Anatomical Models to study Aerosol DElivery to the lUngS for obstructive diseases – AMADEUS

Aerosol therapy consists in the administration of aerosolized drugs and is considered to be one of the cornerstones in the management and treatment of chronic respiratory diseases. Some of the most common are chronic obstructive pulmonary disease (COPD) in adults and bronchiolitis in children. Various forms of treatments helping to dilate major air pathways and improving shortness of breath can help control symptoms and increase the quality of life for people with these diseases. As chronic respiratory diseases continue to grow in prevalence and consume a large portion of healthcare costs, an explicit understanding of the science of aerosol therapy become increasingly important. While numerous clinical trials, literature reviews, and expert panel guidelines assist physicians in their choice of inhaled drugs, deciding which aerosol device best suits a given patient and his clinical settings can seem arbitrary and confusing. As a matter of fact, mastery of both the art and science of aerosol delivery can have a profound impact on appropriately matching medications and delivery devices to optimize patient’s clinical outcomes.

To relate airborne particle exposure to biological effects, it is essential to assess aerosol regional deposition. Identification of deposition sites is a major determinant of dose in tissues and resultant biological effects. As an alternative to in vivo inhalation experiments, ex vivo anatomical models have been developed. However, very few anatomical models mimic a human-like respiratory tract including both extrathoracic and thoracic regions with a physiological breathing. This project focuses on an original solution bridging the existing gap on anatomical respiratory models to assess aerosol regional deposition without ethical restrictions. We aim at developing an ex vivo preclinical model (corresponding to adult or child anatomy) with controlled breathing parameters allowing to simulate numerous respiratory conditions in spontaneous ventilation (from healthy conditions to obstructive pulmonary conditions). Our specifications are to develop a cheaper and easy to use ex vivo preclinical model emphasizing no ethical restriction and a high relevance compared to in vivo human data.

This new experimental concept is composed of a human ENT replica (built by 3D printing) connected to an ex vivo animal pulmonary tract (a porc for adult anatomy; and a rabbit for child anatomy) ventilated artificially by passive expansion with simulated pleural depressions. The animal lungs used in this study do not come from animals dedicated to scientific research but from breeding for human consumption. The lungs are not fit to eat in France and consequently it is an organic waste for the slaughterhouses. Thus, this model is an ethical and inexpensive alternative to in vivo human or laboratory animal experiments because no animal is specifically sacrificed to obtain our model. This chimeric model will allow in a next future a cheaper and faster development of nebulizing technologies by reducing animal testing (3Rs principles) and by reducing the preclinical development cost of nebulizing technologies before to conduct human clinical trials. It will provide a significant gain in terms of innovating perspectives in the existing field of aerosol therapy. Particularly, the major medical/social challenges to undertake thanks to the chimeric models are to assess aerosol drug delivery in the case of COPD in adults and bronchiolitis in children. To sum up, this innovative experimental paradigm aims to improve in mid-term perspective the efficiency of inhaled treatments by nebulization in the case of obstructive pulmonary diseases.

The AMADEUS proposal doubtless contributes to encourage the PI to take responsibility, to develop his scientific autonomy and to tackle scientific hurdles in an innovative in order to consolidate a research team at Mines Saint-Etienne / U1059 devoted to the inhaled nanoparticles with the PI as leader.