Written by Hadrien Mauriac under the supervision of Guilhem Velve Casquillas and Christophe Pannetier.
Dr. Christophe Pannetier is the head of the molecular biology department at Elvesys. He used to be a researcher at the Pasteur Institute in Paris and to be the head of R&D NRBC for Thales Security Systems and the French Department of Defence.
Organs on Chip 2017
INTRODUCING ORGANS ON CHIP
Today, pharmaceutical companies spend more and more, and put less and less new therapies on the market. It is high time to find a solution to accelerate research. Testing on cell cultures in petri dishes do not allow to prove the efficiency of a new therapy: cells do not react as they would in the human body when outside of their natural environment. Furthermore, animal testing is usually long and costly, and not sufficient to prove the efficiency of a treatment on humans. Many drugs pass the animal testing phase of clinical tests with flying colors, to end up proving harmful or toxic to humans. In this context came the first organs on chip: cell cultures, often in 3D, that use microfluidics to reproduce the way a tissue or part of an organ work. Organ on chip research already allowed to create many microfluidic chips that can partially simulate organ function: liver, lungs, gut, etc… and even tumors on chip. The latter could prove very useful when testing new cancer treatments, especially when connected to other organs.
Multi-organs on chip could also allow us to witness the side effects of certain drugs on different organs, not limited to those that the treatment targets. The goal is to be able to link a maximum of parts in order to reproduce a human on chip. On the long run, beyond pre-clinical tests, organs on chip could allow everyone to have access to individualized treatments by using their own cells to test them, which is called personalized medicine. In this review, we will go over the pros and cons of microfluidic organs on chip, before looking at the different organs on chip available today and looking at the issues that are yet to be fixed before the technology can fully replace animal testing.
Pros and cons of organs on chip
ORGAN ON CHIP PROS
- SPEEDING UP RESEARCH
First, the main advantage of these chips is that they can be manufactured for a very low cost and this can allow to test a wide range of concentration in the dosage of medicine. This will allow organs on chips to considerably accelerate scientific research. During the development of a new drug, the first round of tests can be conducted many times without posing much financial difficulty. In addition, there would be none of the ethical issues faced by animal testing, which are widely contested today . More and more debate surrounds the breeding of test animals for medical research, and organs on chips would put an end to the practice.
- A WELL-MIMICKED MICROENVIRONMENT
Compared to Petri dishes, the micro-environment of human cells (oxygen levels, temperature, pH…) is better reproduced inside a chip than in a Petri dish, often due to its three-dimensional aspect, which is most important for the reliability of the tests  . However, organs on chips are more interesting than regular 3D cell culture since the latter does not allow to submit the cells to chemical time gradients . It is also impossible to put the cells through mechanical constraints mimicking, for instance, breathing movements. We will later see that this was made possible with lungs on chips. More than the three-dimensional aspect of organs on chips, it is the use of microfluidics that makes those chips such an interesting and innovative solution for research.
- TECHNOLOGICAL ADVANTAGE
Another advantage of the organs on chips is technological: microfluidic chips are meant to be easy to use, portable, the size of a 1€ coin and can undergo mass production. Due to their small size, many microfluidic systems can now be integrated on a single chip, allowing to save up on room, components and consequently, money . Microfluidic chips have some great advantages compared to the other available technologies. However, some drawbacks remain.
ORGAN ON CHIP CONS
- Surface effects
Due to the dimensions of microfluidics (about a hundredth of a micrometer), surface effects widely dominate volume effects. Despite its few advantages (such as trapping molecules of interest) the phenomenon is also linked to some drawbacks: the quality of analysis can be affected by the adsorption of products of interest on the inner linings  .
Very little mixing during laminar flow
Furthermore, for the relevant fluids in microfluidic dimensions, the Reynolds number will always remain very small, before 1. Consequently, the flow into the chips will remain laminar. It allows for a precise control of experimental conditions, but implies a major problem: this flow does not favor mixing .
