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International Journal of Bioprinting Liver printing: from structure to application

liver failure and other end-stage liver diseases, but it faces respectively, through the hepatic vein. 24–26 The fundamental
the challenge of donor organ shortages. Other potential structural and functional unit of the liver is the hepatic
alternatives to liver transplantation, such as bioartificial lobule, roughly 1 mm in diameter, with an adult liver
liver systems or hepatocyte transplantation therapy, can comprising approximately 500,000–1,000,000 lobules. 27,28
only provide temporary support to extend patient survival Each lobule features a hexagonal structure with a portal triad
and are also constrained by cell availability. In vitro models, (composed of the portal vein, hepatic artery, and bile duct)
9
such as organoids and organ-on-a-chip, have demonstrated at each vertex (Figure 2A). The hepatic lobule is centered
potential in basic liver research, disease modeling, drug around the central vein, with hepatocytes arranged radially
screening, and personalized medicine. However, further outward to form hepatic cords. Adjacent hepatocytes form
research is warranted before clinical treatment due to bile canaliculi structures under the functional seal of tight
the undefined composition of the culture conditions, junctions. 29–32 Between the hepatic cords lie liver sinusoids,
simplistic structure, and limited size. 10–14 The fabrication where blood flows from the portal vein area towards the
of a liver holds significant promise for addressing the central vein area, creating gradients of oxygen, nutrients,
numerous challenges associated with traditional organ and hormones. Hepatocytes are exposed to different
transplantation and providing new treatment options for microenvironments, leading to the spatial zonation of liver
patients with liver diseases. 15,16 Three-dimensional (3D) functions. Around the portal vein (zone 1), activities, such
bioprinting has broad application prospects in the field as oxidative metabolism, gluconeogenesis, amino acid
of organ fabrication due to its advantages in personalized breakdown, and cholesterol biosynthesis, predominantly
manufacturing, replicating complex in vivo structures, and occur. In contrast, areas around the central vein (zone 3)
the orderly arrangement of various materials and cells. are primarily responsible for glycolysis, lipogenesis, and
28
This review aims to summarize the latest advances alcohol detoxification. Zone 2 hepatocytes are the main
and challenges in the field of liver 3D printing, as well contributors to homeostatic proliferation. 33,34 Within the
as future development directions. Firstly, we introduce liver sinusoids, all liver cell types are distributed, including
the functions, cellular composition, and development parenchymal cells (hepatocytes, cholangiocytes), non-
and regeneration processes of the liver, highlighting its parenchymal cells (endothelial cells, Kupffer cells, hepatic
complex structure and diverse functions. Following this, stellate cells), and infiltrating lymphocytes (such as B cells,
the history of liver tissue engineering is reviewed, including T cells, and natural killer [NK] cells) (Table 1; Figure 2B).
the limitations of traditional liver transplantation and the The liver develops from the ventral foregut endoderm
emergence and development of in vitro liver models. The and also gives rise to the lungs, ventral pancreas, and
discussion then focuses on the application of bioprinting thyroid. As early as embryonic day 8.5 (E8.5) in mice, the
technology in liver biofabrication, including cell sources, liver-specific gene for albumin (ALB) is actively expressed
biomaterial selection, and the optimization of bioprinting in the ventral foregut endoderm. By E9.0, the ventral foregut
techniques. Special attention is focused on the progress and region adjacent to the cardiac mesoderm and septum
shortcomings of 3D bioprinting for integrating vascular thickens, forming the hepatic diverticulum. Subsequently,
and bile duct structures into in vitro liver tissues. Finally, in E9.5, the diverticulum further thickens, transitioning
the review concludes by discussing the ongoing challenges from a single layer of cuboidal endodermal cells to
in liver biofabrication and exploring future development multilayered hepatoblasts, which proliferate and invade
directions (Figure 1). the surrounding septum to form hepatic buds. With the
continuous proliferation of hepatoblasts, at approximately
2. Liver function, cell types, development, E11.5, the hepatic buds morphologically transform into
and regeneration distinct liver tissue. From E13.5 to E15.5, bipotential
hepatoblasts begin to differentiate into hepatocytes and
The liver is the largest internal organ in the human cholangiocytes, accompanied by the emergence of ductal
body 17–19 and consists of diverse cell types to perform plates and asymmetric ductal structures. 49–51 Postnatally,
critical functions in metabolism, detoxification, protein the liver volume and cell numbers increase to meet
synthesis, bile secretion, and immune response. 20–22 The metabolic demands. Over 5 weeks, liver weight increases
liver is typically located in the right upper quadrant of the by fivefold, and a lobular structure is formed 52,53 (Table 2).
abdomen, beneath the diaphragm, and adjacent to the top
of the stomach, right kidney, and intestines. It has a cone- The liver possesses remarkable regenerative abilities.
shaped, deep reddish-brown appearance. 19,23 The liver Within 15 h after undergoing a two-thirds partial
receives approximately 13% of the body’s blood supply, hepatectomy (PHx), rat hepatocytes initiated DNA
with blood vessels, such as the hepatic artery and portal synthesis and could restore the original liver weight within
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vein, delivering oxygen-rich and nutrient-rich blood, 10 days (Figure 3A). Generally, liver regeneration is
Volume 10 Issue 5 (2024) 121 doi: 10.36922/ijb.3819