elements:
Prevention of Cruelty to Animals has been established
around the world, which strongly opposes animal microfluidic chip, cells/microtissues, microactuators
experiments. Therefore, research communities are under for physical/chemical stimuli, and microsensors
increasing public pressure as to whether animals can be for monitoring cells status (Figure 1). In practical
used in experiments. experiments, a heart-on-a-chip may not include all
these four elements, but the microfluidic chip and
As to the Petri dish-based cell culture, it is now widely
used due to the simple operation and good controllability. cells/microtissues are necessary. In recent years, with
Despite its merits, there are still some drawbacks to this the advances in manufacturing technology (e.g., 3D
method. For instance, the morphologies are different for bioprinting), microactuators and microsensors have
cells in human body and those in Petri dish. The cells in vivo been integrated within heart-on-a-chip. The purpose of
usually assemble into three-dimensional (3D) structures, microactuators is to promote cardiac cells maturation and
functionalization, while microsensors are to detect cells
while cells in a petri dish lack the 3D scaffolds and thus
form a two-dimensional (2D) flat structure. In addition, status. In the following, we introduce these four elements
Petri dish is unable to provide the microenvironments that sequentially.
are required for cell growth and differentiation, and cannot 2.1. Microfluidic chips
well simulate the cell-cell and cell-extracellular matrix
(ECM) interactions. Cells in vivo are usually subjected Microfluidic chip is the major part of heart-on-a-chip, and
to some mechanical and electrical stimuli. These stimuli it provides habitat for cells. To date, various materials and
are of importance for the maturation and functionalities of fabrication methods have been proposed for microfluidic
cells. However, it is difficult to impose the stimuli in Petri chips.
dish. (1) Materials of microfluidic chips
Since these two methods are not satisfying, a
novel method is required. With the advances of bio- The traditional materials for microfluidic chips include
fabrication, microfluidics, and biosensing techniques, glass, silicon, polydimethylsiloxane (PDMS), polymethyl
organ-on-a-chip has emerged as a new technology. methacrylate (PMMA), and papers . Silicon and
[10]
Organ-on-a-chip is a device for in vitro cell culture glass are compatible to the standard micro- or nano-
which utilizes microfluidic technology to create a fabrication methods (photolithography, etching, etc.). The
highly controllable microenvironment for cells. Various advantages of silicon and glass include high precision,
organs-on-chips, for example, lung-on-a-chip, kidney- reproducibility, and resistance to organic solvents. As to
on-a-chip, intestine-on-a-chip, and even tumor-on-a- the disadvantages, silicon has poor light transmittance,
chip, have been developed for different biomedical which renders direct observation of the cells difficult.
applications . Among them, heart-on-a-chip, as a As a polymer organic silicon compound, PDMS is the
[4]
method to construct heart models in vitro, has attracted most popular material for microfluidic chips. Its main
considerable attention. Various fabrication methods advantages are non-toxic, chemically inert, and optically
have been developed and different applications, for transparent properties as well as simple to use and low
example, drug screening, physiology study and disease cost. The major disadvantage of PDMS is that it has a
modeling, have been proposed . high absorption rate for small molecule chemicals. If the
[5]
There are some well-written review papers on heart-on-a-chip is used for drug screening, the absorption
heart-on-a-chip [6-9] . However, most of them focused on problem should be addressed. PMMA is a transparent
the biomedical applications. In this paper, we review the thermoplastic, which has the advantage of high
recent advances of heart-on-a-chip from the viewpoint biocompatibility, low cost, superior mechanical strength,
of biofabrication. By analyzing the structures of heart- and transparency. Papers are also used for microfluidic
on-a-chip, we found that a highly integrated heart- chips. The merits include good biocompatibility, ease of
on-a-chip includes four elements: Microfluidic chips, fabrication, environmental friendliness, and self-powered
cells/microtissues, microactuators for constructing feature .
[11]
the microenvironment, and microsensors for results With the advances in 3D bioprinting, some printable
detection. The fabrication methods for these elements are materials have been developed for microfluidic chips.
introduced in details, and the applications of heart-on-a- Some representative materials include thermoplastic
chip in the field of biomedical engineering are discussed. polyurethane (TPU) , polycaprolactone (PCL) [13,14] ,
[12]
In the end, the challenges and possible solutions, as well as and silicone . TPU is a versatile multiphase block
[15]
the future directions of heart-on-a-chip are summarized. copolymer. When heated, TPU becomes soft and
International Journal of Bioprinting (2021)–Volume 7, Issue 3 55