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Fang, et al.
which is essential for realistic tumor modeling. It allows (through bioprinting). The tumor-on-a-chip technology
for cell-cell and cell-ECM interactions and modeling of can be automated to run many drug screening assays at
leaky tumor vasculature, which is vital for understanding the same time and identify the response and mechanism
drug delivery to tumors and developing suitable in real-time [108] . Cell migration in the tumor environment,
chemotherapeutic agents. Bioprinting technologies are metastasis events, anticancer drug screening and therapy
amenable to automation and high-throughput testing response, or study of the transport of anticancer medicines
abilities, which are important for screening assays. Despite in tumorous tissue can be achieved by the microfluidic
[25]
these clear advantages of 3D bioprinting, this technology platform . Thus, 3D tumor-on-a-chip platforms enable
is still in its initial stages and facing problems, such as the recreation of tumor-stroma interactions in relevant
scalability, high cost of equipment and labor-intensive ECM mimetic matrices, as well as dynamic manipulation
nature, and difficulty in developing well-established of biochemical and biophysical parameters, such as pH,
vascular networks in tumors. Further problems associated oxygen, nutrients, metabolites, and cells (e.g., immune
with techniques, such as nozzle clogging, cell viability cells, mesenchymal, and stromal cells).
issues, and the use of hydrogels that are not suitable for
luminescence or fluorescence assays by HTS due to their 5.2. Techniques to produce tumor-on-a-chip
vicious nature, necessitate further research to explore the The following variables must be considered while
full potential of bioprinting in cancer applications [16,19,87] . fabricating tumor-on-a-chip systems: Microfluidic
system, 2D/3D cell culture models that comprise
5. Tumor-on-a-chip platforms various cell types and the physicochemical environment,
5.1. Concept stimulus-loading components, and sensors for monitoring
and reading the results [109,110] . The TME and its functional
Tumor-on-a-chip technology, which is based on the parts, including cancer cells, cancer stem cells, and
integration of manufactured tissues into microfluidic stromal cells, as well as the supportive ECM and blood/
devices, has emerged as a unique tool for cancer research. lymphatic-like conduit, require a basic understanding.
This method integrates microfluidics, microfabrication, Suitable tumor-ECM biomimetic biomaterials should
tissue engineering, and biomaterials research, and it has be chosen to fabricate the 3D architecture and these
the potential to revolutionize cancer biology . Three- biomaterials should have suitable rheological properties
[60]
dimensional cell culture models described in section 3.3 to allow for construct maintenance and resolution.
and bioprinting can help generate cancer tumor models Manufacturing techniques, such as photolithography,
that mimic tumor heterogeneity and vasculature in a high- soft lithography self-assembly, replica molding,
throughput and reliable manner. Spheroids, organoids, microcontact printing, and bioprinting, have been used
scaffolds, and bioprinted constructions are static models to produce organ-on-a-chip platforms. Photolithography
that do not recreate aspects of live tissues that are crucial involves the use of masks, photoresists, ultraviolet
for their function, such as tissue-tissue interfaces, light, and etching technology. This approach involves
spatio-temporal gradients of chemicals and oxygen, and creating a mask based on the desired structure and then
mechanically dynamic milieu. The microfluidic approach coating a layer of photoresist on a substrate such as a
is based on the exposure of the constructed tumor tissue to silicon wafer, glass, or quartz. Ultraviolet light is used
a continuous fluid flow to integrate dynamic mechanical to remove portions of the photoresist material from the
cues such as shear stress into these systems [105,106] . substrate surface and create a mold. After that, the design
Interstitial fluid flow in and around the tissues is is transferred to a substrate, resulting in a microfluid
particularly important in tumor models as it affects cell chip with microflow channels [111,112] . The soft lithography
cycle arrest in tumor cell lines, and the migration of cancer technique is based on the use of a microchannel mold
cells in the direction of fluid modulates gene expression prepared by photolithography. To make an elastomeric
and cell proliferation, and helps generate gradients of stamp with patterned microstructures, a liquid polymer
chemicals and biomolecules, which play a role in cancer such as polydimethylsiloxane (PDMS) is poured into
metastasis [105-107] . Oxygen gradients may be created using the mold. By transferring the pattern from the stamp to
microfluidic chips, simulating the physiological effects of other polymer structures, complex 3D microchannels
oxygen on tumor development and metastasis . may be formed. A closed-circuit channel is created and
[62]
The tumor-on-a-chip device is a microfluidic device is then sealed with a glass slide [113-115] . Replica molding
that can develop tumors by providing tissue culture, uses a photolithographically patterned silicon mold,
nutrition and small molecule supply, and means of waste PDMS pouring, and heat curing to build a device that is
disposal . A complex tissue structure comprising tumor affixed to a flat, smooth surface, such as glass, to create
[60]
cells, stromal cells, and blood arteries is developed on the a microfluidic chip with microchannels. Microcontact
chip, either self-organized or spatially arranged by design printing is an extension of the replica molding process

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