SUMMARY ABSTRACT Urolithiasis imposes a substantial and growing public health burden in the United States with a prevalence nearly doubled over the past 15 years, impacting now 1 in 11 Americans in their lifetime. Shock wave lithotripsy (SWL) remains to be the only non-invasive treatment option for kidney stone patients despite the advances in ureteroscopy. The progressive decline in the clinic use of SWL, on the other hand, has been attributed to several key factors, including 1) no fundamental technology breakthrough with problematic dry coupling technique widely employed by contemporary shock wave lithotripters, 2) no real-time monitoring of cavitation activity during clinical SWL, and 3) increased number of shockwaves administered per session with elevated fragment size and non- successful rate. Overall, addressing these critical issues is urgently needed to improve the efficiency and safety of SWL, and ultimately, reinvigorate the confidence of urologists in this non-invasive treatment modality for stone patients. In this competing R01 renewal application, we will leverage the knowledge and expertise that our interdisciplinary team has accumulated in the past ten years through the R37 program. We will focus on developing the next-generation SWL, cavitation monitoring, and miniature wet coupling technologies as well as strategies to produce fine stone fragments in SWL with clear translational potentials. We propose three specific aims: 1) create a SAFE (Steerable and Adjustable Focusing Electrohydraulic) shock wave generator with flexible focal width and beam orientation, and a miniature wet coupling device, 2) develop 3D Dynamic Cavitation Monitoring (3D-DCM) technology for safeguarding SWL while improving stone fragmentation efficiency and treatment outcome , and 3) investigate mechanism of surface acoustic wave (SAW) generation and its contribution to producing fine fragments through synergistic interaction with cavitation in SWL. Achieving these aims will significantly advance the state-of-the-art research activities in SWL, and further propel technology development in the field in close collaboration with lithotripter manufacturers. The new technologies envisioned in this project will improve the safety and efficacy of SWL, while providing the urologist opportunity and flexibility in tailor-designing the treatment protocol for stone patients under various clinical scenarios.