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 pre-clinical models, ultrasound (US) cavitation of microbubble contrast agents can augment limb perfusion through multiple shear-mediated vasoactive pathways. Objectives. 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 non-healing ulcers were randomized to standard care or cavitation therapy which was performed every three days ×6. Definity was infused and US (1.3 MHz, mechanical index 1.3) was performed for fifteen minutes at the wound site and simultaneously over the ipsilateral femoral artery to leverage conducted vasodilation. 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 not control group (median [IQR]: −36.6 [−15.4 to −65.0] vs +3.4 [−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 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 non-healing 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.