Colloque bilan ANR TecSan 2011 26/03/2015, Dourdan OxHelease ANR-11-TecSan-006 Impact of helium-oxygen inhalation on ventilation, blood oxygenation, and aerosol deposition in chronic obstructive respiratory diseases: asthma and emphysema
Dec 14, 2015
Colloque bilan ANR TecSan 2011 26/03/2015, Dourdan
OxHelease ANR-11-TecSan-006
Impact of helium-oxygen inhalation on ventilation, blood oxygenation, and aerosol deposition in chronic obstructive
respiratory diseases: asthma and emphysema
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OxHelease – Planning
5-year project (4 years + 1 1 months extension)
End of Project
Dec2016
Clinical study
Dec 2015
4 years
Technical Development & Pre-clinical (rats)
1 year
Clinical study
Project started
Jan 2012
« Revue à mi-
parcours »
17 Sept 2013
« Colloque Bilan
TecSan 2011 »
26 Mar 2015
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7 Partners + 2 subcontractors
IR4MImagerie par Résonance
Magnétique et Multi-ModalitésParis
CEPR (INSERM U-618)Centre d’Etude des Pathologies
RespiratoiresTours
CNRS DR12 – IRPHEInstitut de Recherche sur les Phénomènes Hors Equilibre
Marseille
UPS / LMOUniversité Paris-Sud 11,
Laboratoire de Mathématiques d'Orsay
UPRES EA 2363Université Paris 13, Service de radiologie, Assistance Publique
Hôpitaux de Paris
IT / TSPInstitut TELECOM / Telecom Sud Paris
CIPA (Centre d'Imagerie du Petit Animal, CNRS Orléans) en consortium avec le CERB (CRO préclinique, Baugy)
Air Liquide Santé InternationalMedical R&D
Paris
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OxHelease budget (funded by ANR)
TOTAL1 021 603 €
Air Liquide115 100 €
IR4M 522 490 €dont
CIPA/CERB 185 000 €
INSERM U61855 563 €
CNRS DR12 _ IRPHE
91 662 €UPS / LMO60 320 €
IT / TSP146 204 €
UPRES EA 236330 264 €
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Objectives
Demonstrate the differences of He/O2 vs. air, used as
- therapeutic gas: He/O2 flows faster than air and reduces work of breathing
- driving gas for aerosol: aerosol particle delivery to distal airways is increased
Understand the mechanisms of action of He/O2
Air vs. He/O2Ventilation, oxygenation & aerosol
transportAsthma & Emphysema (component of
COPD)
OxHelease focus:
Objectives:
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Summary of the Scientific program
■Task 1: Prerequisite studies and developments
■Task 2: Ventilation, work of breathing, and alveolo-capillary oxygen transfer
■Task 3: Aerosol transport and deposition
■Task 4: Clinical study (Ventilation)
Pre-clinical (rats)
Clinical (asthmatic & emphysematous
patients)
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Scientific program
■Task 1: Prerequisite studies and developments
1.1: Animal model and protocol for pathological models production
RatsHealthy
Asthmatics
– Bronchi inflammation
– Decrease of airways diameter
Large pulmonary resistance
Emphysematous
Large pulmonary compliance
– Partial destruction of alveoli wall
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Scientific program CERB1.1: Animal model and protocol for pathological models production
DIAPOS CERB
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Scientific program
■Task 1: Prerequisite studies and developments
1.2: Characterisation of animal airways morphology
■ Micro-CT Scan imaging
■ 3D reconstruction of the rat airways morphology
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Scientific program CIPA1.2: Characterisation of animal airways morphology
DIAPOS CIPA
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Scientific program IT/TSP1.2: Characterisation of animal airways morphology
DIAPOS IT/TSP
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Scientific program
■Task 1: Prerequisite studies and developments
1.3: Gas and aerosol production and administration
■ Development of gas (air & He/O2) and aerosol administration system for small animals & humans
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Scientific program IR4M1.3: Gas and aerosol production and administration
DIAPOS IR4M
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Scientific program CEPR1.3: Gas and aerosol production and administration
DIAPOS CEPR
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Scientific program
■Task 2: Ventilation, work of breathing, and alveolo-capillary oxygen transfer
2.1: In vivo experiments: Ventilation in small animal models
■ Rats: healthy, asthma, emphysema■ Air & He/O2■ Plethysmography (Respiratory functions measurement)■ Krypton ventilation Scintigraphy (81mKr SPECT-CT)
■ Hyperpolarised Helium-3 MRI (Ventilation study)
■ Histology: rat airways morphology (asthma & emphysema)■ Comparison air & He/O2
Same rats
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Scientific program CIPA2.1: In vivo experiments: Ventilation in small animal models
DIAPOS CIPA
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Scientific program
■Task 2: Ventilation, work of breathing, and alveolo-capillary oxygen transfer
2.2: In silico experiments: ventilation in small animal
■ Analytical model of breathing mechanism & oxygen transfer into the blood circulation
■ Numerical Simulation (CFD) of ventilation in the 3D reconstructed morphologies of rat airways
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Scientific program LMO/INRIA2.2: In silico experiments: ventilation in small animal
DIAPOS LMO
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Scientific program
■Task 2: Ventilation, work of breathing, and alveolo-capillary oxygen transfer
2.3: Comparison between in vivo and in silico ventilation data
■ Development of a specific 3D visualization tool
■ Validation of the in silico model
(Example in humans)
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Scientific program IR4M2.3: Comparison between in vivo and in silico ventilation data
DIAPOS AL
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Scientific program
■Task 3: Aerosol transport and deposition 3.1: In vivo experiments: aerosol deposition in small animal models
