Characterization of focused ultrasound blood-brain barrier disruption effect on inflammation as a function of treatment parameters

Abstract

The technology of focused ultrasound-mediated disruption of the blood-brain barrier (FUS- BBB opening) has now been used in over 20 Phase 1 clinical trials to validate the safety and feasibility of BBB opening for drug delivery in patients with brain tumors and neurodegenerative diseases. The primary treatment parameters, FUS intensity and microbubble dose, are chosen to balance sufficient BBB disruption to achieve drug delivery against potential acute vessel damage leading to microhemorrhage. This can largely be achieved based on both empirical results from animal studies and by monitoring the microbubble cavitation signal in real time during the treatment. However, other safety considerations due to second order effects caused by BBB disruption, such as inflammation and alteration of neurovascular function, are not as easily measurable, may take longer to manifest and are only beginning to be understood. This study builds on previous work that has investigated the inflammatory response following FUS-BBB opening. In this study, we characterize the effect of FUS intensity and microbubble dose on the extent of BBB disruption, observed level of microhemorrhage, and degree of inflammatory response at three acute post-treatment time points in the wild-type mouse brain. Additionally, we evaluate differences related to biological sex, presence and degree of the anti- inflammatory response that develops to restore homeostasis in the brain environment, and the impact of multiple FUS-BBB opening treatments on this inflammatory response.