CE19 - Technologies pour la santé

Biomimetic liver-on-chip platform – MIMLIVERonChip

Biomimetic Liver on a Chip platform for drug screening

MimLiveronChip proposes a bioinspired approach to mimic the mandatory steps allowing the study of xenobiotic’s toxicity and metabolism in the liver.

From limited in vitro models to organ on chip

Many molecules dedicated to therapy are nowadays lately removed from the pipeline of drug discovery, in the clinical phases, because their toxicity or lack of efficacy has not been evidenced in preclinical studies. Researchers and pharmaceutical companies outline the critical need in the development of advanced in vitro trials, looking for human cells based organoids able to improve screening’s efficiency and to reduce the number of animal trials, following the 3R rule. <br />Recent progresses in bioengineering and microtechnology pave the way to “organ-on-chip” devices ensuring 3D cell culture in conditions close to physiology. However, such models are still simplistic and not strongly validated.

Based on this analysis, MimLiveronChip proposes a bioinspired approach to mimic the mandatory steps allowing the study of xenobiotic’s toxicity and metabolism in the liver. The original choice is to focus on and to reproduce two key events in series: not only the biotransformation of substances transported by the blood flow, but also (and upfront), their transfer (hindered or not) across the monolayer of endothelial cells, that are very specific in the liver; they are fenestrated in healthy conditions, and loss these properties in early stages of the pathology (steatosis, fibrosis, …). In this project, we will investigate the relevance of several hypotheses regarding the effect of the mechanical and biochemical micro-environment on this fenestrated status, so as to maintain it or in contrast alter it to mimic pathological cases.
Our project also addresses technological issues. As end users, we know that microfluidic devices might appear complex compared to classical 2D culture. Therefore, we propose to develop a fully integrated platform, equipped with flow and pressure controllers, as well as sensors to monitor the cell culture and allow mid throughput assays for drug screening. The newly developed tools will be benchmarked with up-to-date technology employed in CRO or pharma companies. Our goal is to position the organ-on-chip platform in the pipeline of preclinical trials, combining toxicity and metabolism evaluation.
This multi-disciplinary project relies on a close collaboration among four teams bringing complementary expertise: hepatic tissue engineering at different scales (UMR UTC-CNRS Biomechanics and Bioengineering); microsystems and biology of endothelial cells (SMMIL-E UMI CNRS), as far as academia is concerned, to which can be added : a SME leader in devices for microfluidic experiments (Fluigent) and a startup dedicated to the development of advanced in vitro trials based on high throughput imaging (HCS Pharma). Preliminary common studies have demonstrated the relevance and the feasibility of the proposed methodology.

The reconstruction of the endothelial barrier for the liver sinusoid is ongoing. We have produced hydrogels mimicking both healty and pathological situation, according to their mechanical properties.
LSEC fenestration was observed under scanning electron microscopy and with several biological markers. These cells were also cultivated on inserts, for the next coupling to the liver biochip.
For this purpose, co-culture conditions were established. In parallel, hepatic-like cells from a cell line have been successfully implemented and grown in our microfluidic device loeaded with Biomimesys Liver hydroscaffold (from HCS Pharma).
Regarding the perfusion platform, Fluigent has investigated several options. A solution based on passive check valves allows to consecutively perform several perfusion cycles. To extend the method to the perfusion of 12 biochips in parallel, several mechanical bricks have beed adapted to the initial CCDIM platform.

Regarding socio-economical features, the work performed in our project should allow the reduction of attrition rate for drug candidates in the late clinical stages. This will thus decrease the development costs and duration in the pharmaceutical industry, but also for chemicals, in the framework of REACh regulation, for the assessment of the effect of pesticides, and in agro-industry (nutraceutics). Mid throughput cell culture devices developed in MimLiveronChip can also be used for more fundamental research (system biology, regeneration studies), as they better mimic liver structure and functions. Both companies involved in the project will benefit from direct positive feedback since their portfolio will be enriched with new equipment and screening methods, respectively. Finally, demonstrating the benefit of coupling the endothelial hepatic barrier with the 3D hepatocyte transformation unit will offer many innovative strategy integrating other organs on chip, developed in the academic labs involved in the project.

