An Introduction to Organ-on-a-Chip Technology
eBook
Published: September 6, 2023
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Preclinical animal and in vitro models can be extremely useful tools in the development and safety testing of novel drugs. However, such models sometimes struggle to accurately mimic human tissue biology; consequently, 90% of preclinically successful drugs fail in human trials.
Organ-on-a-Chip technology offers a more accurate, reproducible solution by creating a human-relevant environment for drug testing applications from early discovery through to preclinical trials.
This eBook provides an introduction to Organ-on-a-Chip technology and highlights the latest solutions available to support drug discovery.
Download this eBook to discover:
- The common challenges of traditional preclinical drug development models
- Organ-Chip applications, including gene therapy, immunology and toxicology research
- How Organ-Chips can benefit drug development workflows
An Introduction to
Organ-on-a-Chip
Technology
emulatebio.com
Table of Contents
3 An Introduction to Organ-on-a-Chip Technology
4 Challenges with Preclinical Drug Development Models
4 Challenges with Conventional In Vivo Models
5 Challenges with Conventional In Vitro Models
6 Organ-Chip Overview
7 Organ-Chips in the Drug Development Workflow
7 Early Discovery
8 Lead Optimization
8 Preclinical Safety
8 Clinical Trials
9 Organ-Chip Insights & Endpoint Analysis
10 Applications
10 Gene Therapy
11 Immunology & Inflammation
12 Toxicology
13 Organ-Chip User Survey Results: A Comparison to
Conventional Preclinical Models
14 Key Learnings & Additional Resources
15 References
An Introduction to
Organ-on-a-Chip
Technology
Introduction
To bring drugs to market, scientists rely on different types of
preclinical models—from 2D in vitro models to lab animals—that try
to replicate human in vivo conditions. Unfortunately, conventional
preclinical models have a difficult time approximating human
biology and, as such, fall short in predicting how humans will
respond to drugs. This is a major reason why 90% of drugs that
pass the preclinical stage fail when they reach human trials.
Thankfully, scientists have next-generation technology at their
disposal.
With Organ-on-a-Chip technology, researchers can test drugs in a
human-relevant environment, get more accurate data on human
response in a shorter time, and have greater confidence when
sending drugs to clinical trials. Emulate has been leading the
industry in bringing Organ-Chips to labs across the world since
2013. Over 100 peer-reviewed publications have demonstrated the
utility of this technology in improving scientific understanding of
human health and disease.
This guide is for researchers and scientists who are interested in
learning how next-generation Organ-on-a-Chip technology can
improve their disease research and drug development programs
to increase efficiency and bring more life-saving treatments to
market. After reading it, you’ll have a better understanding of the
most pervasive challenges in drug development as well as what
Organ-Chips are, what they can do, and how they can help you
overcome hurdles in developing new drugs.
98% of scientists say species
differences contribute
to high translational
failure rates*
2%
46%
52%
Primary or Major Reason
Contributing Reason
Small or Insignificant Reason
*2021 survey of 125 scientists conducted by the Linus Group.
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2021 survey of 125 scientists conducted by the Linus Group
Challenges with Preclinical
Drug Development Models
To develop drugs, scientists rely on animals like mice, dogs, and non-human
primates (NHPs) as well as in vitro models like 2D cell cultures and organoids/
spheroids to predict human response. However, both in vivo and in vitro
models come with unique sets of issues that can hinder the drug development
process:
Challenges with Conventional In Vivo Models
1. Difficulty in Sourcing NHPs: Since NHPs approximate human biology better than other lab animals,
they are always in high demand; however, there is an ongoing shortage in NHP imports driving up
demand and prices. There are many reasons for this, from extensive regulation, to a crackdown on
breeding practices, to the lingering effects of the COVID-19 pandemic, but the shortage doesn’t
appear to be going away any time soon.
2. Lengthy and Rigid Animal Experiments: Experiments using animal models take a long time and
require significant regulatory oversight. Each kind of animal model will bring its own logistical,
regulatory, and ethical challenges that can further increase experiment costs and timelines.
