Optic nerve head microstructure, biomechanics and susceptibility to glaucoma

摘要 彻底了解青光眼的发病机制将对青光眼的检测和治疗大有裨益 导致神经组织退化，并开发了一种评估眼睛特异性敏感性的技术 在它发生之前破坏。我们的长期目标是开发这种技术。神经组织 早期青光眼的变性通常局限于视神经头(ONH)的特定区域，而衰老 眼压升高会增加患病风险。我们的中心假设是 ONH的结缔组织，特别是筛板(LC)的结缔组织，决定了局部 对眼压的稳健性和敏感性，以及与此相关的早期神经组织损伤的区域易感性 青光眼，各种水平的眼压。在之前的项目期间，我们使用了基于偏振光的成像工具 显微镜(PLM)以获得ONH组织的微米级信息，包括胶原纤维的图谱 纤维的排列和拉伸或松弛的程度，称为卷曲。我们找出了 在ONH和全球范围内卷曲，并与年龄相关的卷曲减少。然而，由于缺乏 在合适的技术中，对眼压敏感性的分析仅限于比较固定在不同眼压下的眼睛。 我们使用建模来预测建筑对组织属性和对IOP的敏感性的影响，但同样， 由于缺乏实验工具，不可能真正测试这种关系。我们已经开发了两种状态- 最先进的成像技术，SPLM和IPOL。SPLM从新鲜的厚厚的ONH组织中提供类似PLM的数据。 结合光学相干断层扫描，它提供了ONH对眼压敏感度的极好细节 通货膨胀。IPOL提高了速度、分辨率和灵敏度，实时解析，不仅是胶原束，而且 形成束状物的纤维的细节。在一种新型微机械测试系统中使用IPOL显示了良好的性能 在受控载荷下的组织细节，从而允许直接测量局部机械特性。 最后，我们开发了一种基于纤维的模拟技术，它允许在高度 现实的方式。我们将使用这些技术在目标1中测量ONH对IOP和IOP的生物力学敏感性 测试已知的早期青光眼易损伤区域对眼压更敏感的假设。 我们检验了年龄与PPS组和LC组的眼压敏感度较低和较高的假设。在……里面 目的2我们验证年龄与ONH组织结构变化相关的预测。 多个比例。在目标3中，我们将直接测量组织的机械性能，并使用建模 为了检验这一假设，即眼压和生物力学特性随年龄的变化可以是 这是由于显微结构的变化造成的。这个项目将回答新的和长期存在的问题 建筑、眼压和衰老在ONH神经组织机械性损伤中的作用 青光眼组织丢失模式的潜在原因。这是朝着最终目标迈出的重要一步 诊断所有年龄和眼压水平的青光眼风险。

SUMMARY Detection and treatment of glaucoma would benefit greatly from a thorough understanding of the mechanisms leading to neural tissue degeneration, and the development of a technique to evaluate eye-specific susceptibility to damage before it occurs. Our long-term goal is the development of such a technique. Neural tissue degeneration in early glaucoma is often localized to specific regions of the optic nerve head (ONH), and aging and elevated intraocular pressure (IOP) increase the risk. Our central hypothesis is that the architecture of the connective tissues of the ONH, and in particular of the lamina cribrosa (LC) within, determines the local robustness and sensitivity to IOP, and with this the regional susceptibility to neural tissue damage in early glaucoma, at all levels of IOP. In the previous project period, we used imaging tools based on polarized light microscopy (PLM) to obtain micron-scale information of the tissues of the ONH, including maps of collagen fiber alignment and the degree of stretch or relaxation of the fibers, referred to as crimp. We identified patterns in the crimp within the ONH and around the globe, and an age-related decrease crimp. However, because of the lack of suitable technology, analysis of the sensitivity to IOP was limited to comparing eyes fixed at different IOPs. We used modeling to predict effects of architecture on tissue properties and sensitivity to IOP, but, again, the lack of experimental tools made it impossible to actually test the relationship. We have developed two state-of- the-art imaging techniques, SPLM and IPOL. SPLM provides PLM-like data, from fresh thick ONH tissues. Coupled with optical coherence tomography, it provides excellent details of the ONH sensitivity to IOP during inflation. IPOL improves speed, resolution and sensitivity, resolving in real time, not just collagen bundles, but the details of the fibers forming the bundles. Using IPOL in a novel micro-mechanical testing system reveals fine tissue details while under controlled load, thus allowing direct measurement of local mechanical properties. Finally, we have developed a fiber-based simulation technique that allows modeling the tissues in a highly realistic way. We will use these techniques to measure, in Aim 1, the ONH biomechanical sensitivity to IOP and test the hypothesis that regions of known susceptibility to damage in early glaucoma are more sensitive to IOP. We test the hypothesis that age is associated with lower sensitivity to IOP in the PPS and higher in the LC. In Aim 2 we test the prediction that age is associated with changes in the architecture of the tissues of the ONH at multiple scales. In Aim 3, we will measure directly the mechanical properties of the tissues, and use modeling to test the hypothesis that the changes in sensitivity to IOP and biomechanical properties with age can be accounted for by the changes in microstructure. This project will answer both novel and long-standing question on the roles of architecture, IOP and aging on the mechanical insult to the neural tissues of the ONH, and the causes underlying the patterns of tissue loss in glaucoma. This is an important step towards the ultimate goal of diagnosing eyes at risk of glaucoma at all ages and levels of IOP.