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Bottom-Up Microvessel Engineering
its mechanical strength is average. Hyaluronic acid is bio-assembling powered by micromanipulation
well known to many people as a material in the fields of techniques provides a robust and highly scalable method
medicine, hygiene, and beauty. However, it also can make to build 3D engineered tissue through assembling micro
flexible hydrogels. When subjected to force, it is prone to modular tissues [20,28,55] . This section lists the typical bio-
deformation. assembling methods depending on the morphology of the
fabricated micromodules.
3.6. Bioinks: composite polymers

Compared with pure polymers, composite polymers are 4.1. Pick-and-place of spheroids
utilized to improve the mechanical properties, modify other The concept of “cell as a material” proposed by Kasza
physical properties of the printed construes, and retain the et al. implies that micro-spherical modular tissues can be
excellent biocompatibility of pure polymers. According to considered as the basic building blocks of blood vessels,
the operation mode, composite materials can be divided into which is a more intuitive and feasible way to realize the
five types: multimaterial, stimuli-responsive, biomolecular, construction of artificial microvascular networks or any
[56]
self-assembling, and materials based on nanotechnology. other engineered tissues with complex architectures .
Many pure bioinks, as described before, have insufficient Using this method, the diameter of the microvessels can
deformability during use, or their nature is not conducive to be controlled under 1 mm. In the process of assembling
3D printing operations. Therefore, they can be doped with the micro spheroids into microvessels, the most commonly
some other substances. For example, calcium ions can add to adopted method is using a high-precision and high-speed
alginate to improve the mechanical strength and crosslinking motorized micromanipulator that can pick and place the
performance ; chitosan hydrogel and hydroxyapatite can spherical modules to the planned locations. This primitive
[51]
mix as artificial cartilage material . Biomolecular material manipulation has high flexibility in the construction of
[52]
is a vital branch of the bioinks for our research, which is microvessels with varied sizes and branches. However,
widely used in the fabrication of engineered vessels. This assembling a huge number of spherical modules can
material includes cytoplasmic matrix, decellularized hardly allow efficient construction. Figure 3A shows an
extracellular matrix, or DNA and other living tissues elements a schematic diagram of building microvascular structures
[33]
as a bioink, which can simulate the life state and mechanical by assembling spherical micro modular tissues . In the
properties of cells to the greatest extent . Essentially, these relevant research, picking progress was avoided to improve
[47]
materials are also a mixture of polysaccharides, lipids, and the fabrication efficiency. Arai et al. designed a high-
proteins. In addition to simple doping methods, controllable speed piezo-driven two-finger microhand system, which
combinations of multiple materials also play an important can realize extremely high-speed automated assembly of
role in enhancing the mechanical properties of materials and the spherical structures with the assistance of computer
vision technique
. Although the pick-and-place
[57,58]
expanding other physical properties (such as magnetism), operations in micro scale become faster and faster, the
where nanotechnology is required, including nanofabrication fabrication efficiency is still the main challenge in building
and nanoparticle reinforced polymer composites. Self- microvessels through assembling spherical modules.
assembling materials are a kind of hydrogel materials with
better mechanical properties by catalyzing the automatic 4.2. Wrapping sheets
combination of proteins or peptides in a specific way or
shape . Besides, current popular bioprinting targets are Due to the tubular structure of the blood vessels, directly
[53]
not only limited to satisfy sufficient mechanical properties assembling the planar 2D cell sheet into microvascular
and biocompatibility but also to provide obvious features structures features high fabrication efficiency. Heureux
so that external field forces can manipulate these structures. et al. first achieved cell-sheet-based tissue-engineered
Researchers gave bioinks additional characteristics such vascular structures in 1998 without the use of any
[59]
as magnetism. Using the magnetic force can expand the synthetic or exogenous biomaterials . Based on this
methods of printing and further operations, achieve higher approach, many more efficient methods have been
precision, and manufacture more stable artificial blood explored to fabricate engineered vessels with smaller
vessels. Nanotechnology is urgently needed among the diameters. Bourget et al. developed a decellularized
above two materials. It is still very important to explore and matrix scaffold generated from dermal fibroblasts or
develop new excellent bioinks in the future. saphenous vein fibroblasts to implant smooth muscle
cells and produce tissue-engineered vascular media
[60]
4. Bio-assembling powered by to shorten the time required for their generation .
micromanipulations This approach reduced the total production time from
6 weeks to 4 weeks (Figure 3B). Moreover, assisted by
Micromanipulation has been widely used to construct micromanipulation tools, it allows the fabrication of sub-
artificial tissues . Adopting the “bottom-up” approach, millimeter vascular structures directly with the smooth
[54]
8 International Journal of Bioprinting (2021)–Volume 7, Issue 3