Fbioe 10 840674
Fbioe 10 840674
Fbioe 10 840674
Organ-On-A-Chip: A Survey of
Technical Results and Problems
Alex Ede Danku 1, Eva-H Dulf 1*, Cornelia Braicu 2, Ancuta Jurj 2 and Ioana Berindan-Neagoe 2
1
Department of Automation, Technical University of Cluj Napoca, Cluj-Napoca, Romania, 2Research Center for Functional
Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca,
Romania
Organ-on-a-chip (OoC), also known as micro physiological systems or “tissue chips” have
attracted substantial interest in recent years due to their numerous applications, especially
in precision medicine, drug development and screening. Organ-on-a-chip devices can
replicate key aspects of human physiology, providing insights into the studied organ
function and disease pathophysiology. Moreover, these can accurately be used in drug
discovery for personalized medicine. These devices present useful substitutes to
traditional preclinical cell culture methods and can reduce the use of in vivo animal
studies. In the last few years OoC design technology has seen dramatic advances,
leading to a wide range of biomedical applications. These advances have also revealed not
only new challenges but also new opportunities. There is a need for multidisciplinary
Edited by: knowledge from the biomedical and engineering fields to understand and realize OoCs.
Xiaotian Wang, The present review provides a snapshot of this fast-evolving technology, discusses current
Beihang University, China
applications and highlights advantages and disadvantages for biomedical approaches.
Reviewed by:
Yuyang Li, Keywords: organs-on-a-chip, microfluidics, personalized medicine, technical details, nanotechnology
Ningbo Institute of Materials
Technology and Engineering (CAS),
China
Jie Zhao, 1 INTRODUCTION
Shenzhen University, China
Organ-on-chip (OoC) is a concept with great interest all around the globe, due to the importance of
*Correspondence:
Eva-H Dulf
their applications in biomedical field. The principle of the OoC is to emulate the behavior of different
[email protected] cells, organs and even multiple-organs, to mimic the complex physiological or pathological processes
(Mauriac et al., 2017c; Sun et al., 2019; van den Berg et al., 2019). From an engineering point of view,
Specialty section: OoC is a microfluidic cell culture system with controlled conditions (flow, velocity, etc.) that imitate
This article was submitted to the physico-chemical microenvironment of tissues in the human body (Figure 1). A difficult goal
Nanobiotechnology, which needs to be achieved is the body-on-a-chip concept, which requires multiple OoC of different
a section of the journal cell type or organs to be linked in order to create a system (Lee et al., 2018). OoC has several
Frontiers in Bioengineering and applications, but the most important is drug development and the effects that they have on different
Biotechnology
organs. Drugs are mostly tested on animals, which in some cases give inaccurate data or raise ethical
Received: 21 December 2021 concerns from organizations such as People for the Ethical Treatment of Animal (PETA), but it is
Accepted: 17 January 2022
considered an important step in tumor research (Mattei et al., 2021). This led to researchers
Published: 10 February 2022
searching for new ways to allow testing on human cells (Wikswo et al., 2013; Marx, 2016; Zheng et al.,
Citation: 2016; Kodzius et al., 2017; Jusoh et al., 2019). The concept of OoC is revolutionary, having a “mini-
Danku AE, Dulf E-H, Braicu C, Jurj A
me” (personalized chip) on which different drugs can be tested on a system similar to that of the
and Berindan-Neagoe I (2022) Organ-
On-A-Chip: A Survey of Technical
Results and Problems.
Front. Bioeng. Biotechnol. 10:840674. Abbreviations: BoC, body-on-a-chip; PDMS, polydimethylsiloxane; ToC, tumor-on-a-chip; ECM, extracellular matrix; OoC,
doi: 10.3389/fbioe.2022.840674 organ-on-a-chip.
