1. 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, blood oxygenation, and aerosol deposition in chronic obstructive respiratory diseases: asthma and emphysema

2. 2 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan OxHelease – Planning 5-year project (4 years + 1 1 months extension) End of Project Dec 2016 Clinical study Dec 2015 4 years Technical Development & Pre-clinical (rats) 4 years Technical Development & Pre-clinical (rats) 1 year Clinical study 1 year Clinical study Project started Jan 2012 « Revue à mi- parcours » 17 Sept 2013 « Colloque Bilan TecSan 2011 » 26 Mar 2015

3. 3 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 3 7 Partners + 2 subcontractors IR4M Imagerie par Résonance Magnétique et Multi-Modalités Paris CEPR (INSERM U-618) Centre d’Etude des Pathologies Respiratoires Tours CNRS DR12 – IRPHE Institut de Recherche sur les Phénomènes Hors Equilibre Marseille UPS / LMO Université Paris-Sud 11, Laboratoire de Mathématiques d'Orsay UPRES EA 2363 Université Paris 13, Service de radiologie, Assistance Publique Hôpitaux de Paris IT / TSP Institut TELECOM / Telecom Sud Paris CIPA (Centre d'Imagerie du Petit Animal, CNRS Orléans) en consortium avec le CERB (CRO préclinique, Baugy) Air Liquide Santé International Medical R&D Paris

4. 4 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan OxHelease budget (funded by ANR) TOTAL 1 021 603 € Air Liquide 115 100 € IR4M 522 490 € dont CIPA/CERB 185 000 € INSERM U618 55 563 € CNRS DR12 _ IRPHE 91 662 € UPS / LMO 60 320 € IT / TSP 146 204 € UPRES EA 2363 30 264 €

5. 5 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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/O2 Ventilation, oxygenation & aerosol transport Asthma & Emphysema (component of COPD) OxHelease focus: Objectives:

6. 6 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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)

7. 7 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific program ■ Task 1: Prerequisite studies and developments  1.1: Animal model and protocol for pathological models production Rats Healthy Asthmatics – Bronchi inflammation – Decrease of airways diameter  Large pulmonary resistance Emphysematous  Large pulmonary compliance – Partial destruction of alveoli wall

8. 8 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific program CERB 1.1: Animal model and protocol for pathological models production DIAPOS CERB

9. 9 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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

10. 10 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific programCIPA 1.2: Characterisation of animal airways morphology DIAPOS CIPA

11. 11 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific program IT/TSP 1.2: Characterisation of animal airways morphology DIAPOS IT/TSP

12. 12 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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

13. 13 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific programIR4M 1.3: Gas and aerosol production and administration DIAPOS IR4M

14. 14 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific program CEPR 1.3: Gas and aerosol production and administration DIAPOS CEPR

15. 15 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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

16. 16 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific programCIPA 2.1: In vivo experiments: Ventilation in small animal models DIAPOS CIPA

17. 17 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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

18. 18 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific programLMO/INRIA 2.2: In silico experiments: ventilation in small animal DIAPOS LMO

19. 19 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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)

20. 20 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific programIR4M 2.3: Comparison between in vivo and in silico ventilation data DIAPOS AL

21. 21 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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

22. 22 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific programIR4M 3.1: In vivo experiments: aerosol deposition in small animal models DIAPOS IR4M

23. 23 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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  ADEPT ■Development of an aerosol deposition predictive tool to study the effect of carrier gas, particle size, disease….  ADEPT

24. 24 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific programLMO/INRIA 3.2: In silico experiments: aerosol deposition in small animal DIAPOS LMO

25. 25 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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)

26. 26 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific program IRPHE 3.3: 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 (D p < 5 µm). ■ Oscillatory flows ■ Flow separations & recirculations measurements ■ Dynamic similitude (scaled model 5/1) ■ Output: experimental dataset for numerical validation and flow analysis

27. 27 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific program IRPHE 3.3: 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 particles generated 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.

28. 28 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific program IRPHE 3.3: 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

29. 29 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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

30. 30 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific programAL 3.4: Comparison between in vivo, in silico, and in vitro aerosol deposition data DIAPOS LMO & IRPHE (comparaison in silico and in vitro)

31. 31 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific programAL 3.4: Comparison between in vivo, in silico, and in vitro aerosol deposition data DIAPOS AL

32. 32 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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 Air He/O2

33. 33 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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

34. 34 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan Scientific programIT/TSP 4.2: In silico experiments: Ventilation in human airways DIAPOS TSP

35. 35 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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

36. 36 OxHelease26/03/2015 Colloque Bilan TecSan 2011 - Dourdan 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