Rationally Designed Acoustic Holograms for Uniform Nanodroplet-Mediated Tissue Ablation

Nanodroplets (NDs) are phase-changing agents that have shown great potential for ultrasound (US) applications. When US is applied, NDs can undergo a phase transition into gas bubbles, enabling cavitation that can be used to reduce the pressure threshold required for mechanical ablation of tissues. Effective tissue fractionation depends on precise vaporization to achieve uniform and predictable bubble formation. This study aimed to optimize ND vaporization using acoustic holograms for improved ND-mediated histotripsy. Tissue ablation was conducted using a two-step approach, where a rotating imaging probe was used for ND vaporization followed by low-frequency US for detonation. We developed and validated three distinct acoustic hologram patterns targeting different regions within a circular area through simulations and experiments. Using custom-made gelatin phantoms designed for optimal ND vaporization imaging, the superpositioned patterns demonstrated significantly more uniform ND vaporization compared to standard single-focus steering, with ND coverage reaching % for the optimized vaporization approach versus % for the single focus steering. Ex vivo chicken liver experiments confirmed the enhanced efficiency of the optimized approach, resulting in significantly larger and more uniform lesion areas. Lesion areas generated by 120 s of treatment reached mm2 compared to mm2 for the standard approach, a 5.1-fold increase. These findings suggest that using acoustic holograms can improve ND vaporization uniformity and enhance the homogeneity of tissue fractionation, thereby potentially enhancing therapeutic outcomes.