3BOPUS

Brain diseases, such as brain tumors and neurodegenerative diseases remain a major medico-economic challenge. The efficacy of pharmaceutical agents is limited in the brain due to their poor penetration through the blood-tumor and blood-brain barriers. Low intensity ultrasound combined with microbubbles has been proven to increase significantly drug access to the brain with proven therapeutic impact in animal studies. Since 2015, two clinical trials have started to bring this technology to the patient bed. However, the ultrasound devices used in these trials were either invasive or not optimized for blood-brain barrier disruption. In this project, we tackle both scientific and technological challenges for making this treatment strategy a realistic option for clinicians and patients (i.e. non-invasive, targeted, and repeatable). We propose to develop a new approach for opening the BBB using an extracorporal focused ultrasound transducer held by a robotic arm. Neuronavigation will be used instead of simultaneous MRI guidance to decrease costs while increasing availability. Acoustic properties of human skull and hair will be studied in silico and in vitro to optimize the transducer and to study the propagation of the ultrasound beam through the complex 3D structure of the skull bone. Cavitation activity of sonicated microbubbles will then be investigated to develop real time feedback of safety and efficacy. The use of robotic assistance will allow both positioning the transducer with high accuracy and performing complex treatment trajectories. Finally, the prototype will be validated in vivo in two large animal species (pig and non-human primate). To do so, our consortium is composed of a multidisciplinary team of experts from 5 partners, all of them with experience in clinical transfer of new medical technologies and two of them being small companies. The expertise within our consortium goes from acoustics, robotics, MRI, electronics to neurobiology, proteomics and animal experiments. More importantly, three clinical experts will ensure a continuous consideration of clinical needs in the three main future fields of application: oncology, neurodegeneration and neuropsychiatry. From a scientific point of view, this project will provide key knowledge in the fields of medical ultrasound and targeted therapies. It will also bring very useful safety and efficacy biological data in animal models more relevant than rodents. From a technological point of view, this project involves new developments in medical robotics, its coupling with ultrasound and in mechatronic design. This project will deliver a prototype of medical device paving the way for new therapeutic actions in brain diseases, which remain largely incurable to date.