Portable In vivo Confocal Ophthalmoscope (PICO) for Accurate and Rapid Diagnosis of Corneal Ulcer

项目摘要/摘要 感染引起的角膜溃疡在420万人中导致失明和视力障碍 每年在全世界范围内流行，并被描述为一种“无声的流行病”。角膜溃疡可由以下几种原因引起 不同的生物体，由真菌或棘阿米巴寄生虫引起的往往与最严重的联系在一起 结果。对致病微生物的准确和快速诊断可以防止组织损伤导致 失明。但临床结果往往很差，因为一线诊断方法，裂隙灯检查， 通常是不准确的，而金标准诊断方法，微生物检测，是耗时的，容易 到假阴性，而且资源密集型。 我们的目标是开发一种便携式在体共焦眼底镜(PICO)，它可以提供准确和 角膜溃疡的快速诊断。我们已经建立了一支领先的眼科和 光学工程专家实现了这一目标：活体共焦显微镜(IVCM)是临床上唯一 可用的成像工具，可以直接可视化患者角膜中的致病微生物。查亚博士 奇丹巴拉姆(英国曼彻斯特大学，Co-I)领导了第一项测试激光扫描IVCM的前瞻性研究 在真菌和棘阿米巴溃疡患者中，建立了高诊断敏感性(86-88%)和 特异性(81-98%)。其他人的进一步研究也证明了同样高的诊断准确率。但 IVCM的广泛采用受到以下缺点的阻碍：1)接触成像，2)有限 视场(FOV)和速度；3)设备成本高(75,000美元)。在寻找一种新的方法来 克服这些弱点，奇丹巴拉姆博士开始与东京康博士(Pi， 亚利桑那大学)。康博士的团队之前发明了世界上第一个基于智能手机的产品， 便携式IVCM设备(成本约4,000美元)，成功地对乌干达350名患者的皮肤病变进行了成像，以及 演示了角膜细胞细节的成像，图像质量与商业IVCM相似。 在这个为期3年的R01项目中，我们将进一步创新我们的皮肤便携式IVCM技术，以开发 Pico装置，(1)实现非接触式角膜成像，(2)将视野提高12倍，速度为8 倍，以及(3)与商业角膜IVCM设备相比，设备成本降低了10倍。我们会 开发一个Pico原型(目标1)，并在体外评估角膜溃疡(真菌亚型)(目标2)。 我们预计Pico将成为全球标准的角膜成像工具，并将使 对诊断和治疗监测角膜溃疡和其他主要角膜疾病的影响，包括 干眼病、Fuchs内皮营养不良和角膜神经评估以筛查外周 帕金森氏病和糖尿病的神经病变。我们的建议直接解决了几个未满足的问题 在NEI的战略计划中确定的需求，包括诊断常见疾病的高分辨率成像技术 角膜疾病，以及早期检测角膜疾病流行的方法。

Project Summary/Abstract Corneal ulcers caused by infection are causing blindness and visual impairment in 4.2 million people worldwide annually and have been described as a “silent epidemic”. Corneal ulcers can be caused by several different organisms, with those caused by fungi or Acanthamoeba parasites often associated with the worst outcomes. Accurate and rapid diagnosis of the causative organism can prevent tissue damage leading to blindness. But clinical outcomes are often poor because the first-line diagnostic method, slit lamp examination, is often inaccurate, and the gold standard diagnostic method, microbiological testing, is time-consuming, prone to false negatives, and resource-intensive. We aim to develop a Portable In vivo Confocal Ophthalmoscope (PICO) that can provide accurate and rapid diagnosis in corneal ulcers. We have established a research team of leading ophthalmology and optical engineering experts to achieve this goal: In vivo confocal microscopy (IVCM) is the only clinically- available imaging tool that can directly visualize causative organisms in the patient’s cornea. Dr. Jaya Chidambaram (Co-I, University of Manchester, UK) led the first prospective study to test laser-scanning IVCM in fungal and Acanthamoeba ulcer patients, which established high diagnostic sensitivity (86-88%) and specificity (81-98%). Further studies by others demonstrated similarly high diagnostic accuracy. But widespread adoption of IVCM has been hampered by the following weaknesses: 1) contact imaging, 2) limited field of view (FOV) and speed, and 3) high device cost (>$75,000). While searching for a new approach to overcome these weaknesses, Dr. Chidambaram began a collaboration with Dr. Dongkyun Kang (PI, University of Arizona) in 2019. Dr. Kang’s team previously invented the world’s first smartphone-based, portable IVCM device (cost = ~ $4,000), successfully imaged skin lesions from >350 patients in Uganda, and demonstrated imaging of cellular details of the cornea with similar image quality to the commercial IVCM. In this 3-year R01 project, we will further innovate our skin portable IVCM technology to develop a PICO device that (1) enables non-contact corneal imaging, (2) increases the FOV 12 times and speed 8 times, and (3) reduces the device cost >10 times compared to the commercial corneal IVCM device. We will develop a PICO prototype (Aim 1) and evaluate for corneal ulcer (fungal subtype) ex vivo (Aim 2). We envision that PICO will become a standard corneal imaging tool worldwide, and will make significant impacts on diagnosis and treatment monitoring of corneal ulcers and other major corneal diseases, including dry eye disease, Fuch’s endothelial dystrophy, and corneal nerve evaluation to screen for peripheral neuropathy in Parkinson’s disease and diabetes mellitus. Our proposal directly addresses several unmet needs identified in the NEI’s strategic plan, including high-resolution imaging techniques to diagnose common corneal disorders, and methods for early detection of corneal disease epidemics.