Investigation of ultrasound exposure in the presence of microbubbles on a LumeNEXT blood-brain barrier model

The blood-brain barrier (BBB) is notoriously difficult to penetrate for the delivery of drugs and therapeutic compounds due to the unique nature of the tight junctions between endothelial cells. Ultrasound in the presence of microbubbles has been discovered to transiently open the BBB, however, little is known about the mechanism and the effects of excitation parameters at a cellular level. In this study, a static vascular lumen in vitro model, LumeNEXT, was utilized to investigate the excitation parameters in a controlled manner. Fibrin lumen hydrogels were lined with human cerebral microvessel endothelial and astrocyte cells. Cells were exposed to ultrasound with and without the presence of microbubbles. The devices were exposed to ultrasound parameters ranging in frequency from 0.5 to 1.55MHz, duty factor from 0.0001–0.001 and pulse repetition frequency of 1–10 Hz. Acoustic and thermal characterization of the device was performed. Effects of microbubble size and composition on the endothelial permeability were also investigated. The transepithelial electrical resistance (TEER) and cell morphology were monitored post-ultrasound exposure to investigate endothelial permeability duration and extent. Understanding the fundamentals of ultrasound-induced permeability in a controlled manner can lead to further investigations and optimization for in vivo and clinical settings.