Ultrasound Cavitation of Microbubbles Augments Limb Perfusion and Promotes Ulcer Healing in Chronic Limb-Threatening Ischemia.

BACKGROUND:In patients with peripheral artery disease and chronic limb-threatening ischemia (CLTI), there is a lack of effective treatment options when arterial revascularization is not feasible. In preclinical models, ultrasound (US) cavitation of microbubble contrast agents can augment limb perfusion through multiple shear-mediated vasoactive pathways. OBJECTIVES:This study aims to evaluate whether US cavitation increases limb tissue perfusion and accelerates healing of ischemic ulcers in patients with CLTI. METHODS:Patients (n = 24) with CLTI and chronic nonhealing ulcers were randomized to standard care or cavitation therapy, which was performed every 3 days × 6. Definity was infused, and US (1.3 MHz, mechanical index: 1.3) was performed for 15 minutes at the wound site and simultaneously over the ipsilateral femoral artery to leverage conducted vasodilation. The primary endpoints at day 18 were change in ulcer area and ulcer microvascular perfusion. RESULTS:Complete or partial ulcer healing occurred in almost all cavitation-treated patients, with a significant reduction in ulcer size only in the cavitation group and not the control group (median: -36.6% [Q1-Q3: -15.4% to -65.0%] vs +3.4% [Q1-Q3: -14.7% to +20.0%]; P = 0.039). In cavitation-treated patients, there was a 2.5-fold increase in ulcer margin perfusion, a 1.6-fold increase in functional microvascular density on super-resolution US microangiography, and a 1.8-fold increase in femoral artery flow (P < 0.05 for all parameters). These flow parameters did not increase in control patients. CONCLUSIONS:In patients with CLTI and nonhealing ulcers, periodic therapy with cavitation of microbubbles using US parameters approved for diagnostic imaging promotes healing of ischemic ulcers, likely through improvement in tissue perfusion and microvascular vascularity.