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Danku et al. A Survey of Organ-On-A-Chip Construction
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Danku et al. A Survey of Organ-On-A-Chip Construction
to another chip. The PDMS became popular due to many of its 4 ANALYZED ORGANS
properties, being transparent it helps the user since they can
see how the OoC behaves. The material is cheap and is known Organs are made up of different types of cells corresponding to
to have a reduced cytotoxicity, making it easy to use in this their role in the human body. Since different organs have different
application. Because PDMS doesn’t degrade it is sometimes roles the structure of their cells is changes depending on cell types.
replaced by other materials (Ahadian et al., 2018; Sosa- Thus, the OoC must be constructed to best suit the
Hernández et al., 2018). However there have been microenvironment the cells experimented on (Mertz et al., 2018).
researchers who tried to 3D print the chip, requiring only
one step, and avoiding any troublesome events that may occur 4.1 Liver
using multiple step methods that would require the The liver is one of the most important organs in the human body,
solubilization of the initial scaffold (Lee and Cho, 2016). mostly for its several functions to maintain normal physiological
Due to the different structure of each organ, different activities. In order to cope with the damages which may be caused
biomaterials are required in order to obtain good results. to it through chemical or physical means, it has great regenerative
For example, collagen is widely used because of its capacity. In some cases, the injuries may be too severe, mostly
advantages, but it requires some mechanical support caused by adverse reactions from different drugs or diseases.
without which the collagen remains intact for a short time. Before the OoC technology there were not many great in vitro
In some cases, external equipment is required in order to models to be used. Most of the drugs were tested in vivo on animal
obtain the best results. Firstly, it is necessary to control the subjects. The subjects are exposed to the adverse reactions of the
external flow of the micro and nanofluids. For this pressure drugs and, in some cases, being fatal to them. The OoC
generators and different types of pumps are used (Ho et al., technology detects if the different drugs harm liver cells. The
2015; Mauriac et al., 2017b). The best way to control flow is to methodology is to seed the chip with liver cells and apply the drug
use hydrostatic pressure. Pressure generators are usually in different channels. The chip is observed and if the cells die the
simple devices, having incorporated a pressure source, for drug is deemed to harmful to be used in vivo. Because of this, it
example a compressor, a pressure regulator and a manometer can be considered that this system can be useful for hepatotoxicity
to measure the current pressure value. Even though the studies (Wikswo et al., 2013).
system is simple it does have major setbacks mostly There are several liver-on-chip methods used: Liver Sinusoid
contained in its limited response time (Perestrelo et al., which replicates the lacuna between adjacent liver plates; Liver
2015; Mauriac et al., 2018). There are, however, methods Lobule, considered the smallest functional unit of the liver;
to bypass this problem, using a pressure multiplexer the Zonation in the lobule is an optimized segregation of the liver
pressure can be changed much faster. Another upgrade to functions in spatial and temporarily defined zones (Wikswo et al.,
pressure generators can be done by adding flux sensors which 2013).
change the control signal from pressure to flow (Esch et al., The engineering behind the liver-on-chips requires to
2016; Mauriac et al., 2017a; Wu et al., 2020). The viscosity and integrate scaffolding materials for achieving 3D cultures, for
density of the cell culture changes after a certain number of cell growth and to maintain the interactions between the cells.
days. When constructing the chip this property has to be Those components may be natural or synthetic, but are practiced
remembered since studies show that the pressure and stress of in many applications. Such applications may vary from drug
the walls increased significantly in the analyzed models. testing to behavior analysis. On a microfluidic chip it was
Pressure syringes are another system usually used for flow observed that coating the chip with collagen supports the
control. They are usually used in perfusions, but scientists have hepatocyte growth and adhesion. For a layer-by-layer
also adopted them in microfluidic research. They have the deposition the cells were coated with nanofilms of fibronectin
advantage of being able to control the flow without being and gelatin which resulted in the reconstruction of liver tissue
affected by perturbations caused by fluid resistance. Same as with high cellular function. Others found that by seeding
the pressure generator, the settling time is high because of the hepatocytes, endothelial cells and stellate cells on fiber
small values the flow pulses use (Mauriac et al., 2017b; Mauriac membranes the tissues formed secreted albumin and urea for
et al., 2018). several days (Kimura et al., 2018).
