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International Journal of Bioprinting Droplet-based bioprinting of tumor spheroids

development cycle time, high result heterogeneity, and spheroid. The entire fabrication process is labor-intensive
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poor result reproducibility are collectively an urgent call and time-consuming, and the variability of spheroids
for developing reliable in vitro models. reduces the accuracy and sensitivity of downstream
analysis and screens. Alternatively, 3D bioprinting has
In recent years, two-dimensional (2D) and three-
dimensional (3D) cultures have been regarded as received widespread attention due to its high flexibility
and controllability in the spatial arrangement of cells and
potential platforms for in vitro tumor model development.
Nevertheless, in the 2D culture approach, the cell biomaterials. Among them, the droplet-based bioprinting
arrangement is altered, making it difficult to replicate solid technology has advantages, such as high throughput, high
tumor cell–matrix interactions with high fidelity and thus precision, excellent reproducibility, and wide adaptability
reducing the accuracy of mimicking the tumors in vivo. For to biomaterials, making it suitable for fabricating spheroids.
instance, MCF-7 cells showed lower resistance to tamoxifen Here, we review the fabrication of tumor spheroids
and lower level of expression of caspase-3 protein in 2D based on droplet-based bioprinting and the progress in
culture, and a series of pathological phenomena caused applications (see Figure 1). First, we present a comparison
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by hypoxia cannot be simulated. Conversely, 3D culture of the characteristics and technical parameters of droplet-
exhibits higher degree of physiological similarity and based bioprinting technologies for fabricating spheroids,
testing accuracy. Cell differentiation occurs spontaneously including their strengths and shortcomings. Second, the
upon cellular contacts and signals from soluble factors in a latest progress in the fabrication of distinct spheroids
3D environment, while in 2D culture, this is usually non- by droplet-based bioprinting is reviewed, followed by a
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spontaneous. However, 3D culture models are complex summary of representative applications of spheroids in
and often show poor reproducibility. tumor heterogeneity, angiogenesis, metastasis, and in
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vitro anti-cancer drug screening. Finally, we discuss the
Spheroids are simple but efficient in vitro 3D models.
They are generated by aggregating cells in a natural challenges and potentials in this emerging field and suggest
or synthetic microenvironment, which facilitates some future directions.
the interactions between adjacent cells, thus better 2. Droplet-based bioprinting technologies
recapitulating the tumors in vivo. Over the past decades,
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numerous methods have been developed to fabricate Droplet-based bioprinting employs cell-containing
spheroids, such as hanging drops, agitations, and non- droplets, generated by the printhead, to dispense cells into
adhesive microwells. However, it is difficult to control the receiving substrate, where spheroids are formed after
the shape and size of the spheroid with these methods, culture. During droplet generation, the cell numbers and
which, to some extent, limit their applications. In addition, cell types can be manipulated to control the formation of
the spheroid usually needs to be manually placed into spheroids. Different from extrusion-based bioprinting,
the culture dish, which may disrupt the integrity of droplet-based bioprinting works in a contact-free manner

Figure 1. Schematic of droplet-based bioprinting technology for fabrication of tumor spheroids and the representative applications.

Volume 10 Issue 1 (2024) 108 https://doi.org/10.36922/ijb.1214