Development and Validation of Photothermal Optical Coherence Tomography for Retinal Imaging

项目摘要 黑色素天然存在于眼睛中的脉络膜、虹膜和视网膜色素上皮（RPE）内，是一种单一的黑色素。 视网膜中位于感光器后面的上皮细胞层。视网膜色素改变 通常随着年龄的增长而发生，并存在于许多眼部疾病中。例如，与年龄相关的黄斑 老年性黄斑变性（AMD）是美国65岁以上成年人视力丧失的主要原因， RPE功能障碍和色素沉着变化。在早期阶段，AMD的特征通常是 色素沉着和玻璃疣的存在。在干性AMD中，数据表明RPE中的色素沉着过度（来自 色素减退（来自RPE细胞的损失）出现在 光感受器或脉络膜毛细血管的功能障碍，并且可以预测疾病进展。 视网膜疾病的管理需要稳健的方法来量化视网膜黑色素，特别是在RPE中。 然而，目前成像视网膜黑色素的技术具有限制，其阻止黑色素的3D体内成像 眼睛里的水平。例如，近红外自发荧光和光声显微术遭受差的 相对于其他结构不能分辨RPE的轴向分辨率，而偏振敏感光学 由于色素颗粒的散射，相干断层扫描难以恢复准确的黑色素水平 和窄的动态范围。因此，目前没有标准的体内技术来量化黑色素 眼睛里的水平。考虑到黑色素作为早期疾病标志物的潜力，非常需要一种新的治疗方法。 眼科成像技术来量化患者和动物模型中的黑色素水平。 该提案的目标是开发光热光学相干断层扫描（PT-OCT），以成像和 量化活体人眼中的黑色素水平。PT-OCT检测组织中的光学吸收体，具有类似的 PT-OCT信号强度与OCT的分辨率和成像深度成比例。 吸收器（例如，黑色素），其允许黑色素浓度的定量3D图像。我们已经证明 PT-OCT可以特异性地测量小鼠和斑马鱼模型的RPE中的黑色素。重要的是，光 PT-OCT在眼睛中的暴露水平在安全标准范围内，FDA最近将PT-OCT指定为 眼睛作为非重大风险研究。PT-OCT对于RPE中的黑色素成像是有利的，因为它 对色素沉着的小变化敏感，并且光热信号容易量化， 样品之间的比较。该提案旨在确定PT-OCT黑色素敏感性范围，并且首先- 在人体内的可行性，使定量3D成像的黑色素在眼睛中的体内。

PROJECT SUMMARY Melanin is naturally present in the eye within the choroid, iris, and retinal pigment epithelium (RPE), a single layer of epithelial cells located posterior to the photoreceptors in the retina. Changes in retinal pigmentation normally happen with aging and are present in many ocular diseases. For example, age-related macular degeneration (AMD) is the predominant cause of vision loss in adults over 65 years old in the US and involves dysfunction of the RPE and changes in pigmentation. In early stages, AMD is usually characterized by changes in pigmentation and the presence of drusen. In dry AMD, data suggest that hyperpigmentation in the RPE (from dysfunction in the RPE cells) followed by hypopigmentation (from the loss of RPE cells) appear before dysfunction in the photoreceptors or choriocapillaris and could be predictive for disease progression. Management of retinal diseases requires robust methods to quantify retinal melanin, specifically in the RPE. However, current techniques to image retinal melanin have limitations that prevent 3D in vivo imaging of melanin levels in the eye. For example, near-infrared autofluorescence and photoacoustic microscopy suffer from poor axial resolution that cannot resolve the RPE with respect to other structures, while polarization-sensitive optical coherence tomography has difficulty recovering accurate melanin levels due to scattering of pigment granules and a narrow dynamic range. As a result, there are currently no standard in vivo techniques to quantify melanin levels in the eye. Given the potential for melanin as an early disease marker, there is a great need for an ophthalmic imaging technique to quantify melanin levels in patients and animal models. The goal of this proposal is to develop photothermal optical coherence tomography (PT-OCT) to image and quantify melanin levels in the living human eye. PT-OCT detects optical absorbers in tissues, with similar resolution and imaging depth as OCT. The PT-OCT signal intensity is proportional to the concentration of the absorber (e.g., melanin), which allows for quantitative 3D images of melanin concentration. We have shown that PT-OCT can specifically measure melanin in the RPE of mouse and zebrafish models. Importantly, light exposure levels for PT-OCT in the eye are within safety standards and the FDA recently designated PT-OCT in the eye as a non-significant risk study. PT-OCT is advantageous for melanin imaging in the RPE because it is sensitive to small changes in pigmentation and the photothermal signal is easily quantified for robust comparisons between samples. This proposal aims to determine PT-OCT melanin sensitivity ranges and first- in-human feasibility to enable quantitative 3D imaging of melanin in the eye in vivo.