This Direct to Phase II SBIR project addresses the need for safe and effective drug delivery after lower extremity angioplasty. Globally over 200 million people suffer from peripheral arterial disease (PAD). Both the disease and economic burdens of PAD are projected to grow rapidly, with the US PAD population projected to grow to 22M in 2020 as costs currently exceed $20B. The leading cause of this growth is an aging US population that faces a disease whose prevalence increases with advancing age. In the advanced stages of PAD, angioplasty, the expansion of an occluded artery, is the state of the art for treatment. However, the lifespan of angioplasty can be as brief as 3 months in the periphery due to restenosis, the re-occlusion of the blocked artery by the overgrowth of its own cells. As a result, it is recommended that interventionalists wait to perform angioplasty on patients until the onset of critical limb ischemia (CLI), a catastrophic vessel blockage that results in severe pain and can lead to amputation. In order to address these needs, SoundPipe is commercializing a platform to deliver drugs that can prevent restenosis, the Guidance by Ultrasound Imaging and Delivery Enhancement of Therapeutics (GUIDE-Tx) system. This novel catheter-based system uses ultrasound to simultaneously image the vasculature and enhance delivery of restenosis preventing drugs after angioplasty. The drugs are carried by microbubbles ejected from the tip of the catheter where they are guided to a precise location by intravascular ultrasound. There, under ultrasound image guidance, the ultrasound and microbubbles enhance permeabilization of the cell membrane and release the drug from the microbubbles. This technique controls drug dose and spatial coverage, providing a versatile method for preventing restenosis after angioplasty. SoundPipe?s technology will improve angioplasty by: 1) allowing the interventionalist to control drug dose, type, and coverage and 2) offering image guidance during drug delivery. The added versatility will foster innovation in the field of intravascular drug delivery. This Direct to Phase II SBIR will use a series of in vivo swine and rabbit studies to evaluate whether 1) drug delivered by GUIDE-Tx is of a sufficient dose and is retained by the artery, 2) GUIDE-Tx reduces neointimal hyperplasia, 3) systemic doses of drug following GUIDE-Tx treatment are safe and low. Key technological innovations for this project include a dual mode intravascular drug delivery and imaging system. Plans for Phase III include clinical trials to demonstrate the safety and efficacy of GUIDE-Tx.