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International Journal of Bioprinting Droplet-based bioprinting of tumor spheroids

membrane protein showed an increase in tumor cell development of droplet-based bioprinting technology
resistance to 5-FU, as well as a decrease in proliferation. allows for the fabrication of spheroids with better quality
and more functions, thereby further pushing the boundaries
4.4. In vitro diagnosis and high-throughput anti- of applications. However, to this end, there are still many
cancer drug screening challenges that need to be addressed.
Radiotherapy and resection are the principal methods for
treating tumors. However, a line of evidence indicates that Compared with other methods, droplet-based
these two methods usually cannot completely cure cancer bioprinting technology has the advantage of automated
and may cause severe damage. In recent years, cancer operation, high-throughput biomanufacturing, and high
treatment methods have attained rapid advances, thanks to reproducibility. However, the properties of each droplet
the better understanding of TME and the development of in bioprinting modality should be considered in terms of
vitro tumor models. For instance, it was found that tumor the applications and tumor types it can accommodate.
proliferation could be inhibited by blocking angiogenesis For instance, inkjet bioprinting technology is prone to
and weakening tumor cell metastasis. Tumor spheroid damage cells, causing a decrease in the viability of printed
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models are also widely used in the preclinical diagnosis tissues, and the nozzle of printhead can be clogged easily
and high-throughput drug screening owing to the high when printing high-concentration cells. Acoustic and
accuracy, low cost, and fewer testing cycles involved microfluidic bioprinting methods result in minimal
compared to 2D culture systems and animal models. Lee cell damage and have good controllability of printing
et al. demonstrated the photothermal therapy (PTT) for process, but the printers are generally complex. Based
neural stem cells (NSCs) tumor spheroids with responsive on microvalve, acoustic, and microfluidic bioprinting
nanocomposites (Figure 4D). They found that rGO- technologies, various tumor spheroids have been
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BPEI-PEG nanocomposites were non-toxic and could be successfully fabricated in a high-throughput manner.
absorbed by tumor cells, and observed that the viability of However, single cells are still randomly distributed in one
tumor spheroids, irradiated with near-infrared light after spheroid, leading to more inconsistent results in practical
rGO-BPEI-PEG treatment, decreased to 55%. Utama et applications compared with when using real tumor
al. tested the penetration rate of doxorubicin in the SK-N- tissues. Future droplet bioprinting technology should
BE(2) spheroids and found that doxorubicin could only be developed with the capability of precise control over
penetrate the periphery of spheroids due to the tight cell the locations of single cells in spheroids. Droplet-based
arrangement. Yu et al. observed that the survival rate of bioprinting technology is becoming more precise and high
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LCCR/Her2 spheroids decreased in a dose-dependent throughput. Although the fabrication of spheroids with a
manner with doxorubicin concentration (Figure 4E). single type or multiple types of cells has been validated
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Besides, they found that tumor spheroids showed higher by bioprinting, the lack of selective sorting during
resistance to doxorubicin compared with monolayer tumor printing process leads to uncontrollable composition
cells. Johnson et al. demonstrated that the drug resistance and distribution in the spheroid. The integration of cell
of 3D spheroids was significantly higher than that of 2D sorting into the printhead will benefit the manipulation
monolayer cells. They treated spheroids fabricated from of cell numbers and cell types in spheroids. This can
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four CRC cell lines (LS147T, SW620, SW480, and CACO2) be achieved with the combination of microfluidics and
with 5-FU and oxaliplatin (OX) for 72 h. Compared with 2D conventional droplet-based bioprinting, as demonstrated
model, the mean log CI50 value of the 3D spheroids was by the single-cell printing technology.
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two-fold higher for 5-FU and nine-fold higher for OX in To further enhance the bioprinting performance,
most cases. The diffusion ability of drugs may be responsible other technologies, such as artificial intelligence (AI)
for the differences in resistance to different drugs. and measurement modalities, can be integrated into the

5. Conclusion and perspectives bioprinting platform. The performance of a bioprinter is
influenced by many parameters (see Table 1). It is challenging
Droplet-based bioprinting has been demonstrated as a for designing a bioprinter and subsequently optimizing
powerful tool to fabricate tumor spheroids. It achieves good the bioprinting process. With high-quality training data,
control over the size and composition of spheroids and AI can assist with the selection of process parameters and
improves the reproducibility of fabricated models. Diverse reduce the experiments required to test the bioprinting
types of spheroids have been fabricated and demonstrated performance. For example, Shi et al. designed a fully
biological functionalities similar to those of tumor tissues connected neural networks (FCNNs) model to optimize
in vivo. Thus, they can be utilized for applications, such as the process parameters in PIJ bioprinting. The optimized
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disease modeling and drug screening, to study the tumors PIJ bioprinter could rapidly generate uniform and smaller
and accelerate the drug development. We foresee that the droplets without satellites. Moreover, with the integration

Volume 10 Issue 1 (2024) 118 https://doi.org/10.36922/ijb.1214