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Peripheral artery disease is a severe medical condition commonly characterized by critical or acute limb ischemia. Gradual accumulation of thrombotic plaques in peripheral arteries of the lower limb may lead to intermittent claudication or ischemia in muscle tissue. Ischemic muscle tissue with lesions may become infected, resulting in a non-healing wound. Stable progression of the non-healing wound associated with severe ischemia might lead to functional deterioration of the limb, which, depending on the severity, can result in amputation. Immediate rescue of ischemic muscles through revascularization strategies is considered the gold standard to treat critical limb ischemia. Growth factors offer multiple levels of protection in revascularization of ischemic tissue. In this review, the basic mechanism through which growth factors exert their beneficial properties to rescue the ischemic limb is extensively discussed. Moreover, clinical trials based on growth factor and stem cell therapy to treat critical limb ischemia are considered. The clinical utility of stem cell therapy for the treatment of limb ischemia is explained and recent advances in nanocarrier technology for selective growth factor and stem cell supplementation are summarized.

Del1-secreting hydrogels increased the size of KO fracture calluses (11.74 mm 3 , p < 0.01) vs control KO calluses (9.65 mm 3 ), and approached the size of WT calluses (16.34 mm 3 ) (n ¼ 5). In MST, KO bones with added Del1 protein had strength of 20.1N, stronger than control KO (16.1N) and approaching strength of WT bones (26.8N, p < 0.05, n ¼ 9). CONCLUSIONS:We have shown enhanced bone fracture healing with addition of Del1 protein to KO mice, reversing its deleterious effects. This suggests that exogenous addition of Del1 protein after bony surgery in humans could enhance bone fracture healing.