3. Lack of Reproducibility: Regardless of the measures scientists take to standardize animal model
experiments, each lab animal will be unique and highly susceptible to factors that scientists can’t
anticipate, which can impact study results. In fact, one Amgen study showed that only ~10% of in
vivo experiments submitted as part of clinical development could be reproduced by an in-house
group of researchers1
. Even factors like the way scientists handle lab animals or the technician’s
gender can influence the way an animal will respond in experiments. This makes reproducibility,
which is essential to any kind of research, difficult to maintain.
4. Species Translation Issues: Despite efforts made to humanize animal models, inherent differences
in species biology will always be a limiting factor in predicting human response. In fact, 98% of
scientists agree that species differences contribute to high translational failure rate2
. As the drug
pipeline shifts towards biologics, immune cell therapy, and other human-specific treatments, these
challenges will only grow.
4
say their progress is limited
‘sometimes’ or more often by
conventional research models
92%
of Industry
95%
of Academics
emulatebio.com
Challenges with Conventional In Vitro Models
1. Limited In Vivo Relevance of Immortalized Cell Lines: Scientists
often rely on immortalized cell lines due to their ability to survive and
continuously proliferate under cell culture conditions. However, because
of the genetic manipulation needed to turn them immortal, they can
behave differently than primary human cells, leading to incomplete or
inaccurate understanding of disease biology and drug effects.
2. No Organ-Specific Microenvironment: In vivo, cells’ functionality is heavily influenced by their
environment—the extracellular matrix (ECM), mechanical forces, and stroma that surround them.
Conventional in vitro models, however, lack these environmental features and can function
differently than cells would in vivo.
3. Lack of In Vivo Complexity: In the human body, cells are constantly in communication with other
cells. These interactions are integral to proper cell function. In vitro models, however, often only
include a single cell type, leading them to respond to drugs in ways that do not reflect in vivo
function.
4. Limited iPSC Differentiation: While induced pluripotent stem cells (iPSCs) hold significant promise
for studying human biology outside of patients, it is difficult to unlock this potential. When cultured
under static conditions, iPSCs often fail to differentiate fully into the cell type of interest.
Thankfully, many of these challenges can be overcome with next-generation Organ-on-a-Chip technology.
Read on to learn more.
0 10
Not predictive
at all
Completely predictive
of human response
Conventional 2D cell
culture models
Animal in vivo
models
4.5 6.3
Scientists agree: Neither conventional cell culture models nor
animal models adequately predict human response
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2021 survey of 125 scientists conducted by the Linus Group
Organ-Chip Overview
Organ-on-a-Chip technology allows researchers to recreate the functional unit of an organ using living
human cells and an organ-specific microenvironment, offering a real-time window into the inner workings
of human biology. The chips are small, flexible devices that contain two parallel channels. Many types of
human-relevant cells can be seeded into these channels—including primary cells, iPSCs, organoids, and
immune cells. The channels are separated by a thin, porous membrane, which creates a tissue-vascular
interface for cell-cell communication. The membrane is coated with a tissue-specific extracellular matrix
(ECM), helping to further drive tissue maturation as one would see in vivo.
A key feature of Organ-Chips is that researchers can easily control and finely tune the mechanical forces
cells experience. When Organ-Chips are placed under media flow and cyclic mechanical strain, cells
experience the mechanical forces they would in the body—such as peristalsis in the intestines, breathing
in lungs, and blood flow through vessels.
All of these features combined—multicellular complexity, cell-cell interactions, tissue-specific ECM, and
mechanical forces—result in more in vivo-relevant gene expression, morphology, and functionality than
is possible with conventional cell culture methods. Read on to learn
where Organ-Chips fit into drug development workflows and
how they can improve your odds of clinical success.
1. Top channel
2. Epithelial cells
3. Vacuum channel
4. Porous membrane
5. Endothelial cells
6. Bottom channel
Organ-Chips consist of two parallel microfluidic channels (1, 6), with distinct
channels for epithelial cells (2) and endothelial cells (5). A porous membrane (4)
separates the two channels while enabling inter-channel communication and
cell migration. Vacuum channels (3) alongside the microfluidic channels provide
tunable mechanical stretch across the membrane.
Schematic of an
Organ-Chip
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Organ-Chips in the
Drug Development Workflow
With Organ-Chips delivering greater human relevance, the question becomes how to use them most
effectively throughout the drug development pipeline. When we look at their applications, we see multiple
benefits across the entire pipeline.
