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.
