OxHelease ANR-11-TecSan-006 Colloque bilan ANR TecSan 2011 26/03/2015, Dourdan OxHelease ANR-11-TecSan-006 Impact of helium-oxygen inhalation on ventilation,

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

2 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan

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

http://www.agence-nationale-recherche.fr/

3 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan3

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



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 €



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:



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)



Scientific program


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



Scientific program CERB1.1: Animal model and protocol for pathological models production

DIAPOS CERB



Scientific program


1.2: Characterisation of animal airways morphology

■ Micro-CT Scan imaging

■ 3D reconstruction of the rat airways morphology



Scientific program CIPA1.2: Characterisation of animal airways morphology

DIAPOS CIPA



Scientific program IT/TSP1.2: Characterisation of animal airways morphology

DIAPOS IT/TSP



Scientific program


1.3: Gas and aerosol production and administration

■ Development of gas (air & He/O2) and aerosol administration system for small animals & humans



Scientific program IR4M1.3: Gas and aerosol production and administration

DIAPOS IR4M



Scientific program CEPR1.3: Gas and aerosol production and administration

DIAPOS CEPR



Scientific program


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



Scientific program CIPA2.1: In vivo experiments: Ventilation in small animal models

DIAPOS CIPA



Scientific program


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



Scientific program LMO/INRIA2.2: In silico experiments: ventilation in small animal

DIAPOS LMO



Scientific program


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)



Scientific program IR4M2.3: Comparison between in vivo and in silico ventilation data

DIAPOS AL



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



Scientific program IR4M3.1: In vivo experiments: aerosol deposition in small animal models

DIAPOS IR4M



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



Scientific program LMO/INRIA3.2: In silico experiments: aerosol deposition in small animal

DIAPOS LMO



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)



Scientific program IRPHE3.3: In vitro experiments: Aerosol deposition in idealized models


(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





(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.





(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



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


Exemple of 3D visualisation in humans



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)



Scientific program AL3.4: Comparison between in vivo, in silico, and in vitro aerosol deposition data

DIAPOS AL



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



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



Scientific program IT/TSP4.2: In silico experiments: Ventilation in human airways

DIAPOS TSP



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




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


Documents

OxHelease ANR-11-TecSan-006 Colloque bilan ANR TecSan 2011 26/03/2015, Dourdan OxHelease ANR-11-TecSan-006 Impact of helium-oxygen inhalation on ventilation,