Research axe
Biological Activity of inhaled Particles
BioPi
Our aim is to improve the understanding of the fate of inhaled (nano)particles in terms of biodistribution, biological activity (therapeutic or toxicological) and biopersistence. We are interested in the characterisation of inhaled particles in complex biological matrices, the impact of the physico-chemical properties of particles on their cellular response in vitro, and finally the protein adsorption phenomena on (nano)particles responsible for their biological identity. We are also involved in the technological development and clinical evaluation of innovative aerosolisation medical devices for many types of vectors (nucleic acids, proteins, drugs, viruses, bacteria). We work in two main application areas: (i) Nanomedicine and aerosol therapy: this work is based on translational research that promotes technological innovation with the development of therapeutic and diagnostic solutions centred on the disease and the patient, with a strong industrial partnership. (ii) Health and environment: this work is based on understanding the toxicity mechanisms of inhaled (nano)particles in combination with their physico-chemical properties to assess potential health risks.
Projects
Refitting Ex-VivO LUng perfusion with negative pressure ventilation and mobilizaTION
REVOLUTION
Description
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.
Members
Project Leader : Dr. Jeremy Pourchez & Dr. Edouard Sage
Researchers involved :
- Nathalie PREVOT
- Sophie PERINEL-RAGEY
- VIM Unité de recherche Virologie et Immunologie Moléculaires
- Hopital Foch Département de chirurgie thoracique
- CIML Centre d’immunologie de Marseille-Luminy
- SAINBIOSE SAnté INgenierie BIOlogie Saint-Etienne
Lab scientists involved:
Student involved :
Juan-Pablo VASCO-MARIN
Funding
ANR
Vaping nicotine salts : toxicological issues and pharmacological impact on nicotine delivery
Description
Developments of e-liquid formulation and vaping devices have recently emerged on the French market. These new trends, using nicotine salts and POD technologies, lead to specific issues: 1) Sanitary issue: the lung toxicology induced by the addition of organic acids in e-liquid vaporized is poorly documented (harmful neoformed compounds after vaporization, intrinsic toxicity of certain acids …). 2) Addiction and smoking cessation: the modification of the absorption of inhaled nicotine induced by the presence of organic acids could make vaping more addictive (e.g. for young people), or on the contrary more effective in a context of smoking cessation. 3) Regulatory issue: The presence of organic acids may alter the pharmacokinetics profile of inhaled nicotine. The use of these additives to formulate nicotine salt e-liquids would then become non-compliant with Directive 2014/40/EU and could lead to a ban on these products on the French market. To meet these challenges in an interdisciplinary way 3 work-packages (WP) were defined: WP1: Exposure – Characterization of emissions from POD devices using nicotine salt e-liquids. The aim is to determine whether the vaping of nicotine salt e-liquids can lead to exposure to airborne harmful chemicals. The deliverable will be to determine the emission rates of the newly formed toxic substances (e.g. volatile organic compounds) as well as ingredients initially present in the e-liquid formulation (e.g. organic acids), for different experimental conditions (e-liquid formulations with different organic acids and nicotine content, commercial sample containing flavorings). These data will allow to precisely evaluate the specificities in terms of exposure induced by the vaping of nicotine salts. WP2: Hazard – In vitro toxicological assessment at the air-liquid interface of emissions from POD devices using nicotine salt e-liquids. The objective is to generate relevant in vitro toxicological data on several experimental conditions of exposure based on controlled e-liquid compositions. We will use in vitro cellular lung models and advanced exposure technologies to e-cig emissions developed in our laboratory (innovative air-liquid interface exposure system coupled with a vaping machine). The deliverable will be a hazard assessment to identify the experimental conditions (e.g., type or dosage of nicotine salts using homemade e-liquids, commercial samples) generating cytotoxicity, pro-inflammatory response or oxidative stress. WP3: Pharmacokinetics of nicotine – In vitro and in vivo studies on the impact of nicotine salt e-liquids on the pharmacokinetics of inhaled nicotine using POD devices. We propose an integrative approach in vitro at the air-liquid interface, and then in vivo on healthy volunteers (clinical study promoted by the Saint-Etienne University Hospital). The in vitro study on cellular systems exposed to e-cigarette emissions, will allow to evaluate the absorption of nicotine across in vitro models of pulmonary barrier. This preliminary study will allow us to identify the 5 most relevant experimental vaping conditions (i.e. nicotine salts dosage, type of organic acid, …), in order to carry out in a second time a clinical study on 20 healthy volunteers to provide insights on the impact of nicotine salts on the pharmacokinetics of nicotine inhaled by vaping devices.
Members
Project Leader : Dr. Jeremie Pourchez
Researchers involved :
- Dr. SLEIMAN Mohamad (Université Clermont)
- Pr. Xavier DELAVENNE
Lab scientists involved:
Student involved :
KAOUANE Ghalia (DVH)
FRAISNE Jasmine (DVH)
Funding
New medical device to deliver exogenous surfactant in preterm infants with neonatal respiratory distress syndrome: efficacy, safety and practicality
ENDOSURF
Description
Lung immaturity at birth in preterm newborns (respiratory distress syndrome or RDS) requires the exogenous surfactant administration shortly after birth. Current surfactant administration techniques, although described as “less” invasive (Less Invasive Surfactant Administration or LISA), still require the use of laryngoscopy which remains a painful and complex procedure to learn. Sedation-analgesia represents a challenge for these patients, with the balance between the need to prevent or reduce the pain generated by laryngoscopy and the need to maintain efficient spontaneous breathing.
In this project, we propose the development and validation of a new medical device based on endoscopy and atomization for the administration of exogenous surfactant in preterm neonates with RDS. The objectives of the device are to i) decrease pain and discomfort and therefore the need for analgesia, ii) improve clinical tolerance and efficiency of surfactant administration (endoscopy and atomization of surfactant), and iii) have a better learning curve than LISA.
The development and validation of the efficacy and safety of the EndoSurf device is based on a multidisciplinary collaboration. The different steps of the project include i) the validation of the atomization process with the characterization of the atomized particles, the physicochemical properties of the atomized surfactant and the study of surfactant distribution within the lung in an ex-vivo model, ii) the study of the surfactant distribution and efficacy on an animal model of RDS (comparison with the LISA method), iii) the development of the prototype for industrialization and certification for clinical use, iv) the evaluation of the learning curve in medical simulation laboratory and v) a pilot clinical study on 20 preterm infants with RDS (comparison with a historical LISA cohort).
Members
Project Leader : Dr. Eric Dumas de La Roque & Dr. Jeremie Pourchez
Researchers involved :
- Dr. Sophie PERINEL-RAGEY
- SAINBIOSE SAnté INgenierie BIOlogie Saint-Etienne
- ISM INSTITUT DES SCIENCES MOLECULAIRES
- Pôle Pédiatrie du CHU de BORDEAUX
- Vygon
- CRCTB CENTRE DE RECHERCHE CARDIO-THORACIQUE DE BORDEAUX
Lab scientists involved:
Student involved :
Ghalia KAOUANE
Funding
ANR
Team
Jeremie Pourchez, PhD
Head of Biological Inhaled Particle axe
MCU-PHSophie Perinel Ragey, PhD
ProfessorValerie Forest, PhD
Laboratory scientistLara Leclerc, PhD
