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Stephanie Knowlton, Ashwini Joshi, Bekir Yenilmez, et al.

applications, these diseased vascular structures may be mimetic tumor models via bioprinting, it is important
replicated in vitro using bioprinting in order to test to consider practical fabrication approaches for bio-
targeted therapies and assess drug delivery. printing within microfluidic platforms. 3D microor-
gans have been generated via direct cell writing into
2.3 Forming Tumor Spheroids
microfluidic circuits which were fabricated using stan-
Tumor spheroids are known to closely resemble the dard soft-lithography techniques using PDMS follo-
tumor microenvironment [24,25] and express the bio- wed by bonding of the PDMS channels to a glass sl-
chemical gradients associated with tumor growth [24] . ide [30] . One study compared two approaches for introdu-
Thus, tumor spheroids are widely used to study cancer cing cells into microfluidic devices fabricated via pre-
processes and therapies [25] . Recently, 3D projection cision extrusion deposition and replica molding [31] . In
printing was used to fabricate concave polyethylene one approach, cells were placed directly into the ex-
glycol (PEG) hydrogel structures that facilitated the posed channels of the replica-molded microfluidic cha-
growth and viability of tumor spheroids in the long nnels and then covered with a PDMS cover compo-
term [25] . In this study, the properties of a breast cancer nent. In an alternative approach, cells were guided to
spheroid grown to day 10 closely matched the hypoxic form networks along open channel walls and then
and necrotic properties expected of a tumor spheroid. embedded fully in PDMS to produce a leak-resistant
These spheroids were stained for HIF-1α, a marker for open channel network with a simplified fabrication
hypoxia, and found to contain the characteristic hy- method. Another proposed fabrication technique in-
poxic core that prompts further tumor growth in vivo. volves digital micro-mirroring to fabricate the channel
The 3D-printed concave hydrogel structures are a pro- structure combined with multi-nozzle biological depo-
mising low-cost, reproducible platform for long-term sition to print cells into the channels of the device [32] .
spheroid culture and high-throughput cancer studies. Bioprinting has also been performed in parallel with

3. Bioprinting for Tumor-on-a-chip Models the chip fabrication using an integrated solid freeform
fabrication system, reducing the need for photomasks
3.1 Modeling Tumors in Microfluidic Platforms and eliminating the long fabrication process and harsh
chemicals traditionally used for fabrication [33] . The pla-
Tumor models in microfluidic platforms have demon- tform utilized a four print-head system, each capable
strated promising results in studying cancer growth, of 3D motion: a photopolymer head to deposit photo-
metastasis and treatments in vitro. One study generat-
ed a device, dubbed “disease-on-a-chip,” to grow phe- resist for the chip architecture; a photolighographic
notypically normal breast epithelial tissue, which head to crosslink the photoresist after deposition; a
modeled mammary ducts and mimicked the develop- plasma treatment head to treat channels with helium
ment of tumor nodules within a breast tissue environ- and oxygen plasma prior to cell deposition; and a bi-
ment [26] . That study showed that tumor nodules within ologics head for cell deposition into the microchannels.
the biomimetic platform displayed morphological and This approach has been applied to generate a cancer
anti-cancer drug sensitivity differences compared to co-culture model within a microfluidic environment.
cultures on flat surfaces. Another study demonstrated 4. Conclusion and Future Perspectives
the ability to model natural fluidic streams using con-
tinuous laminar flow in microfluidic chips [27] . The Incorporation of bioprinted tumor models into lab-on-
microfluidic chips in this work enabled studies on the a-chip platforms presents a promising direction for
effect of shear stress on tumor cell metastasis and cancer research, offering the ability to mimic physio-
ovarian cancer nodule formation. Results showed logical, mechanical and chemical cues and conduct
flow-induced changes in E-cadherin protein expres- high-throughput studies [15] . Novel bioprinting tech-
sion and an increase in vimentin leading to increased niques are essential to precisely fabricate tumor con-
metastatic potential. Tumor models have been also structs in lab-on-a-chip platforms. A promising applica-
used in screening for optimal nanoparticle transport tion for this technology is high-throughput drug scree-
for nanoparticle-based therapies [28,29] . ning of anti-cancer drugs using microfluidic-based
tumor-on-a-chip models. Bioprinted cancer models
3.2 Bioprinting-assisted Fabrication in Microfluidic offer several advantages over animal and human mod-
Platforms els to test drugs. As obtaining FDA approval for a new

In light of the demonstrated potential to generate bio- drug costs a great deal of time (up to 15 years) and
International Journal of Bioprinting (2016)–Volume 2, Issue 2 5