- Not so portable
At last, the attractiveness of portable microfluidics might warrant some moderation. In order to obtain reliable analysis, bulky tools sometimes need to be used, for pluripotent induced stem cells processing for instance, which is a pillar of personalized medicine. However, this last point could be dealt with by integrating measuring systems directly into the chip. As a matter of fact, the I-Wire heart-on-chip created by Wiskwo & al. (2017)  integrated measuring systems for distortion and electric potential.
The drawbacks are common to all organs on chips since they are linked to the nature of the device. Each of them also has minor drawbacks, we will later go over each one. However, they are largely compensated for by the advantages of this technology, especially compared to the existing alternatives.
The different organs on chips
Lungs on chips
The development of new solutions to treat pulmonary diseases has become today a goal of primary importance. According to studies, pulmonary diseases are the fifth global cause of death and were predicted to become the third by 2020  . In that context, we could consider using lungs on chips to facilitate the development of new treatments.
As of today, we are still unable to mimic an entire lung on a microfluidic chip. However, Huh et al.  have managed to reproduce the function of an alveolo-capillary membrane, which is the smallest functional unit in the lung. That organ is vital to test new medicine since it constitutes the physical barrier between the body and the external world. In order to reproduce this membrane, Polydiméthylsiloxane (PDMS) was used, covered in collagen for a better cell adherence, separating epithelial cells in contact with the air on one side, and endothelial cells in contact with a fluid made of nutrients in lieu of blood, on the other. The experiment was also conducted by Jain et al.  by using blood instead of a nutrient fluid, in order to get as close as possible to a real lund. Along this microfluidic channel run two empty micro-channels, in order to reproduce the compression cycle that the alveolo-capillary membrane undergoes during breathing. Here is the main advantage of lungs on chips compared to traditional cell culture, as the following example shows.
Ingber et al. wanted to observe the effects of pollution on lung cells. They placed toxic nanoparticules on the surface of epithelial cells. Then, they noticed that even more toxic particules went from the air into the blood when artificial respiration was activated. This shows that tests on traditional cell cultures underestimated the toxicity of pollution on our bodies .
In order to test how well the chip was functioning, Huh et al.  introduced bacteria in the air flow and white blood cells in the blood flow. They could observe how white blood cells moved to the epithelial cells to fight bacteria. This chip was then used to measure the maximum dosage of interleukine-2 (IL-2) to administer before triggering a pulmonary edema .
Interleukine-2 can be used to treat kidney cancer that has spread, but it can have dangerous side effects, such as fluid in the lung alveolas. It was then vital to measure how much IL-2 triggered the side effects. Lungs-on-chips also helped to prove the efficiency of angioprotein-1 as a IL-2 inhibitor.
Despite having already proved its worth, the lung-on-chip will need to be engineered further, maybe with muscle cells, to allow us to test the effects of any treatment on the lungs. This could also allow us to find out the what causes bronchial spasms.
Liver on chip
Developing a liver-on-chip is essential to research for new medicine. Hepatotoxicity is the main reason why potential treatments fail past the animal testing phase  . Using livers-on-chips could save a significant amount of money. However, liver cells are among the most difficult to keep alive in a Petri dish . The most important was to find a way to mimic their environment in order to lengthen their lifespan. Yang et al.  proved that when mesenchymal cells from human placenta were put together with liver cells, the liver cells multiplied and their metabolic activity surged. In order to optimize the process, the ratio between the two types of cells is of the utmost importance.
Chen-Ta et al.  have recreated, on a microfluidic chip, a lover lobule which is the functional unit of the liver, by dielectrophoresis. This lobule consists in liver cells and endothelial cells. The main advantage of the liver on chip is its capacity to replicate microscopic details, for more reliable tests .
The liver on chip becomes all the more important as part of a bigger multi-organs-on-chip, as we will see later on. However, they remain to be perfected: PDMS, the material used by Chen-Ta et al., is currently facing some scrutiny.
It can sometimes absorb small hydrophobic compounds, as well as some medicine, which can skew test results. Nonetheless, newly discovered polymers based on polyurethane do not present this fault. They present the same characteristics as PDMS (transparent, biocompatible, easy to use…) and could soon replace the material .
