The Woodruff School

SUMMARY

Microbubble-enhanced focused ultrasound (MB-FUS) is an emerging technology especially for drug delivery in the brain as it enables non-invasive, reversible, and targeted physical opening of the blood-brain barrier (BBB). MB dynamics (i.e., radius change as a function of time) during FUS excitation plays a key role in the efficacy and safety of this procedure. Thus, reproducible tuning and monitoring of the MB dynamics to an effective strength while avoiding collapse of MB, which has been associated with tissue damage, is essential. Several past studies have proposed algorithms to control MB dynamics in the brain. However, a robust method that ensures safety and adapts to the highly non-linear bubble oscillation and dynamic environment in the brain remains an open problem. The overall objective of the thesis is to design and evaluate control methods to attain and sustain desired microbubble dynamics in the brain using their acoustic emissions (e.g., spectral contents). Specific aims of the project are 1) to design an acoustic emission-based algorithm to control MB dynamics in the brain and assess the performance and efficacy in healthy brains and glioblastoma (GBM) tumor model (GL261) in rodents; 2) to improve the safety of the controller using machine learning methods, and 3) develop acoustic based methods to directly monitor microbubbles’ radius in both in vitro conditions and induce different BBB phenotypes linked to MB dynamics in radius. By bridging the MB dynamics with their biological responses, this work will not only refine our understanding on the role of MB dynamics during MB-FUS technology, but also support the development of novel diagnostic (e.g., liquid biopsy) and therapeutic strategies against brain diseases (e.g., brain cancer immunotherapy). Furthermore, in combining MB-FUS treatments with existing therapeutic strategies, the ability to control the MB dynamics using acoustic methods will ultimately support their safe application in humans along with the widespread adoption of this technology.

SUBJECT:	Ph.D. Dissertation Defense

BY:	Hohyun Lee

TIME:	Wednesday, August 14, 2024, 12:30 p.m.

PLACE:	Whitaker Ford Building, 1214

TITLE:	Microbubble Dynamics Control and Monitoring for BBB Opening with Focused Ultrasound

COMMITTEE:	Costas Arvanitis, Chair (ME) Levent Degertekin (ME) Levi Wood (ME) Karim Sabra (ME) Spencer Bryngelson (COC)

SUMMARY Microbubble-enhanced focused ultrasound (MB-FUS) is an emerging technology especially for drug delivery in the brain as it enables non-invasive, reversible, and targeted physical opening of the blood-brain barrier (BBB). MB dynamics (i.e., radius change as a function of time) during FUS excitation plays a key role in the efficacy and safety of this procedure. Thus, reproducible tuning and monitoring of the MB dynamics to an effective strength while avoiding collapse of MB, which has been associated with tissue damage, is essential. Several past studies have proposed algorithms to control MB dynamics in the brain. However, a robust method that ensures safety and adapts to the highly non-linear bubble oscillation and dynamic environment in the brain remains an open problem. The overall objective of the thesis is to design and evaluate control methods to attain and sustain desired microbubble dynamics in the brain using their acoustic emissions (e.g., spectral contents). Specific aims of the project are 1) to design an acoustic emission-based algorithm to control MB dynamics in the brain and assess the performance and efficacy in healthy brains and glioblastoma (GBM) tumor model (GL261) in rodents; 2) to improve the safety of the controller using machine learning methods, and 3) develop acoustic based methods to directly monitor microbubbles’ radius in both in vitro conditions and induce different BBB phenotypes linked to MB dynamics in radius. By bridging the MB dynamics with their biological responses, this work will not only refine our understanding on the role of MB dynamics during MB-FUS technology, but also support the development of novel diagnostic (e.g., liquid biopsy) and therapeutic strategies against brain diseases (e.g., brain cancer immunotherapy). Furthermore, in combining MB-FUS treatments with existing therapeutic strategies, the ability to control the MB dynamics using acoustic methods will ultimately support their safe application in humans along with the widespread adoption of this technology.