Commonly, there are two types of pumps used for flow Most liver-on-a-chip models that study nanotoxicological
control, the first one being simple pumps used for liquids effects are 2D systems. One of the more predominant roles of
which have the disadvantage of having a nonlinear model. the liver is to filter the blood and remove the toxins from it. Due to
However, there exists a linear equation, used as an alternative the nature of this task the toxins can accumulate in the liver
in order to model the system easier. The systems usually causing changes to its function and cellular morphology. One of
require a good sensor in order to detect small flow the improvements to the liver-on-a-chip concept include the use
fluctuations. The other type of pumps are the electro- of perfusions, the effect being the prolonged lifespan of the cells
osmotic ones, which do not have flow fluctuation problems and improved drug metabolism. An innovative idea is the use of
and are resistant to high counter pressure, but have the multi-species liver-on-a-chip system which uses the liver cells
disadvantage of requiring low conductivity liquids in order from multiple animals, this is done to prove that each species can
to work properly (Mauriac et al., 2017b; Wu et al., 2020). react differently to certain drugs. In the example given, the drug
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Danku et al. A Survey of Organ-On-A-Chip Construction
killed the human liver cells, but the rat cells remained alive (Lu better understanding this disease, one of the methods is with the
and Radisic, 2021). aid of the OoC. The researchers use OoC technology to study the
behavior of insulin producing cells in order to better understand
the phenomenon. It is expected that with help of OoC the efforts
4.2 Breast Tissue and the Tumor-On-A-Chip of studying and understanding the disease should be accelerated
Concept (Wu et al., 2018; Glieberman et al., 2019).
Understanding breast cancer anatomy is useful to better study
breast cancer, a frequent malignancy among women. Its danger 4.4 Lungs
comes from its invasive properties and the difficulty in curing it. Lungs do not possess great regenerative properties, as such any
Different 2D models have been used throughout the years with damage caused to them might be permanent. In addition,
little success, due to the models not being able to replicate in an pulmonary cancer is one of the more common types of
accurate way the manner in which the tumor behaves. As in many cancers that may occur to a human, smokers being especially
other fields different in vivo experiments were studied on animals affected by this disease. Also, many areas have a high degree of air
with the downside of these models being the lack of pollution, such as china, causing heavy damage to the lungs.
reproducibility of the obtained results (Bano, 2017). Under these conditions the research on lung cells is deemed
The concept of tumor-on-chip (ToC) is a microfluidic 3D important. The increasing popularity of OoC means that
system designed to mimic the tumor behavior, biological researchers already try to model the lungs on this technology.
activities, mechanical properties and different responses of the There are certain researchers who accomplished this task using
tumor cells. In the case of breast cancer these ToC devices are microfluidic devices and harvesting lung cells on these devices.
used for drug screening by studying different chemotherapeutic They simulate the behavior of the lungs by increasing and
drugs and its effects on the model, or for personalized medicine decreasing the pressure of the device, while the cells replicate
when using primary cells (Chen et al., 2018). Knowing the factors the behavior of the lungs (Wang et al., 2021). The researchers
that can induce resistance to tumor cells can lead to the discovery observed that the cells would react as if they were in their normal
of new therapeutic strategies for treating this disease. With this environment in the body, the alveola contracted and expanded
knowledge, the risks of the treatments can be reduced and mimicking the breathing, while the porous membrane expanded
personalized drugs can be the next step of curing and contracted according to the pressure given. Having this
malignancies. For example, these models can be used to study technology, different reactions can be analyzed, ranging from
the interaction of the malignant clone with adipocytes the behavior of tumor cells to the reaction of lung cells to smoking
considering that this type of cells are prone for tumorigenesis or other environmental toxic agents. Different drugs can be tested
and can promote drug response (Gao et al., 2020). as well to determine their effects on some diseases and to observe
their potential side effects (Kimura et al., 2018).
4.3 Pancreas OoC can be used to study the effects of different
Pancreatic cancer is one of the types of cancer having one of the environmental factors on human organs. Such a study is done
worse prognostics, due to its high resistance to the drugs used on by Rick and Milica who analyze the adverse effects of
it and the difficulty of removing the tumor through surgery. The nanoparticles and their toxicity. The nanoparticles are the
poor outcomes of this disease are believed to be caused by the remains from plastic and other non-biodegradable materials
cancer cells which have high invasiveness features, thus the cancer with the addition of fossil fuels and nitric oxide. It is proven
reaching advanced stages in a short period of time (F. De Miollis that these have a toxic effect by the experiments done. Lungs
et al., 2019). exposed to these toxins are more likely to develop pulmonary
Researchers took the OoC approach by using clear, flexible complications like pulmonary fibrosis, asthma or pulmonary
plastic chips which contained microfluidic channels. In order to edema. Some of the problems occur due to the rapid
replicate the behavior of the disease they use pancreatic cancer advancements in technology and people not understanding
cells harvested from mice in one channel and seed the how toxic can some of the newly developed fuels can be,
neighboring channel with human endothelial cells. The chip is should be considered for application on environmental
then observed in order to study the behavior of these cells. After toxicology. Most experiments regarding OoC are focused on
the experiment is concluded the same procedure is executed, but either toxicity or diseases around the alveoli, only a fraction of
instead of mouse pancreatic cancer cells, human cells are used. the entire respiratory system, however there are different airway-
The same behavior is seen suggesting that across different species on-a-chip models and even innovative approaches which use 3D
the behavior for the disease does not change. This discovery printing and constructing in addition to the OoC concept (Lu and
means that whatever treatment is used on test subjects, such as Radisic, 2021).
