PORTEFEUILLE

Most current in-vitro cell cultures are performed in Petri dishes, an invention that is more than 130 years old. In these cell culture plates, cells are immerged in a big soup of nutrients that consists of a static solution of physiological medium. This cell culture environment does by far not reproduce the complex in-vivo conditions found for instance in the lung. In the alveoli, where the blood gets oxygenated and the carbon dioxide leaves the body, the cells are cyclically stretched by the respiratory movements and stressed by the viscous forces induced by the blood flow in tiny capillaries. Although, these forces significantly affect the cell behavior, no in vitro tools exist to date that reproduce these conditions.

To tackle this problem, we propose to develop an advanced in vitro model that better reproduces the in vivo conditions of the alveoli. This highly interdisciplinary development, based on microfabrication techniques and cell biology, will focus on the development of thin stretchable membranes, on which human lung cells can be seeded, and of tiny microchannels aimed for the cell culture perfusion. This ground-breaking device, called «lung on chip», is intended to be a tool for toxicologists and research scientists, and will be implemented to assess the toxicological response of chemical compounds and test potential drugs.

In this in vivo-like environment, the cells cultured in the lung on chip will behave like in a real alveolus. This project supported by the Gebert Rüf Stiftung is thus expected to set a new bar in the field of in vitro cell culture aimed for fundamental pulmonary research, toxicity assessment and drug safety. The continuous interactions between lung clinicians, physicists, biologists and engineers are a tremendous asset of this project, whose outcome is expected to be a working prototype enabling a quick transfer from the laboratory to the industry.

A breathing lung-on-chip was developed in the frame of this project, which mimics the pulmonary parenchymal environment, including the thin, alveolar barrier and the three-dimensional cyclic mechanical strain induced by the breathing movements. The actuation mechanism, based on a micro-diaphragm used to stretch the alveolar barrier, is inspired by the in-vivo diaphragm, the main muscle responsible for inspiration. The design of the lung-on-chip does not only best reproduce the in-vivo conditions found in the lung parenchyma, but does also aim at a simple and reproducible handling. An innovative concept, based on the reversible bonding of the device, has been produced that enables the accurate control of the concentration of cells cultured on the membrane.

The functionality of the air-blood barrier could be restored by using a co-culture of epithelial and endothelial cells that formed tight monolayers on each side of the thin, porous membrane. We further investigated the effect of the physiological strain on the epithelial barrier permeability, which was found to be significantly affected by the mechanical stress. The relative transport through the barrier for small hydrophilic molecules (FITC-Na) was increase by more than 45% when the cells were exposed to stress in comparison to cells cultured in a static environment. In contrast, the transport through the membrane did not change for larger molecules (RITC-Dextran). This finding is in agreement with in-vivo experiments performed with hydrophilic solutes in human lungs. These results demonstrate the potential of this device and confirm the importance of the mechanical strain induced by the breathing in pulmonary research.

To enable researchers as well as pharmaceutical companies to benefit from this innovative lung-on-chip model, a start-up company, AlveoliX, will be created to produce and commercialize these advanced in-vitro platforms. This start-up project was recently awarded two Venturekick awards (Phase 1 and Phase 2) as a result of the commercial potential of this innovation.

Andreas O. Stucki,ab Janick D. Stucki,ab Sean R. R. Hall,de Marcel Felder,ab Yves Mermoud,a Ralph A. Schmid,de Thomas Geiserce and Olivier T. Guenat*acd, A lung-on-a-chip array with an integrated bio-inspired respiration mechanism, Lab on a Chip, 2015 http://pubs.rsc.org/en/Content/ArticleLanding/2014/LC/C4LC01252F?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FLC+%28RSC+-+Lab+Chip+latest+articles%29&utm_content=Google+International#!divAbstract (open access)
A. Stucki, J. Stucki, S. Hall, M. Felder, Y. Mermoud, R. Schmid, T. Geiser, O. Guenat, Advanced alveolar lung in-vitro model, 9th World Congress on Alternatives and Animal Use in the Life Sciences (WC9) in Prague, August 2014;
J. Stucki, A. Stucki, S. Hall, M. Felder, Y. Mermoud, R. Schmid, T. Geiser, O. Guenat, A microfluidic array of cyclically stretchable lung air-blood barrier, MicroTAS, San Antonio, October 2014;
A. Stucki et al, A lung-on-chip array with an integrated bioinspired respiration mechanism, submitted.

14. Januar 2015, Der Bund: Grosse Preise für Miniatur-Tropfen und biokünstliche Mini-Lungen
13. Januar 2015: Das Forschungsteam Lung-on-Chip gewinnt den 2. Platz des 7. Ypsomed Innovationspreises http://www.innovationsfonds.ch/Medienmit-Ypsomed-Innovationsfonds-2015-01-14.pdf
venture kick: http://venturekick.ch/index.cfm?CFID=396347435&CFTOKEN=78558870&page=129746&profil_id=6712&BackPage=129738