SBIR-STTR Award

An estimated two million people a year are affected by arterial and venous thrombosis. Treatment with thrombolytic drugs is effective, but current procedures are successful at rapidly dissolving the thrombi only 70% to 80% of the time. The applicant organization, EKOS, has developed an ultrasound catheter device and demonstrated an enhanced thrombolytic effect in vitro and in vivo. The underlying acoustic and biochemical mechanisms for this enhancement are unknown. Understanding the fundamental mechanisms of ultrasound-assisted drug transport through clots is critical for optimizing the ultrasound catheter device and protocols for its use. The specific aims are: 1. Develop a confocal and epifluorescence imaging system to visualize in vitro fibrin clots under conditions of lysis and regimens of catheter-delivered ultrasound, and to test and optimize different probe designs; 2. Characterize the action of catheter delivered ultrasound of varying intensity and frequency on the penetration and binding rates of fluorescently labeled problems into purified fibrin gels and in vitro clots; and 3. Develop a computer algorithm that will: (1) provide theoretical upper limits for ultrasound-assisted thrombolysis; (2) facilitate compute aided design of improved catheter geometry and operation; and, (3) facilitate in- house technology transfer of knowledge gained with thrombolysis to new applications for ultrasound catheters.

The applicant organization, EKOS, has developed a drug delivery catheter device that utilizes low energy ultrasound to enhance drug-mediated thrombolysis. Despite the progress in animal studies and human trials, the underlying acoustic and biochemical mechanisms for the enhancement of thrombolysis are not fully understood. The applicants hypothesized ultrasound can enhance thrombolysis further than currently observed, but new experimental assays and models are needed in order to optimize the effects of the ultrasound and to better understand the fundamental mechanisms. In Phase II, the applicants proposed to continue to investigate acoustic mechanisms of thrombolysis and acoustic protocols that may further enhance thrombolysis by characterization of kinetic and transport parameters in well defined and controlled experiments. In addition, they proposed to focus on the mechanisms by which microbubbles further enhance the ultrasound-mediated thrombolytic process. This has been shown in vitro and in vivo but there is little understanding of how best to use microbubbles to maximize their synergistic effect with ultrasound in a therapeutic rather than diagnostic mode. These studies are critical to determining how the EKOS ultrasound catheter can be optimized for use in human patients as well as to provide insight into the development of future thrombolytic products.