However, the longevity of these livers on chip, despite its reputation as being better than those of regular cell cultures, rarely exceeds two weeks . This can become an issue, as the response of the liver need to be studied on the long term, especially in the case of new treatments. It is then necessary to try to increase the longevity of the liver cells in liver-on-chip cultures. At last, human cell availability can pose a problem. In order to precisely study the response of the human liver, it is better to use human liver cells, but the demand is higher than the offer for the moment . We could consider replacing the liver cells by induced pluripotent stem cells, but production and differentiation of those is expensive. Other issues arise with the use of a “scaffold”, and a new version of liver on chip was developed by Weng YS et al. , to reconstruct the architecture of the liver without using a scaffold. To keep working on livers on chips, those issues will need to be resolved.
Heart on chip
Hearts on chips were also developed, especially because of the significant difference between animal and human heart cells. They aim to study heart diseases and cardio-toxicity of chemical treatments. Compared to regular cell culture, microfluidic chips allowed to collect more relevant morphometric and electrophysiological data [20, 22]. The chips could become the best tool to study new treatments against heart disease.
Today, many hearts on chips have been developed by different research teams for several applications . We know that heart cells play a role in managing calcium ions. Therefore, changes in the concentration levels of those ions are often linked to arrhythmia or heart failure [23, 24]. Martewicz et al.  have proven with the help of a heart on chip, through cofocal microscopy, that when heart cells loaded in Fluo4 are reaching a state of hypoxia, differences can be observed in calcium ion concentration.
Agarwal et al.  have tested isprotenerol, a medicine used in case of heart failure or bradycardia, on a rat cells based heart on chip, in doses between 1nM and 0,1mM. The experiments, although they were conducted on non-human cells, show us the potential of hearts on chips to test a wide range of medicine concentrations. The final results were similar to those previously found with a real live rat. This example shows how reliable those microfluidic chips can be, on top of their other advantages.
In order to continue developing hearts on chips, we need to develop new diseases on chips, such as a heart with ischemia. Furthermore, PDMS has a major defect: cell fixation is less than optimal . This remains one major domain calling for improvements with hearts on chips, despite Annabi et al. working on the problem before, by developing a layer of gel covering the PDMS to facilitate cell fixation .
Brain on chip
Research helped to reproduce a small part of the brain, the blood-brain barrier, on chip. This barrier has an essential function: it protects the brain from all the pathogens in the blood flow and only lets through the nutrients the brain needs. However, this barrier can be a problem for some drug treatments because it bars some active sites from accessing the brain (such as medicine against Parkinson’s disease) . Just like with the heart, it can work very differently between humans and animals. Hence the importance of working on human cells. The advantage of brain on chip over other in vivo and in vitro models comes from more realistic dimensions and geometry. Those microfluidic chips allow to test the flow of a physiological fluid on the epithelium . This flow mimics the blood flow and allows the brain cells proper differentiation and maturation. Brains on chips have proved more accurate than static cultures to predict permeability of the blood-brain barrier [30, 31]. Dauth et al.  have also managed to build a multi-region brain on chip that could help model neurodegenerative diseases very close to the in vivo models.
Today, research for blood-brain barrier microfluidic chips is only starting out , but several models already exist [30, 31].
For instance, Emulate recently studied lateral amyotrophic sclerosis by developing a chip with the cells of a patient. It allowed them to better understand the disease and can be used later to test new treatments. They also showed that the neurons in the chip were functional, proving that this microfluidic chip was a relevant way to study the disease .
However, brains on chips can be very different from one research team to another . If this proves that organs on chips can be used for many purposes, it prevents from comparing the results of different teams, which can slow down research. It would be interesting, in the future, to find a universal model for the blood-brain barrier and to model other sub-organs of the brain.
Gut on chip
The last organ here is the gut on chip, and more especially one specific application. Kim et al.  managed to develop a two-layers gut on chip system, not unlike the lung on chip we discussed before. Similarly to the lung on chip, using microfluidic chips for this application proved to be very important since it allowed to re-create the mechanical tension, simulating peristaltic movement. Geraldine Hamilton (President and CSO of Emulate and co-writer of the Kim et al. article) presented an application for this gut on chip, in May 2016 at a Wired Health conference . She collected stem cells from a patient with digestive issues, and developed a gut on chip to study its response to certain types of food and new treatments. This example comes to show what personalized medicine could look like, with organs on chips. The gut is a key organ for the absorption of medicine, and these breakthroughs would help us better understand these issues and fast forward research.
