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Gastrointestinal Tract on Chip - An automated microfluidics-based modular device for complete simulation of the processes of digestion and absorption of orally ingested bioactive compounds

Periodic Reporting for period 1 - GASTRIC (Gastrointestinal Tract on Chip - An automated microfluidics-based modular device for complete simulation of the processes of digestion and absorption of orally ingested bioactive compounds)

Période du rapport: 2020-10-16 au 2022-10-15

People can only ingest food through the mouth and oral administration remains the preferred route for the delivery of drugs or dietary supplements. However, any orally ingested compound must first survive digestion and then be absorbed at the small intestine to reach systemic circulation. Failure to predict the amount of orally administrated foods or drugs that reaches the blood using pre-clinical models can lead to the lack of success of new candidates in expensive clinical trials. This entails important consequences for society including i) elevated costs for the development of new drugs, ii) delayed research of new pharmaceutical and food compounds iii) continuous use of animal models, and potentially iv) the introduction of drugs with suboptimal properties.

The overarching goal of the GASTRIC project was to develop and fabricate the first automated microfluidics-based device for complete simulation of the processes of digestion and intestinal absorption of orally ingested bioactive compounds. The device should offer the possibility to study minute sample amounts, with high resolution and with the potential for high-throughput analysis, which is key for its adoption by large pharmaceutical and food industries with high economic and social impact.

As main conclusions, the GASTRIC project resulted in 2 alternative designs that could effectively simulate human intestinal digestion in a miniaturised manner. The second device iteration is fully automated and sensorised with pH and temperature sensors allowing to control both parameters using a closed feedback loop. The output of the Digestion devices could then be studied in another cell-laden device that simulates intestinal absorption under dynamic fluid flow conditions - the GASTRIC Gut Chip, which integrates sensors for real-time TEER monitoring. In addition, primary human colon samples were used to derive intestinal organoids with the aim of integrating these cultures in the Gut Chip to add physiological relevance and potentiate personalised patient-specific studies. Finally, important studies with primary gut microbiota samples delineated culture conditions for including gut commensal bacteria in the Gut Chip model.
Microfluidic devices to simulate the processes of digestion and cell-based intestinal absorption were designed and fabricated as planned. The project delivered two alternative designs to simulate digestion. The first was based on an elastomer and allowed digestion simulation under continuous flow and with minimum user interface. The second design was built in PMMA and was sensorised to include automatic regulation of pH and temperature (two critical features of digestion), and integrated an on-chip peristaltic pump to execute ‘gastric emptying’ from the stomach to the intestinal chamber. This improved on design one as it allowed to study digestion in a dynamic manner – which is more physiologically relevant.

Another device was designed to study intestinal absorption. This was equally fabricated using an elastomer and consisted of two parallel superimposed channels separated by a semi-permeable membrane. Human intestinal cells were cultured on the membrane to form an intestinal epithelium barrier. The device worked under continuous flow and cell differentiation was fully achieved just after 7 days. Importantly, we were able to study the intestinal absorption of samples digested in our devices following a simple treatment to avoid cytotoxicity derived from serine proteases present in the digestion fluids. Our Gut-Chip yielded permeability values that were in line with those reported for ex vivo studies using primary human samples.
In addition, we studied the effect of short-chain fatty acids derived from the fermentation products of primary human faecal bacteria on the same epithelium barrier that we used on-chip. This will be important to inform on the parameters to be used when co-culture gut microbiota with human cells on-chip.

Finally, we optimised within our lab the isolation, culture and expansion of human intestinal organoids derived from primary colon samples obtained from patients undergoing cancer resection surgeries. The use of primary intestinal organoids within our Gut Chips will be pivotal to create disease models and patient-specific tissues for personalised medicine.

The work done within the GASTRIC project has resulted in the publication of 3 articles (1 review and 2 original rsearch) in international peer-reviewed journals, with another 3 publications planned for the following months. In addition, the fellow has presented his work at Nanobiotech Montreux 2021 and EMBL Microfluidics 2022 where he delivered two oral presentations, and as an invited keynote speaker at two national conferences. The work was also disseminated to the general public through the participation in outreach events including the European Researcher’s Night (2021 and 2022) and the Scale Travels programme, which connects art with science to bring it to a wider audience.
The miniaturised and sensorised (pH, temperature) digestion-chip developed within the GASTRIC project is the first of its kind. Indeed, it should be able to bridge the gap between established static digestion protocols and the highly-informative, but complex, dynamic digestion simulators, thus allowing to study minute sample amounts using a robust and reproducible protocol. This could be used by the food and pharmaceutical industries for high-throughput studies with the potential to reduce the cost and delay time for the development of new compounds for human use. The combination of an automated digestion-chip with a microfluidic Gut-Chip for combined bioaccessibility and intestinal absorption studies is equally innovative; and while it has thus far in the project been achieved in 2 separate steps, their combination in a single automated platform is the subject of our current research goals. Finally, the use of primary intestinal organoids within our Gut Chips will be pivotal to create disease models and patient-specific tissues for personalised medicine.
Left: Epithelial cells grown on-chip; Middle: Gut-Chip; Right: Primary Intestinal Organoi