The project leader invented a new device for hypothermic pulsed perfusion, named INOVAGRAFT (2 patents, Inserm Prize 2015 for Innovation), which would drastically enhance the duration of grafts transport. Associated with a new carrier of O2 derived from marine worms (HEMO2life®, patented by the company Hemarina), INOVAGRAFT could be at the origin of a paradigm shift in heart transplantation, with the possibilities: - (1) to greatly extend the preservation time, - (2) to allow the use of hearts from donors in circulatory arrest (Donor Cardiac Death). INOVAGRAFT- HEMO2life® would therefore partly overcome the dramatic shortage of cardiac grafts. INOVAGRAFT is an imaging compatible device that would also enable the evaluation of the graft viability by multimodal imaging: MRI, Ultrasound, X, and PET in order to characterize: - (a) edema and tissue hardening - (b) microperfusion and vascular permeability - (c) energy status of the graft.

Subarachnoid hemorrhage (SAH) occurs in the setting of a ruptured cerebral aneurysm or arteriovenous malformation (AVM). The socio-economic impact of SAH is important because it affects young subjects with around one third of the survivors who maintain severe neurological aftereffects. SAH leads, in a large number of cases, to the death of patients before their first medical contact. In the remaining cases, the underlying vascular lesion is treated by endovascular or neurosurgical interventions to reduce the risk of re-bleeding. Nevertheless, survivors are prone to complications that include hydrocephalus, re-bleeding, seizures, cardiac dysfunctions and finally delayed cerebral ischemia (DCI). Our knowledge of the mechanisms responsible for post-SAH delayed cerebral ischemia are limited, with no clinical treatment which has show a proven efficacy. The objective(s) of our proposal are: 1. The development of a reproducible and clinically relevant model of DCI post-SAH in mice. 2. The development of ultrasound-based imaging techniques with an unprecedented spatio and temporal resolution to reveal vascular brain microdamages (microthrombosis, micro-inflammation and vasospams). 3. The exploration of the mechanisms that drive the occurrence of post-SAH DCI. 4. The development and validation of strategies to reduce the occurrence of DCI and of its behavioral impact. To succeed in meeting these objectives, we will combine our expertise in the field of neurovascular disorders and imaging (Inserm UMR-S U919, GIP Cyceron – D. Vivien) with the use of a set of innovative ultrasonic approaches implemented by the group of M. Tanter (Inserm UMR-S U979, Institut Langevin, ESPCI). The first expected result is the development of a DCI post-SAH mouse model with comprehensive evaluation including histology, imaging and behavior. This model will improve our knowledge about the pathophysiology of SAH and DCI and will allow us to evaluate different strategies for brain protection post-SAH. Beyond basic research on prevention of delayed ischemia, ultrasonic imaging modalities developed in the framework of our project could be translated in clinics in a very near future. Our innovative techniques could be implemented for conventional radiology. Furthermore, microbubbles used as contrast agents for ultrasound localization microscopy of endothelial adhesion molecules may be further developed for future pre-clinical and clinical applications.

The Valvosoft project aims to develop a revolutionary non-invasive ultrasound therapeutic strategy for the treatment of calcific aortic stenosis (CAS), a major public health issue. This valvular disease affects 2% of people over 65 and 12% of people over 75. The survival time is 2 to 5 years for patients with the most severe cases (1.3 million patients in Europe). Currently, the only medical answer is open heart surgery, a risky and extensive intervention which involves replacing the aortic valve. Morbidity and cost to the public health systems are very high. Moreover, many patients are not eligible for cardiac surgery. Percutaneous valve replacement has emerged as an effective solution to replace cardiac surgery but this technique is currently limited to only those who have a contraindication for traditional surgery and it comes at the cost of a high morbidity rate with vascular and hemorrhaging-related complications in over 20% of cases with a significant number of strokes. In Valvosoft, we propose a novel approach no longer based on valve replacement but rather on restoring the valve function through the application of an ultrasound beam precisely focused on the valve. This intense ultrasound beam enables a softening of the valve which in turn improves the valve opening and allows blood to reach vital organs. This innovative approach developed in Valvosoft fits perfectly into the current trend in heart surgery and interventional cardiology to be less and less invasive, safer for the patient and more cost-effective for public health systems. The objectives of this 30 months project are twofold: 1) enhance the existing technology with novel imaging capabilities for better targeting and monitoring in order to improve the efficacy and safety of the procedure and 2) perform the first proof of concept experiment on human patients. The first work package (WP1) is dedicated to the technological development of the novel imaging and monitoring tools to ensure the safety and the efficacy of the therapy. The second work package (WP2) aims to demonstrate the therapeutic efficacy and safety of the procedure on in vitro and in vivo preclinical models. The last work package (WP3) is the first in man pilot study of non-invasive calcified valve therapy. To achieve these objectives, the Valvosoft consortium combines the unique knowledge of two high-level academic research teams, highly specialized in imaging and ultrasound therapy (Inserm U979, Langevin Institute), in cardiovascular translational research and valve disease (HEGP) and an industrial partner, Cardiawave, an innovative young company created in 2014 to develop and commercialize a non-invasive therapeutic device for calcified aortic stenosis. This innovation will be a real breakthrough and is expected to have a strong impact on the quality of care (including reductions in mortality and morbidity rates, relief of pain), an impact on the cost of care (the resources used to develop it and provide it to patients, relative to those used for current practice), and an impact on the value of care (changes in quality relative to changes in cost).

Chronic pain diseases affect 30% of the European population. Unfortunately, only 50% of patients receive appropriate alleviation, due to a lack of treatment specificity and efficacy, as a result of a current poor understanding of the underlying mechanisms. The project ‘PINCH’ is a transdisciplinary and innovative project, based on an integrated approach whose aim is to provide highly relevant information on the brain’s function during the experience of acute pain (in healthy animals) and aberrant hypersensitivity (in neuropathic animals). Using a highly innovative neuroimaging technique (fUS) in freely moving animals pioneered by the partners of this consortium, this project will determine selective biomarkers of acute/neuropathic pain, i.e. decipher the brain areas and brain networks differentially activated during the multiple components of acute or chronic pain. In addition, we will determine the specific alterations of brain networks concomitant with the emergence of either anxiety or depression. Finally, the last part of this project, proposes a general framework for the optimized and personalized treatment of chronic pain based on functional connectivity monitoring. In this proof-of-concept study, we propose to use individual analysis of functional connectivity assessed by ultrasound for a personalized pain relief strategy. Such approach is key for a future clinical transfer in chronic pain patients.