New microfluidic chips
Tumors on chips
With the growing success of organs on chips, researchers have started to develop tumors on chips. The goal was to mimic the micro-environment in which cancer cells interact, physically and chemically. It would then be possible to study the survival and proliferation of malignant cells. Research to reproduce tumor environment is much faster than for other chips: many articles already cover the subject [33-35].
Many tumors on chips were developed in order to test new treatments with different dosage . Kim et al.  developed an automatic, programmable system in order to determine the optimal concentration. The efficiency of their system was proven on PC3 cells (prostate cancer cells) by using a combination of doxorubicine and mitoxantrone.
Those tumors on chips are especially interesting when linked to other organs, which is why we will get back to how interesting they are for cancer research in the next part, with tangible examples.
Multi-organs on chips
If developing organs on chips and tumors on chips already proved useful for testing certain treatments, in order to definitely replace animal testing or to generalize personalized medicine, it is necessary to link the organs together. When developing a new treatment, it is necessary to make sure that it won’t have any ill effects on the rest of the body. For instance, in order to test medicine, the main organ is usually linked to a liver on chip, so as to test out the hepatotoxicity of the medicine . This is the case in a study by Midwood et al. .
Those multi-organs systems have also allowed to study absorption and metabolism, on top of the efficiency of four treatments over cancer . Imura et al. have paired gut and liver cells with breast cancer cells, in order to study the route of the samples tested in the setup. Two years later, they improved their setup by adding gastric acid to simulate stomach digestion of a treatment taken orally .
The previous case showed an example of how tumors on chips can be used to test the effect of anti-cancer treatments. However, those multi-organ setups can have other uses. They have allowed, for instance, to observe metastasis of breast cancer cells in bones, through live monitoring with a high resolution microscope . The technique was also used by Xu et al. to observe lung cancer metastasis .
Multi-organs on chips have already allowed to conduct tests on already existing medicine, as well as the progress of anti-cancer research, as we have just seen. However, in order for those to completely replace animal testing in the development of new medicine, we are still facing many challenges.
Organ on chip applications
ORGAN ON CHIP APPLICATIONS - Introduction
Applications for microfluidic organs on chips: Since 2012, more and more companies and laboratories have been turning to organs on chips. Those cell cultures allow, with the help of microfluidic technology, to mimic the micro-environment of cells in the human body. Those chips could become incredible research accelerators, and they could become the default pre-clinical testing solution which would replace animal testing and could even pave the way for personalized medicine. Here are the main applications for organs on chips.
ORGAN ON CHIP APPLICATIONS - USE OF LOW TECHNOLOGY READINESS LEVEL ORGANS ON CHIPS
Organs on chips could prove extremely useful in a future where they are more than a research subject to become a research tool. When a researcher discovers a new molecule which could, for instance, fight a certain type of bacteria, they need years to amass the money necessary to conduct the first trials that could guarantee success. This is why organs on chips, cheap and widely reproducible could be decisive. They could allow testing at a very low cost, without years of waiting periods. They also present no ethical concern and could allow researchers to move much faster in their research without reaching a testing limit.
ORGAN ON CHIP APPLICATIONS - ACCESS TO PERSONALIZED MEDICINE
On the 100 patients receiving the same treatment, in the same proportions, not all will react similarly. Some will even experience negative side effects. In order to solve those issues, personalized medicine, which adapts the treatment to the patients and their characteristics, could be developed thanks to organs on chips. We could recreate the patient on a cell with their induced pluripotent stem cells and directly test the treatment on the cells, in order to adapt the dosage.
ORGAN ON CHIP APPLICATIONS - THE BATTLE AGAINST CANCER
Of course, organs on chips will allow to fight against cancer by helping to develop new treatments as we have seen just before, but that is not all. Today, we can already create tumors on chips. We reproduce the micro-environment on which cancer cells interact physically or chemically, in order to study the survival and proliferation of malignant cells. Then, we should be able to directly test the treatments on tumors. It would also be possible, by using humans on chips with several organs on the same chip, to determine the side effects of those treatments in advance.
