Biomechanics and Respiratory Apparatus: A Multi-Scale Approach

Contacts

Bruno Louis Head Bruno Louis

Tél.: +33-(0)1 49 81 36 76
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Marcel Filoche Co-head Marcel Filoche

Tél.: +33-(0)1 49 81 49 32
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The team develops a multidisciplinary research at the interface between biomechanics, bioengineering and the biomedical sciences. Our program is dedicated to further deciphering the physiological and pathophysiological mechanisms of acute and chronic respiratory failure and proposing more efficient treatments for patients. Our approach is based on the idea that mechanical factors acting all scales, have to be delineated in order to (i) be integrated in comprehensive models of biological mechanisms and (ii) improve therapeutic processes.

The team is primarily accredited by INSERM/UPEC, and by the CNRS as a secondary affiliation.

Our activity can be schematised by the association of 3 main complementary themes: i) optimisation of mechanical ventilation; ii) airway obstruction & cilia beating; iii) molecular and cellular biomechanics.

 

Optimization of Mechanical Ventilation

This activity focuses on the optimisation of mechanical ventilation. Our group acquired worldwide recognition through its involvement in non-invasive ventilation with positive pressure support, a successful therapeutic for patients suffering from acute exacerbation of chronic obstructive pulmonary disease or from neuromuscular disease. One of our goals is to develop the explorations of premature newborns and children. These explorations are especially difficult due to limited accessibility and tissue fragility, while the effect of mechanical ventilation in terms of distensibility and humidity of the airways and their consequences on epithelial cells and mucociliary clearance remain an issue. Optimizing mechanical ventilation requires measuring, monitoring, and refining the physiological and clinical interpretation of the global mechanical parameters generally obtained at the airway opening (flow, pressure, respiratory impedance). This approach is partly performed on bench and physical/simulation models and partly in vivo with bedside investigations. It also includes the development of ex vivo cellular models to investigate biological effects at multiscale (cell/cytoskeleton/receptor) in an attempt to find new protective criteria, and their translation at the organ level with the aim of defining new protective ventilatory modes.

 

Airway Obstruction & Cilia Beating

This activity focuses on the biomechanical aspects of physiopathological mechanisms relevant to airway obstruction and the role of cilia beating in mucociliary clearance. Biomechanical models of airflow and mucus motion, particles and gas transport (from mouth through to alveoli) in realistic airway geometries, including obstructive geometries, will be developed. Our team has acquired very extensive experience in the development and adaptation to clinical conditions of non-invasive methods of upper airway investigation (e.g. acoustic reflectometry or rhinomanometry). Cilliary dysfunction can thus be studied and quantified simultaneously with clinical exploration. Ciliary dysfunctions belong to a newly emerging group of diseases caused by defects in cilia and in many cases revealed by respiratory disorders, due to impaired mucociliary clearance. We recently developed a kinematic analysis of cilia beating based on high-speed videomicroscopy. The biomechanics approach, permitted by the association of high-speed videomicroscopy , atomic force microscopy (kinematic parameter of the beating, mucus transport get by micro bead tracking and foces generated by cilia) enriched by mathematical modelling , may help to develop new treatments, aimed at restoring normal ciliary beating and improving patient management, based on an interdisciplinary approach.

 

Molecular and Cellular Biomechanics

This activity focuses on molecular and cellular biomechanics. In this relatively fundamental approach, we will develop micro/nanomanipulation tools specifically for the ex vivo study of cellular models, and will introduce new concepts taken from biorheology and statistical physics to better control the effect of forces and mechanical stimulation on cellular function. Notably, the role of modified cellular environment, altered intracellular tension, and changes in cell-cell or cell-extracellular matrix interactions will be studied, first in the respiratory context, and possibly in other organs or diseases. It is postulated that any biomechanical or structural defect at the molecular or cellular scale might be at the origin of functional deficiencies expressed at larger scales. Our team has developed very specific biomechanical tools (i.e. Magnetic bead Twisting Cytometry and atomic force microscopy platforms), to reveal cellular functionalities that could not be obtained with conventional biological tools. We are now able to evaluate the parameters directly related to the stiffness of the cytoskeleton, intracellular tension, acto-myosin contraction, the kinetics of receptor-ligand bonds and, soon, the force developed by cilia and molecular motors. We have now collected a set of experimental and theoretical arguments to demonstrate that the mechanical properties of the intra- and extracellular media play a role in the control of cell adhesion and more general cellular function. In connection to mechanotransduction, the question of the sensitivity and adaptation of cells to their environment is fundamental to most biological processes, including adhesion, migration, and differentiation. From this perspective, the multiple nature of bond association, characterising cellular adhesion sites, remains one the hotspots in which the team wants to pursue theoretical thinking, using stochastic adhesion models and starting with new experimental investigations into cell adhesion

