Embolotherapy involves the occlusion of blood flow for therapy, such as treatment of tumors or fibroids, and has traditionally used solid emboli.1 In our novel approach, gas bubbles, rather than solid particles are used for occlusion. The bubbles originate as <6 ?m-diameter albumin- or lipid- encapsulated liquid droplets of perfluorocarbon (PFC), mixed in saline,2, 3 and are injected into the vascular system. The droplets are small enough to pass through capillary beds, so they can circulate until the next stage of the therapy. By strategic placement of an ultrasound source, vaporization of the droplets, which we have termed Acoustic Droplet Vaporization (ADV), can be induced in or near the tumor. The resulting bubble volume is ~125-150 times the droplet volume, and the bubbles resulting from an approximately 5 ?m droplet are large enough to lodge in the microcirculation and occlude blood flow to the tumor. This gas embolotherapy approach is minimally invasive, would allow selective delivery of gas emboli to the tumor or fibroid, and is well suited to repeated doses and long-term use. The first funding period of this grant was focused on understanding the underlying biofluid mechanics involved in ADV, transport, and lodging of these novel emboli. Now that we understand the bubble and droplet dynamics well enough to allow us to effectively target regions of healthy tissue for occlusion, we are ready to apply this knowledge to study the potential for lodged microbubbles to induce bioeffects that may lead to localized hypoxia and tissue necrosis. Successful treatment of cancer by the proposed methodology is one of our long-term goals, and understanding how lodged microbubbles affect tumors is essential to reaching that goal. Therefore, the specific aims of this renewal application are: 1. Characterize ADV of adherent droplets, and transport and lodging of resulting bubbles, including ability of functionalized droplets to increase residence time of resulting bubbles. 2. Characterize the ability of lodged bubbles to induce hypoxia. 3. Characterize the ability of lodged bubbles to induce hypoxia related changes in tumors. 4. Assess the ability of lodged bubbles to induce tumor cell apoptosis and to slow tumor growth.

Public Health Relevance

This work provides a proof concept test of the ability of a novel gas embolotherapy to treat tumors. This treatment modality aims to starve tumors by occluding blood flow to them, with or without drug delivery. The findings of this work will be instrumental in assessing the clinical potential of gas embolotherapy. Many types of cancer may be well suited to treatment by gas embolotherapy, including hepatocellular carcinoma, the most common form of liver cancer, and renal and breast cancer.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Lopez, Hector
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University of Michigan Ann Arbor
Biomedical Engineering
Schools of Engineering
Ann Arbor
United States
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Valassis, Doug T; Dodde, Robert E; Esphuniyani, Brijesh et al. (2012) Microbubble transport through a bifurcating vessel network with pulsatile flow. Biomed Microdevices 14:131-43
Qamar, Adnan; Wong, Zheng Z; Fowlkes, J Brian et al. (2012) Evolution of acoustically vaporized microdroplets in gas embolotherapy. J Biomech Eng 134:031010
Nieuwstadt, Harm A; Seda, Robinson; Li, David S et al. (2011) Microfluidic particle sorting utilizing inertial lift force. Biomed Microdevices 13:97-105
Eshpuniyani, Brijesh; Fowlkes, J Brian; Bull, Joseph L (2008) A Boundary Element Model of Microbubble Sticking and Sliding in the Microcirculation. Int J Heat Mass Transf 51:5700-5711