Electrical stimulation combined to molecular approach is a promising way for the reformation of damaged neural circuit in the central nervous system after a lesion or a neurodegenerative disease. Placing neural stimulators all along the reforming circuit is certainly key for the complete re-innervation. However, the current tethered neural stimulation technologies do not allow to position the implants over several centimetres in a custom way because of their large spatial clutter. Thus new implantable neurostimulation technologies must be developed to meet this need. In order to fill this gap, the present project suggest to create wireless and battery-free stimulators powered by ultrasound. In order to reach dimensions below 200µm required for intracerebral implants, the consortium will fabricate and use piezoelectric micromachined ultrasonic transducers coupled to stimulating microelectrodes. This new concept of wireless and battery-free electric neural stimulator will be tested in vitro on retinal explants, a gold standard to study axonal regeneration.

Ventricular arrhythmias (VAs) account for the vast majority of the 250,000 cases of sudden death recorded in Europe each year. VAs occur mainly in patients with cardiomyopathy. Intra fibrotic electrical reentrant circuits are the dominant electrophysiological mechanism. Catheter ablation is the main option for invasive treatment, involving destruction of the slow conducting channels within the scar to block the electrical circuits. Challenges related to adequate catheter placement over the target area, sufficient energy diffusion into the tissue, and lack of intramyocardial dynamic mapping result in only 30-50% of patients experiencing freedom from recurrence after ablation. The aim of the CALAMAR (ChemicAL Ablation and Mapping of ARrhythmias) project is to evaluate the use of ultrasound to 1) Map the myocardium during ablation procedure using electromechanical wave imaging (EWI); 2) Validate a disruptive strategy of "chemical" ablation combining microbubbles and ultrasound to open the blood-myocardium barrier, and lipid nanoparticles loaded with cardiotoxic agents to induce a chemical dechannelization.

Presbyopia is the loss of accommodation affecting any individual after the age of 45 and preventing close reading. Although its consequences have been known and corrected by converging glasses since antiquity, biological aging, which modifies the biomechanics of the lens and makes it lose its flexibility, has only recently been understood. To date, no one has developed a treatment that restores the natural biomechanical properties of the aging crystalline lens. The expertise in focused ultrasound applied to ophthalmology is a very strong point of our territory. Also, by bringing together 2 laboratories and 2 industrial partners with major scientific expertise in ophthalmology, ultrasound, cell biology, biochemistry, optics, biomechanics and engineering, we are equipped to meet this ambitious challenge through PRESB-INNOV-US: moving towards a radical paradigm shift to overcome (finally)presbyopia.

