In this study, we will explore how ultrasound exposure of ultrasound contrast agents, which produces beneficial shear-mediated bioeffects, can be used to treat patients with severe non-healing ulcers secondary to peripheral arterial disease (PAD). The primary outcome measure is whether ultrasound exposure to microbubble contrast agents in the inflow artery and at the wound site can accelerate wound healing. A secondary outcome measure is whether cavitation-related changes occur in tissue perfusion in the treated limb and wound measured by ultrasound perfusion imaging and skin flow.

Inclusion Criteria:

• Known history of unilateral or bilateral PAD diagnosed by reduced ankle-brachial index (<0.9) or non-compressible vessels
• Diagnosis of CLI (Rutherford class IV-VI), and a non-healing ischemic ulcer defined as no change in the prior 3 months.

Exclusion Criteria:

• Major medical illness other than PAD affecting the limb (muscle disease, blood diseases that influence flow or rheology, severe heart failure [NYHA class IV]).
• Pregnant or lactating females
• Hypersensitivity to any ultrasound contrast agent or to polyethylene glycol (PEG, macrogol).
• Hemodynamic instability (hypotension with systolic BP <90 mm Hg, need for vasopressors).
• Expected amputation or revascularization procedure within the ensuing 1 month.