CARIBBBOU

It has been recognized that the blood brain barrier (BBB) presents a major obstacle to the entry of therapeutic molecules into the central nervous system (CNS). It has been shown that, using ultrasound with the presence of microbubbles to locally enhance acoustic cavitation in CNS capillaries, the CNS-blood permeability can be significantly increased due to the temporal opening of the BBB, thus providing a promising strategy to increase delivery of therapeutic agents into brain tumors. Understanding the mechanisms underlying molecular uptake stimulation and ultrasound-based cell modification in brain tissue is crucial, with the key requirement of a better control of the various aspects of cavitation phenomenon.

The CARIBBBOU project is an international consortium whose aim is to focus on the in-vitro and in-vivo control of any kind of ultrasound cavitation activity, with application to the enhancement of BBB opening and brain gene delivery for CNS neurodegenerative diseases. This project is funded by the French National Research Agency (ANR) in combination to the Ministry of Science and Technology (MOST) in Taiwan, for a grant of 750 k€. The french PI is Claude Inserra (LabTAU) and taiwanese PI is Dr When-Shiang Chen (NTUH, Taiwan).

The CARIBBBOU project is a multidisciplinary consortium gathering four international partners, described below.

LabTAU INSERM U1032

Participating staff:

• INSERRA Claude (Associate Professor) : french PI
• BERA Jean-Christophe (Professor)
• GILLES Bruno (Associate Professor)
• PADILLA Frederic (CNRS Researcher)
• MESTAS Jean-Louis (INSERM Researcher)
• LAFON Cyril (INSERM Research Director)
• NGO Jacqueline (Biological Engineer)
• GUEDRA Matthieu (Postdoc)
• CORNU Corentin (PhD student)

Institute of Light and Matter, ILM, Lyon

This laboratory, including the Biophysics laboratory headed by Jean-Paul Rieu, is one of the leanding French institutes in condensed matter, atomic, molecular and optical physics, with a strong expertise in nanoscience, soft matter and interfaces.

Participating staff:

• RIEU Jean-Paul (Professor)
• DELANOE-AYARI Hélène (Associate Professor)
• RIVIER Charlotte (Associate Professor)

Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Taipei, Taiwan

The Therapeutic Ultrasound Lab, led by Dr Wen-Shiang Chen, endeavors to basic research and translational studies of therapeutica ultrasound for years. Lab members include biologists from medical school of NTU, engineers from National Health Research Institute and medical doctors of NTUH. NTUH is the best-known and most renowned medical center in Taiwan.

Participating staff:

• CHEN Wen-Shiang (Associate Professor)
• LO Chia-Wen (Postdoc)
• LEE Jyun-Lin (Research Assistant)
• LIAO Wei-Hao (Postdoc)

Medical Ultrasound Lab, Department of Electrical Engineering, Chang-Gung University, Taoyuan, Taiwan

The principal investigator of this research team, devoted to the scientific development of therapeutic ultrasound, is led by Dr Hao-Li Liu. The laboratory put most of the research emphasis on the use of ultrasound-triggered cavitation effect in ultrasound brain therapy, particularly for BBB opening and brain drug delivery.

Participating staff:

• LIU Hao-Li (Professor)
• HSU Po-Hong (Postdoc)
• CHU Po-Jun (PhD student)
• TSAI Wen-Yen (PhD student)

Publications in international journals:

• Dynamics of nonspherical microbubble oscillations above instability threshold. M Guedra, S Cleve, C Mauger, P Blanc-Benon, C Inserra. Physical Review E, 96: 063104, 2017
• A derivation of the stable cavitation threshold accounting for bubble-bubble interactions. M Guedra, C Cornu, C Inserra. Ultrasonics Sonochemistry, 38: 168-173, 2017.
• Experimental evidence of nonlinear interactions between spherical and nonspherical oscillations of microbubbles. M Guedra, C Inserra, C Mauger, B Gilles. Physical Review E, 94: 053115, 2016.

International communications with published acts:

