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

项目摘要 在人类中，角膜前泪膜（PCTF）是一层薄薄的（约3-5 μm）复杂的生物流体， 眼表面，用于滋养和保护眼表面，并提供平滑的屈光光学 表面视觉。在干眼症中，PCTF变得更薄，并迅速不稳定（蒸发），导致 高渗透压、炎症和眼表干燥。美国有超过3000万人 各国都受到干眼症的影响，对社会造成的经济负担估计超过500亿美元。 干眼症仍然是诊断、监测和治疗的挑战，因为许多干眼症测试都是 进行不一致，缺乏足够的可靠性或准确性，并不与症状的 疾病泪膜动力学的临床测量（变薄和破裂）本质上是主观的， 缺乏有效性和可重复性。因此，需要高度可靠且 为了更好地诊断疾病，除了监测治疗的影响外，还需要准确的数据。 在之前的工作中，我们发表了一个数学模型，系统地分析了从 角膜表面利用该模型，PCTF的厚度对来自角膜或角膜的噪声不敏感。 光源的使用基于光纤的干涉测量系统的模型进行了验证。主要的缺点是 干涉测量系统的另一个优点是它在空间上限于角膜顶点处的单个点（~30 µm）。虽然 我们以前的研究表明PCTF在眼表的分布是不同的， 在大视场中对这些属性进行表征将为诊断和监测提供关键信息 干眼症，由于热成像系统的聚焦性能差，目前的系统仅限于单个点。 光源的超连续谱（SC）光源可以将现有系统升级为点扫描系统。 此外，所提出的SC干涉仪将通过定制的物镜实现PCTF的宽视场视图 透镜。该透镜将根据我们以前的研究开发，具有专门设计用于 在角膜表面上成像。这种创新的干涉仪将实现前所未有的厚度灵敏度 （~0.33 µm）的泪液膜。目的一是构造一个超连续谱光源 干涉仪具有高分辨率（~0.33 µm）和宽视场。在目标2中，测试和验证新的 系统通过检查体外一致性和方差与平面厚度标准和弯曲玻璃模型眼。 目的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驱动泪膜的机制的理解 动态，以更好地了解疾病的机制或开发新的治疗方法， 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.