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International Journal of Bioprinting 3D bioprinted vascularized tissue models

As a combinatorial approach using coaxial and embedding 3.2. 3D bioprinting of vascularized liver models
bioprinting methods, Gao et al. described 3D in-bath The liver is the largest solid organ in the human body
[40]
coaxial cell printing with vascular-specific ECM bioinks to and performs multiple physiological functions, including
mimic the regular straight, stenotic, and tortuous models of metabolism, detoxification, bile production, and filtration.
arterial constructs (Figure 1C). They designed a customized The liver constitutes complex hepatic lobules that are
triple coaxial nozzle composed of PF-127/CaCl solution tightly assembled into a 3D hexagonal structure. This
2
in the core nozzle, human umbilical vein endothelial cells distinct micro-structural organization confers the multi-
(HUVECs)-laden VdECM/alginate hybrid bioink in the cellular communication primarily responsible for hepatic
middle nozzle, and human coronary artery smooth muscle function . A compelling need has emerged to develop
[45]
cells-laden VdECM/sodium alginate bioink in the outer a liver model that replicates the morphological and
nozzle. Several triple-layer artery equivalents with tunable biological complexities of the liver for tissue development,
geometries (e.g., regular straight, stenotic, and tortuous disease modeling, and drug screening applications. Recent
models) were fabricated by tuning the printing bath and advances in 3D bioprinting encourage the development of
moving speed. In addition, the proposed triple-layer a 3D biomimetic hepatic in vitro model that more precisely
model could recapitulate the hallmark events in early-stage emulates the complex microenvironment of the liver.
atherosclerosis, such as endothelial activation, macrophage Using 3D bioprinting, several liver tissue models have been
adhesion and differentiation, low-density lipoprotein constructed to achieve liver functions in vitro for different
accumulation, and foam cell formation. Furthermore, the research objectives. Lee et al. proposed a one-step 3D
[46]
developed model was implemented to evaluate the dose- bioprinting approach to design and fabricate a 3D liver-on-
dependent effect of atorvastatin on the suppression of a-chip platform introducing a co-culture of multiple cell
foam cell formation, thus highlighting the advantages of types (Figure 2A). The housing and micro-fluidic channels
the in-bath coaxial bioprinting approach and its potential of the chip were built using poly(ethylene/vinyl acetate)
for a drug screening platform. Despite significant efforts in (PEVA), while the heterotypic cell-laden bioinks were
creating readily perfusable vascular channels, there is still precisely placed in the desired location within chip frame.
a lack in the production of micro-vascular networks owing Furthermore, HepaRG-laden liver dECM and HUVEC-
to the limitation of the extrusion-based printing resolution. laden gelatin bioinks were printed into the two fluidic
To circumvent this, Son et al. interestingly proposed channels, respectively (a vascular channel on top and a
[44]
a micro-vascular induction strategy that introduced biliary channel bottom), resulting in a bilayer structure
angiogenic factor-secreting cells—that is, normal human to simulate the liver-biliary duct system that is critical for
dermal fibroblasts (NHDFs)—to create angiogenic factor bile acid excretion. A 3D liver-on-a-chip with vascular/
gradients along a bridge pattern (Figure 1D). With a biliary fluidic channels induced better biliary formation
coordinate pattering approach, a multi-cellular construct and improved liver-specific gene expression and hepatic
composed of EC patterns, an angiogenic factor-secreting function when compared to a chip without a biliary system.
cell pattern, bridge patterns, and a surrounding fibrin Further, the chip was assessed using acetaminophen, and
matrix was designed to produce a functional, multi-scale the results showed a more sensitive drug response in the
micro-vasculature with tissue-specific capillary networks. chip than in the 2D culture condition, highlighting the
Following this method, the spatial gradient of angiogenic feasibility of 3D-bioprinted liver-on-a-chip to investigate
factors secreted from the NHDFs resulted in inducing drug metabolism and toxicity. Another study by Liu et al.
[47]
biological self-assembly to direct angiogenic sprouting and utilized sacrificial printing to create centimeter-scale
micro-vascular networks formation. The study evaluated liver-like tissues using cell-laden GelMA-fibrin ink and
the morphological and functional connectivity between fugitive PF-127 ink (Figure 2B). A 3D-bioprinted hepatic
endothelialized channels and capillary networks, which tissue with branched perfusable vascular networks was
may have potential in the fabrication of high-density and obtained by endothelializing the printed macro-scale
organotypic multi-scale micro-vasculature. channels along with capillary networks through cell self-
Various bioprinting approaches have been used assembly, showing enhanced hepatic marker expressions
[48]
alone or in combination to fabricate a perfusable micro- and higher levels of albumin secretion. Taymour et al.
channel with endothelialized networks, allowing improved recently employed coaxial bioprinting to develop a liver
vascular function and maturation in an integrated sinusoid-like model composed of a core compartment
perfusion platform. We envision adopting 3D bioprinting with pre-vascular structures and a shell compartment with
that offers a promising avenue for the generation of human hepatocytes (Figure 2C). For the core part, gelatin was
organ-specific vascularization with excellent structural added to a natural ECM-like core ink based on collagen
complexity and physiologically relevant levels of function. and fibrinogen with human ECs and fibroblasts to form a
stable pre-vascular network. The shell part was based on

Volume 9 Issue 5 (2023) 23 https://doi.org/10.18063/ijb.748