Ultrasound in the presence of microbubbles in a dynamic invitro microfluidic blood-brain barrier model

Abstract

Controllable, localized permeability of the blood-brain barrier (BBB) has been a goal of health professionals for enhanced delivery of drugs and therapeutic compounds for cancer and other neurological medical conditions. The transient permeability induced by transcranial ultrasound exposure in the presence of microbubbles has been shown to be a promising option, but little is known about the exact mechanism and response on a cellular level. A microfluidic device developed to recreate the in vivo microenvironment, including physiological fluid flow, was seeded with human cerebral microvessel endothelial cells surrounded by a matrix of astrocytes. The devices were exposed to ultrasound with and without the presence of microbubbles. The ultrasound parameters ranged in frequency from 0.5 to 1.55 MHz, duty factor from 0.0001–0.001 and pulse repetition frequency of 1 Hz–10 Hz. Microbubble size, composition, and concentration within the pumped fluid were also varied, along with varied flow rate. The transepithelial electrical resistance (TEER) and cell morphology were monitored throughout and post ultrasound exposure to understand the effects on permeability and cell viability. With this controlled variation of the ultrasound and microbubble parameters, a greater understanding of the induced permeability could lead to more success for clinical utilization.