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International Journal of Bioprinting New challenges in liver tissue engineering

MASLD or hepatitis. There seems to be a final pathway in have also been explored for the treatment of liver disease.
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the pathogenesis of HCC, regardless of the cause, wherein Liver cell transplantation using hepatocytes, macrophages,
repetitive hepatocyte injury begins a vicious cycle of cell or stem cells has been suggested as an alternative or
death and regeneration that eventually results in genomic bridging technique to reduce liver disease mortality and
instability and onset of the disease. Different treatments morbidity. The first attempts at liver cell-based therapies
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are available for HCC, including surgical resection, liver focused on inherited metabolic disorders produced by
transplantation, chemotherapy, and immunotherapy, but the lack or dysfunction of a single enzyme, although cell
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most patients received the diagnosis of HCC when the transplantation has been also applied in different liver
disease has already progressed into an advanced phase or diseases. 32,33 Other approaches such as bioartificial liver
when their liver function become compromised, leaving support systems have also been proposed, and promising
them with limited number of therapeutic choices. results have been obtained in animal models. However,
DILI is one of the principal factors contributing to more clinical studies are warranted to establish the safety
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acute liver failure (ALF) and a major cause of drug attrition and efficacy profile of the procedure.
in the preclinical and clinical phases of drug development 3. Liver microenvironment
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or withdrawals after they have been commercialized.
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It involves high costs to both the pharmaceutical The liver has a uniform anatomical structure, and its
companies working on the drug development process and structural unit is the hepatic lobule, which is hexagonal and
healthcare organizations due to its associated morbidities consists of hepatocyte plates that radiate from the central
and mortality. 25,26 DILI reactions are frequently intricate vein in the center of the hexagon following a honeycomb-
processes that involve multiple interactions between like pattern. The portal triad is composed of a vein, an
4
hepatocytes and non-parenchymal cells. Furthermore, artery, and a bile duct, and is located at each vertex of the
drugs can induce DILI by different mechanisms such as hexagon (Figure 1). Blood rich in oxygen and different
4
immune-mediated responses, mitochondrial damage, soluble factors enters through the portal vein and hepatic
oxidative stress induction, steatosis, or cholestasis. artery and flows concentrically toward the center of the
lobule, whereas the bile flows outward from the center
Inherited metabolic liver diseases represent a 35
heterogeneous group of rare disorders mostly characterized to the bile duct in the vertex of the lobule. The areas
surrounding the central vein are known as pericentral,
by a defect in a single enzyme or protein with metabolic while those close to the portal triad are called periportal.
functions, e.g., receptors or transporters. 27,28 Some examples
of these disorders include urea cycle disorders due to With an anatomically diverse and complex landscape,
defects of urea synthesis and related metabolic pathways; the liver functions are performed in parallel according
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Crigler–Najjar syndrome type 1 caused by mutations of to the zones, a phenomenon known as liver zonation.
the UDP glucuronosyltransferase 1A1 that produce severe Liver zonation has been implicated in the initiation and
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hyperbilirubinemia; Wilson disease due to mutations progression of liver disease; therefore, new cell-based
of the ATP7B gene, involved in copper transport; and models have been created to simulate liver zonation, for
instance, by modulating oxygen tension.
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glycogen storage diseases caused by mutations that alter
the accumulation of glycogen. Although these diseases, 3.1. Liver cells
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which are typically treated with organ transplantation, do The liver is formed by distinct cell types of different
not normally present changes in the liver architecture, the embryological origins that carry out unique functions.
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characteristics of these disorders underline the feasibility Hepatocytes are the major liver cell type and perform most
of using cell therapy treatment as the ideal therapy. 14 of its secretory and metabolic functions. Cholangiocytes
2.2. Treatment of end-stage liver disease are epithelial cells that form the bile duct. The non-
Although liver transplantation is the only effective parenchymal cells include Kupffer cells (KCs) which are
treatment for end-stage liver disease and presents a high liver-resident macrophages, HSCs, and liver sinusoidal
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survival rate (85% after 1 year), the world is facing an organ endothelial cells (LSECs). Figure 1 depicts the distribution
29
scarcity problem, and many patients experience worsening of the different cell types in the hepatic lobule.
disease condition or may even die while still being put Hepatocytes account for approximately 80% of the total
on the waiting list. New strategies have been explored cell volume mass and are responsible for most of the liver
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to amplify the number of available organs or improve functions. They express the greater part of circulating plasma
their quality (i.e., dynamic preservation, living donors). proteins like albumin, transporters, blood clotting factors,
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Despite these efforts, the next-generation treatments such and immune modulators. Hepatocytes synthesize different
as cell transplantation or other bioengineering approaches proteins such as albumin (involved in the maintenance of

Volume 10 Issue 3 (2024) 118 doi: 10.36922/ijb.2706