Develop disease
models with closerto-human gene
expression to identify
and validate drug
targets.
Study candidate
efficacy to rank
order and optimize
lead candidates.
Predict diverse
mechanisms of
unexpected human
toxicity for preclinical
drug candidates
and assess human
relevance of toxicity
observed in preclinical
animal studies.
Perform follow-up
studies to assess
efficacy mechanisms,
or mechanisms of
toxicity for drugs that
have unexpected
safety signals in the
clinic.
Early Discovery Lead Optimization Preclinical Safety Clinical Trials
Early Discovery
In the early stages of drug discovery, Organ-Chips can be used to develop
disease models with closer-to-human gene expression in order to identify
and validate drug targets. In many experimental situations, two-dimensional
cell culture methods are unable to replicate the appropriate cellular
microenvironment, and animal models are unsuitable due to species differences.
Organ-Chips have been used to generate human-relevant models for multiple
organs and diseases, including bone cancer metastasis, bacterial vaginosis,
thrombosis, environmental enteric dysfunction, and COVID-19, just to name a
few. These models enable researchers to better understand underlying disease
mechanisms and develop more effective treatments.
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Lead Optimization
In the lead optimization phase, Organ-Chips provide human-relevant data to
rank order and optimize lead candidates that show the most efficacy and least
toxic profiles. By including Organ-Chip studies in this stage of drug development,
a chemical compound that produced a toxic signal in a human Organ-Chip could
be deprioritized from early in vivo studies, thus reducing animal testing and
permitting safer candidates to progress through the development pipeline.
Preclinical Safety
In the preclinical safety phase, Organ-Chips can be used as a valuable
screening tool to predict diverse mechanisms of unexpected human toxicity3.
They can also be used in this phase to assess the human relevance of toxicity
that may have been observed in preclinical animal studies4. Organ-Chips are
particularly beneficial at this stage for evaluating newer drug modalities that are
increasingly human-specific, such as biologics and immunotherapies.
Clinical Trials
Lastly, Organ-Chips can even benefit the clinical trial phase of drug
development. For drug candidates that produce unexpected safety signals in
the clinic, Organ-Chips can be used to perform follow-up studies in order to
assess mechanisms of toxicity, and researchers can use that information to
prioritize back-up compounds.
Organ-Chip Case Study
Researchers from Emulate worked with Janssen to evaluate the hepatoxicity of Atabecestat, a BACE
inhibitor developed by Janssen that caused drug-induced liver injury (DILI) in clinical trials, by testing the
compound on the human Liver-Chip. Through the study, they confirmed the hepatotoxicity of the compound,
identified treatment-related mechanistic and injury biomarkers, and confirmed that the mechanism of action
was oxidative stress triggering an inflammasome response. Ultimately, these results enabled Janssen to help
screen safer back-up compounds.
As you can see, Organ-Chips can benefit the drug development pipeline at every stage. The next section of
this eBook will further discuss the various insights that Organ-Chip experiments can provide.
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Organ-Chip Insights
Each Organ-Chip enables researchers to collect and analyze rich,
human-relevant data. Organ-Chips are compatible with endpoint
assays used in conventional cell culture or in the clinic.
• Effluent-based analysis enables researchers to
independently sample the effluent from each channel
throughout an experiment. Effluent can be analyzed
to measure relevant functional endpoints, such as
biomarkers of tissue health and damage, apparent
permeability (Papp), cytokine release, and metabolomics.
• Imaging analysis allows researchers to assess cell
morphology, protein expression, and behavior, such
as cell migration. Organ-Chips are compatible with a
variety of imaging techniques, including brightfield,
phase contrast, widefield fluorescence, confocal,
multiphoton, and scanning electron microscopy.
High-content imaging can be performed to capture
the entire culture area across both chip channels,
providing the maximum amount of data for
quantification and downstream analysis.
• Omics-based analysis can be performed to assess
Organ-Chip similarity to in vitro tissue or genetic
differences between healthy and diseased tissue,
enabling researchers to identify relevant disease
pathways. Each chip contains enough genetic material
for analysis on a chip-by-chip level, providing the
opportunity for single-cell or bulk RNASeq as well as
proteomic analysis.
