Feasibility of transcranial histotripsy for pediatric neuro-oncology applications using a hemispherical transducer

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Pediatric patients have a real and urgent unmet need for less invasive treatments which can efficiently and safely treat brain tumors without incurring significant late effects. The long-term goal of this proposal is to develop an efficient non-invasive treatment modality without any late effects for safe treatment of both benign and malignant pediatric brain tumors. This will be done utilizing tissue-liquification by focused ultrasound (FUS)-induced histotripsy. The overall objectives in this application are to (i) elucidate the degree to which high acoustic pressures and non-linear shocking mediate the tissue liquification process and what contribution each of three possible histotripsy mechanism may play when using a hemispherical FUS transducer; and (ii) systematically investigate the parameter space that supports mechanical liquification by hemispherical transducers both ex vivo and in vivo with pediatric skulls in the FUS beam path. The central hypothesis is that carefully designed experiments can be performed to understand the mechanism of action behind tissue liquification using low f-number (e.g., hemispherical) transducers, and that histotripsy can be feasibly accomplished within at least a subset of the pediatric population. The rationale for this project is that understanding the mechanism responsible for tissue liquification using existing and regulatory approved hemispherical transcranial FUS transducers, together with in vivo parameter optimization, is likely to offer strong scientific support for the feasibility of pediatric brain tumor histotripsy treatments. The central hypothesis will be tested by pursuing two specific aims: 1) conduct carefully designed computational, benchtop, and ex vivo experiments to determine the contribution each of three possible histotripsy mechanism have on the tissue liquification process; and 2) investigate the parameter space that supports mechanical liquification by hemispherical transducers through pediatric skulls. The research proposed in this application is innovative, in the applicant’s opinion, because it proposes to determine the mechanism of action behind histotripsy tissue liquification using low f-number FUS transducers, as well as optimize the FUS pulsing parameters. The proposed research is significant because it is expected to provide a strong scientific justification for further studies of transcranial histotripsy for the pediatric population. Ultimately, this novel non-invasive treatment modality has the potential to help the approximately 4,300 children who are diagnosed with brain tumors in the US every year, 30% of whom do not survive past five years after diagnosis, with a safe an efficient treatment option.