Thrombosis is a leading cause of death and disability in the United States. While conventional treatment methods for thrombosis carry high-risks side effects, non-invasive ultrasound treatments have shown promise, especially when microbubbles are included to enhance lysis rates at lower ultrasound intensities. However, the physics behind microbubble enhanced thrombolysis involves complex and inter-coupled mechanisms, such as bubble and structure dynamics, bubble cloud, bubble-flow, and cloud-clot interactions. As a result, the biophysics of microbubble enhanced thrombolysis remains poorly understood, which poses a major barrier to effective clinical applications. To address this challenge, this proposed SBIR project aims to develop a biophysics- based numerical platform for the accurate characterization of microbubble-enhanced ultrasound and its interaction with blood clots, as well as the resultant clot removal. This platform will allow for the accurate prediction of clot lysis rates under various operating conditions such as bubble size, concentrations, and ultrasonic properties etc. Innovation will center on overcoming the technical challenges of meeting performance requirements for both accuracy and efficiency, by incorporating multi-scale, multi-discipline physics into a systematical multi-material modeling framework, along with significant speedup through novel High Performance Computing scheme developments. The proposed efforts will extend the capabilities of a previous in-house, viscous compressible multi-material flow solver that was demonstrated in microbubble-enhanced high-intensity focused ultrasound (HIFU) for tumor ablations. Essential new development will be to incorporate appropriate strain stress relations to consider the viscoelastic properties of blood clots and integrate a two-way coupled Discrete Singularity Model for microbubbles to capture nonlinear bubble cloud dynamics and its interaction with acoustic fields and evolving structures. This single-code strategy will avoid the drawback of coupling different codes, which poses a barrier to biomedical researchers for clinical applications. In addition, the simulations will be greatly accelerated by High Performance Computing schemes to be fast enough to be practical for real-world problems. This project has the potential to significantly benefit the health and welfare of millions of people in the United States and around the world by accelerating and promoting the wide clinical applications of microbubble -enhanced sonothrombolysis. This will greatly reduce risks and enhance the efficiency of conventional FDA-approved sonothrombolysis.