Dynamics of Vascular Microbubbles and Microdroplets in Gas Embolotherapy

描述（由申请人提供）：栓塞治疗包括阻断血流的治疗，如肿瘤或肌瘤的治疗，传统上使用实体栓塞在我们的新方法中，气泡而不是固体颗粒被用于遮挡。气泡起源于直径< 6¿m的白蛋白或脂质包裹的全氟碳（PFC）液滴，混合在生理盐水，2,3中并注入血管系统。这些液滴足够小，可以通过毛细血管床，因此它们可以循环到下一阶段的治疗。通过策略性地放置超声源，液滴的汽化，我们称之为声液滴汽化（ADV），可以在肿瘤内或肿瘤附近诱导。产生的气泡体积约为液滴体积的125-150倍，并且由大约5¿m的液滴产生的气泡足够大，可以进入微循环并阻塞流向肿瘤的血液。这种气体栓塞治疗方法是微创的，可以选择性地将气体栓塞输送到肿瘤或肌瘤，并且非常适合重复剂量和长期使用。该基金的第一个资助期侧重于了解这些新型栓子的ADV，运输和住宿所涉及的潜在生物流体力学。现在我们已经很好地了解了气泡和液滴的动力学，使我们能够有效地靶向健康组织区域进行封堵，我们已经准备好应用这些知识来研究驻留微气泡诱导可能导致局部缺氧和组织坏死的生物效应的潜力。通过提出的方法成功治疗癌症是我们的长期目标之一，了解驻留的微泡如何影响肿瘤是实现这一目标的关键。因此，此续期申请的具体目的是：1。表征粘附液滴的ADV，以及所产生气泡的运输和倒伏，包括功能化液滴增加所产生气泡停留时间的能力。2. 描述滞留气泡诱导缺氧的能力。3. 描述滞留气泡诱导肿瘤缺氧相关变化的能力。4. 评估气泡诱导肿瘤细胞凋亡和减缓肿瘤生长的能力。

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.