Regulatory science tools for ultrasound activated microbubble products for neurological applications
High-Intensity Therapeutic Ultrasound (HITU) combined with microbubbles injected into the bloodstream represent a promising tool for noninvasively treating a wide variety of neurological disorders, such as Parkinson’s disease, Alzheimer’s disease, brain tumors, or stroke. Treatment can be administered into the brain by opening the blood-brain barrier (BBB) using ultrasound and bubbles. These methods have a risk of causing vessel rupture and cellular damage, and very little is known about the thresholds, mechanisms, and relevant mechanobiology under rupture. As a result, the U.S. Food and Drug Administration requires comprehensive safety testing in animal and/or human clinical trials for new devices using microbubbles, or existing devices that change the microbubble or ultrasound methods. The need addressed in this project is that of reliable regulatory science biomarker tools for predicting vascular and cellular integrity in emerging technologies utilizing HITU + Microbubbles under clinical conditions. This dissertation describes important advances made in the development of these tools. The first tool is a predictor of the likelihood of vessel damage in HITU procedures. It is based upon a novel earthworm model, in which microbubbles were perfused into the vessels and damaged in response to sonication was observed. A second tool, to assess and evaluate bulk-cellular and vascular damage, involved development of a 3D-printed US-compatible BBB Bioreactor model. The third tool, a tomographic microscopic method, is useful for assessing integrity and damage of single cells on a nanoscale. The driving frequencies used were 0.5, 1.1, 2.5, and 3.3 MHz. The pulse repetition frequencies used were 1, 3 and 10 Hz. The duty factor was held at 0.1%. Polydisperse microbubbles ranged from 1.7 to 8.5 um in diameter for a 60 nL bolus delivery. The bubbles were composed of perfluorobutane gas core and a lipid surfactant blend: DSPC (main lipid) and DSPE-PEG2000 (co-emulsifier). By conducting regulatory research and creating a publicly available vessel rupture database, a new biomarker was developed to predict vessel bioeffects. These regulatory tools can improve regulatory science in the area of therapeutic ultrasound and accelerate delivery of new treatments to patients.