mice, would work on humans as well. OoC are used in the search
for a cure as well, by adding experimental cures to the cells of the 4.5 Brain
chip then observing their behavior. In some cases, the spread of The brain might be the most complex organ and the hardest to
the cancer cells is slowed indicating that that substance should be create an OoC after. The functionality of the brain is far too
tested in vivo. complex and differs from person to person, as such in most
Diabetes is a common disease that has a compromising effect papers the models do not cover this aspect, but rather go over and
on the functioning of the pancreas. There are several ways of analyze cell ratios use the transporting properties of the brain and
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TABLE 1 | Summary for organs that have been recreated using organ-on-a-chip models.
Liver Maintains physiologic properties; Wikswo et al. (2013), Kimura et al. (2018), Lu and Radisic, (2021)
Great regenerative properties;
Breast Tissue Mainly used in cancer study and treatment; Bano, (2017), Chen et al. (2018), Gao et al. (2020)
Difficult to treat;
Pancreas Mainly used in cancer and diabetes study; Wu et al. (2018), De Miollis et al. (2019), Glieberman et al. (2019)
Hard to treat due to small number of vessels;
Lungs Bad regenerative properties; Kimura et al. (2018), Lu and Radisic, (2021), Wang et al. (2021)
Successful replication of functionality by modifying the
pressure;
Brain Complex due to functionality; Vassanelli, (2011), Wikswo et al. (2013), Bang et al. (2019)
Differs from person to person;
Can be recreated by separating the soma and axons;
Blood Multiple cell types; Wikswo et al. (2013), Ramadan and Gijs, (2015), Mao et al. (2020), Mandrycky et al. (2021)
OoC uses all cell types;
Need for small chambers;
analyze the neuro vascular unit and the blood brain barrier. What interaction with some organs, like kidneys and intestines,
makes the cell ratios of neurons and glial cells is that the ratio but the purpose of the paper is to present a wide variety of
changes depending on the brain section which is analyzed applications and to observe the development of the technology.
(Wikswo et al., 2013). The next challenge of the researchers is to realize the human
There have been successful in vitro cell cultures in open body on a chip device. The previously mentioned devices take
environment such as glass substrates or Petri dishes. The all the different organs on chip and model the functioning of
technique used in the culture of the BoC is called multistep the whole body. This is a challenge because bonding all the
lithography. It consists of separating the soma and axon. The devices is a task of its own and obtaining the desired behavior
technique allowed the study of the axon, its regeneration and from all the organs is not guaranteed.
treatment using different drugs on the axon. The models created Reports exist of the body-on-a-chip being realized by
are used to study neurodegenerative diseases and understanding research groups. Multiple organ chambers are developed
the behavior and the effects it has on the brain cells (Bang et al., having different organ cells on the device which have to
2019). perform their physiological role (Table 1). The device is
Three categories of BoC development are developed: 3D high used on drug testing, observing the biological effects of the
content systems used to mimic the brain tissue environment; drugs on the whole complex system. The research team also
interconnected multichip system which is used to simulate obtained promising results for different anticancer drugs and
interactions between multiple cells and organs; high- successful kidney excretion functions. Even though this
throughput systems, screening of experimental conditions. technology has been researched and there are successful
results, the models created are still far from mimicking the
4.6 Blood whole human physiology to a greater extent. Currently there is
The blood is made of different components: red blood cells, a mathematical modeling approach being combined with the
white blood cells, platelets and plasma. The models created body-on-a-chip technology to recreate the human body
with the organ on chips use these components in order to behavior (REF).
