Dynamics of Vascular Microbubbles and Microdroplets in Gas Embolotherapy

描述(申请人提供)：栓塞术涉及闭塞血流以进行治疗，如治疗肿瘤或肌瘤，传统上使用固体栓塞剂。1在我们的新方法中，使用气泡而不是固体颗粒进行闭塞。这些气泡起源于直径为-lt；6�m的白蛋白或脂类包裹的全氟化碳液滴，混合在生理盐水中，2，3，然后注入血管系统。这些液滴足够小，可以穿过毛细血管床，因此它们可以循环到下一阶段的治疗。通过战略性地放置超声源，可以在肿瘤内或肿瘤附近诱导液滴汽化，我们称之为声学液滴汽化(ADV)。产生的气泡体积是液滴体积的~125-150倍，由大约5�m的液滴产生的气泡足够大，足以滞留在微循环中并阻断流向肿瘤的血流。这种气体栓塞治疗方法是微创的，允许选择性地将气体栓子输送到肿瘤或肌瘤，并且非常适合重复剂量和长期使用。这笔赠款的第一个资助期专注于了解这些新型栓子的ADV、运输和寄宿所涉及的潜在生物流体机制。既然我们对气泡和液滴的动力学有了足够的了解，从而使我们能够有效地针对健康组织的区域进行闭塞，我们就准备应用这一知识来研究滞留的微泡诱导可能导致局部缺氧和组织坏死的生物效应的可能性。通过建议的方法成功治疗癌症是我们的长期目标之一，而了解滞留的微泡如何影响肿瘤对于实现这一目标至关重要。因此，此次更新应用的具体目标是：1.表征附着液滴的ADV以及所产生的气泡的运输和倒伏，包括功能化液滴增加所产生气泡的停留时间的能力。2.表征滞留气泡诱导低氧的能力。3.表征滞留气泡诱导肿瘤缺氧相关改变的能力。4.评价气泡诱导肿瘤细胞凋亡和延缓肿瘤生长的能力。

DESCRIPTION (provided by applicant): 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.