Ultrasounds trigger reversible permeability of the cerebrovascular endothelium in a novel 3D-bioprinted model of the human blood-brain barrier

Abstract

The blood-brain barrier (BBB) restricts the penetration of therapeutic agents to the brain. Focused ultrasound (FUS) insonation of microbubbles has enhanced drug delivery via a temporary opening of the tight junctions of the BBB. Rodents are often used for testing novel therapeutic strategies. However, biological discrepancies existing between rodents and humans impedes the translation of some results. We investigated the effect of FUS transient disruption of a human microphysiological model of the BBB consisting of human brain endothelial cells cultured within a 3D-bio printed scaffold designed to reconstitute the architecture of a perfused blood vessel. Cavitation activity was detected in the model when perfused with Lumason microbubbles and exposed to 500 kHz ultrasound at 0.4 MPa for 10 ms pulse duration and 2 Hz pulse repetition frequency. An increase in extravasation of a dye beyond the endothelial layer was detected within 2–3 h of ultrasound insonation. Our results support that this system could be used for targeted BBB opening with a human cell culture model. Moreover, this system holds a promise to further the translational study on US-mediated drug delivery and the development of personalized therapies for patients with brain cancer and other neurovascular disorders.