replicate the behavior of the blood. Each of the different blood In their study Christian et al. break down important aspects
cell type is added to different channels, being separated, due to of the blood-on-a-chip concept. Since the blood vessels are
each component having a separate role, from being part of the organized in a hierarchical network it has different diameters
immune system components and emphasis the interaction as well as different roles. Some of the vessels are used to carry
among the key components. The hardest challenge is to the oxygenated blood and are named arteries while the ones
recreate the circulatory system (Mao et al., 2020), since that carry the deoxygenated blood are the veins. The use of
most cells mentioned before can be split into even more flow systems is required with this type of OoC, since laminar
specific types (Ramadan and Gijs, 2015). The chip itself is and disturbed flow has an effect on cytoskeletal model. These
made of a PDMS prepolymer through the photolithography systems are also used to study blood clots. Over the years
process. The channels were 500 um to 1 mm wide. The different microfluidic approaches have been found. For
obtained part is then bonded to a glass slide. Polystyrene example, PDMS based structures went from modelling
beads are used to pack the channels (Wikswo et al., 2013). breathing and vascular models to anaerob intestine-on-a-
These are just some of the organs which are modeled using chip and laying the foundation for the body-on-a-chip
the OoC technology. The list can be expanded to see the concept (Mandrycky et al., 2021).
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Collagen Biocompatible; Need of chemical bonding for stability; Cardiac; Ahadian et al. (2018), Satoh et al. (2018), Sun et al.
Immunogenetic; Need of mechanic support for the cells Hepatic; (2019), Arlk et al. (2021)
to remain intact;
Enzymatic degradation; Vascular;
Major component of ECM; Kidney;
Cells can remodel the ECM gel; Neurons;
Solid tumors;
Fibrin Biocompatible; Weak mechanic properties; Vascular tissue; Wikswo et al. (2013), Ahadian et al. (2018), Sun
Noninflammable; Lungs; et al. (2019)
Biodegradable; Skeletal muscles;
Gel modeling at room
temperature;
Protein delivery system;
Hyaluronic Acid Biocompatible; Weak mechanic properties; Metastasis; Rothbauer et al. (2018)
Natural component of ECM; Tissue barrier;
Structural component of tissues;
Regulable elasticity;
Gelatin Biocompatible; Need of chemical bonding for stability; Cardiac; Ho et al. (2015)
Biodegradable; Vascular;
Similar composition as collagen; Muscle;
Good elasticity;
Synthetic Regulable mechanic properties; Immune responses need to be Cardiac; Ahadian et al. (2018), Sun et al. (2019)
biomaterials evaluated;
Less variable than natural Can have cytotoxic effects; Hepatic;
biomaterials;
Chemically modifiable;
Degradable;
Can be modelled;
Chitosan Biocompatible; Mechanical weakness; Vascular; Wikswo et al. (2013), Osório et al. (2021)
Biodegradable; Unstable;
Flexible;
Similar structure as
glycosaminoglycans;
Alginic acid Biocompatible; Uncontrolled degradation; Cardiac; Esch et al. (2016)
Degradable; Limited protein absorption; Tumors;
Missing the binding cells; Liver;
Marrow;
applications as collagen. Such as its strengths, gelatin shares its degradability, biocompatibility and low toxicity. It has been
disadvantages with collagen, since it requires chemical used in vascular, and even bone tissue modeling. The
coupling for its stability (Ho et al., 2015). downsides of this biomaterial are the weak mechanical
Synthetic biomaterials, which can be classified as metals, properties and it is considered unstable (Wikswo et al., 2013).
ceramics, nonbiodegradable and biodegradable polymers, can Alginic acid is known to be used as a medicine for hearth
be used to model cardiac and hepatic tissues and there are burns. It can be used as a biomaterial in OoC as a throwaway
expectations of using them in the modelling of neurons. It is material. It is biocompatible and degradable, but its degradation
considered to have good mechanical and degradation cannot be controlled and it can absorb very limited amounts of
properties. It is more reliable than other natural proteins. It is used to model different tumors and cardiac, liver
biomaterials. It uses polyesters which are known to degrade and marrow tissues (Esch et al., 2016).
