Mechanisms of dual-frequency focused ultrasound regulation of acoustic droplet vaporization-enhanced thermal lesion formation.

Dual-frequency focused ultrasound combined with phase-change nanodroplets offers a promising strategy for improving thermal ablation; however, the mechanisms by which dual-frequency excitation reshapes acoustic droplet vaporization (ADV) and lesion formation remain unclear. Here, we developed a coupled numerical model to investigate how dual-frequency ultrasound governs ADV-enhanced thermal lesion formation through ADV nucleation, bubble-cloud evolution, acoustic-field redistribution, and acoustic energy deposition. The model incorporated nonlinear acoustic propagation, a modified classical nucleation theory for ADV, iterative bubble-cloud expansion, gas-volume-fraction-dependent effective acoustic properties, and bioheat transfer, and was qualitatively assessed against in vitro phantom experiments using a confocal 1 MHz + 5 MHz transducer system. In the presence of phase-change nanodroplets, single-frequency exposure produced delayed ADV after thermal build-up and generated a teardrop-shaped lesion, whereas dual-frequency exposure triggered immediate multisite ADV, accelerated bubble-cloud growth, and yielded a more triangular lesion. Increasing low-frequency acoustic power promoted a transition from teardrop-like to triangular lesions, while increasing nanodroplet concentration enhanced acoustic shielding and shifted lesion formation toward the proximal side of the bubble cloud. These results suggest that dual-frequency ultrasound regulates ADV-enhanced thermal ablation primarily by controlling where ADV is initiated, how the bubble cloud evolves, and where acoustic energy is deposited. The proposed model provides a mechanistic framework for optimizing dual-frequency ADV-mediated ultrasound therapy and engineering controllable lesion geometries.