Abstract The objective of this renewal project is to advance the forward viewing catheter-directed microbubble-enhanced sonothrombolysis (FV-CAMUS) technique to the integrated dual-frequency catheter-accelerated sonothrombolysis system (iDUCAS) for treatment of deep vein thrombosis (DVT) that affects two million Americans every year. Current DVT treatment techniques including systemic administration of thrombolytic drugs and mechanical thrombectomy are challenged with major limitations such as long treatment procedures (> 16 hours) and safety concerns including extensive bleeding and vessel wall damage. In the prior project period, our team demonstrated a novel FV-CAMUS technology to treat DVT with fast lysis and with reduced off-target effects using cavitation agents. Despite our significant advancements in FV-CAMUS based sonothrombolysis, the clinical translation challenges remain in treatment of long (> 2 cm) retracted clots because of the lack of image guided catheter motion control and the relatively low cavitation efficiency of phase-change nanodroplets. Thus, in this renewal, we propose to develop the iDUCAS system by integrating intravascular imaging into a dual- frequency ultrasound catheter, integrating motorized catheter advancement with feedback, and improving low- power catheter-driven thrombolysis by combining microbubbles with nanodroplets. In Aim 1, an IVUS imaging integrated iDUCAS system will be developed consisting of a dual lumen 6-French (2 mm) catheter integrated with a dual frequency (500 kHz and 30 MHz) imaging-therapy transducer and a liquid injection conduit (contrast agents and thrombolytic agent), the automated catheter motion control, and IVUS imaging and therapy control units. In Aim 2, optimal nanodroplet-microbubble mixture formulation will be evaluated for use with iDUCAS system. In Aim 3, thrombolysis efficacy and safety via in-vitro and ex-vivo tests using the iDUCAS system will be validated, and the associated in-vitro and ex-vivo sonothrombolysis parameters will be optimized. In Aim 4, thrombolysis efficacy and the safety of the iDUCAS system combined with low dose of thrombolytic agent will be evaluated in the in-vivo swine DVT model with clots of different ages. We expect that the proposed iDUCAS technology will provide a new tool enabling effective and safe treatment of DVT and other venous and arterial thrombosis diseases.