There are two main forms of liver tumors: primary hepatic cancer (cancer that starts in the liver, mainly hepatocellular carcinoma: HCC) and liver metastases from other tumors, mainly of the gastrointestinal tract. In 201 there were approximately 63 400 new cases of primary liver cancers in Europe and 62 100 deaths. Liver cancer is the 2nd most common cause of cancer death worldwide. Primary liver cancer occurs most commonly in previously damaged livers (viral hepatitis, alcohol abuse and obesity). Treatment involves multiple strategies including liver replacement therapy, local therapy (resection, ablation), and regional therapy. However, to date, only about 25% of the patients are considered to be suitable candidates for curative treatment. The second most common incident form of cancer in Europe in 2012 was colorectal cancer (371 706, 13% of all incident cases). Nearly half the patients will develop liver metastases at some point during the course of the disease. Whatever the treatment, the survival at 5-years is only about 10% and surgery remains the only potentially curative treatment. However, only 10–20% of patients are eligible for surgery. Techniques involving focal destruction, such as radiofrequency ablation, have been used as a tool to expand the number of patients treated with a curative intent. However, there is a risk of inadequate treatment due to the blood flow, they do not allow reliable real-time monitoring, they require intra-parenchymal introduction of a probe, only small hepatic volumes can be targeted and a high rate of local recurrence has been described. HIFU is a therapeutic technology allowing the creation of a thermal lesion selectively in biological tissues by focusing ultrasonic energy. Commercial products are currently available for the treatment of uterine fibroids, prostate cancer and abdominal cancers. Although there are many research groups worldwide who are actively working on this technique, the liver is a particularly challenging organ for HIFU treatment due to the combined effect of respiratory-induced motion, partial blocking of the rib cage and high perfusion/flow. Several technical and clinical solutions have been investigated during the past 15 years but to date without providing effective solutions. Although hepatocellular carcinoma and metastatic liver disease require completely separate analysis and study protocols, the technological approach of HIFU treatments is similar. We have shown at early clinical stage that a new form of treatment using toroidal HIFU transducers can be a promising tool for treating liver metastases. Before developing sophisticated devices a first prototype was built to be used intraoperatively (during surgery). This toroidal HIFU transducer achieved fast, selective, safe and well-tolerated large volume of liver ablation (the ablation rate is more than 30 times faster than any other local therapy) and without puncture in the organ. Thanks to this initial experience we now aim to move forward a completely non-invasive HIFU treatment in the liver for treating primary and secondary tumors. Based on additional innovations about surface modulation of the emitting surface we recently patented it is now possible to deposit precisely energy inside the liver by taking into account the specificity of intervening tissues and their acoustic characteristics. A pragmatic approach was selected for focusing the ultrasound energy through the rib cage by using a truncated transducer. Ablations created by a toroidal transducer are independent from perfusion. Moreover, in order to compensate respiratory-induced motion, we propose to develop next-generation tools in the fields of HIFU simulation, guidance of the treatment and estimation of the created effect in tissues.

Interest in bubble-induced shear stress is motivated by a variety of technological, chemical, and biomedical applications where this effect is used. Often acoustic cavitation bubbles are involved, and ultrasonic cleaning, micromixing of liquids, intensification of chemical reactions, or heat-exchange processes are examples of such applications in the engineering field. In the biomedical field, ultrasound-mediated drug delivery, ultrasound-induced blood-brain barrier opening, bacteria lysis, or disinfection are examples of bubble-mediated bioeffects. During decades research works mainly focused on the violent mechanisms resulting from cavitation bubble collapses, including shockwave emissions and the generation of microjets. Recent sensitive applications have demonstrated that more weakly oscillating bubbles may also produce significant mechanical effects on rigid or elastic surfaces through the generation of shear stress. This shear stress results from the liquid flows created in vicinity of the oscillating bubbles. Up to now, the influence and modification of surfaces by bubble-induced shear stress has mostly been investigated qualitatively. The quantitative measurement of shear stress, as well as the potential control of the force exerted by an oscillating or a collapsing bubble near rigid and elastic surfaces, remain challenging. The CaviStress project consequently focuses on the quantification of bubble-induced shear stress, through theoretical, numerical and experimental investigations of the interplay between a cavitation bubble and an in-vicinity interface. The main objective of the project is the control and optimization of wall-near stresses induced by oscillating or collapsing bubbles, and its application in two different fields: (i) the cleaning of solid surfaces, and (ii) the molecular uptake of biological cells. We investigate theoretically and numerically the shear stress induced by oscillating and collapsing bubbles both in bulk fluid, and near rigid and elastic walls. The bubble-induced liquid flows are derived theoretically. The fundamental findings are compared to controlled experiments, from the single bubble case to a realistic multibubble streamer where turbulence and mixing occur. Once the liquid flows are characterized, the shear stress is theoretically and numerically quantified. Experimental investigation of the impact of shear stress on rigid walls focuses on its scaling dependence, thus allowing to identify parameter ranges where damage-free cleaning of sensible surfaces is feasible. In parallel, experimental studies of the shear stress on elastic walls focus on the penetration of molecules into biological cells by evaluating the cell poration efficiency from well controlled oscillating or collapsing bubbles. The expected quantification and differentiation of the bubble-induced mechanical effects pave the way towards improved ultrasound based procedures for cleaning and drug delivery through bubbles.