Cascade-AMplified UltraSound focal ablation (CAMUS)

Magnetic resonance-guided high-intensity focused ultrasound is considered to be a promising treatment for localized cancer. Depending on the anatomical target, commonly recognized challenges for the transfer of this technology towards the clinical routine are: acoustic obstacles (bones, air filled cavities, calcifications, scars), tissue motion (respiratory and cardiac) and heat sink in perfused organs (requiring sustained sonication). An increasing number of recent publications tried to address these issues, individually or simultaneously. However, based on our own solid experience with MRgHIFU in vivo studies with upper abdomen applications, it appears that a challenging complication of HIFU ablation is the far field heating of hard acoustic interfaces, for instance spinal bone structures or tissue-to-air interfaces, that represent a severe and frequent side effect. Indeed, any HIFU transducer forms an energy beam that is first concentrated at a focus then continues its post-focal propagation while losing the spatial controllability as a consequence of diffraction.

That is, the spatial profile of the acoustic intensity in the far field loses its correlation with the emission pattern at the surface of the transducer and there is little or no possibility of manipulating the HIFU source in order to directly reduce the far field energy deposition, unlike the near field situation. Therefore, to reduce this side effect there is an urgent need to search for new methods to enhance the thermal contrast achievable between the focus and the far field areas. Various attempts to solve this problem are known: use of shock waves with non-linear enhancement of focal absorption, thermally induced boiling core of water steam, or use of ultrasound contrast agents as adjuvants. Each suggested approach has demonstrated some potential interest, whilst exhibiting drawbacks that prevent it being applied 'as is' in a realistic clinical scenario. We propose an alternative method that does not have the same drawbacks as previously published approaches. It consists of using exogenous microparticles as a source of in situ boiling core induction, only at the focal point of the HIFU beam. These microparticles are perfluorocarbon droplets stabilized by fluorinated surfactants, whose evaporation is triggered using low to moderate HIFU energy, as a joint effect of temperature and acoustic pressure. The evaporation process will induce a cascade of positive-feedback ('chain reaction', or 'self-amplified') energy deposition that will result in the use of lower energy to perform ablation and reduced HIFU side effects. Indeed, the vaporized microparticles will act as a strong reflector for the incident beam. This will protect organs or bones located in the far field by partly blocking the forward propagation of the wave. The superposition of the incident and reflected wave at the distal frontier of the boiling core will yield enhanced absorption and heating.

This will finally re-trigger the evaporation of new particles freshly supplied by the blood flow and the process will be self-maintained until the sonication stops or the renewal of the particles stops. Our goal in this project is to achieve a proof-ofconcept for this cascade-amplified focal ultrasound ablation, first in tissue mimicking gels, then in ex vivo perfused kidney, and eventually in living animal liver. This joint application between Swiss and French work groups will take advantage of the complementary skills and available resources of the involved partners, covering the chemistry and physics of microparticle synthesis and characterization, hybrid ultrasonography and MR imaging and thermometry for simultaneous monitoring of cascade-amplified focal ultrasound ablation treatments, and animal research facilities for in vivo proof of concept.