A Blood–Brain Barrier-on-Chip Approaching In Vivo Tightness for Quantitative Ultrasound-Mediated Opening
Year: 2026
Type: preprint
Abstract: The blood–brain barrier (BBB) remains one of the greatest obstacles to the treatment of neurological diseases, preventing the delivery of nearly all large therapeutics and most small molecules to the brain. Although ultrasound-activated microbubbles offer a promising strategy for transient BBB opening, quantitative in vitro models capable of reproducing physiological barrier properties while allowing controlled ultrasound studies remain scarce. Here, we report a human BBB-on-chip that combines near-physiological barrier tightness with real-time quantitative permeability measurements under ultrasound exposure. We identify the key physical parameters governing barrier formation, demonstrating that microenvironment geometry and hydrogel confinement play a decisive role in establishing a functional endothelial barrier. The optimized platform exhibits permeability coefficients for 10 and 70 kDa dextran that approach in vivo values despite relying on a simple endothelial monoculture under static conditions. To quantitatively characterize barrier integrity, we compare three permeability formulations commonly used in the literature and introduce a complementary impermeability index describing barrier dynamics. Finally, we demonstrate that ultrasound-activated microbubbles increase barrier permeability by more than sixfold, enabling the extravasation of fluorescent tricaprylin nanodroplets into the hydrogel compartment.
Source: ChemRxiv
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7220473944