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 湿性年龄相关性黄斑变性（AMD）是发达国家中不可逆失明的主要原因。 世界抗血管内皮生长因子（VEGF）治疗目前是湿性AMD的金标准 治疗然而，一些患者对这种疗法的反应不佳，或长期产生耐药性 使用.最近的一项研究表明，每月接受雷珠单抗治疗的患者中， 和贝伐单抗。另一项研究表明，20%的患者在5岁后仍然是法定失明。 多年重复抗VEGF治疗。因此，开发一种用于AMD患者的替代疗法， 抗VEGF治疗的低反应者是眼科临床强烈需要的。这最终的目的 研究的目的是研究一种新的、非侵入性的治疗技术的能力， 消除导致湿性AMD患者视力丧失的脉络膜新生血管（CNV）。这种技术 称为光介导的超声治疗（PUT）是无试剂的，具有高精度和高选择性， 移除微血管。PUT采用由同时施加的短持续时间激光脉冲产生的空化 和超声波爆发。重要的是，PUT不会通过激光汽化引起空化;相反， 通过光致伸缩或由于瞬时热弹性应力引起的组织分裂产生空化。因此，我们认为， PUT所需的激光强度远低于传统的视网膜激光，大大降低了风险 对视网膜造成不必要的损伤 所提出的研究的目标是：1）进一步理解和优化微血管的PUT去除， 和2）评估图像引导PUT在诱导发育良好的CNV消退中的安全性和有效性。 动物模型核心假设是，通过与先进的眼睛成像系统相结合，PUT可以 特异性地去除CNV产生的微血管而不损伤周围组织。两个具体目标将 来检验这个假设。目的1）：通过在成熟的体外模型上的实验， 数学建模，确定PUT产生的空化在多大程度上诱导血液的血管收缩 容器。激光和超声波在PUT过程中的作用将在体外全血中进行实验评估 通过量化空化气泡的形成来建立模型。目的2）：通过对家兔模型的研究，评价其疗效 影像引导下经皮脉络膜穿刺清除脉络膜内单个病变微血管的安全性。到 优化技术，以预期未来对患者进行个性化治疗的研究， 光学相干断层扫描（OCT）和光声（PA）功能将被集成， 反馈和指导。眼底照相，荧光素血管造影，吲哚菁绿色血管造影，OCT， 将进行视网膜电图、组织病理学、电子显微镜和免疫组织化学检查， 治疗后一个月，以确定PUT治疗CNV消退的有效性和安全性。