• Focused shockwave induced blood-brain barrier opening. Y Kung, L Chiang, CS Yeh, YH Hsu, APH Huang, WS Chen. Ultrasound in Medicine and Biology, 43(1): S237, 2017.
• Noninvasively delivering therapeutic monoclonal antibodies into the brain: opportunity in prinary brain tumor / breast cancer metastatsis treatment. HL Liu. Ultrasound in Medicine and Biology, 43(1): S12-13, 2017.
• Ultrasound noninvasive gene delivery for Parkinson's disease treatment. HL Liu. Ultrasound in Medicine and Biology, 43(1): S234, 2017.
• Real-time cavitation control for enhancing in-vitro gene transfection. C Inserra, WS Chen, JC Bera. Ultrasound in Medicine and Biology, 43(1): S233, 2017.
• Time-resolved dynamics of micrometer-sized bubbles undergoing shape oscillations. M Guedra, S Cleve, C Mauger, C Inserra, P Blanc-Benon. Proceedings of Meetings on Acoustics, 141(5): 3736, 2017.
• Real-time monitoring and control of stable cavitation activity in pulsed sonication. C Cornu, M Guedra, C Inserra, JC Bera. Proceedings of Meetings on Acoustics, 141(5): 3793, 2017.
• Periodic onset of bubble shape instabilities and their influence on the spherical mode. M Guedra, C Inserra, C Mauger, B Gilles. IEEE International Ultrasonic Symposium, 2016.

International communications:

• Noninvasive and targeted CNS gene delivery using focused ultrasound. HL Liu. International Symposium on Frontier Ultrasound, Shenzhen, China, December 5, 2017.
• Shockwave-induced BBB opening for gene transfer. WS Chen. International Conference on Biomedical Ultrasound, ICBMU 2017, Hong-Kong, China, December 3-4, 2017.
• Nonspherical oscillations of gas microbubbles: threshold, dynamics and nonlinearity. C Inserra, M Guedra, S Cleve, C Mauger, P Blanc-Benon. Acoustic bubbles in Therapy, Tours, France, October 23-24, 2017.
• Focused shockwave induced blood-brain barrier opening. Y Kung, L Chiang, CS Yeh, YH Hsu, APH Huang, WS Chen. The 16^th World Federation for Ultrasound in Medicine and Biology Congress, WFUMB 2017, Taipei, Taiwan, October 13-17, 2017.
• Noninvasively delivering therapeutic monoclonal antibodies into the brain: opportunity in prinary brain tumor / breast cancer metastatsis treatment. HL Liu. The 16^th World Federation for Ultrasound in Medicine and Biology Congress, WFUMB 2017, Taipei, Taiwan, October 13-17, 2017.
• Ultrasound noninvasive gene delivery for Parkinson's disease treatment. HL Liu. The 16^th World Federation for Ultrasound in Medicine and Biology Congress, WFUMB 2017, Taipei, Taiwan, October 13-17, 2017.
• Real-time cavitation control for enhancing in-vitro gene transfection. C Inserra, WS Chen, JC Bera. The 16^th World Federation for Ultrasound in Medicine and Biology Congress, WFUMB 2017, Taipei, Taiwan, October 13-17, 2017.
• Comportement non linéaire des oscillations de surface de bulles micrométriques. M Guedra, C Inserra, S Cleve, C Mauger, P Blanc-Benon. Journées Scientifiques Ultrasons et Procédés, Toulouse, France, July 4-5, 2017.
• Time-resolved dynamics of micrometer-sized bubbles undergoing shape oscillations. M Guedra, S Cleve, C Mauger, C Inserra, P Blanc-Benon. 173^rd Meeting of the Acoustical Society of America and the 8^th Forum Acusticum, Boston, USA, June 25-29, 2017.
• Real-time monitoring and control of stable cavitation activity in pulsed sonication. C Cornu, M Guedra, JC Bera, C Inserra. 173^rd Meeting of the Acoustical Society of America and the 8^th Forum Acusticum, Boston, USA, June 25-29, 2017.
• Development of an alpha-synuclein (SNCA)-based mouse model for Parkinson's disease by ultrasound-guided CNS delivery. CY Lin, YX Lin, HL Liu. 17^th International Symposium on Therapeutic Ultrasound, Nanjing, China, May 31 - June 2, 2017.
• An acoustic emission-feedback planar ultrasound system for localized blood-brain barrier opening and monitoring. YX Lin, YC Lin, C Inserra, WS Chen, HL Liu. 17^th International Symposium on Therapeutic Ultrasound, Nanjing, China, May 31 - June 2, 2017.
• Real-time control of the stable cavitation activity in free- and vessel-confined bubble cloud. C Cornu, M Guedra, JC Bera, WS Chen, HL Liu, C Inserra. 17^th International Symposium on Therapeutic Ultrasound, Nanjing, China, May 31 - June 2, 2017.
• Periodic onset of bubble shape instabilities and their influence on the spherical mode. M Guedra, C Inserra, C Mauger, B Gilles. IEEE International Ultrasonics Symposium, Tours, France, September 18-21, 2016.
• Real-time monitoring and control of cavitation activity for enhancing ultrasound transfection and bubble-cell interactions. C Inserra, JC Bera, P Muleki-Seya, WS Chen. 16^th International Symposium on Therapeutic Ultrasound, Tel Aviv, Israel, March 14-16, 2016.