True Sub-Micron Ocular Diagnostics with Visible Light Optical Coherence Tomography

摘要： 光学相干断层扫描（OCT）极大地推进了许多视网膜病变的诊断和管理， 通过实现视网膜的体积结构成像来治疗疾病。通常，视网膜OCT在近- 红外（NIR）波长，限制了在视觉中起作用的分子的轴向分辨率和对比度。 尽管NIR OCT定义了量化干性年龄相关性黄斑变性（AMD）进展的生物标志物， 近红外光学相干断层扫描还不能描绘出最细微的结构和功能变化，定义早期AMD，或预测 地图状萎缩是AMD的晚期可见光OCT有望实现前所未有的轴向分辨率 和分子对比度，但迄今为止可见光OCT系统还没有实现这一承诺。 最近，我们的团队在可见光OCT中发现了许多技术障碍，其中一些是社区未知的。 通过我们的创新解决方案，我们现在可以直接成像和单独量化布鲁赫膜，视网膜 色素上皮（RPE）和精细感光层在形态正常的视网膜，没有临床 在NIR OCT系统无法达到的细节水平上，这些成像能力是 通过可见光提供的定量分子信息进一步增强。 在本提案中，我们将开发基于光纤的可见光OCT仪器和协议，以评估亚微米 随着年龄的增长和黄斑变性的变化。采用一系列体外和体内研究 在啮齿动物和人类中，我们提出验证拓扑测量外层视网膜，RPE， 和BM形态、色素和黑色素密度以及光感受器功能。我们将验证和测试 这些结构和功能测量的可重复性，并将其应用于研究与年龄相关的变化 在正常人的横截面上。最后，我们将进行初步临床成像研究，首先，比较 第二，鉴定玻璃疣进展为萎缩的候选早期生物标志物。如果 成功的，这一建议将奠定基础，更广泛的纵向研究，研究AMD 在人类视网膜中的进展，以及将新的生物标志物纳入临床试验。

Abstract: Optical Coherence Tomography (OCT) has greatly advanced the diagnosis and management of many retinal diseases by enabling volumetric structural imaging of the retina. Usually, retinal OCT is performed at near- infrared (NIR) wavelengths, limiting both axial resolution and contrast for molecules that play a role in vision. Though NIR OCT defines biomarkers that quantify progression of dry age-related macular degeneration (AMD), NIR OCT cannot yet delineate the finest structural and functional changes that define incipient AMD, or predict geographic atrophy, an end stage of AMD. Visible light OCT holds the promise of unprecedented axial resolution and molecular contrast, but visible light OCT systems to date have not delivered on this promise. Recently, our group identified numerous technical barriers, some unknown to the community, in visible light OCT. With our innovative solutions, we can now directly image and individually quantify Bruch’s membrane, the retinal pigment epithelium (RPE), and fine photoreceptor layers in morphologically normal retina without clinically detectable pathology, at a level of detail not attained by NIR OCT systems. These imaging capabilities are further enhanced by quantitative molecular information provided by visible light. In this proposal, we will develop fiber-based visible light OCT instrumentation and protocols to assess sub-micron changes with aging and macular degeneration in human eyes. Employing a range of in vitro and in vivo studies in rodents and humans, we propose to validate protocols that topographically measure the outer retina, RPE, and BM morphology, photopigment and melanin density, and photoreceptor function. We will validate and test the reproducibility of these structural and functional measurements, and apply them to study age-related changes in a cross-section of normal subjects. Finally, we will perform pilot clinical imaging studies to firstly, compare aging to early AMD, and secondly, identify candidate early biomarkers for progression of drusen to atrophy. If successful, this proposal will lay the groundwork for more extended longitudinal studies to study AMD progression in the human retina, and incorporation of new biomarkers into clinical trials.