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International Journal of Bioprinting Three-dimensional bioprinting in toxicological research

for example, the intestinal epithelium. Liver epithelial cell 3. Liver structure and function
maintenance is primarily mediated through self-duplication
of terminally differentiated cells. Despite the slower rate of In the case of the liver, it is especially true that function and
cell proliferation in the liver tissue, the liver is still capable structure define each other, and this 3D structure allows:
of extraordinary self-renewal and regeneration, although (i) the control of carbohydrate, protein, lipid, and hormone
it is exposed to many damaging effects. If these effects are metabolism; (ii) a number of detoxification mechanisms;
chronic, they may however lead to liver function defects (iii) the storage of glycogen, Vitamins A, D, and B12,
and irreversible fibrotic damage. After partial surgical ferritin, and blood; and (iv) the production of bile, bile
resection of the liver, a regeneration process takes place by acid, and bile dye, bilirubin metabolism and excretion, and
the remaining healthy mature hepatocytes that respond to selenium cofactor production essential for the function
injury-induced signals (e.g., tumor necrosis factor alpha of various enzymes. Histologically, the liver is made up
and interleukin [IL]-6) and restore physiological liver of the right and left lobes, which consist of three types of
mass within a week [16-19] . This phenomenon has greatly hexagonal lobules (classical, portal, and hepatic acinar). In
improved the method of organ transplantation and liver the lobes, there are islands of hepatocytes in direct contact
resection in patients suffering from cancer. Nevertheless, with the sinusoids, where the metabolic exchange between
toxin-mediated damage or chronic liver disease, such as the blood and the hepatocytes takes place. Branches of the
non-alcoholic fatty liver disease, results in impaired liver central vena cava are in the center of the hexagonal classical
cell function, so the regeneration process that restores lobules, and the edges are connected by the branches of the
liver mass cannot take place, as can be observed after hepatica arteria, the portal vein, and the bile duct forming
partial hepatectomy. In this case, an alternative pathway is the portal triad. The liver is made up of different cell
activated, during which the ductal cells become activated types, such as the parenchyma (hepatocytes arranged in a
and begin to proliferate, thus restoring the liver tissue to single-cell-thick disk), connective tissue stroma in direct
its original state. Due to its large and remarkable ability contact with Glisson’s sheaths covering the outer surface,
to regenerate and self-renew, the liver-derived cells are sinusoidal capillaries (which are capillaries covered with
extremely important in vitro tools in applied research, discontinuous and highly fenestrated endothelial cells
as they provide insights into development, function, and between hepatocyte discs), and perisinusoidal or space
various diseases of liver (Figure 2A) [15-22] . of Disse located between the sinusoidal endothelium
and hepatocytes containing Kupffer cells and stellate
A cells [15,16,20,23-29] .
Due to their functions, hepatocytes are highly involved
in the drug metabolism and transport, thus they are well-
polarized and carry functionally different membrane
domains to perform drug processing. Each side has a
distinct function: the sinusoidal membrane part exchange
solutes with blood, the lateral side shapes junctions between
cells (tight junctions, desmosomes, and gap junction),
while the canalicular membrane secretes bile through its
efflux transporters. Circulation and drug uptake take place
through the fenestrated sinusoidal membrane into the
B perisinusoidal space. Small lipophilic molecules can pass
through the sinusoidal membrane by diffusion, while less
lipophilic, amphipathic, and polar drugs are transported by
sinusoidal uptake transporters. The canalicular membrane
contains many efflux transporter proteins mainly from the
ATP-binding cassette superfamily, which are responsible
for bile salt export, multidrug, and toxin elimination.
Since the basolateral membrane also includes some efflux
proteins, where hepatocytes extrude the metabolites into
the bloodstream, the direction of the drug transport
Figure 2. Structure and cell types of the liver. (A) The hexagonal building pathway can be controlled by the liver. These facts
blocks determine the metabolic activity of the cells. (B) Cells that play
key roles in drug metabolism, niche and homeostasis of the liver. Image corroborate that proper 3D structure and diversity of the
created with BioRender.com. liver are necessary for its function (Figure 2B) [15,16,20,23,28-31] .

Volume 9 Issue 2 (2023) 200 https://doi.org/10.18063/ijb.v9i2.663