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Li, et al.
Since the vascular networks can be created through significantly regulated by laminar shear stress and promote
vasculogenesis and angiogenesis, it is necessary to vasculogenesis. Yamamoto et al. proved that laminar
choose the appropriate strategy according to the normal shear stress can effectively animate the proliferation of
physiological characteristics of the target organs. In endothelial progenitor cells and promote the migration of
organ 3D printing, the “bioinks” used in 3D printing of ECs . Thus, a dynamic microenvironment has a positive
[32]
vascular networks should present the special hierarchical influence on vasculogenesis. VEGF is an important
vascular structure generation capability to promote cell angiogenic activator secreted by ECs and can induce EC
accommodation, survival, growth, and differentiation. chemotaxis. In 3D printing, exogenous VEGF can also be
Besides, the biochemical properties of the polymeric used to accelerate the formation of the expected vascular
“bioinks” should conform to specific engineering networks.
configures, which are biocompatible, biodegradable, Smooth muscle cells are very important in the outer
and feasible for implantation. The selection of versatile layer of ECs in large blood vessels. These cells can self-
“bioinks” will be discussed in the following section. migrate and integrate, and have important physiological
functions during the processes of large vessel formation
2.3. Blood vessels and cell sources and vasodilation. After 3D printing, coculture of different

As stated above, the blood vessels can be classified types of cells, especially vascular cells, in a construct
into arteries, veins, and connecting capillary networks can effectively simulate the physiological environment
with different dimensions and layers to fulfill various and promote angiogenesis. For example, the coculture of
biochemical and biophysical functions [26,27] . For vascular ECs and human mesenchymal stem cells can stimulate
3D printing, it is important to take into account the cell viability and activate angiogenesis [30,33] . Levenberg
differences in blood vessel types associated with their et al. cocultured myoblasts, embryonic fibroblasts,
specific physiological functionalities when designing an and ECs in the ratio of 40:13:47 on poly-L-lactic acid/
extracorporeal vascular system. The selection of cell types polylactic-glycolic acid (PLGA) scaffolds and achieved
[34]
needs to be taken into serious consideration according to a maximize vascularization in a mouse model .
the targeted organs, especially for capillary construction. Consistent vessel generation was achieved in the
To make sure that the 3D-printed bioartificial organs transplantation. The vascularization level was measured
are fully functional, sufficient blood supply is critical in terms of the EC areas, the number of lumens, and the
for stabilizing the cell survival microenvironments. total lumen area. In another study, ECs were cocultured
For arterial blood vessel construction, a large amount with keratinocytes and fibroblasts on a porous collagen
of smooth muscle cells is necessary to form a thick scaffold [35,36] . When the 3D-printed bioartificial skin was
concentric elastic muscle wall, and effectively cope with implanted in animals, the vascular network fused with
high blood pressure and lateral shear stress. In contrast, the vasculature of the host. It was found that porous
ECs in the vein are surrounded by a thin layer of smooth structures, such as hollow channels within silk fibroin
muscle cells with medium mechanical properties. Until scaffolds, could also effectively increase the adhesion
present, it is hard to mimic the one direction valves in of ECs, and promote angiogenesis with vascular cell
the veins to prevent backflow and promote circulation of fusion after transplantation . These studies indicated
[37]
blood . that the coculture of functional parenchymal cells of the
[28]
In the vascular networks of a natural organ, the target organs with ECs could activate vascular network
capillary wall is the thinnest, only composed of ECs, generation and stabilization when the combinations were
perivascular cells, and ECMs. The stability of the transplanted in vivo.
capillary is mainly dependent on the arrangement of
ECMs. The velocity of blood in capillaries is relatively 3. 3D printing technologies and “bioinks”
slow for efficient oxygen and nutrition perfusion . Until 3.1. 3D printing technologies
[29]
the present, constructing a complete vascular network
with delicate capillaries through 3D printing is still 3D printing, also named as rapid prototyping (RP),
challenging. solid freeform fabrication, or additive manufacturing,
ECs are one of the basic elements of vascular is based on the dispersion-accumulation (i.e., discrete
composition. As the innermost cells of the vascular accumulation) principle of computer-aided manufacturing
walls, ECs are widely involved in various physiological techniques. Before 3D printing, an object can be divided
activities of blood vessels. It is, therefore, one of the into numerous two-dimensional (2D) layers by computers
important cell types in 3D printing vascular networks . with a defined thickness. These 2D layers can be piled
[30]
In general, ECs are derived from endothelial progenitor up by selectively adding the desired materials in a high
cells, which are derived from the supportive cells in reproductive layer-by-layer manner under the instruction
bone marrow . Endothelial progenitor cells can be of computer-aided design (CAD) models [38-40] .
[31]
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