First in-vivo Demonstration of Bilateral Blood-Brain Barrier Opening Using Acoustic Holograms in Mice

Abstract

[EN] Focused ultrasound (FUS) with microbubbles allows for non-invasive targeted drug delivery into the central nervous system (CNS) by temporally and locally disrupting the bloodbrain barrier (BBB). However, current FUS technologies are not able to simultaneously target several brain structures. In this work, we open the BBB in two regions in a murine brain using a single-element transducer with a coupled 3D-printed holographic lens, which is designed to simultaneously create two symmetric foci in anesthetized mice in vivo. The proposed approach shows many advantages: (1) simple and low-cost; (2) correction of aberrations due to skull and water cone; and (3) multiple BBB opening (BBBO) locations with only one sonication, becoming a time- and cost-effective therapeutic system for neurological diseases. For the in-vivo experiment, contrast-enhanced, T1- weighted MRI scan was conducted following BBBO, showing gadolinium extravasation at two symmetric focal spots. The two BBBO regions were separated by 3.0 +- 0.7 mm (n=5 mice) compared to 5.3 mm in full-wave simulations. This work shows the capability of bifocal ultrasound generation in separate animals using a unique uCT scan. A bilateral BBBO was achieved with a single sonication using a holographic lens in mice, thus improving the efficiency and defining a new approach for several neurodegenerative diseases targeting symmetric brain structures, e.g. hippocampus, putamen or caudate. This study demonstrates the feasibility of hologram-assisted BBBO for targeted drug delivery in the CNS in symmetric regions in separate hemispheres.