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: 8505588
• 负责人: JOSEPH L BULL
• 金额: $ 57万
• 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/8505588
• 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）：栓塞疗法涉及阻塞血流以进行治疗，例如治疗肿瘤或肌瘤，并且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阻塞。气泡起源于 < 6 ¿直径为 m 的白蛋白或脂质封装的全氟化碳 (PFC) 液滴，与盐水混合，2, 3 并注射到血管系统中。这些液滴足够小，可以穿过毛细血管床，因此它们可以在下一次消除。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蒸发，我们将其称为声学液滴蒸发（ADV）。气泡体积约为液滴体积的 125-150 倍，并且气泡由大约 5 ¿ m 液滴足够大，可以滞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输送到肿瘤或肌瘤，并且非常适合重复剂量和长期治疗。这笔资助的第一个资助期重点是了解 ADV、运输和这些新型栓塞的住宿所涉及的基础生物流体力学，现在我们已经足够了解气泡和液滴动力学了。有效地瞄准健康组织区域进行闭塞，我们准备应用这些知识来研究滞留微泡诱导生物效应的潜力，这些生物效应可能导致局部缺氧和组织坏死，通过所提出的方法成功治疗癌症是我们的长期目标之一。术语目标，并且了解滞留微泡如何影响肿瘤对于实现该目标至关重要，因此，该更新应用的具体目标是： 1. 表征粘附液滴的 ADV 以及所得液滴的运输和滞留。气泡，包括功能化液滴增加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。气泡诱导肿瘤细胞凋亡并减缓肿瘤生长。