4 communications submitted and selected in international congress (TERMIS, ESAO).
3 invited talks/lectures on Organ on Chip (ANSM, GDR Organoides, Académie de médecine)
Booth on Organ on Chip at «Village de la science de l'UTC«.

Many molecules dedicated to therapy are nowadays lately removed from the pipeline of drug discovery, in the clinical phases, because their toxicity or lack of efficacy has not been evidenced in preclinical studies. Researchers and pharmaceutical companies outline the critical need in the development of advanced in vitro trials, looking for human cells based organoids able to improve screening’s efficiency and to reduce the number of animal trials, following the 3R rule.
Recent progresses in bioengineering and microtechnology pave the way to “organ-on-chip” devices ensuring 3D cell culture in conditions close to physiology. However, such models are still simplistic and not strongly validated.
Based on this analysis, MimLiveronChip proposes a bioinspired approach to mimic the mandatory steps allowing the study of xenobiotic’s toxicity and metabolism in the liver. The original choice is to focus on and to reproduce two key events in series: not only the biotransformation by hepatocytes of substances transported by the blood flow, but also (and upfront), their transfer (hindered or not) across the monolayer of endothelial cells, that are very specific in the liver: they are fenestrated in healthy conditions, and lose these properties in early stages of the pathology (steatosis, fibrosis, …). In this project, we will investigate the relevance of several hypotheses regarding the effect of the mechanical and biochemical micro-environment on this fenestrated status, so as to maintain it or in contrast alter it to mimic pathological cases.
Our project also addresses technological issues. As end users, we know that microfluidic devices might appear complex compared to classical 2D culture. Therefore, we propose to develop a fully integrated platform, equipped with flow and pressure controllers, as well as sensors to monitor the cell culture and allow mid throughput assays for drug screening. The newly developed tools will be benchmarked with up-to-date technology employed in CRO or pharma companies. Our goal is to position the organ-on-chip platform in the pipeline of preclinical trials, combining toxicity and metabolism evaluation.
This multi-disciplinary project relies on a close collaboration among four teams bringing complementary expertise: hepatic tissue engineering at different scales (UMR UTC-CNRS Biomechanics and Bioengineering); microsystems and biology of endothelial cells (SMMIL-E UMI CNRS), as far as academia is concerned, to which can be added : a SME leader in devices for microfluidic experiments (Fluigent) and a startup dedicated to the development of advanced in vitro trials based on high throughput imaging (HCS Pharma). Preliminary common studies have demonstrated the relevance and the feasibility of the proposed methodology.
Regarding socio-economical features, the work performed in our project should allow the reduction of attrition rate for drug candidates in the late clinical stages. This will thus decrease the development costs and duration in the pharmaceutical industry, but also for chemicals, in the framework of REACh regulation, for the assessment of the effect of pesticides, and in agro-industry (nutraceutics). Mid throughput cell culture devices developed in MimLiveronChip can also be used for more fundamental research (system biology, regeneration studies), as they better mimic liver structure and functions. Both companies involved in the project will benefit from direct positive feedback since their portfolio will be enriched with new equipment and screening methods, respectively. Finally, demonstrating the benefit of coupling the endothelial hepatic barrier with the 3D hepatocyte transformation unit will offer many innovative strategy integrating other organs on chip, developed in the academic labs involved in the project.

Project coordination

Cecile LEGALLAIS (Biomécanique et bioingénierie)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

HCS PHARMA HCS PHARMA
FLUIGENT
BMBI Biomécanique et bioingénierie
SMMiL-E Laboratory for Integrated Micro Mechatronics Systems

Help of the ANR 586,753 euros
Beginning and duration of the scientific project: September 2019 - 42 Months

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