Acoustic hologram-enabled simultaneous multi-target blood-brain barrier opening (AH-SiMBO)

Focused ultrasound-induced blood-brain barrier (BBB) opening enables targeted brain drug delivery. However, achieving simultaneous multi-target BBB opening across various depths and regions remains challenging and cost-prohibitive. Here we address these challenges by employing encoded acoustic holograms combined with a single-element plane-wave transducer to generate precise focused acoustic fields. The holograms designed using an iterative angular spectrum approach and fabricated via 3D printing produce single or multiple foci at different depths and regions, which are confirmed by simulations and hydrophone-based measurements. Beam steering capability is demonstrated and further validated in vivo. We design a hologram with less than 10% variation in amplitude across different foci and successfully achieve biplane multi-target (≥3) BBB opening in the bilateral hippocampus and medial septum of mice in a single sonication session with no adverse effects. This innovative acoustic holographic approach for simultaneous multi-target BBB opening is time-efficient and cost-effective, presenting broad potential applications in brain drug delivery and neuromodulation.