through hydrolysis. Can be reshaped easily and can be
chemically modified to absorb bioactive cells. The main 5.2 Biometric Microfluidic Devices
flaws of the synthetic biomaterials are the cytotoxic effect, Microfluidic devices are used in research centers, clinics and
degradation might cause. Also, the immune responses must be hospitals being powerful tools for monitoring, diagnostics and
checked (Ahadian et al., 2018; Sun et al., 2019). drug delivery. They were integrated in the OoC technology and
Chitosan is one of the most abundant polymers used in revolutionized the fields of drug screening and toxicology studies
medical and bio chemical applications due to it being easily (Figure 3) (Perestrelo et al., 2015).
obtained from chitin. Its crystalline nature makes it possible to The concept itself is associated with the control and
be processed with different methods in order to create gels, manipulation of liquids at a small scale, as small as
nanofibers and even sponges (Osório et al., 2021). It has good microliters. The advantages of microfluidics are vast: small
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risking the wellbeing of the patient may even save lives. There have further development can lead to new and revolutionary
been several reports and news of people receiving wrong medication discoveries. The human-body-on-a-chip can be considered one
because of the side effects the drugs they were given affected them of them. In most cases the medicine used to cure a certain type of
differently due to the doctors not checking for a specific condition. disease may help in the recovery of a certain organ, but there are
In order to test a drug on a control group, specific parameters side effects which may occur in other organs. Having a model of
are required and some conditional environments might be the human body which consists of a system of OoC connected
needed. If some patients need to be started on antibiotics for a could put an end to animal testing and would mean a speed-up in
bacterial infection, for each person several OoC will be used to the pharmaceutical industry. New biomaterials and techniques
test the effects of different antibiotics to check which one should which may allow some of the harder and more complex
be used with the least side effects. The patients might react physiological functions to be modeled with ease. For the
differently to the medication they receive, with this method fabrication of the OoC 3D printing, soft lithography, hot
none of them risk to be mistreated (Raje and Raje, 2019; van embossing and injection molding are all commonly used and
den Berg et al., 2019). each has some advantage over the other (Tajeddin and
In order to implement such a complex concept, physiologic Mustafaoglu, 2021). Recently the concept of bioprinting has
functions need to be implemented, such as breathing or muscle been used by many researchers which could lead to more
contraptions (Zheng et al., 2016). One of the more complex cost-efficient fabrication of the OoC. Soft-lithography and
experiments realized is maintaining a certain glucose level by the photolithography, cost, time and design improvements are all
use of liver and pancreatic cells (Wikswo et al., 2013; De Miollis more advantageous if bioprinting is used (Carvalho et al., 2021;
et al., 2019). Thakare et al., 2021). More importantly the different paths that
The main drawback of the personalization of the OoC is that are opened can reach to the automation of medical procedures
due to its complexity, some processes cannot be implemented yet and the elimination of mistreatment.
and due to the specifics, it can be realized only with specific
equipment.
AUTHOR CONTRIBUTIONS
5 CONCLUSION Conceptualization, CB, E-HD; methodology AD, E-HD, and CB;
validation IB-N; resources, AD and AJ; writing—original draft
The concept of OoC has been around for a long time and they preparation, AD and AJ; supervision E-HD and CB; funding
have led to a lot of new discoveries in the medical field. The acquisition, E-HD and CB. All authors have read and agreed to
applications range from disease studying to drug testing the published version of the manuscript.
considering the complex environmental interaction among
different cell types. In the present times single-organ-on-a-
chip models have already been created for almost all organs, FUNDING
with some studies on multiple OoC devices interconnected
(Goldstein et al., 2021). One of the next development steps is This research was funded by a grant of the Romanian National
the integration of sensors into the chips, which makes monitoring Authority for Scientific Research, CNDI–UEFISCDI, project
key physiological parameters easier (Clarke et al., 2021; number PN-III-P2-2.1-PED-2019-2536, contract number
Rothbauer et al., 2021). It is an important field which with 557PED⁄ 2020.
Bein, A., Shin, W., Jalili-Firoozinezhad, S., Park, M. H., Sontheimer-Phelps, A., Tovaglieri,
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Personalised Organs-On-Chips: Functional Testing for Precision Medicine. potential conflict of interest.
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