Innovative technology solutions to explore effects of the microbiome on intestine and brain pathophysiology

Informations projet

IMBIBE

N° de convention de subvention: 723951

DOI

10.3030/723951

Projet clôturé

Date de signature de la CE 24 Octobre 2017

Date de début 1 Octobre 2017

Date de fin 31 Mars 2023

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 992 578,00

Contribution de l’UE

€ 1 992 578,00

Coordonné par

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom

Periodic Reporting for period 4 - IMBIBE (Innovative technology solutions to explore effects of the microbiome on intestine and brain pathophysiology)

Période du rapport: 2022-04-01 au 2023-03-31

Résumé du contexte et des objectifs généraux du projet

The human gut is host to over 100 trillion bacteria that are known to be essential for human health. Intestinal microbes can affect the function of the gastrointestinal (GI) tract, via immunity, nutrient absorption, energy metabolism and intestinal barrier function. Alterations in the microbiome have been linked with many disease phenotypes including colorectal cancer, Crohn’s disease, obesity, diabetes as well as neuropathologies such as autism spectrum disorder (ASD), stress and anxiety. Animal studies remain one of the sole means of assessing the importance of microbiota on development and well-being, however the use of animals to study human systems is increasingly questioned due to ethics, cost and relevance concerns. In vitro models have developed at an accelerated pace in the past decade, benefitting from advances in cell culture (in particular 3D cell culture and use of human cell types), increasing the viability of these systems as alternatives to traditional cell culture methods. This in turn will allow refinement and replacement of animal use. In particular in basic science, or high throughput approaches where animal models are under significant pressure to be replaced, in vitro human models can be singularly appropriate. The development of in vitro models with microbiota has not yet been demonstrated even though the transformative role of the microbiota appears unquestionable. The IMBIBE project is focussed on using engineering and materials science approaches to develop complete (i.e. human and microbe) in vitro models to truly capture the human situation. IMBIBE benefits from cutting edge organic electronic technology which will allow real-time monitoring thus enabling iterative improvements in the models employed. The result from this project will be a platform to study host-microbiome interactions and consequences for pathophysiology, in particular, of the GI tract and brain.

At the conclusion of the project, we are pleased to announce that the funding we received enabled us to make a breakthrough device platform to study the gut-brain-microbiome axis and has laid the foundation for many impactful research projects to come. An ERC proof of concept project is currently underway on these devices, and we anticipate that we will be able to achieve translation to industry for our platform to be truly of use to European citizens in the future.

For more information please see this article published on the CORDIS website and translated into six languages: https://cordis.europa.eu/article/id/446117-organ-on-a-chip-yields-insights-into-gut-permeability?WT.mc_id=exp

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Our ultimate goal is the connected model of gut-brain and microbiome, however, individual modules are interesting as test models for a variety of laboratories worldwide. Many groups are keen to test bacterial products or mimic diseases such as Crohn’s disease to determine how they might use microbes or their derivatives to protect against or even reverse deleterious effects on the gut (and brain). In the short term, this project has the potential to dramatically change how such things are studied in vitro. In the long term, our work will contribute towards the understanding of diseases related to microbial imbalances in the human body.

What exactly did we achieve?
We developed conducting polymer devices that are made of honeycomb like scaffolds. These scaffolds provide a template for cells to grow and they measure the cells as the grow and mature into tissue.
We developed protocols to grow multiple types of cells together in our devices, optimising conditions and tuning the scaffolds to be as like native tissue as possible, resulting in tissue structure that resembles the gastrointestinal (GI) tract outermost layer - the mucosa, and the neurovascular unit.
We succeeded in developing a platform that allowed us to grow live microbes on our devices, mimicking the way that the microbiome resides in the GI tract. We showed that we can screen individual bacterial components or mixtures of microbes as well as their products, assessing how they affect gut and brain health
We have begun working with clinicians to integrate cells from patient biopsies, thus developing personalised models. Biopsies from patients with diseases such as inflammatory bowel disease will allow us to test potential therapeutics in the future.

An ERC proof of concept project is currently underway on integration of our devices into commercially available microfluidic platforms for Organ on Chip. In addition, our devices are being expanded beyond gut and brain, to being used for lung models, liver models and more. The continuous monitoring afforded is extremely useful as a live monitor of tissue health.
A patent was filed on the conducting polymer scaffold device. We anticipate starting a company shortly.
We have published many papers during the grant, and presented the work at a large number of conferences internationally.
A full list of our manuscripts is available here
https://scholar.google.com/citations?user=kCDJLFYAAAAJ&hl=en

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Our scaffold devices are widely considered to be both novel and highly unconventional compared to existing organ on chip type platforms. Although a growing number of organ-on-chip applications have begun to integrate electrodes to allow for real-time monitoring of barrier integrity very few of these are adapted to 3D cultures. Not only do we provide a highly biomimetic tissue environment, we show evidence of real-time tissue monitoring.
The tunable properties of PEDOT:PSS and the in situ fabrication process we adopted allowed us to fine-tune the electrical, mechanical and biochemical properties of the scaffolds. This allows really interesting tissue engineering applications, where cell growth and fate can be determined by changing the combination of these stimuli in vitro.

The configuration/design of our device enables real-time, non-invasive monitoring of cell activity and tissue formation on the scaffolds, as evidenced by modulation of their electrical properties. In addition, the configuration of our bioelectronic platform enables bi-modal operation of the device – both as electrode and as a transistor – thereby providing us with more electrical readouts, analysis of which reveals valuable information for the biological model in real time, cross-validated with optical analysis. The unique integration of in-line sensing components in a 3D intestinal system achieved with our system highlights the potential of this technology for building more advanced experimental models of the human gut as tools for studying disease pathology, host-pathogen and host-microbiome interactions, as well as for identifying novel therapeutic targets.

At the conclusion of the project, one change was the shift from the tubular fluidic device to a Transwell format. This change was made following consultation with biologists and clinicians (and industry contacts) who indicated that the need for high throughput, lower cost solutions, compatible with existing industry standards was hugely important. This was validated in our manuscript published in Science advances
https://www.science.org/doi/full/10.1126/sciadv.abo4761
We are happy to report that this was a worthwhile venture and we are getting an enormous amount of mileage thanks to the user friendly nature of this device

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