■ Rats: healthy, asthma, emphysema■ Air & He/O2 – Micro & nanometric aerosols■ Tc-99m radiolabelled aerosol deposition measured by SPECT-CT*
method of reference
■ Aerosol deposition measured by Hyperpolarised Helium-3 MRI No radiation Still in development
=> Validation of the Hyperpolarised Helium-3 MRI method by comparison with SPECT-CT
*Single Photon Emission Computed Tomography & X-ray Computer Tomography
Same rats
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Scientific program IR4M3.1: In vivo experiments: aerosol deposition in small animal models
DIAPOS IR4M
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Scientific program
■Task 3: Aerosol transport and deposition 3.2: In silico experiments: aerosol deposition in small animal
■ Development of a theoretical model of aerosol transport and deposition ■ Numerical simulation of aerosol transport and deposition in the 3D reconstructed
morphologies of rat airways
■ Development of an aerosol deposition predictive tool to study the effect of carrier gas, particle size, disease…. ADEPT
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Scientific program LMO/INRIA3.2: In silico experiments: aerosol deposition in small animal
DIAPOS LMO
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Scientific program
■Task 3: Aerosol transport and deposition 3.3: In vitro experiments: Aerosol deposition in idealized models
■ Development of simplified 3D in vitro models of animal airways singularities
■ PIV (particle image velocimetry)-PLIF (planar laser induced fluorescence) experiments
Study of air and OxHel flow in a simplified lung model, in physiological conditions (sinusoidal breathing, frequency and flow rate controlled)
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Scientific program IRPHE3.3: In vitro experiments: Aerosol deposition in idealized models
■ PIV (particle image velocimetry)-PLIF (planar laser induced fluorescence) experiments
(1) physiological respiratory flow in a curved geometry
■ PIV measurement in idealized models with Air or OxHel (on going) as carrier gas: investigation of flow pattern
■ Incens particles (Dp < 5 µm).
■ Oscillatory flows
■ Flow separations & recirculations measurements
■ Dynamic similitude (scaled model 5/1)
■ Output: experimental dataset for numerical validation and flow analysis
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Scientific program IRPHE3.3: In vitro experiments: Aerosol deposition in idealized models
■ PIV (particle image velocimetry)-PLIF (planar laser induced fluorescence) experiments
(2) Aerosol deposition
■ Phase Doppler Anemometry: local measurement of the size of particlesgenerated by a medical vibrating membrane nebuliser
■ Liquid particles
■ Steady flow■ Dynamic similitude (scaled model 5/1)
■ Output 1 : Real performance of typical medical nebuliser
■ Output 2: Accurate knowledge of particle injection properties for deposition study.
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Scientific program IRPHE3.3: In vitro experiments: Aerosol deposition in idealized models
■ PIV (particle image velocimetry)-PLIF (planar laser induced fluorescence) experiments
(2) Aerosol deposition (on going)
■ PLIF Measurement of aerosol deposition in idealized models
■ Rhodamine 6G doped liquid particles■ Oscillatory flow
■ Dynamic similitude (scaled model 5/1)
■ New calibration scheme for the calibration of concentration measurement
■ Based on removable plugs and fluorometric analysis
■ Modification of the set up have been completed and the tests are scheduled in the early spring
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Scientific program
■Task 3: Aerosol transport and deposition 3.4: Comparison between in vivo, in silico, and in vitro aerosol deposition
data
■ Development of a specific 3D visualization tool
■ Validation of the in silico model
Exemple of 3D visualisation in humans
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Scientific program AL3.4: Comparison between in vivo, in silico, and in vitro aerosol deposition data
DIAPOS LMO & IRPHE (comparaison in silico and in vitro)
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Scientific program AL3.4: Comparison between in vivo, in silico, and in vitro aerosol deposition data
DIAPOS AL
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Scientific program
■Task 4: Clinical study 4.1: In vivo experiments: Ventilation in healthy, asthmatic, and
emphysematous humans
■ CT scanners
■ Hyperpolarised Helium-3 MRI (Ventilation study)
Hôpital Avicenne (Paris)
6 healthy subjects 6 asthmatics
6 emphysematous
AirHe/O2
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Scientific program
■Task 4: Clinical study 4.2: In silico experiments: Ventilation in human airways
■ 3D reconstruction of human airways from CT scans
■ Numerical simulation of the ventilation in the reconstructed morphologies
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Scientific program IT/TSP4.2: In silico experiments: Ventilation in human airways
DIAPOS TSP
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Scientific program
■Task 4: Clinical study 4.3: Comparison between in vivo and in silico ventilation data
■ Comparison of :- 3D ventilation images and in silico results on human airways- 3D dynamic oxygen pressure map and results of oxygen transfer model
■ Validation of the in silico model
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Conclusion
■ Technical contribution: Development of gas and aerosol administration systems adapted to
He/O2 and MRI systems Database of 3D morphology of rat and human airways Development of a unique prediction tool for ventilation, aerosol
deposition and oxygen transfer into the blood Validation of the Hyperpolarised Helium-3 MRI method
■ Direct impact for Air Liquide and partners:
Scientific proof and understanding of the advantages of He/O2 vs. Air in asthma and emphysema, used alone or as a driving gas for aerosols
Publications in international scientific journals Human ressources