In short, a wide variety of endpoints can be measured on Organ-Chips to
better understand human physiology and disease. And through detailed
endpoint protocols, Emulate can guide researchers throughout OrganChip analyses. Keep reading to learn more.
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In hemophilia, AAV6 is one of the
leading vectors for therapeutic
research. To assess the use of the
Emulate Liver-Chip for predicting
AAV transduction and hepatoxicity
risk, Liver-Chips were treated
with AAV6 vector encoding
green fluorescent protein (GFP).
AAV6 demonstrated a timeand concentration-dependent
transduction, while the hepatocytes
and liver sinusoidal endothelial cells
maintained a healthy morphology
with no toxic signals present.
Applications
Here, we highlight a few of the many ways Organ-Chips are being used to provide more physiologically
relevant insights into the mechanisms of human disease and the effects of drug candidates.
Gene Therapy
Gene therapy holds enormous promise for treating inherited and acquired genetic diseases, but progress in
developing those therapies remains slow. Take for example adeno-associated virus (AAV)-based gene therapy:
While there have been over 136 clinical trials for AAV-based therapies to date, there are only two approved
therapies currently on the market. Additionally, 35% of those trials had severe adverse safety events, because
conventional in vitro and in vivo models were unable to accurately predict toxicity.
With the AAV transduction application forthe Emulate human Liver-Chip, researchers can rapidly iterate on AAV
design in a human-relevant model ofthe liver sinusoid to accelerate vector optimization ahead of clinical trials.
Users can administer a test AAV vector in the epithelial channel and monitortransduction efficiency and toxicity
signals for up to seven days, enabling researchers to assess response in a time- and dose-dependent manner.
Transduction efficiency can be quantified through GFP expression in the hepatocytes, while the potential toxicity
of AAV vectors can be measured by functional biomarkers such as albumin secretion and ALT release levels.
AAV transduction is just one area within gene therapy where Organ-Chips can be applied. In addition to
improving the development of AAV-based therapies, this workflow can be adapted to evaluate vectors other
than AAV, including both viral and non-viral vectors. The flexibility and agility of this technology may be key
to decreasing the timeline of bringing effective and safe gene therapies to patients. By enabling researchers
to generate human-relevant data in just weeks—as opposed to the months it would take in non-human
primates—Organ-Chips can facilitate rapid iterations on vector design to ensure that the most robust vector
candidates proceed to clinical trials.
Vehicle Control
Days Post-Treatment
Day 7 Day 3 Day 1
AAV6 Null
500k MOI
AAV6 GFP
100k MOI
AAV6 GFP
500k MOI
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Learn more about testing the transduction of AAV-based therapeutics in the Liver-Chip.
One-way ANOVA of full dataset,
n=5, ****p ≤ 0.0001
Immune Cell Recruitment
8000
6000
4000
2000
0
Top Channel
Membrane
Endothelium
****
Cytokine (TNF-α)
Priming Stimulus PBMC Count
- +
Immunology & Inflammation
Inflammation plays a role in many prominent diseases, with chronic inflammatory diseases causing 3 out of 5
deaths worldwide5
. However, the mechanisms of human inflammation remain poorly understood due to the
challenge of modeling complex immune response in vitro and the fundamental differences in the immune
systems of animals and humans. Because existing models can only capture individual aspects of immune
response, researchers are left with an incomplete picture of the processes that drive human inflammation.
Organ-on-a-Chip technology can be used to build more human-relevant models of inflammation,
allowing researchers to incorporate the cellular diversity seen in vitro into a tissue-specific and human
microenvironment. The flexibility of Organ-Chip models allows researchers to precisely control and study the
individual contributions of various factors in the inflammatory process—including resident and circulating
immune cells, inflammatory cytokines, cell-cell interactions, and tissue-relevant mechanical forces—to better
understand disease pathology and drug effects.
Take inflammatory bowel disease (IBD), for example. The Emulate human Colon Intestine-Chip can accurately
model dysregulated immune cell recruitment, the driver of IBD pathogenesis. When immune cells flow
through the chip vascular channel in the presence of proinflammatory stimuli, they undergo the entire
process of immune cell recruitment—from attachment, to migration, to downstream effector function
and barrier damage. This is the only model demonstrated to capture this full process in a tissue- and
inflammation-specific manner, enabling a more complete window into disease pathogenesis. Four clinically
relevant IBD therapeutics with different mechanisms of action have been assessed on the model, showing
that Organ-Chips can be used to evaluate drug efficacy and rank order lead candidates.
