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Andy Wen Loong Liew and Yilei Zhang

will be focusing on in this report—the problem of enclosed within a 3D extra-cellular matrix (ECM)
vascularization. environment where they attach and proliferate. The
As previously mentioned, the incorporation of a results of experiments utilizing these 2D in vitro mod-
mature, inter-connected vascular network within a els may not be an accurate representation as it is
tissue construct is vital in tissue engineering as it helps known that cells function differently when cultured in
to prevent the development of a necrotic core due to 2D vs 3D cellular environments, affecting cellular
nutrient deficiency of cells deep within the construct, cues, differentiation, adhesion, and morphogenesis,
and provides a readily perfusable network for nutrient among others [19–21] . 3D in vitro models are able to
perfusion throughout the construct during the fabrica- more closely replicate the cellular environment found
tion stage, or after implantation in a patient [15] . The in our native tissue, thus providing researchers with
implantation of a pre-vascularized tissue construct more reliable results compared to using 2D in vitro
minimizes the need for vasculogenic and angiogenic models [22] . However, the fabrication and application of
processes to occur after implantation, and has been 3D in vitro models are not as trivial as cell monolayers.
shown to induce rapid vascularization and inoscula- A common problem faced by the application of 3D
tion with host vasculature upon implantation into mice in vitro models is the loss of cell viability in long-term
when compared to un-vascularized constructs [16] . These culture [23] , thus driving research to improve the lifes-
studies demonstrate the importance of pre-vascu- pan of these models through modifications to the sys-
larizing a tissue construct in vitro before implantation. tem [24] . Vascularized 3D tissue models have the poten-
Today, success in the vascularization of tissue con- tial to remain viable for long periods while still able to
structs has been limited to the vascularization of thin accurately replicate native vascularized tissue. As we
(2D) tissue slices, and the vascularization of large 3D know, cell-cell interactions and signaling plays a vital
tissue constructs has seen slower progress. The lack of role in determining cell functionality in vivo. As such,
viable fabrication techniques has been a prime hin- monoculture tissue models may not accurately depict
drance to our progress in this area. Successful vascu- and account for the cellular interactions between pa-
larization of large 3D tissue constructs would un- renchymal cells (i.e., hepatocytes and cardiomyocytes)
doubtedly provide invaluable contribution in the field and endothelial cells (ECs) which occur repeatedly in
of tissue engineering and bring us a step closer to fa- our organs, given that blood vessels are found
bricating whole organs. throughout our entire body. The development of vas-
cularized 3D tissue models is crucial in this regard.
2.2 In Vitro Tissue Models Moreover, vascularized 3D tissue models could al-
so be used to boost our understanding of vascular
Besides its obvious applications in regenerative medi-
cine, the ability to vascularize large 3D tissue con- physiology such as vasculogenesis, angiogenesis, and
structs would also contribute to the development of in the physiology involved in vascular pathogenesis
vitro tissue models which better replicate our native which would help to improve treatment of patients
suffering from arterial diseases such as thrombosis
tissues. The use of animal models and ex vivo (cada-
veric) human tissue models for various studies, such and atherosclerosis. Vascularized 3D tissue models
could also be useful in pharmacology studies and drug
as pathophysiology and pharmacology, has resulted in
groundbreaking findings over the years. However, screening.
there are inherent limitations with the use of these 3. Current In Vitro Vascularization Approaches
models. Cadaveric human tissue models offer excep-
tional replication of native tissue; however, they suffer Different vascularization techniques have been re-
from limited availability. The use of animal mod- cently reported in literature, including the in vivo ap-
els brings rise to issues with species-specific tissue proach where perforated, un-vascularized tissue con-
response [17] , as well as ethical issues with regards to structs are implanted to allow the host’s peripheral
the well-being of lab animals. These shortcomings vascular system to naturally vascularize the tissue
have driven researchers to develop more advanced construct [25] . This method requires the timely invasion
in vitro tissue models which accurately mimic native of the host vasculature into the un-vascularized tissue
tissue and are easily fabricated without the need for construct through angiogenic sprouting in order to
donor tissue and animal experiments. The most com- provide the cells within the tissue construct with ade-
mon in vitro model still being used in scientific re- quate nutrients to survive. Naturally, it would take a
search today is the cell monolayer, i.e., 2D cell longer time to vascularize larger tissue constructs by
culture [18] . As we know, the cells in our bodies are this approach. Thus, this approach may not be viable
International Journal of Bioprinting (2017)–Volume 3, Issue 1 5