Cross-section of multicellular bioprinted human liver tissue, stained with hematoxylin & eosin (H&E).
the loss of function has limited their usefulness. What is needed is a method whereby hepatocytes can be maintained in culture environments that support polarisation and three-dimensionality and so retain critical functions for longer periods outside the body.
Cross-section of bioprinted human liver tissue demonstrating compartmentalisation between the hepatocytes (shown as blue nuclei), endothelial cells (red) and hepatic stellate cells (green).
The image above shows formation of intercellular junctions between hepatocytes in bioprinted liver tissue, highlighted by E-Cadherin immunochemistry (green).
“... bioprinting ... enables fabrication and comparative testing ... so that winning combinations can be identified systematically based on histological and functional outcomes.”
Bioprinted liver tissue model Organovo’s NovoGen Bioprinting platform has
activities, including CYP1A2 and CYP3A4.
using Organovo’s proprietary 3D bioprinting
been used to generate bioprinted liver tissue
Production of the liver-specific protein, albumin,
technology that builds functional living tissues
prototypes that contain both parenchymal and
was 5 to 9 times greater on a per-cell basis when
containing precise and reproducible architecture.
non-parenchymal cells in spatially controlled, user-
compared to matched 2D controls. These functional
The tissues are functional and stable for at least
defined geometries that reproduce compositional
data, combined with the unique histological features
42 days, which enables assessment of drug effects
and architectural features of native tissue.
of the tissues, suggest they may be a compelling
over study durations well beyond those offered by
One advantage of the automated bioprinting
alternative to traditional 2D hepatocyte cultures
industry-standard 2D liver cell culture systems.
platform is that it enables fabrication and
for predictive studies, especially those involving
Organovo has previously shown that exVive3D
comparative testing of multiple compositions and
longer-term tissue toxicity assessments or studies
Liver Models produce important liver proteins
geometries so that winning combinations can be
of disease development and progression where
including albumin, fibrinogen and transferrin,
identified systematically based on histological and
results need to be interpreted in the context of
synthesise cholesterol and possess inducible
cytochrome P450 enzymatic activities, including
Beginning with hepatocytes (the predominant
The overall goal of studies like these is to
CYP 1A2 and CYP 3A4. The exVive 3D Liver has
parenchymal cells of the liver), designs were created
develop living, multicellular human tissues that can
successfully differentiated between structurally
based on shapes and cellular interfaces found
be maintained in the laboratory environment for
related compounds with known toxic and non-
in native liver tissue. Non-parenchymal cells,
extended periods of time and sampled serially for
toxic profiles in human beings and the model has
including endothelial cells and hepatic stellate
both functional and histological changes in response
also been employed successfully in the detection
cells, were positioned in defined locations relative
to injury, pathogens or treatments.
of metabolites at extended time points in vitro.
to hepatocytes, creating a compartmentalised
Importantly, the configuration of the bioprinted liver tissues enables both biochemical and histologic
fabrication and substantially maintained over
3D bioprinted human liver tissue now available
time in culture.
Using 3D bioprinting technology, Organovo
compound responses at multiple levels.
architecture that was established at the time of
data to be collected so that a customer can investigate
In addition to the cell type-specific
Holdings has released its exVive3D Human Liver
The durability and functionality of the 3D
compartmentalisation, two histomorphological
Tissue for preclinical drug discovery testing. This
liver product enable the assessment of the effects
features can be appreciated in these bioprinted
model is intended to provide human-specific data
of low dose or repeated dosing regimens across a
liver tissues: 1. The development of microvascular
to aid in the prediction of liver tissue toxicity or
spectrum of biochemical, molecular and histologic
networks within the tissue; and 2. the formation of
ADME outcomes in later-stage preclinical drug
end points. Initially, users will be able to access the
tight intercellular junctions among the hepatocytes.
technology through Organovo’s contract research
Importantly, these multicellular, 3D liver tissues
Organovo’s exVive3D Liver Models are
services program. All testing will be performed at
possess critical attributes central to liver function,
bioprinted, living 3D human liver tissues consisting
Organovo’s facility by the company’s laboratory
including production of liver-specific proteins
of primary human hepatocytes, stellate and
services tissue experts.
such as albumin and transferrin, biosynthesis
endothelial cell types, which are found in native
of cholesterol and inducible cytochrome P450
human liver. The exVive3D Liver Models are created
Organovo Holdings www.organovo.com
44 | LAB+LIFE SCIENTIST - January 2015