Complex immune response, including immune cell recruitment, can be modeled. Shown here is the recruitment of PBMC
immune cells from the vascular channel into the epithelial channel—a key step in IBD pathogenesis.
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Learn more about modeling inflammatory immune cell recruitment.
TAK-875 (μM): 0 10 30 AdipoRed CellROX TMRM CDFDA
Toxicology
Biopharmaceutical companies encounter many challenges in developing safe and effective drugs,
but evaluating human toxicity can be particularly challenging. Approximately 30% of drugs fail during
clinical trials due to toxicity—despite having passed preclinical safety screenings in animals6. Put simply,
conventional models lack the predictive value required to confidently transition drug candidates to the clinic.
Organ-Chips enable researchers to translate to the clinic with confidence by predicting human
response earlier in drug development. To measure how much Organ-Chips could improve patient safety,
researchers qualified the Emulate human Liver-Chip against the guidelines defined by IQ MPS, an affiliate
of the International Consortium for Innovation and Quality in Pharmaceutical Development. The study
demonstrated that the Liver-Chip was able to correctly identify 87% of the tested drugs that caused
drug-induced liver injury (DILI) in patients despite passing animal testing evaluations. At the same time,
the Emulate human Liver-Chip did not falsely identify any drugs as toxic, supporting its use in toxicology
screening workflows3.
To demonstrate how using Organ-Chips in preclinical workflows can improve outcomes in clinical trials,
consider this use case: TAK-875 was a drug candidate discontinued during phase III trials due to DILI. When
the compound was retrospectively studied on the Liver-Chip, results showed that prolonged exposure to the
compound caused mitochondrial dysfunction, oxidative stress, lipid droplet formation, and an innate immune
response—all harbingers of DILI for susceptible patients7
. Had the Liver-Chip study been performed prior to
clinical trials, researchers could have found human-specific toxicity concerns earlier, deprioritized TAK-875 as
a drug candidate, and moved forward with safer candidates.
Identifying risk for idiosyncratic DILI.
Human Liver-Chips were treated daily
with TAK-875 at the equivalent of
human Cmax (10 μM) to determine if they
could detect DILI. Confocal microscopy
analysis showed that treatment resulted
in a dose-dependent decrease in MRP2
activity, as measured by biliary efflux
of the MRP2 substrate CDFDA (green).
It also showed that treatment had an
effect on mitochondrial membrane
potential, confirmed by a dose-related
and time-dependent redistribution of
tetramethylrhodamine methyl ester
(TMRM), lipid droplet accumulation, and
formation of reactive oxygen species
(ROS). These results align with the clinical
outcome of TAK-875 treatment, supporting
the use of detecting idiosyncratic DILI in
the Liver-Chip.
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Learn more about assessing compound toxicity with Organ-Chips.
Organ-Chips vs Conventional In Vitro Models Organ-Chips vs In Vivo Models
Organ-Chip User Survey Results:
A Comparison to Conventional
Preclinical Models
Organ-Chips are such a powerful technology because they can help scientists predict human response
earlier throughout drug discovery and development. Experienced Organ-Chip users agree, with 97% saying
Organ-Chips are more predictive than conventional in vitro models. The more surprising finding, however, is
that 70% of experienced Organ-Chip users rate the technology as more predictive than in vivo models, with
an additional 21% rating the technology as similarly predictive2
. These survey results speak directly to the
impact that incorporating Organ-on-a-Chip technology can have on one’s research program.
Opinions on Organ-Chips vs Conventional Models
Explore All Emulate Organ-Chip Applications by Clicking Below
Organ-Chips
less predictive
Similarly predictive
Organ-Chips more
predictive
Experienced
user
3%
97%
Never used
11%
56%
33%
Organ-Chips
less predictive
Similarly predictive
Organ-Chips more
predictive
9%
70%
21%
65%
3%
32%
Experienced
user
Never used
13 emulatebio.com
Cancer Gene Therapy Immunology Infectious Disease
Microbiome Neuroscience Toxicology
Model Type Challenge How Organ-Chips Can Help
Conventional
in vivo models
Difficulty in sourcing NHPs
Organ-Chips provide human-relevant insights and can minimize the number
of NHPs needed by enabling researchers to perform lead optimization
studies in Organ-Chips before proceeding to NHP studies.
