Development of a supercontinuum laser source interferometer with sub-micron resolution to understand tear film structure and function in dry eye disease

项目概要 在人类中，角膜前泪膜 (PCTF) 是一层薄薄的（约 3-5 µm）复杂的生物液体，覆盖在角膜上。 眼表，用于滋养和保护眼表并提供平滑的屈光光学 视觉表面。在干眼病中，PCTF 变得更薄，并迅速不稳定（蒸发），导致 导致高渗透压、炎症和眼表干燥。美国有超过3000万人 各州都受到干眼病的影响，社会经济负担估计超过 500 亿美元。 干眼病仍然是诊断、监测和治疗的一个挑战，因为许多干眼测试 进行不一致，缺乏足够的可靠性或准确性，并且与症状不相关 疾病。泪膜动力学（变薄和破裂）的临床测量本质上是主观的，并且通常 缺乏有效性和重复性。因此，高度可靠且新颖的非侵入性光学测量 除了监测治疗的影响之外，还需要准确的数据来更好地诊断疾病。 在之前的工作中，我们发布了一个数学模型来系统地分析从 角膜表面。使用该模型，PCTF 的厚度对角膜或角膜产生的噪声不敏感。 光源。使用基于光纤的干涉测量系统对该模型进行了验证。其主要缺点是 干涉测量系统的缺点是它在空间上仅限于角膜顶点的单个点（~30 µm）。虽然 我们之前的其他研究表明，PCTF 在眼表面的分布各不相同，并且 在大视野中表征这些属性将为诊断和监控提供关键信息 干眼症时，由于热成像的聚焦性能较差，目前的系统仅限于单点。 光源。超连续谱（SC）光源可以将当前系统升级为点扫描系统。 此外，拟议的 SC 干涉仪将通过定制物镜实现 PCTF 的宽视野 镜头。该镜头将根据我们之前的调查而开发，其焦场专门设计用于 角膜表面成像。这种创新的干涉仪将实现前所未有的厚度灵敏度 (~0.33 µm) 跨越人类角膜的泪膜。目标1是构建超连续谱光源 具有高分辨率（~0.33 µm）和宽视场的干涉仪。在目标 2 中，测试并验证新的 系统通过检查体外与平坦厚度标准和曲面玻璃模型眼睛的一致性和方差。 目标 3 将应用新系统来表征患有和不患有干眼病的人类受试者的 PCTF。 这项研究的长期影响将提高我们对泪膜驱动机制的理解 更好地了解疾病机制或开发新的治疗方法来解决 泪膜不稳定的机制。

Project Summary In humans, the precorneal tear film (PCTF) is a thin layer (~3-5 µm) of a complex biological fluid coating the ocular surface, that serves to nourish and protect the ocular surface and provide a smooth refractive optical surface for vision. In dry eye disease, the PCTF becomes thinner, and destabilizes (evaporates) rapidly leading to hyperosmolarity, inflammation, and ocular surface desiccation. More than 30 million people in the United States are impacted by dry eye disease and the economic burden to society is estimated to be over $50 billion. Dry eye disease continues to be a challenge to diagnose, monitor, and treat because as many dry eye tests are conducted inconsistently, lack sufficient reliability or accuracy, and do not correlate with symptoms of the disease. Clinical measures of tear film dynamics (thinning and breakup) are subjective in nature and generally lack validity and repeatability. Therefore, novel, non-invasive optical measures that are highly reliable and accurate are needed to better diagnose the disease, in addition to monitor the impact of treatments. In prior work, we published a mathematical model to systematically analyze the light reflected back from the cornea surface. With this model, the thickness of the PCTF is insensitive to the noise arising from the cornea or light source. The model was validated using a fiber-based interferometry system. The main drawback of that interferometry system is that it is spatially limited to a single point at the apex of the cornea (~30 µm). Although our other previous studies revealed that the distribution of PCTF varied over the ocular surface, and the characterization of these attributes in a large fieldview will provide critical information to diagnose and monitor dry eye disease, the current system was limited to a single point due to the poor focusing property of the thermal light source. A supercontinuum (SC) light source can upgrade the current system to a point-scanning system. Furthermore, the proposed SC interferometer will enable a wide field view of the PCTF by a customized objective lens. The lens will be developed based on our previous investigation, with a focal field specifically designed for imaging over the cornea surface. This innovative interferometer will achieve unprecedented thickness sensitivity (~0.33 µm) of the tear film across the human cornea. Aim 1 is to construct a supercontinuum light source interferometer with a high resolution (~0.33 µm), and a wide field-of-view. In Aim 2, test and validate the new system by examining in vitro agreement and variance with flat thickness standards and curved glass model eyes. Aim 3 will apply the new system to characterize the PCTF of human subjects with and without dry eye disease. The long-term impact of this research will improve our understanding of the mechanisms driving tear film dynamics to better understand mechanisms of disease or to development novel treatments that address mechanisms of tear film instability.