Developing a Novel High-Fidelity Model to Investigate the Feasibility of Ultrasound-Targeted Nanodroplets Opening the Blood-Brain Barrier

Focused ultrasound (FUS) combined with microbubbles or nanodroplets has been investigated for its ability to transiently and reversibly open the Blood-Brain Barrier (BBB) to enhance drug delivery to the brain. Currently, monolayer models are the predominant platforms used to study the physical mechanisms and influencing factors of ultrasound on the BBB, but they exhibit limited functionality and low relevance to disease processes. This study developed a novel high-fidelity in vitro BBB model by co-culturing brain microvascular endothelial cells (bEnd.3) and astrocytes (C8-D1A) on a microfluidic platform, which mimics the native BBB structure. The model employs fluidic flow to simulate blood flow, more accurately replicating the microenvironment of the BBB and promoting the formation of tight junctions. Experimental results demonstrated significantly elevated transendothelial electrical resistance (TEER) values, significantly reduced permeability (Papp) values, and robust expression of ZO-1 protein, indicating the model’s maturity and integrity. Subsequently, this study utilized the model to demonstrate that ultrasound combined with drug-loaded droplets could significantly open the BBB and enhance the permeability of gene drugs. This high-fidelity BBB model provides a valuable tool for investigating the effects of ultrasound-mediated BBB opening in drug delivery research.