Title: 3D Real-time Super-resolution Passive Cavitation Mapping in Laser Lithotripsy of Urinary Stone Disease Abstract: In the United States, 1 in 11 individuals will experience a urinary stone disease (USD) in their lifetime. Laser lithotripsy (LL) via ureteroscopy, in which pulsed laser light is used to progressively break the stones, has become the choice of treatment for USD patients. In particular, “dusting” mode with low pulse energy and high frequency has gained clinical popularity over “fragmenting” mode because of the fine dust produced, which eliminates the need for basket retrieval and ureteral access sheaths, and thus greatly shortens the procedure time. Growing evidence by us and others have discovered that cavitation bubble collapse plays a significant role in stone dusting by Ho:YAG lasers, and maximizing cavitation activities is critically important for improving LL efficiency. Despite the growing enthusiasm, the exact mechanism of cavitation in LL is not well understood and the optimal LL settings for efficient dusting have not been defined. Such a paucity of knowledge is partially due to the lack of imaging technologies for real-time feedback of cavitation activities during the LL treatment. B-mode ultrasound imaging (or active cavitation mapping) is compatible with LL, but cannot image the short-lived transit bubbles that undergo inertial cavitation and may also interfere with the bubble dynamics. Other imaging technologies, such as x-ray CT, fluoroscopy and MRI, cannot detect cavitations due to the lack of contrast. In light of the clinical need for more efficient LL, we propose to develop 3D super-resolution passive cavitation mapping (3D-SR-PCM) that (1) is totally noninvasive and fully compatible with the LL treatment; (2) is capable of real-time monitoring of the 3D cavitation activities at clinically-relevant depths (>10 cm deep) without background interference; and (3) can achieve a cavitation localization resolution of ~50 µm, which is 10-fold better than the B-mode ultrasound imaging. Our long-term objective of this project is to better understand the therapeutic impact of cavitation in LL treatment, and develop more efficient LL with less adverse effects. Our central objective of this proposal is to develop, validate, and optimize a safe, reliable, and precise imaging technology for real-time analysis of 3D cavitation activities during LL treatment. We will pursue three specific aims: (1) develop the first 3D-SR-PCM system with super-resolution bubble localization, automatic fiber tracking, and real-time cavitation analysis; (2) thoroughly validate and optimize the 3D-SR-PCM system on kidney phantoms, and identify the most relevant cavitation characteristics with stone damage under clinically realistic settings; and (3) apply the optimized 3D- SR-PCM system on a swine model in vivo to evaluate the treatment efficiency with cavitation-imaging guidance, and demonstrate its clinical feasibility through a pilot study on U...