Correlating the microstructural thickness variations of the tear film lipid layer with clinical characteristics of dry eye with a novel optical method

项目摘要 在前眼，角膜前泪膜(PCTF)作为眼表和眼表之间的界面。 外在环境对维持眼表动态平衡起着至关重要的作用。在干眼症中 (DED)，PCTF变薄，并迅速不稳定(蒸发)导致高渗透压， 炎症和眼表干燥症。2020年，国家眼科研究所(NEI)发布了一份关于 前段倡议(ASI)的特殊利益(NOSI)，“新技术的确定和发展” 诊断干眼症的生物标志物和有效方法。该通知强调，迫切需要 在症状出现前诊断DED的生物标志物和方法。这项提案的总体目标是 泪膜脂层(TFLL)的微结构厚度变化及其与 DED的临床特点。TFLL是PCTF的最外层，覆盖在水相上，充当 阻挡蒸发的水分损失，并通过促进其水舱的扩散来稳定它 和降低表面张力。然而，TFLL延缓泪水蒸发和 促进PCTF的稳定性仍然知之甚少。例如，虽然大多数人会同意制服和 更厚的TFLL将更好地防止蒸发，从而防止DED，这种关系仍然存在 在文献中有争议；这一争议的解决构成了这一提议的基础。在NIH/NEI下 2021年(R21EY033029)，我们构造了一种新型的激光源点扫描干涉仪，使 以前所未有的分辨率对PCTF及其相关结构进行体内评价 敏感度。使用这一强大的系统，我们建议解决关键但以前未被探索的问题，并经常 TFLL与PCTF检查结果之间的不一致关联。的核心假说 建议的研究是TFLL微结构中的厚度变化与临床相关 DED的特征。我们将在同时的特定目标中测试这一假设：目标1：验证和量化 TFL厚度与PCTF蒸发率呈负相关。我们假设TFLL的厚度 与PCTF的蒸发成反比，TFLL的“薄”区域允许过多的水分损失 泪水。目的2：量化TFLL厚度变化对PCTF不稳定性的影响。我们假设这个陡峭的 在TFLL的“薄”区和“厚”区之间的界面处的应力梯度导致了PCTF不稳定性。 总的来说，拟议的研究将引入两个新的参数来表征脂层 微观结构，并将它们与PCTF蒸发和不稳定性相关联，这将通过以下方法进行测试和验证 我们的新型高分辨率干涉系统。通过进一步的临床验证，这些参数将允许 早期、非侵入性地评估DED，并为开发新的治疗方法提供信息，以减缓或预防 DED的发展。

Project Summary In the anterior eye, the precorneal tear film (PCTF) acts as the interface between the ocular surface and external environment and plays a critical role in maintaining ocular surface homeostasis. In dry eye disease (DED), the PCTF becomes thinner, and destabilizes (evaporates) rapidly leading to hyperosmolarity, inflammation, and ocular surface desiccation. In 2020, the National Eye Institute (NEI) released a Notice of Special Interest (NOSI) for the Anterior Segment Initiative (ASI), “Identification and Development of New Biomarkers and Effective Methods to Diagnose Dry Eye Disease.” The notice highlighted a critical need for biomarkers and methods to diagnose DED prior to the onset of symptoms. The overall goal of this proposal is to characterize microstructural thickness variations of the tear film lipid layer (TFLL) and their association with clinical characteristics of DED. TFLL, the outmost layer of PCTF, overlies the aqueous phase, and serves as the barrier against evaporative aqueous loss, and stabilize it by facilitating the spread of its aqueous compartment and reducing surface tension. However, the exact mechanism by which the TFLL retards tear evaporation and promotes PCTF stability remains poorly understood. For instance, while most would agree that a uniform and thicker TFLL would be more protective against evaporation, and therefore prevent DED, this relationship remains controversial in the literature; resolution of this controversy forms the basis of this proposal. Under a NIH/NEI grant in 2021(R21EY033029), we constructed a novel laser source point-scanning interferometer that enables the in vivo assessment of dynamics of PCTF and related structures of TFLL with unprecedented resolution and sensitivity. Using this powerful system, we propose to address critical yet previously unexplored and often inconsistent associations between TFLL and examination findings of PCTF. The central hypothesis of the proposed research is that thickness variations in the microstructure of TFLL are associated with clinical characteristics of DED. We will test this hypothesis in concurrent Specific Aims: Aim 1: Verify and quantify the inversely relationship between TFLL thickness and PCTF evaporation rate. We hypothesize that TFLL thickness is inversely proportional to PCTF evaporation, with “thin” regions of the TFLL allowing excessive loss of aqueous tears. Aim 2: Quantify the impact of TFLL thickness variations on PCTF instability. We hypothesize that steep stress gradients at the interface between “thin” and “thick” regions of the TFLL cause PCTF instability. Collectively, the proposed studies will introduce two new parameters to characterize the lipid layer microstructure and correlate them with PCTF evaporation and instability, which will be tested and validated with our novel high-resolution interferometric system. With further clinical validation, these parameters will allow for early, non-invasive assessment of DED and inform the development of new therapeutics to slow or prevent the development of DED.