 

key words: biomechanics – biophysics – biomedical – cilia – mechanical ventilation – obstructive disease – ENT diseases – upper airways – respiratory distress – mucociliary clearance- modeling


 

Selected publications

Angely, C., N. M. Nguyen, S. Andre Dias, E. Planus, G. Pelle, B. Louis, M. Filoche, A. Chenal, D. Ladant and D. Isabey. "Exposure to Bordetella Pertussis Adenylate Cyclase Toxin Affects Integrin-Mediated Adhesion and Mechanics in Alveolar Epithelial Cells

Biol Cell. 2017 Aug;109(8):293-311

Bottier, M., S. Blanchon, G. Pelle, E. Bequignon, D. Isabey, A. Coste, E. Escudier, J. B. Grotberg, J. F. Papon, M. Filoche and B. Louis. "A New Index for Characterizing Micro-Bead Motion in a Flow Induced by Ciliary Beating: Part I, Experimental Analysis

PLoS Comput Biol 13(7):e1005605. doi: 10.1371/journal.pcbi.1005605

Bottier, M., M. Pena Fernandez, G. Pelle, D. Isabey, B. Louis, J. B. Grotberg and M. Filoche. "A New Index for Characterizing Micro-Bead Motion in a Flow Induced by Ciliary Beating: Part Ii, Modeling

PLoS Comput Biol 13(7):e1005552. doi: 10.1371/journal.pcbi.1005552

Louis, B., E. Bequignon, M. Devars du Mayne, F. Zerah-Lancner, C. Larger, D. Isabey, A. Coste and J. F. Papon. "Nasal Compliance Measurement for Diagnosis of Idiopathic Non-Allergic Rhinitis: A Prospective Case-Controlled Study of 63 Patients

Clin Otolaryngol. doi: 10.1111/coa.12935

Nguyen, N. M., C. Angely, S. Andre Dias, E. Planus, M. Filoche, G. Pelle, B. Louis and D. Isabey. "Characterisation of Cellular Adhesion Reinforcement by Multiple Bond Force Spectroscopy in Alveolar Epithelial Cells

Biol Cell. 2017 Jul;109(7):255-272. doi: 10.1111/boc.201600080. Epub 2017 Jun 23

Ayzac, L., R. Girard, L. Baboi, P. Beuret, M. Rabilloud, J. C. Richard and C. Guerin. "Ventilator-Associated Pneumonia in Ards Patients: The Impact of Prone Positioning. A Secondary Analysis of the Proseva Trial

Intensive Care Med 42(5):871-8. doi: 10.1007/s00134-015-4167-5

Isabey, D., G. Pelle, S. Andre Dias, M. Bottier, N. M. Nguyen, M. Filoche and B. Louis. "Multiscale Evaluation of Cellular Adhesion Alteration and Cytoskeleton Remodeling by Magnetic Bead Twisting

Biomech Model Mechanobiol 15(4):947-63. doi: 10.1007/s10237-015-0734-5

Manolidis, M., D. Isabey, B. Louis, J. B. Grotberg and M. Filoche. "A Macroscopic Model for Simulating the Mucociliary Clearance in a Bronchial Bifurcation: The Role of Surface Tension

J Biomech Eng 138(12). doi: 10.1115/1.4034507

Filoche M, Tai CF, Grotberg JB. Three-dimensional model of surfactant replacement therapy.

Proc Natl Acad Sci U S A. 2015. 112(30):9287-9292

Jeanson, L., B. Copin, J.F. Papon, F. Dastot-Le Moal, P. Duquesnoy, G. Montantin, J. Cadranel, H. Corvol, A. Coste, J. Desir, A. Souayah, E. Kott, N. Collot, S. Tissier, B. Louis, A. Tamalet, J. de Blic, A. Clement, E. Escudier, S. Amselem and M. Legendre, RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes.

Am J Hum Genet, 2015. 97(1): p. 153-162.