RESEARCH PROJECT: ABSTRACT Urinary stone disease (USD) is a benign but severely painful genitourinary disease that affects nearly 1 in 11 Americans, with an annual health expenditure of over $2 billion in the US. The introduction of high power/high frequency Holmium (Ho): YAG lasers and Thulium Fiber Laser (TFL) have fundamentally altered the mode of laser lithotripsy (LL), which is the treatment of choice for USD. Pop-dusting is a technique widely used in the final stage of LL, whereby the laser fired in a renal calyx causes the sizable fragments to move rapidly to grind them down to dust, which potentially leads to significant temperature increase in the kidney. Benchtop in vitro, porcine in vivo, and FDA adverse event reports all raise concerns for dangerous thermal dose accumulation and potentially permanent thermal injury. Our recently published findings lead us to hypothesize that cavitation bubble collapse with resultant microjet impact on the stone surface or streaming-induced shear may contribute to this process. In other words, the absorption of laser power of the fluid plays a critical role in the pop-dusting behavior. Therefore, by enhancing the Ho:YAG laser or TFL absorption, we can lower the power requirement for generating equivalent or stronger bubble activities to improve pop-dusting efficiency, while concurrently lowering the risk of thermal damage to the kidney tissue. The overarching objective of the Research Project (RP) of the Duke FORWARD P20 Urology Center is to extend the research efforts of the Center for Urological Research and Engineering (CURE) at Duke University by incorporating previously unexplored nanotechnology approaches. We plan to utilize nanophotonic science to develop a specialized nanofluid with high and selective absorption of the laser and investigate its benefits on LL efficiency, toxicity, and clinical safety from a benchtop model to in vitro and in vivo studies. The center's Research Project has three Specific Aims focusing on (1) Develop biologically safe nanoparticles with absorption peak optimized for Ho:YAG laser (λ = 2.1 μm) and TFL (λ = 1.94 μm) and assess cavitation dynamics and cell injury in an optical cuvette model. (2) Investigate the effects of nanoparticle-enhanced pop-dusting in a hydrogel-based kidney model and examine treatment efficiency and thermal damage risk in vitro. (3) Explore the effects of nanoparticle-enhanced pop-dusting in a porcine model and evaluate toxicity, safety, and pop-dusting efficiency in vivo. By achieving these aims, we envision successful progress and critical preliminary data collection, both in vitro and in vivo, for supporting future R01 applications on nanotechnology-enhanced LL. We further anticipate that the synergy and new knowledge created by this FORWARD P20 program will greatly enhance and promote our existing and future collaborations within the broader NIDDK CAIRIBU program, including the U54 Center at Columbia and the KURe K12 program at Duke, as we...