Organoids on a chip, these mini-organs that fit on a medium the size of a credit card, result from the combination of several research fields: organoids, laboratories on a chip and microfluidics. In Grenoble, the Commissariat for Atomic Energy and Alternative Energies (CEA) is taking advantage of its interdisciplinarity to push this technology, which has multiple applications, to the industrial level.
“The CEA is positioning itself to support the industrial maturation of organoids on a chip, and therefore to move from laboratory prototypes to large-scale production, in order to have them adopted by hospitals and doctors for precision medicine”says Fabrice Navarro, head of the Microfluidic Systems and Bioengineering Laboratory at the CEA.
The organoids are derived from stem cells — whether they are of embryonic, fetal or adult origin or whether they are induced pluripotent stem cells called iPS — capable of self-organizing in three dimensions, in the form of spheroids, in an appropriate culture medium (a hydrogel) and to differentiate into different cell types in order to reproduce at least one function of the organ of origin.
Miniaturized and controllable systems
Along with the emergence of these organoids, organs on chips have also developed. “The first organ-on-a-chip was developed by Americans to mimic the primary function of the lung. They developed a 2D system consisting of two cell layers separated by a kind of membrane, with lung cells on one side and blood vessel cells on the other, in order to reproduce the function of the alveolar-capillary barrier ( 1)”explains Fabrice Navarro.
Microfluidics, which allows the manipulation of fluids on a very small scale using microchannels (of the order of a few micrometers), has made it possible to complicate this device, which mimics pulmonary function and stimulates the alveolar-capillary barrier function. “Microfluidics, inspired by microelectronics manufacturing techniques, has made it possible to improve the functionality of this cellular bilayer, in particular by providing the ability to stretch”continues the researcher.
Based on this approach, laboratories on a chip have also been devised, ie miniaturized systems making biological analyzes possible outside the laboratory. Labs on a chip thus integrate biological protocols to detect proteins, peptides or nucleic acids from very small volumes of a biological sample.
Towards on-chip multi-organoids
“With organoids, we have self-organizing systems, but we don’t control the process. By combining it with microfluidics, we are able to better control the various parameters, which allows us to have an even more complete and complex biological system, which can be perfused and vascularized”, emphasizes Xavier Gidrol, head of the large-scale biology laboratory at the CEA. It is also possible to sample what the organoid will secrete into the medium.
The objective is then to develop multi-organoids on a chip, whereas this approach makes possible the exchanges between several organoids integrated in the same chip. On-chip organoids tend to become more and more sophisticated systems, whereas simple organoids were faced with the limit of the absence of communication with the outside.
Relevant human models
The applications are vast. On-chip organoids are useful in basic research to better understand developmental biology and the causes of disease. They also represent a growing interest in pharmaceutical research. They can also be used to identify new therapeutic targets, but above all “they constitute human models that are as close as possible to the physiological reality of the organ and thus allow us to study the efficacy and toxicity of molecules”explains Xavier Gidrol.
For Fabrice Navarro, this approach is very relevant for evaluating drugs of biological origin and testing their compatibility with human material. “It is also useful for testing immunotherapies, because the immune system of a mouse is very different from that of humans”, he says. On-chip organoids thus represent an alternative to animal models. “Animal models do indeed have scientific limitations, not to mention ethical limitations”notes Xavier Gidrol.
Organoids on a chip in the hospital within 10 years
Beyond fundamental and pharmaceutical research, CEA researchers believe that organoids on a chip also have their place in the care pathway and hospital practice. “We really believe they open up possibilities in personalized medicine, when it will be possible to create organoids on a chip with the patient’s cells”, considers Xavier Gidrol. Each patient will then have their own avatar on which various treatments can be tested.
“In a slightly more distant future, we also believe that the complexification of organoids on a chip will make it possible to improve the success of clinical trials, by limiting the risks for patients with clinical trials which will be carried out first ex-vivo on chip », continues the researcher. Organoids on a chip will in particular make it possible to better study populations that are little included in trials, such as pregnant women. The tests will then be more specialized and less expensive.
Organoids on a chip also raise hopes in regenerative medicine. They could compensate for a damaged function while waiting for an organ transplant, for example.
“In Grenoble, we have an ecosystem rich in interdisciplinarity, with all the skills necessary to be able to succeed ultimately to organoids on chips that are functional and validated in laboratories, emphasizes Fabrice Navarro. But we must also be able to manufacture them on a large scale and ensure that they are reproducible. This is why we must integrate, from the first stages of research, the constraints of the manufacturing processes and the different needs for materials, such as silicon. »
At the CEA, the next five years should thus see the advent of organoids on a chip and multi-organoid chips, while their integration into the care pathway by hospitals and physicians is planned within 10 years.
(1) D.Huh et al. Science, 2010. doi: 10.1126/science.1188302