Precisely removing microvessels by photo-mediated ultrasound therapy

光介导超声治疗精准去除微血管

• 批准号: 9769058
• 负责人: Xinmai Yang
• 金额: $ 44.47万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769058
• 关键词: Acoustics; Address; Aftercare; Age related macular degeneration; Alternative Therapies; Angiography; Animal Model; Atrophic; Back; Behavior; Blindness; Blood; Blood Vessels; Choroid; Choroidal Neovascularization; Clinic; Clinical; Contrast Media; Detection; Development; Diabetic Retinopathy; Disease; Electron Microscopy; Electroretinography; Ensure; Evaluation; Excision; Eye; Feedback; Fluorescein Angiography; Fundus photography; Future; Goals; Gold; Histopathology; Immunohistochemistry; In Vitro; Indocyanine Green; Laser vaporization; Lasers; Liquid substance; Mediating; Methods; Modeling; Normal Cell; Ophthalmology; Optical Coherence Tomography; Optics; Oryctolagus cuniculus; Outcome; Outcomes Research; Pathologic; Patient imaging; Patients; Peripheral; Phase; Photoreceptors; Photosensitization; Physiologic pulse; Research; Resistance development; Retina; Retinal; Risk; Role; Safety; Stress; Techniques; Technology; Temperature; Testing; Therapeutic; Time; Tissues; Ultrasonic Therapy; Ultrasonography; United States; Vascular Endothelial Growth Factors; Vision; Whole Blood; base; bevacizumab; design; experimental study; image guided; imaging system; improved; in vitro Model; in vivo; innovation; intravitreal injection; laser photocoagulation; legally blind; mathematical model; microscopic imaging; millisecond; multimodality; neovascularization; novel therapeutics; outcome forecast; outcome prediction; particle; personalized medicine; pressure; ranibizumab; real time monitoring; response; retinal damage; retinal imaging; side effect; soft tissue; synergism; technology development; vasoconstriction

Abstract/Project Summary Wet age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. Anti- vascular endothelial growth factor (VEGF) therapy is currently the gold standard for wet AMD treatment. However, some patients have poor response to this therapy, or develop resistance over long-term use. A recent study demonstrated persistent fluid in 53% and 71% of patients treated monthly with ranibizumab and bevacizumab, respectively. The other study shows that 20% of patients still become legally blind after 5 years of repeat anti-VEGF therapy. Therefore, development of an alternative therapy for AMD patients especially poor-responders to anti-VEGF therapy is strongly desired by ophthalmology clinic. The ultimate goal of this research is to study the capability of a new, noninvasive therapeutic technique for safely and efficiently eliminating choroidal neovascularization (CNV) that causes vision loss in patients with wet AMD. This technique termed photo-mediated ultrasound therapy (PUT) is agent free with high precision and high selectivity in removing microvessels. PUT employs cavitation produced by concurrently applied short duration laser pulses and ultrasound bursts. Importantly, PUT does not induce cavitation through laser vaporization; instead, the cavitation is produced via photospallation, or tissue cleavage due to transient thermoelastic stress. Therefore, the laser intensity required for PUT is much lower than conventional retinal laser, significantly reducing the risk of unwanted damage to the retina. The objectives of the proposed research are 1) to further understand and optimize PUT removal of microvessels, and 2) to evaluate the safety and efficacy of image-guided PUT in inducing regression of CNV in a well-developed animal model. The central hypothesis is that, by combining with an advanced eye imaging system, PUT can specifically remove microvessels created by CNV without damaging surrounding tissues. Two Specific Aims will be developed to test this hypothesis. Aim 1): Via the experiments on a well-developed in vitro model and mathematical modeling, determine to what extent PUT-produced cavitation induces vasoconstriction of a blood vessel. The role of laser and ultrasound during PUT will be evaluated experimentally in an in vitro whole blood model by quantifying cavitation bubble formation. Aim 2): Via the studies on a rabbit model, evaluate the efficacy and safety of imaging-guided PUT for removing single pathological microvessels in the choroid in vivo. To optimize the technology in anticipation of future studies on personalized treatment of patients, an imaging system with optical coherence tomography (OCT) and photoacoustic (PA) functions will be integrated for real-time feedback and guidance. Fundus photography, fluorescein angiography, indocyanine green angiography, OCT, electroretinography, histopathology, electron microscopy, and immunohistochemistry will be performed up to 1 month following treatment to determine the efficacy and safety of PUT on treating CNV regression.

摘要/项目摘要 与年龄相关的黄斑变性（AMD）是发达的不可逆失明的主要原因 世界。抗血管内皮生长因子（VEGF）疗法目前是湿AMD的黄金标准 治疗。但是，一些患者对这种疗法的反应较差，或者长期发展抗药性 使用。最近的一项研究表明，用ranibizumab治疗的53％和71％的患者持续液体 和贝伐单抗。另一项研究表明，20％的患者在5之后仍在法律上盲目 多年重复抗VEGF疗法。因此，为AMD患者开发替代疗法 眼科诊所强烈需要对抗VEGF治疗的不良反应。最终目标 研究是研究一种新的无创治疗技术来安全有效的能力 消除脉络膜新生血管形成（CNV），导致湿AMD患者的视力丧失。这项技术 所谓的照片介导的超声疗法（PUT）是无精度和高选择性的代理 删除微型花序。 PUT使用同时应用的短持续时间激光脉冲产生的空化 和超声爆发。重要的是，PUT不会通过激光蒸发诱导空化。相反， 通过瞬时热弹性应激引起的光斑或组织裂解产生空化。所以， 放置所需的激光强度远低于常规视网膜激光，大大降低了风险 对视网膜的不必要损害。 拟议的研究的目标是1）进一步理解和优化删除微血管， 2）评估图像引导的安全性和功效在诱导CNV的回归中的安全性和功效。 动物模型。中心假设是，通过与先进的眼部成像系统结合使用，可以 特异性去除由CNV产生的微血管，而不会损害周围组织。两个具体的目标将 开发以检验这一假设。 AIM 1）：通过实验在一个发达的体外模型上， 数学建模，确定在多大程度上推出生产的空化引起血液的血管收缩 血管。在PUT期间激光和超声波的作用将在体外全血中进行实验评估 通过量化空化气泡形成模型。目标2）：通过兔模型的研究，评估功效 和成像引导的安全性，用于去除体内脉络膜中的单个病理微血管。到 优化技术，以预期对患者个性化治疗的未来研究，成像系统 具有光学相干断层扫描（OCT）和光声（PA）功能将进行实时集成 反馈和指导。眼底摄影，荧光素血管造影，吲哚氰胺绿色血管造影，OCT， 电视图，组织病理学，电子显微镜和免疫组织化学最多将进行1个 治疗后的一个月，以确定投掷治疗CNV回归的功效和安全性。