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Advancing cancer research using bioprinting for tumor-on-a-chip platforms

therapies in vitro. Traditional two-dimensional (2D) 2. Advantages of Bioprinting for Tumor-on-a-
approaches to cancer research have left significant chip Fabrication
gaps in our understanding of the disease as well as our
ability to develop effective treatments. This is partly 2.1 Mimicking Tumor Heterogeneity
due to the inability of 2D cancer models to recapitu- To mimic the tumor microenvironment, 3D-printed
late the microenvironment of a tumor which exists in tissues must mimic various features of in vivo tumors,
the human body. Past studies have demonstrated a including heterogeneous distribution of several dif-
significant difference in cell behavior between 2D and ferent cell types and biomolecules, in order to serve as
3D models, specifically in terms of protein express- a physiologically-relevant model for cancer research.
[3]
[2]
ion and gradient profiles , drug response [4,5] , as With the bioprinting technology, cell-aggregate based
[6]
[8]
[7]
well as cell migration , morphology , proliferation bioinks can contain multiple cell types [16] such as can-
[7]
and viability . Cell-cell and cell-matrix interactions cer-associated fibroblasts, immune cells and endo-
are enhanced in 3D models compared to 2D, offering thelial cells that create vascular networks [17] . Bio-
a more physiologically-relevant microenvironment. printing has been used to fabricate a 3D co-culture
Bioprinting offers the ability to generate cancer mod-
els with 3D complexity in a high-throughput, repro- tumor model comprised of cancer and fibroblast cells
ducible manner which better reflects tumor anatomy, with a high degree of spatial control over the micro-
[18]
biology and function and will serve as a platform for environment . It is also important to consider the
[9]
further cancer research . heterogeneous distribution of biologically-relevant
Integration of fabricated tissues into microfluidic proteins and growth factors in the tissue scaffold,
devices has given rise to a new field of interest, called which are essential to control cell signaling, prolifera-
[19]
“organs-on-a-chip,” adding a new level of complexity tion, and migration . For example, biomolecule gra-
[20]
in the ability to model living organs in vitro. Use of dients which may signal cancer metastasis can be
microfluidic devices as a platform for tissue engineer- recreated using bioprinting techniques. In summary,
ing offers several advantages over static culture [10,11] . bioprinting provides a method to mimic the heteroge-
Exposing tissues to continuous fluid flow over a pro- neous tumor microenvironment in vitro with a high
longed time allows integration of dynamic mechanical level of precision, throughput and reproducibility.
cues into biomimetic systems. These cues, such as 2.2 Modeling Tumor Vasculature
shear stress, are crucial to accurately mimic the physi-
ological microenvironment in in vitro systems. In par- Tumor vasculature differs greatly from the vessels that
ticular to tumor models, it has been shown that inters- supply healthy tissue, specifically in the heterogeneity,
titial fluid flow in and around the tissue generates permeability, multi-directional blood flow, and irregu-
shear stress, which causes cell cycle arrest in tumor lar distribution throughout the tumor [21] . These ab-
cell lines [12] . It has also been shown that cancer cells normalities can be mimicked by using 3D-printed
migrate along the direction of fluid streamlines in 3D vascular networks which can be further utilized to test
scaffolds [13] , further highlighting the importance of and compare the behavior of healthy and abnormal
mechanical cues to modulate molecular signals, gene vasculature under different conditions and therapies.
expression, and cell proliferation and migration. Mor- In one study, 25, 45, and 120 micron channels were
eover, due to the small dimensions of microfluidic 3D printed based on micro-computed tomography
channels, the flow in these devices is laminar, thus (µCT) scans of rat capillaries [22] . This biomimetic chip
affording the ability to generate complex and highly was used to observe the differences in cancer cell mi-
controllable fluid flow regimes. For example, this ca- gration through vessels of different sizes.
pability enables generation of sustainable gradients of Understanding tumor vasculature is also crucial to
chemicals and biomolecules to study cell response to understanding drug delivery to tumors and developing
chemotactic stimuli. Chemotaxis is known to be im- effective chemotherapeutics. The leaky and poorly-
portant for tumor cell homing, which plays an integral organized blood vessels supplying tumors significantly
role in cancer metastasis [14] . Lab-on-a-chip platforms impact drug delivery [23] . This makes it difficult to test
not only recreate a biomimetic microenvironment, but drugs in alternative tissue models due to differences in
also offer high throughput for systematic testing, such drug permeability through normal vasculature com-
as drug screening [15] . pared to leaky vessels. However, in future bioprinting

4 International Journal of Bioprinting (2016)–Volume 2, Issue 2