Subcellular Cavitation Bubbles Induce Cellular Mechanolysis and Collective Wound Healing in Ultrasound‐Inflicted Cell Ablation

Abstract Focused ultrasound (FUS) has been widely adopted in medical and life science researches. Although various physical and biological effects of FUS have been well‐documented, there is still a lack of understanding and direct evidence on the biological mechanism of therapeutic cell ablation caused by high‐intensity ultrasound (HIFU) and the subsequent wound healing responses. This study develops an enclosed cell culture device that synergistically combines non‐invasive FUS stimulation and real‐time, on‐the‐fly live‐cell imaging, providing an in vitro platform to explore short and long‐term biological effects of ultrasound. The process, mechanism, and wound healing response of cell ablation induced by HIFU are elucidated, revealing a unique mechanism, termed ultrasound‐inflicted cellular mechanolysis, that is mediated by growing subcellular cavitation air bubbles under confined contact with cells. This provides a previously unappreciated mechanism for understanding the biomechanical principles of ultrasound‐based ablative therapy. A post‐ablation phantom layer is also revealed that serves as a guiding cue for collective cell migration during wound healing, thereby providing a biomimetic model for studying wound healing after HIFU‐inflicted damage. Together, this study provides theoretical and technological basis for advancing the understanding of the biological effects of ultrasound‐based ablative therapy and inspiring clinically relevant applications in the future.