However, this is not all that organs on chips can bring into the battle against cancer. By linking several organs on the same chip, we have already been able to study the metastasis of breast and bone cancer cells, with a live monitoring through high-resolution microscopes. When organs on chips have become research tools, the battle against cancer will benefit from those new weapons.
ORGAN ON CHIP APPLICATIONS - ANTI-AGING RESEARCH
Organ on chip development could also give new weapons to anti-aging research. Today, we know of a number of biological causes of aging. We could test anti-aging treatments with organs on chips, by focusing on some parameters that we understand (telomere length, division speed, senescent cells build-up…) This would help determine if the treatments are efficient against cellular aging. However, it will be difficult to come to a conclusion on the efficieny of those treatments, unless the lifespan of organs on chips incredibly increases.
LAST CHALLENGES FOR LARGE SCALE ORGAN ON CHIP IMPLEMENTATION
TO DETERMINE THE RELATIVE SIZE OF ALL ORGANS ON CHIPS
When coupling organs on chips, whether it is to measure the efficiency of a treatment of to study the interactions between organs, the relative size of the models matters. If a micrometric lung is linked to a millimetric liver, the latter will not react to the traces of medicine that went through the lung. Once we master the switch between organ sizes, we can create models that are more accurate when compared to the human body than animal models are today. We will also be able to model bodies of varying ages to personalize medicine even more .
However, is is extremely difficult to find the right scale for this model. Must we base it on organ mass? organ volume? Fluid flow? Wikswo et al. proposed a new lead to solve this issue: to make organs big enough to ensure their main function .
TO DETERMINE THE QUANTITY OF FLUID INSIDE THE CHIPS
Since there are approximately 5 liters of blood in the human body, we could imagine that a microhuman would have 5 microliters of blood . Too much volume could dilute the treatment or hormones secreted by the different organs, and skew the results of the tests. However, this total volume of 5 microliters implies many challenges. We need to be able to create microfluidic pumps and valves of the right size for such small volumes. They must be very cheap as well, since microfluidic chips are looking to become mass-produced in order to allow a great number of tests over a wide rnge of concentrations.
TO FIND A UNIVERSAL SUBSTITUTE FOR BLOOD
Despite finding what can be substituted for blood in organs on chips, we need to find a universal substitute that would be common to all humans on chips . It should be able to irrigate and maintain dozens of different types of cells alive for as long as possible, on top of ensuring the regular functions of blood in the human body (carrying oxygen, proteins, nutrients, metabolites…) Jain & al. (2017]  managed, through the isolation of vascular endothelial cells, to replace the culture medium with blood (recalcified citrated whole blood) in a lung on chip. The use of recalcified citrated blood in thrombosis study had already been proven relevant in another context by Rajwal (2004) . However, all organs don’t have the same needs. Sometimes, serum cannot be used, as it would negatively affect the capacity of cells to reproduce . In such cases, proteins must be added to ensure biochemical homeostasis. Zhang et al. managed to create a blood substitute for four types of cells: liver, lung, kidney and fat cells . They achieved it from the environment specific to each type of cell, and by adding components (such as the growth factor) to optimize physiological functions. One solution could be to locally add some components to the medium, that are necessary to the function of certain organs but harmful to others. We would also need to know how to remove toxic molecules produced by an organ before they reach another one .
ORGANS ON CHIPS - CONCLUSION
This review showed us the importance of organs on chips for the future of medicine: systematic use of organs on chips would help the pharmaceutical industry save time and money, and would as well limit the breeding of animals destined to clinical testing. The chips could also become formidable research accelerators, since they could allow to conduct many trials, much more rapidly, early in the research phase. Although the use of the organs on chips was proven again and again, some of them already being used today in some cases, we are still far from making a proper human on chip. At the moment, connecting the organs is too difficult and research in this field cannot continue without some breakthroughs in biology research. In the meantime, those chips can still be used to determine which drug should be tested first. Once the last few issues are dealt with, this technology could help us set up personalized medicine for everyone. Each person could be given the appropriate treatment, in the right proportion, based on their stem cells.
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