Dynamics of Vascular Microbubbles and Microdroplets in Gas Embolotherapy

气体栓塞治疗中血管微泡和微滴的动力学

• 批准号: 8651436
• 负责人: JOSEPH L BULL
• 金额: $ 59.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-12 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651436
• 关键词: Acoustics; Affect; Albumins; Animals; Apoptosis; Blood Vessels; Blood flow; Caliber; Catheters; Cell Death; Clinical; Clinical Trials; Dose; Drug Delivery Systems; Drug Formulations; Drug Transport; Embolism; Encapsulated; Fibroid Tumor; Fluorocarbons; Funding; Gases; Goals; Grant; Hypoxia; Image; Interruption; Knowledge; Lead; Lipids; Liquid substance; Malignant neoplasm of liver; Mechanics; Methodology; Microbubbles; Microcirculation; Modality; Necrosis; Outcome; Permeability; Primary carcinoma of the liver cells; Rattus; Renal carcinoma; Saline; Solid; Source; Staging; Study models; Testing; Therapeutic Embolization; Time; Tissues; Ultrasonography; Vascular System; Work; base; cancer therapy; cancer type; capillary bed; cremaster muscle; density; drug efficacy; in vivo; malignant breast neoplasm; minimally invasive; neoplastic cell; novel; novel strategies; particle; public health relevance; residence; tumor; tumor growth; vaporization

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.

描述（由申请人提供）：栓塞治疗涉及闭塞血流进行治疗，例如治疗肿瘤或肌瘤，传统上使用固体栓塞。1在我们的新方法中，使用气泡而不是固体颗粒进行闭塞。气泡起源于直径<6 m的白蛋白或脂质包裹的全氟化碳（PFC）液滴，混合在盐水中，2，3并注射到血管系统中。液滴小到足以通过毛细血管床，因此它们可以循环直到治疗的下一阶段。通过超声源的战略性放置，可以在肿瘤中或肿瘤附近诱导液滴的汽化，我们称之为声学液滴汽化（ADV）。产生的气泡体积约为液滴体积的125 - 150倍，并且由大约5 μ m的液滴产生的气泡足够大，可以停留在微循环中并阻塞流向肿瘤的血流。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物输送到肿瘤或肌瘤，并且非常适合重复剂量和长期使用。这项资助的第一个资助期的重点是了解基本的生物流体力学参与ADV，运输和住宿的这些新的栓子。现在，我们已经足够好地理解了气泡和液滴动力学，使我们能够有效地靶向健康组织的区域进行闭塞，我们准备应用这些知识来研究滞留微泡诱导可能导致局部缺氧和组织坏死的生物效应的潜力。通过所提出的方法成功治疗癌症是我们的长期目标之一，了解微泡如何影响肿瘤对于实现这一目标至关重要。因此，本次续展申请的具体目的是：1.表征粘附液滴的ADV以及所得气泡的运输和停留，包括官能化液滴增加所得气泡停留时间的能力。2.表征滞留气泡诱导缺氧的能力。3.表征滞留气泡诱导肿瘤缺氧相关变化的能力。4.评估滞留气泡诱导肿瘤细胞凋亡和减缓肿瘤生长的能力。