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3D Bioprinting for Anticancer Drug Screening
in which the PDMS stamp is printed on a substrate considerably affected by the leaky and poorly structured
along with biofunctional molecules, such as proteins [116] . blood arteries feeding tumors, and these changes are
The majority of the technologies discussed above using difficult to mimic in other tissue models. Bioprinting
photolithography, which is costly and time-consuming, enables in vitro replication of altered vascular structures to
can only create microfluidic chips without microtissues, better assess the effects of drug treatments and delivery .
[99]
stimulus-loading components, or readout sensors, all of Bioprinting minimizes the unpredictability imposed by
which require additional procedures to create [114] . standard cell seeding methods in microfluidic chips by
Due to features such as optical transparency, allowing for spatially controlled deposition of cell-laden
breathability, biocompatibility, and flexibility, PDMS is ECM-biomimetic hydrogel bioinks within a microfluidic
the most popular material utilized to create microfluidic device [121] . The combination of on-chip biosensors with
chip devices, allowing for continuous viewing of the capabilities of microfluidic systems to screen many
tumor constructions for real-time monitoring of cell anticancer drugs concurrently enables high-throughput
behavior and therapy response. PDMS substrates offer screening in real time, speeding up the drug screening
a higher porosity and flexibility compared to glass or process. Thus, bioprinting is an emerging technology that
plastic mimicking the soft tissues. However, PDMS can create tumor-on-a-chip platforms through its ability
is hydrophobic and can bind or adsorb hydrophobic to mimic physical, chemical, and mechanical cues and
molecules that are problematic during drug screening. perform high-throughput studies.
Poly(methyl methacrylate) (PMMA) substrates bound The next section focuses on examples in literature
to etched polyethylene terephthalate membrane are that have used bioprinting technology to fabricate tumor-
impermeable to lipophilic molecules [117,118] . Other materials on-a-chip systems to evaluate drug effects and for drug
used to prepare microfluidic devices include gelatin, screening.
photocrosslinked GelMA, bacterial cellulose paper, and
basement membrane extract (BME/Matrigel) . 5.4. Examples of bioprinted tumor-on-a-chip in
[62]
anticancer drug screening
5.3. Bioprinting to fabricate tumor-on-a-chip
constructs Biomimetic 3D in vitro tumor models or personalized
bioprinted constructs, such as tumor-on-a-chip models,
Recently, bioprinting has emerged as a preferred choice are emerging tools that can be used to test an array of
for tumor-on-a-chip fabrication. Bioprinting allows for chemotherapeutic agents. Bioprinted tumor-on-a-chip
the 3D simultaneous printing of multiple cell types and systems can recapitulate the TME, recreate tumor-stroma
biofunctional materials directly onto a cell-compatible interactions in ECM-mimetic matrices, and allow for the
substrate with high reproducibility and spatial resolution. manipulation of factors such as pH, oxygen, nutrients,
This is essential because it allows bioinks containing and cells.
numerous cell types, such as CAFs, immunological cells, The PubMed database (https://pubmed.ncbi.nlm.
and endothelial cells. that may form vascular networks nih.gov) was searched using identifying terms such
to replicate the heterogeneous tumor environment. as “tumor-on-a-chip,” “tumor-on-a-chip,” “tumor-on-
Bioprinting also aids in the heterogeneous distribution chip,” “tumor-on-chip,” “3D bioprinting”, “cancer,” and
of physiologically relevant proteins and growth factors associated MesH terms with the objective of identifying
that are involved in tumor signaling, proliferation, and articles that report works using tumor-on-a-chip or
migration [119-121] . Bioprinting allows for the effect of microfluidic platforms fabricated by bioprinting for drug
non-malignant cells on tumor evolution to be evaluated screening. Figure 5 shows a flowchart for the selection of
through tumor-stroma interactions. Another advantage of appropriate publications for this review.
bioprinting that is particularly important in manufacturing Table 1 shows the characteristics of the studies
is that it can directly print or pattern cells in microfluidic related to the use of bioprinting technology to make
devices, modeling vasculature, and biological barriers. tumor-on-a-chip platforms. Hamid et al. developed a
Furthermore, 3D bioprinting technique enables the microfluidic system to assess drug metabolism. A tissue
engineering of vessel-like tubular constructs for platform was constructed using photolithography with a
assembling 3D vascular components during the PDMS enclosure. SU-8, an epoxy-based resin material
fabrication process, allowing for real-time personalization was used to create microfluidic chips with channels of
as opposed to pre-programmed channel architectures different porosities (300, 500, and 700 µm). MDA-
used in standard microfluidic chip manufacturing [122] . MB-231 cell lines (human breast adenocarcinoma cells)
This feature of bioprinting is particularly critical owing were bioprinted into the channels using an extrusion-
to the deregulated tumor vasculature that differs in terms based method. Fluorescent staining revealed similar
of heterogeneity, permeability, and multi-directional flow cell growth in all three chips. Cell proliferation studies
from the supplying healthy tissue [122] . Drug distribution is showed an increasing trend of proliferation in all three

54 International Journal of Bioprinting (2022)–Volume 8, Issue 4