A Swine Hind Limb Ischemia Model Useful for Testing Peripheral Artery Disease Therapeutics.

ABSTRACT

Currently, there is no large animal model of sustained limb ischemia suitable for testing novel angiogenic therapeutics for peripheral artery disease (PAD) such as drugs, genes, materials, or cells. We created a large animal model suitable for efficacy assessment of these therapies by testing 3 swine hind limb ischemia (HLI) variations and quantifying vascular perfusion, muscle histology, and limb function. Ligation of the ipsilateral external and bilateral internal iliac arteries produced sustained gait dysfunction compared to isolated external iliac or unilateral external and internal iliac artery ligations. Hyperemia-dependent muscle perfusion deficits, depressed limb blood pressure, arteriogenesis, muscle atrophy, and microscopic myopathy were quantifiable in ischemic limbs 6 weeks post-ligation. Porcine mesenchymal stromal cells (MSCs) engineered to express a reporter gene were visualized post-administration via positron emission tomography (PET) in vivo. These results establish a preclinical platform enabling better optimization of PAD therapies, including cellular therapeutics, increasing bench-to-bedside translational success. A preclinical platform for porcine studies of peripheral artery disease therapies including (1) a hind limb ischemia model and (2) non-invasive MSC viability and retention assessment via PET.