Refitting Ex-VivO LUng perfusion with negative pressure ventilation and mobilizaTION – REVOLUTION

The method involves the development of a hypobaric chamber prototype that enables EVLP with Negative Pressure Ventilation and graft mobilization. Trials using pig and human models will assess the device’s effects on lung structure and function, inflammatory responses, and oxidative stress levels through histological, molecular, and transcriptomic analyses.

Expected results include significant reductions in tissue damage, oxidative stress, and inflammation through the combined use of NPV and dynamic graft mobilization. These advancements are anticipated to maintain the functional integrity of the lungs during EVLP and improve the quality of grafts for transplantation.

The REVOLUTION device has the potential to transform the management of marginal lungs, significantly increasing the number of successful lung transplants. In the long term, it could become a reference technology for ex-vivo lung rehabilitation, with international applications and industrial commercialization prospects.

RAS

Lung transplantation is the last therapeutic option of chronic respiratory diseases. Its management has improved due to the normothermic ex vivo lung perfusion (EVLP) which extends the number of suitable donor lungs. However the procedure should be improved for increasing the conversion rate from EVLP to transplantation to further expand the number of suitable grafts. Indeed standard EVLP with positive pressure ventilation drive to 1) pulmonary edema, 2) heterogeneity in the distribution of pulmonary ventilation and 3) strong modification of gene expression of inflammatory and stress pathways leading to failure of the procedure. Several therapies have been tested for mitigating the side effects and the inflammatory response during EVLP however the negative pressure ventilation (NPV) and the mobilization of the grafts (MG) are key points that we will focus in REVOLUTION.
We propose to develop a new device bridging the gap on the standard EVLP strategy combining NPV and MG to assess the potential beneficial effects of the procedure. The prototype will be tested on a pig model for evaluating physiological parameters (ventilatory and hemodynamic) and inflammatory responses in different EVLP protocols. The screening methods will include Luminex/multiplex cytokine assays, LDH/lactate and ROS detection, immune-histo-fluorescence analyses, and bulk RNA-seq. The most promising protocol regarding physiological parameters and anti-inflammatory parameters will be tested on a preclinical human lung model. The cellular response will be analyzed by single cell RNA-seq in order to identify the functions and signaling pathways modified by standard EVLP in comparison to NPV + MG, at the cell subset level in human lung.
The implementation of the REVOLUTION project will be conducted in optimal conditions by the rare combination of complementary expertise with biomedical engineers, thoracic surgeons, immunologists, bio-informaticians and statisticians. The new device developed during the REVOLUTION project is promising impact at the medical level by increasing the number and quality of grafts, at the socio-economic level by reducing the costs due to EVLP failures and by creation of a spin-off, and at the scientific level by an improved understanding of the biological response to ex vivo organ maintenance. The EVLP with the REVOLUTION device may be in the future the new gold standard for optimizing non-optimal lung and improving the results of transplantation.