Transcranial Therapy for Intracerebral Hemorrhage and Other Brain Pathologies using Histotripsy

Abstract

Brain pathologies including stroke and cancer are a major cause of death and disability. Intracerebral hemorrhage (ICH) accounts for roughly 12% of all strokes in the US. ICH is characterized by the rupture of vessels resulting in bleeding and clotting inside the brain. The presence of the clot causes immediate damage to surrounding brain tissue via mass effect with delayed toxic effects developing in the following days. This leads to 30-day mortality rate of 40% and motivates the need to quickly evacuate the clot. Craniotomy surgery and minimally invasive methods using thrombolytics are common procedures but are limited by morbidity and susceptibility to rebleeding, leading to poor outcomes. Histotripsy is a non-thermal ultrasound ablation technique that uses short duration, high amplitude rarefactional pulses (>26 MPa) delivered via an extracorporeal transducer to generate targeted cavitation using the intrinsic gas nuclei in the target tissue. The rapid and energetic bubble expansion and collapse of cavitation create high stress and strain in tissue at the focus that fractionate it into an acellular homogenate. This dissertation presents the role of histotripsy as a novel ultrasound technology with potential to address the need for an effective transcranial therapy for ICH and other brain pathologies. The first part of this work investigates the effects of ultrasound frequency and focal spacing on transcranial clot liquefaction using histotripsy. Histotripsy pulses were delivered using two 256-element hemispherical transducers of different frequency with 30-cm aperture diameters. Treatment durations ranged from 0.9-42.4 min. Liquefied clot volumes ranging from 6-59 mL were drained via catheter and syringe. The second part addresses safety concerns for histotripsy ICH treatment through investigation in a porcine ICH model. 1.75-mL clots were formed in the porcine brain. The cores of the clots were liquefied with histotripsy 48-h after formation, and the liquefied contents were either evacuated or left within the brain. A control group was left untreated. The cores of clots were liquefied without damage to the perihematomal tissue. An average volume of 0.9±0.5 mL was drained after histotripsy treatment. The third part presents the development of a catheter hydrophone method for transcranial phase aberration correction and drainage of the clot liquefied with histotripsy. A prototype hydrophone was fabricated to fit within a catheter. Corrections with the catheter hydrophone resulted in improvements in focal pressure of up to 60% at the geometric focus and 27%-62% across a range of electronic steering locations. The cores of clots liquefied with histotripsy were readily drained via the catheter. The fourth part focuses on the development of a preclinical system for translation to human cadaver ICH models. A 360-element, 700 kHz hemispherical array with a 30-cm aperture was designed and integrated with a surgical navigation system. Calibrated simulations of the transducer suggest an effective therapeutic volume between 48-105 mL through the human skull. The navigation system allows real-time targeting and placement of the catheter hydrophone via a pre-operative CT or MRI. The fifth part of this work extends transcranial histotripsy therapy beyond ICH to the treatment of glioblastoma. This section presents results from an investigation into cancer immunomodulation using histotripsy in a mouse glioblastoma model. The results suggest histotripsy has some immunomodulatory capacity as evidenced by a 2-fold reduction in myeloid derived suppressor cells and large increases in interferon-γ concentrations (3500 pg/mL) within the brain tumors of mice treated with histotripsy.