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In vitro pre-vascularization strategies for tissue engineered constructs–Bioprinting and others

can be treated using this approach. A biopsy is first niques need to be developed to allow the fabrication
performed to extract healthy autologous (skin) cells of larger tissue constructs which demonstrate long-
from the patient. These cells are cultured and ex- term viability post implantation. A promising app-
panded in vitro to obtain a sufficient number of cells roach to this problem is the pre-vascularization of tis-
needed for the treatment. The cells are then seeded sue implants, where techniques are used to incorporate
onto a biodegradable scaffold which will then be cul- functional vascular networks within a tissue construct
tured to maturity. When the tissue-engineered graft is in vitro before implantation. Compared to an un-vas-
fully matured, it can then be transplanted onto the pa- cularized tissue construct, a pre-vascularized tissue
tient’s injury site to enhance the wound healing process. construct has shown enhanced anastomosis with host
Research in this field is expanding quickly and has vasculature post implantation, thus providing adequate
given rise to many tissue engineering companies nutrients to encapsulated cells and improving viability.
which carry out research and manufacture human Tis- The vascularization of tissue engineered constructs is
sue-Engineered Products (hTEPs) for clinical use to- deemed to be vital to the progress of tissue engineer-
day. Tissue engineering is still in its early initial phas- ing today and in the future [12] . In this review, we high-
es, thus only few hTEPs have been successfully trans- light the significance of pre-vascularization and its
lated into commercial availability. These commercial- impact on tissue engineering. We also identify recent-
ly available hTEPs mainly comprise skin products, ly developed in vitro vascularization techniques which
followed by cartilage, and lastly bone products. By have shown promising results, categorized based on
2003, more than 20 skin replacement products were the technologies they employ, and describe each of
[3]
available in USA and Europe . Tissue-engineered their fabrication processes.
cartilage products have found widespread application
today to treat traumatic knee joint damage by under- 2. Significance of Pre-Vascularization
going Autologous Chondrocyte Transplantation (ACT) 2.1 Tissue Engineering for Regenerative Medicine
[3]
surgery . The application of tissue-engineered bone
products is limited to the treatment of small bone le- With avascular tissue products such as skin and carti-
sions as larger defect sites still remain untreatable by lage already made commercially available, tissue en-
this approach and autologous bone grafts still remain gineers are now looking to engineer larger, more com-
the preferred approach. With the successful translation plex tissue which could potentially be used as a viable
of these hTEPs into clinical application, tissue engi- treatment option for patients suffering from critical
neering has proven its legitimacy as a promising can- diseases. However, there are a host of crucial chal-
didate for the treatment of injured tissue, sparking lenges to be addressed to meet this goal. Our native
more and more research in the field. Today, research tissues possess highly specific architectures, and dif-
groups all over the world are working to create hTEPs ferent tissues have their own unique structural organi-
[6]
from various tissues such as cardiac [4,5] , liver , cor- zation. It is imperative that tissue engineers accurately
[8]
[7]
[9]
nea , trachea , artery and many others. emulate the intrinsic heterogeneous architecture of
Various research groups have published works re- these complex tissues when fabricating their tissue
porting the successful engineering of functional tissue engineered construct as there is a well-accepted corre-
in vitro, such as bladder [10] tissue, although they have lation between tissue architecture and pathogenesis [13] .
not yet been used in clinical trials due to its early stage Tissue-engineered constructs that do not accurately
of development. Many of these published works re- mimic the heterogeneous nature of native tissues
port the successful engineering of only very thin, mi- could lead to disease and be carcinogenic when im-
croscale tissue constructs. One of the main reasons for planted into a patient. The successful engineering of
this is the fact that cells encapsulated deep within a complex tissue also requires control of differentiated
large tissue construct have limited access to oxygen function of the cells within the tissue engineered con-
and nutrients, causing them to die during long-term struct, failing which could cause the tissue-engineered
culture. We know that cells located more than 200 μm construct to be dysfunctional and malignant. There are
away from a nutrient source (blood vessels) do not many other challenges in the pursuit of engineering
receive sufficient nutrients for survival [11] . With the large, complex tissue constructs such as matrix stiff-
ultimate goal of tissue engineering in mind, which is ness, molecular gradients and hierarchical struc-
to successfully engineer complete organs, new tech- ture [14] , but one of the main challenges is the one we

4 International Journal of Bioprinting (2017)–Volume 3, Issue 1