Targeted Delivery of Bone Marrow Mononuclear Cells by Ultrasound Destruction of Microbubbles Induces Both Angiogenesis and Arteriogenesis Response

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Abstract
Objective— Ultrasound (US)-mediated destruction of contrast microbubbles causes capillary rupturing that stimulates arteriogenesis, whereas intramuscular implantation (im) of bone marrow mononuclear cells (BM-MNCs) induces angiogenesis. We therefore studied whether US-targeted microbubble destruction combined with transplantation of BM-MNCs can enhance blood flow restoration by stimulating both angiogenesis and arteriogenesis. Methods and Results— US-mediated destruction of phospholipid-coated microbubbles was applied onto ischemic hindlimb muscle and subsequently BM-MNCs were transfused. A significant enhancement in blood flow recovery after Bubble+US+BM-MNC infusion (34% increase, P<0.05) was observed compared with Bubble+US (25%). The ratio of capillary/muscle fiber increased by Bubble+US+BM-MNC-i.v (260%, P<0.01) than that in the Bubble+US group (172%), into which BM-MNCs were incorporated (angiogenesis). Smooth muscle α-actin–positive arterioles were also increased, and angiography showed augmented c... Ultrasound (US)-targeted microbubble destruction combined with transplantation of bone marrow mononuclear cells (BM-MNCs) enhances blood flow restoration by stimulating both angiogenesis and arteriogenesis. Release of proinflammatory factors from platelets activated by Bubble+US play a key role for adhesion of BM-MNCs on endothelium. This cell delivery system is efficient for therapeutic angiogenesis and arteriogenesis.

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