Date of Award
5-14-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Focused ultrasound (FUS) has emerged as a promising noninvasive technique for noninvasive and transient opening of the blood-brain barrier (BBB). FUS-induced BBB opening enables "two-way trafficking" between the brain and bloodstream to benefit the development of effective therapeutic approaches and advance the diagnosis of brain diseases. This technology not only enables targeted drug delivery to the brain for the treatment of various neurological disorders but also can enhance the release of brain-specific biomarkers from the FUS-targeted brain location into the blood circulation for noninvasive and localized molecular diagnosis of brain diseases, a technique called sonobiopsy. However, the lack of precise control during FUS-induced BBB opening procedures can lead to unintended consequences, including tissue damage, inconsistent permeability modulation, and variable therapeutic outcomes. To address these challenges, the development of an individualized closed-loop feedback control system is essential to monitor and adjust FUS parameters in real-time, ensuring both safety and efficacy throughout the procedure. The implementation of a feedback control algorithm is crucial in FUS-induced BBB opening procedures to ensure precise and controlled modulation of BBB permeability. Without real-time monitoring and feedback controlled FUS parameters, there is a risk of overexposure to ultrasound energy during FUS-induced BBB opening procedure, exceeding safe acoustic pressure levels, leading to tissue damage, hemorrhage, and other adverse effects. Moreover, without individualized feedback control system for each subject, the efficacy of BBB opening may be inconsistent across different subjects. Lack of control over the procedure may also limit the reproducibility and reliability of results, impeding the advancement of FUS-based therapies, hindering the translation of FUS-based therapies into clinical practice. However, among various feedback control systems, an individualized closed-loop feedback control algorithm offers several advantages. An individualized control system that tailors FUS parameters to the specific characteristics of each subject, such as skull thickness, microbubble variations and vasculature differences. Adopting an individualized system can optimize treatment efficacy while minimizing risks. Furthermore, a closed-loop system continuously monitor and adjust FUS parameters in real time, ensuring precise control from the initiation to the completion of the procedure, thus enhancing safety and efficacy. This thesis work developed an individualized closed-loop feedback control system and evaluated its performance from mice to pigs and eventually to clinical studies. Initially validation was performed in mouse models and demonstrated its ability to accommodate inter-subject variability and optimize treatment parameters for each individual mouse (Chapter 2). Subsequent optimization was performed in a large animal model. A porcine model was chosen due to their physiological resemblance to humans. The large animal study further refined the system's performance and bridged the translational gap between preclinical studies and clinical application (Chapter 3). Before applying the proposed feedback control system in clinical practice, a comprehensive quality assurance (QA) protocol was developed to ensure the consistent and safe operation of FUS-induced BBB opening procedures in patients (Chapter 4). The QA protocol encompassed rigorous assessment of FUS device functionality, acoustic coupling integrity, and procedural consistency, mitigating potential risks and ensuring reproducibility across clinical settings. Clinical studies employing the proposed feedback control system demonstrated its feasibility in in brain tumor patients. Real-time monitoring and adjustment of FUS parameters facilitated personalized treatment delivery, enhancing therapeutic outcomes while minimizing risks. These findings highlight the potential of individualized closed-loop feedback control systems to revolutionize therapeutic interventions in neurological disorders and improve patient outcomes. The proposed feedback control system, from preclinical to clinical stages, enhances the safety and effectiveness of FUS-induced BBB opening for brain disease diagnosis and treatment. The design and implementation of the proposed individualized closed-loop feedback control system represents significant advancements in the medical ultrasound field.
Language
English (en)
Chair
Hong Chen