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Bottom-Up Microvessel Engineering
included in the constructed large three-dimensional (3D) up” approaches. In most “top-down” approaches, a
functional tissues by diffusion which is limited within scaffold is fabricated first, and cells are then seeded
an area of smaller than 200 μm [12-15] . Traditional tissue on the scaffold. In the following culture process, cells
engineering strategies adopt the “top-down” approach, in populate on the scaffold and generate the appropriate
which cells are seeded on a biodegradable scaffold. The extracellular matrix with the external chemical and
seeded cells then populate on the scaffold and generate mechanical stimulations. While developing the “top-
the appropriate extracellular matrix [16-20] . However, this down” approaches, researchers focus on improving the
approach can only fabricate vessels larger than 6 mm, fabrication of scaffold or testing various combinations of
which are mainly used to replace the damaged vessels of the cell sources and stimulation ways during culture [16-21] .
patients with cardiovascular diseases . It is a formidable Nowadays, the main challenge in applying “top-down”
[21]
challenge to regenerate microvessels and build a approaches to the construction of the independent
microvascular network, mimicking the cellular viabilities vascular networks or tissues including the microvascular
and activities in the engineered organs, such as the liver, architectures is that “top-down” approach is by nature
the heart, and the kidney, with traditional, or existing a 2D construction strategy. The cells are seeded on the
manufacturing techniques [9-11,21] . surface of the scaffold which is a 2D space. Along with
Modular tissue engineering adopting the “bottom- increasing the complexity of the scaffold architectures,
up” approach builds one-dimensional (1D) or two- it becomes difficult for seeding the cells on the scaffold
dimensional (2D) modular tissues in micro scale first and and giving the necessary support or stimulations to the
then uses these modules as building blocks to generate seeded cells. Moreover, “top-down” approach features
large tissues and organs [22-32] . It allows recreating extremely low flexibilities in constructing tissues with
complex but indispensable microstructural features of the varied sizes and architectures.
engineered tissues. Building the microvascular network Different from the “top-down” approaches, “bottom-
using this approach could be appropriate and adequate. up” approaches start from constructing fabricating the
However, fabricating the basic modular tissues and micro modular tissues with cells and biocompatible
building the microvessels with these modules in micro materials [22-32] . As shown in Figure 1, 1D or 2D modules
scale face tough challenges in precision, efficiency, and such as spheroids, rings especially for engineering
configuration complexity. Existing methods using the microvessels, fibers, plates with arbitrary shapes, and
“bottom-up” concept developed to fabricate microvessels cell sheets can be fabricated through cell aggregation and
can be divided into bio-assembling powered by developing microfabrication techniques with mass production. Then,
micromanipulation techniques and bioprinting utilizing these micromodules as the basic blocks can be used to
varied solidification mechanisms. Some researchers tend build the large tissues with desired micro architectures
to treat bioprinting as a particular assembly approach including the microvascular networks. The existing
in modular tissue engineering. The main difference “bottom-up” approaches for engineering microvessels
of bioprinting from the common bio-assembling is its can be divided into bio-assembling and bioprinting.
ability to create modular tissues and build 3D structures Some researchers also classify the bioprinting into
simultaneously . a particular bio-assembling way. In engineering
[33]
In this review, we describe the bio-assembling and microvessel by bioassembling, the key is the geometry
bioprinting strategies for engineering the microvessels. design of the micro modules, which governs the selection
First, we introduce the 1D or 2D modular tissues with of the micromanipulation methods in the assembling
different geometries for assembling the microvessels procedure. The geometry of the micromodules and the
and the bioinks used in bioprinting. Then, assembly micromanipulation utilized in the assembling determines
methods applying different micromanipulation the fabrication efficiency, complexity, and size of the
techniques and bioprinting devices adopting different constructed microvessels. In engineering microvessel by
mechanisms are reviewed. Finally, we compare and bioprinting, the bioink compositions and solidification
discuss the features of the artificial microvessels mechanisms are the two major factors as they influence the
constructed by these two strategies from the aspects of mechanical property, curing time, curing degree, printing
the fabrication efficiency, the sizes of the engineered speed, and printing resolution. In the following sections,
microvessels, and the ability to construct the complex we will introduce existing bio-assembling approaches
3D microvascular networks. utilizing various micro modular tissues and bioprinting
approaches based on different printing mechanisms.
2. Engineering microvessels from the bottom
up 3. Modules and bioinks

At present, there are two construction strategies in According to the morphology, we divide modules for
tissue engineering, which are “top-down” and “bottom- assembling microvessels into five categories: fiber,

4 International Journal of Bioprinting (2021)–Volume 7, Issue 3