Lengthy and rigid
experiments
Organ-Chip studies can be designed and executed without any regulatory
oversight required. Additionally, Organ-Chip studies can be easily adjusted to
adapt to insights gained throughout the study.
Lack of reproducibility Organ-Chip kits with pre-qualified human cells enable researchers to
generate robust, reproducible results.
Species translation issues Organ-Chips use physiologically relevant human cells to avoid species
translation challenges.
Conventional
in vitro models
Limited in vivo relevance of
immortalized cell lines
Organ-Chips are compatible with a wide variety of human-relevant cell
sources, including primary cells, iPSCs, and organoids.
No organ-specific
microenvironment
Organ-Chips recreate organ-specific microenvironments by incorporating
a tissue-specific ECM, microvasculature, and the relevant biomechanical
forces caused by fluid flow and stretch.
Lack of in vivo complexity
Organ-Chips can incorporate multiple cell types, including epithelial cells,
endothelial cells, resident and circulating immune cells, and even microbes
to recapitulate the complex cellular interactions that occur in vivo.
Limited iPSC differentiation
Organ-Chips improve iPSC differentiation by providing a more physiologically
relevant microenvironment to drive gene expression that more closely
resembles organ-specific in vitro transcriptomes.
Key Learnings & Additional Resources
As discussed throughout this eBook, Organ-on-a-Chip technology can help researchers overcome several
challenges associated with conventional in vitro and in vivo models. The following table summarizes some
of the most common challenges and how Organ-Chips can help.
14 emulatebio.com
To make Organ-Chips accessible and user friendly for researchers, Emulate has developed the lab-ready
Human Emulation System® consisting of instruments, consumables, and software. With this complete
solution, researchers can use Organ-Chips to replicate the biology and function of any organ.
Continue your Organ-Chip journey by exploring new topics at the following links:
Learn more about the Human
Emulation System
See how to get started with
Organ-Chips
Read examples of how Organ-Chips
have been used
References
1. Begley, C. G., & Ellis, L. M. (2012, March 28). Raise standards for preclinical cancer research - Nature. Nature.
https://doi.org/10.1038/483531a
2. Survey of 125 scientists conducted by the Linus Group on behalf of Emulate (2021)
3. Ewart, L., Apostolou, A., Briggs, S. A., Carman, C. V., Chaff, J. T., Heng, A. R., Jadalannagari, S., Janardhanan, J.,
Jang, K. J., Joshipura, S. R., Kadam, M. M., Kanellias, M., Kujala, V. J., Kulkarni, G., Le, C. Y., Lucchesi, C., Manatakis,
D. V., Maniar, K. K., Quinn, M. E., . . . Levner, D. (2022, December 6). Performance assessment and economic
analysis of a human Liver-Chip for predictive toxicology - Communications Medicine. Nature.
https://doi.org/10.1038/s43856-022-00209-1
4. Jang, Kyung-Jin, et al. “Reproducing Human and Cross-Species Drug Toxicities Using a Liver-Chip.”
Science Translational Medicine, vol. 11, no. 517, 6 Nov. 2019, p. eaax5516, stm.sciencemag.org/content/
scitransmed/11/517/eaax5516.full.pdf, https://doi.org/10.1126/scitranslmed.aax5516
5. Pahwa, R., Goyal, A., & Jialal, I. (2022, August 8). Chronic Inflammation - StatPearls - NCBI Bookshelf. Chronic
Inflammation - StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK493173/#_article-19530
6. The NIH microphysiological systems program: developing in vitro tools for safety and efficacy in drug
development - PubMed. (2019, October 1). PubMed. https://doi.org/10.1016/j.coph.2019.09.007
7. Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes: Review of the Global Clinical Trial
Experience - PubMed. (2018, June 1). PubMed. https://doi.org/10.1007/s40264-018-0642-6
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