Development and Validation of Photothermal Optical Coherence Tomography for Retinal Imaging

项目总结 黑色素自然存在于眼睛的脉络膜、虹膜和视网膜色素上皮(RPE)中，是一种单一的 位于视网膜光感受器后面的一层上皮细胞。视网膜色素沉着改变 通常随着年龄的增长而发生，并出现在许多眼科疾病中。例如，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，涉及 RPE功能障碍和色素沉着改变。在早期阶段，AMD的特征通常是变化 在色素沉着和黄褐斑的存在。在干性AMD中，数据表明RPE中的过度色素沉着(来自 RPE细胞功能障碍)，随后出现色素减退(由于RPE细胞的丧失) 光感受器或脉络膜毛细血管的功能障碍，可以预测疾病的进展。 视网膜疾病的管理需要强有力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局限性，阻碍了黑色素的3D活体成像 眼睛里的血药浓度。例如，近红外自发荧光和光声显微镜的性能较差。 轴向分辨率，不能相对于其他结构分辨RPE，而偏振敏感光学 由于色素颗粒的散布，相干断层扫描很难恢复准确的黑色素水平 和较窄的动态范围。因此，目前还没有标准的活体技术来量化黑色素 眼睛里的血药浓度。考虑到黑色素作为早期疾病标志物的可能性，非常需要一种 用于量化患者和动物模型中黑色素水平的眼科成像技术。 该方案的目标是发展光热光学相干层析成像(PT-OCT)来成像和 量化活着的人眼中的黑色素水平。PT-OCT检测组织中的光吸收体，具有类似的 分辨率和成像深度，如OCT。PT-OCT信号强度与浓度成正比 黑色素吸收剂(例如黑色素)，可定量显示黑色素浓度的3D图像。我们已经证明了 PT-OCT可以特异性地测量小鼠和斑马鱼模型RPE中的黑色素。重要的是，光线 PT-OCT在眼睛中的暴露水平在安全标准之内，FDA最近将PT-OCT指定为 眼睛作为一项非重大风险研究。PT-OCT有利于RPE中的黑色素成像，因为它是 对色素沉着的微小变化很敏感，并且光热信号很容易量化以实现稳健 样本之间的比较。本建议旨在确定PT-OCT黑色素敏感范围，并首先- 在人体内实现眼部黑色素三维定量成像的可行性。

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.