Espace Presse – Organoids on a chip insert

What are organoids on chips or Organ on chips (OoCs)?

Xavier Gidrol : OoCs are the fruit of the dazzling advances made over the last two decades in the fields of organoids and organs on a chip. Objects of cell biology studies, organoids come from stem cells grown in a hydrogel, which self-organizes in three dimensions.

Thanks to the work of Shinya Yamanaka in 2007 – which earned him the Nobel Prize in Medicine in 2012 – these stem cells no longer come from embryos, effectively removing the ethical issues associated with this use. This Japanese researcher has actually discovered how to “de-differentiate” specialized adult cells in the laboratory to transform them into stem cells, called “induced pluripotent”.

It is therefore these that researchers today mainly use, or in certain clinical situations, adult stem cells from a patient’s organ. These cells reproduce the cellular diversity found in the original tissues of all living beings.

Organoids thus make it possible to at least partially mimic the function of the tissues from which they come, making them a good model for
study the normal or pathological development of these tissues in humans.

Chip developed to study the behavior of bone marrow stem cells. It reproduces its spatial organization with a bone compartment and a blood compartment. © M. Théry / CEA


Fabrice Navarro : For their part, engineers have developed “labs on chips,” microfluidic devices to perform biochemistry with very small amounts of reagents. From the mid-2000s, they began to implant layers of cells on microfluidic chips to mimic certain physiological functions (Microphysiological Systems (MPS)).

The canonical example, and the starting point for this domain, was published in 2010 by an American team. A layer of epithelial cells and one of endothelial cells, placed on either side of a semipermeable membrane, the first in contact with the air and the second with the culture medium, were placed on an elastic support to reproduce the biomechanical stresses during breathing. It does not look like a lung, but is enough to model the gas exchanges at the level of the lung alveolus. The Americans called it “lung on a chip” and created the company Emulate to market it.

Xavier Gidrol : In short, if you want it
study a biological model that actually resembles an organ, an organoid must be created. But if we want to reproducibly control its shape and size, properly monitor its functions, etc., we need to put this organoid on a chip. It is therefore a question of bringing together the best of both worlds.

microfluidic card

Microfluidic card © L. Godart / CEA

How does an OoC work?

Fabrice Navarro : Specifically, the cells are grown in a
credit card-sized microfluidic system. Composed of valves, channels, cultivation areas, sensors and ultimately microelectronics, this microfluidic architecture is designed to accommodate, through microchannels, the culture media necessary for the growth of the cells that are there, have been submitted on in advance.

This system, called a “chip”, will
partially reproduce an organism’s environment and its functionalities, including in pathological conditions. It is thanks to this chip that the researchers are able to better control the cells’ physical and chemical environment by acting on the addition or removal of elements in the culture medium, on perfusion and on mechanical constraints. The cells then organize themselves in this medium.

cultured cerebroids (organoid consisting of brain cells)

Cerebroids in culture (organoid made up of brain cells) © R. Guittet / CEA

What are the expected benefits of organoids on chips?

Xavier Gidrol : OoCs have enormous potential. Fundamental biologists expect it
access to the complexity of life to better understand its function, normal or pathological.

The pharmaceutical industry is interested in
improve and accelerate the screening of candidate molecules for treatment, a process that is currently long, expensive… and less and less efficient. Countless molecules are tested in vain, partly because of the limited relevance of animal models. On-chip human organoids would be more suitable for proof-of-concept stages, but also for preclinical efficacy and toxicity testing. OoCs are key to developing relevant human models. In doing so, they would ultimately limit animal testing.

Fabrice Navarro : Doctors mainly think of
personal support : an organoid developed from a patient’s cells will provide valuable information about his individual response to treatment. Being able to test it in advance at an OoC will make it much more efficient on the medical side and more comfortable for the patient as the treatment time will be limited. In the long term, we hope to be able to, for example, investigate sequelae or predict complications associated with certain pathologies. A trend is emerging: to complete the general model of pathology, sometimes digitally, taking into account the specificity of the individual.

Xavier Gidrol : My team is already developing, because
pancreatic cancer, on-chip tumoroids. Derived from tumor cells taken from a patient, they will help the oncologist choose the best molecule from the arsenal of chemotherapy at his disposal. In the longer term, we are also considering
regenerative medicine. It would then be a matter of growing organoids from a patient’s stem cells to reimplant them to compensate for the lack or loss of an organ until an eventual transplant.

Fabrice Navarro : Considering the use of OOoCs in pharmacology, and even more so in the clinic, will involve a change of approach to facilitate their use. It is precisely the ability to move from a research object to an industrializable technology that is the strength and originality of the CEA project.

Bioprinted pancreas on chip

Bioprinted pancreas on chip © A. Aubert / CEA

Is there a market and industrial structure for OoCs?

Fabrice Navarro : Only a few organs on a chip are currently marketed: Emulates “lung”, a few others for toxicity research. In 2018, the global market represented $30 million, and that’s it
in very strong growtharound 25% per year. The most lively segment in the near term is high-throughput pharmaceutical screening. The use of such objects by researchers to
improve understanding of disease processes should also see the light of day quickly within two years. Personalized medicine and “tumor banks” should emerge in the medium term. However, it will be necessary to wait longer, perhaps a decade, to see support for regenerative medicine emerge.

What is the added value of CEA in the development of OoCs?

Fabrice Navarro : CEA hasinternationally recognized expertise in micro- and nanotechnology and more broadly in innovative technologies for health, used for several years in the optimization of the production of biomedicine. Microelectronics, cellular engineering, microfluidics or even miniaturized sensors: CEA brings together all the skills necessary for a strategic positioning within OoCs.

clean-room-leti.jpg

CEA-Leti clean room, for integration of microsensors on silicon. © A. Aubert / CEA

Xavier Gidrol : The topic of OoCs is moreover rather emblematic and certainly unifying for CEA : Basic research and technological research have come together and complemented each other to the point where the classic pattern of upstream/downstream research is eliminated. The OoCs are designed together by the various CEA research departments, both on very fundamental issues and on valuation and applications. The teams are working on to lift the technical and biological barriers of organoids on a chipby optimizing the choice of support materials, by introducing reproducibility, by lowering future production costs.

Finally, and if the OoCs are part of the search for a better understanding of the functioning of the human body, they also constitute an undeniable asset in
reduction of costs and delays (for clinical trials, refinement of research into drug candidates, etc.). So much so that some observers do not hesitate to announce their development as
a “paradigm shift”in the health field, which constitutes a key question for the latter, and around which the research is organized. It is only logical that CEA is gearing up to support this technological advancement.

Fabrice Navarro : At CEA, we are able to develop an object up to TRL 5 level (validation of components and/or models in the laboratory), then we support manufacturers or start-ups to further increase to TRL, until maturity (TRL7) , for example via consortium approaches (the pre-industrialization platform HUB4AIM – Hub for Accelerating your Innovation in Medtech – for example). But we have no calling to become a producer, to make commercial series. We are currently looking for an equipment supplier that is able to scale up. We are considering two major phases in the promotion of our progress in the field. First come the microfluidic supports, without biological components, developed to order for the pharmaceutical industry or research centers. In the longer term, we will develop complete on-chip organoids with their biological component.

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