Date of Award
5-14-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Brain cancer is a devastating disease characterized by the abnormal growth of cells within the brain. It disrupts neurological function, carries a grim prognosis, and significantly decreases the quality of life. Glioblastoma (GBM), the most common malignant primary brain tumor in adults, is particularly aggressive, with less than 5% of patients surviving for five years. The conventional treatment portfolio, including radiation therapy, chemotherapy, and surgical resections, is less effective for GBM than other cancer diseases due to its high spatial heterogeneity and adaptability to treatment. This suggests that an accurate and comprehensive diagnosis of the molecular subtypes is critical for advancing treatment strategies and patient care for GBM and other brain cancer diseases. The challenges in detecting brain cancer at an early stage contribute to the poor survival rate, mainly because accurate diagnosis often requires invasive surgical biopsy. Current diagnostic approaches typically involve neuroimaging followed by tissue biopsy to confirm the diagnosis and obtain the tumor's molecular profile. While tissue biopsy is considered the definitive method for molecular characterization, it carries significant risks for patients due to its invasive nature. An alternative approach, liquid biopsy, offers a minimally invasive method for genetic profiling by detecting tumor-derived biomarkers in the blood. However, the effectiveness of blood-based liquid biopsy is limited by the presence of the blood-brain barrier (BBB), which hinders the release of molecular biomarkers into the bloodstream. Consequently, achieving high detection sensitivity for glioblastoma (GBM) poses a challenge. Therefore, the development of novel techniques or strategies that can overcome the limitations imposed by the BBB is crucial for enhancing early detection and improving outcomes for individuals with brain cancer. One such technique is sonobiopsy, which utilizes focused ultrasound in the brain combined with intravenously injected microbubbles to temporarily open the blood-brain barrier and allow the release of crucial disease-specific biomarkers into the bloodstream. Our research group has been developing and testing sonobiopsy since 2017, initially using healthy mice models and then progressing to large animal models and clinical studies upon the completion of this thesis. To advance the clinical application of sonobiopsy, I developed and tested a clinical system that uses neuronavigation as guidance instead of MRI guidance, significantly reducing the resources required for performing sonobiopsy in a clinical setting. Neuronavigation guidance, which is widely used in neurosurgery rooms, ensures a seamless transition for sonobiopsy into clinical practice. The clinical system was modified to be compatible with the clinical neuronavigation system, StealthStation S8, and related Medtronic surgical tools. Additionally, I developed a novel acoustic trajectory planning and simulation software called SonoLink, which facilitates the study's pre-treatment planning. The feasibility, safety, and efficacy of the developed clinical system and sonobiopsy techniques were tested in a clinical trial involving five patients with late-stage brain tumor diseases. To further improve sonobiopsy's targeting accuracy, a phased array device was integrated into the clinical system to compensate for skull aberration caused by differences in skull sound speed and shape during ultrasound propagation. Ray tracing and time-reversal simulations were incorporated into the SonoLink software to calculate the element-wise phase profile needed for patient aberration correction. Lastly, I explored the possibility of a patient-specific and wearable-focused ultrasound device that allows repeated and long-term monitoring of brain tumor diseases using sonobiopsy in an outpatient setting. Overcoming the challenge of coupling through hair, I developed a novel use of mineral oil as an alternative coupling medium. I tested its efficacy in a mice study. A patient-specific helmet prototype was developed and tested on a head phantom, and the effectiveness of oil coupling was tested using human hair integrated with the helmet, using a passive-cavitation detector as a readout for coupling quality. This study opens up the practical application of sonobiopsy technology in outpatient settings and its more comprehensive application for non-cancer diseases such as Alzheimer's. In summary, this work has advanced the sonobiopsy technology to clinical trials by developing, testing, and validating its safety and efficacy in large animals and clinical studies. The system has been further improved by integrating a phased array focused ultrasound device to address tumor targeting accuracy. Additionally, the feasibility of a wearable and patient-specific ultrasound device for sonobiopsy in outpatient settings has been demonstrated, paving the way for broader adoption of sonobiopsy techniques.
Language
English (en)
Chair
Hong Chen