Precisely removing microvessels by photo-mediated ultrasound therapy

摘要/项目摘要 湿性老年性黄斑变性(AMD)是发达国家不可逆性失明的主要原因 世界。抗血管内皮生长因子(VEGF)治疗是目前治疗湿性AMD的金标准 治疗。然而，一些患者对这种疗法的反应不佳，或长期存在耐药性。 使用。最近的一项研究表明，每月接受雷尼比单抗治疗的患者中，53%和71%的患者存在持续性液体 和贝伐单抗。另一项研究表明，20%的患者在5岁后仍会合法失明 多年重复的抗血管内皮生长因子治疗。因此，开发一种治疗AMD患者的替代疗法尤其重要 抗血管内皮生长因子治疗应答率低是眼科临床迫切需要的。这样做的最终目的是 研究是研究一种新的非侵入性治疗技术的能力，以安全和有效地 消除导致湿性AMD患者视力丧失的脉络膜新生血管(CNV)。这项技术 光介导型超声治疗(PUT)是一种无试剂、高精度、高选择性的治疗方法 移除微血管。PUT使用由同时施加的短脉冲激光脉冲产生的空化 和超音波爆发。重要的是，PUT不会通过激光汽化来诱导空化；相反， 空化是通过光旋转或由于瞬时热弹性应力引起的组织分裂而产生的。因此， PUT所需的激光强度比传统的视网膜激光低得多，显著降低了风险 对视网膜造成不必要的损伤。 拟议研究的目标是1)进一步了解和优化PUT去除微血管， 2)评价影像引导下PUT在正常人群中诱导CNV消退的安全性和有效性。 动物模型。中心假设是，通过与先进的眼睛成像系统相结合，Put可以 特别是在不损害周围组织的情况下，清除CNV产生的微血管。两个具体目标将 被开发来检验这一假设。目的1)通过在成熟的体外模型上的实验 数学模型，确定放置产生的空化在多大程度上诱导血液的血管收缩 船只。激光和超声波在放置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)：通过对兔模型的研究，评价其疗效。 影像引导下PUT去除脉络膜单个病理性微血管的安全性。至 优化技术以期未来对患者的个性化治疗进行研究，这是一种成像系统 利用光学相干层析成像(OCT)和光声(PA)功能将进行实时集成 反馈和指导。眼底照相、荧光素血管造影术、吲哚青绿血管造影术、OCT 将进行视网膜电描记术、组织病理学、电子显微镜和免疫组织化学检查。 观察治疗后1个月PUT对CNV消退的疗效和安全性。

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.