Enhanced backscattering instrument for assessing optical biomarkers of glaucoma

项目总结： 青光眼是人类不可逆转失明的主要原因。青光眼是常见的 与眼压升高有关，但眼压本身既不能预测视力丧失，也不能 疾病进展的唯一风险因素，以及它随时间波动的趋势，使其成为次优 筛查工具和预后指标。细胞外基质的结构和生物力学特性 基质，特别是组成巩膜的胶原蛋白，被广泛认为是一种 在青光眼易感性中的重要作用，尽管这种关系的确切性质仍未解决。 考虑到巩膜特性对眼压分布和视神经头变形的公认影响 和青光眼的损害，迫切需要非侵入性的、经济有效的方法来量化 巩膜内胶原蛋白的显微结构。光散射的检测和量化对 组织的结构组织，小到纳米级，远低于其他组织的衍射极限分辨率 成像方法。增强背向散射(EBS)已在临床环境中应用于癌症筛查 风险。我们假设青光眼相关巩膜胶原结构的差异是可以量化的。 使用EBS。然而，EBS以前没有被应用于巩膜等纤维组织，并且评估 巩膜胶原结构将需要开发新的组织特异性EBS方法和硬件，如 以及用于分析的新模型。要克服这一障碍，更清楚地了解 青光眼病理生物学中的巩膜胶原结构，最终目标是开发一种 关于翻译潜力，我们提出了两个具体目标。目标1：我们将建立第一个偏振EBS 专门针对巩膜进行了优化的器械。这种新型仪器将包括角带宽。 与巩膜的更高散射和偏振控制相匹配，以提供对双折射的敏感性 纤维组织。该仪器将使用精密微球模体进行验证，并在 获得正常和青光眼巩膜测量值的独特青光眼动物模型 标本体外。在目标2：我们将开发一个计算模型来将EBS测量与组织联系起来 用二次谐波产生显微镜和基于散射的方法测定胶原结构 用光散射法测量巩膜的相函数。在光学方面最显著的差异 基团间的散射特征将被认为是一个很有前途的生物标志物。加在一起，这些 实验将提供一种新的仪器和模型，有可能转化为临床前和临床 设置。特别是，该测试的非侵入性将允许进行亟需的纵向研究 自发性青光眼患者体内胶原特性的变化及其反应的变化 年龄和干预措施。

Project Summary: Glaucoma is a leading cause of irreversible blindness in the human population. Glaucoma is frequently associated with elevated intraocular pressure (IOP), but IOP alone is neither predictive of vision loss, nor the sole risk factor for disease progression, and its tendency to fluctuate over time makes it a suboptimal screening tool and prognostic indicator. The structural and biomechanical properties of the extracellular matrix, and in particular the collagen that makes up the sclera, have been widely implicated as playing a significant role in glaucoma susceptibility, though the precise nature of this relationship remains unresolved. Given the recognized influence of scleral properties on both IOP profile and optic nerve head deformation and damage in glaucoma, there is a critical need for non-invasive, cost-effective methods to quantify collagen microstructure in the sclera. Detection and quantification of optical scattering is sensitive to structural organization of tissue down to the nanoscale, well below the diffraction limited resolution of other imaging methods. Enhanced Backscattering (EBS) has been applied in a clinical setting to screen for cancer risk. We hypothesize that glaucoma-associated differences in scleral collagen structure can be quantified using EBS. However, EBS has not previously been applied to fibrous tissues like sclera, and assessment of scleral collagen structure will require development of new tissue-specific EBS approaches and hardware as well as new models for analyses. To overcome this barrier to clearer understanding of the role played by scleral collagen structure in glaucoma pathobiology, with the ultimate goal of developing a tool with translational potential, we propose two specific aims. In Aim 1: we will build the first polarimetric EBS instrument specifically optimized for sclera. This novel instrument will incorporate angular bandwidth matched to higher scattering by sclera and polarization control to provide sensitivity to birefringence of this fibrous tissue. The instrument will be validated using precision microsphere phantoms and applied in a unique animal model of glaucoma with acquisition of measurements from normal and glaucomatous sclera specimens ex vivo. In Aim 2: We will develop a computational model to relate EBS measurements to tissue collagen structure as determined by second harmonic generation microscopy, and based on scattering phase function from sclera using light scattering goniometry. The most significant differences in optical scattering signature between groups will be identified as a promising biomarker. Together, these experiments will provide a novel instrument and model with potential for translation to pre-clinical and clinical settings. In particular, the non-invasive nature of the test will permit much needed longitudinal studies of changes in collagen properties within individuals with spontaneous glaucoma, and also changes in response to age and interventions.