Optic nerve head microstructure, biomechanics and susceptibility to glaucoma

摘要 彻底了解青光眼的机制将大大受益于青光眼的检测和治疗 导致神经组织变性，以及开发评估眼睛特异性易感性的技术 在损坏发生之前。我们的长期目标是开发这种技术。神经组织 早期青光眼的退化通常局限于视神经乳头 (ONH) 的特定区域，并且衰老 眼压（IOP）升高会增加风险。我们的中心假设是 ONH 的结缔组织，特别是其中的筛板 (LC)，决定了局部 对 IOP 的稳健性和敏感性，以及早期神经组织损伤的区域易感性 青光眼，各个眼压水平。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) 获取 ONH 组织的微米级信息，包括胶原纤维图 纤维的排列和拉伸或松弛程度，称为卷曲。我们确定了其中的模式 ONH 内和全球范围内的压接，以及与年龄相关的压接减少。然而，由于缺乏 由于没有合适的技术，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结构对组织特性和 IOP 敏感性的影响，但是，同样， 缺乏实验工具使得无法实际测试这种关系。我们开发了两种状态- 最先进的成像技术，SPLM 和 IPOL。 SPLM 提供来自新鲜厚 ONH 组织的类似 PLM 的数据。 与光学相干断层扫描相结合，它可以提供 ONH 对 IOP 敏感度的出色细节。 通货膨胀。 IPOL 提高了速度、分辨率和灵敏度，实时解析，不仅是胶原蛋白束，而且 形成束的纤维的细节。在新型微机械测试系统中使用 IPOL 揭示了良好的性能 在受控负载下的组织细节，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，可以对组织进行高度建模。 现实的方式。在目标 1 中，我们将使用这些技术来测量 ONH 对 IOP 和 检验以下假设：早期青光眼中已知易受损伤的区域对 IOP 更敏感。 我们检验了这样的假设：年龄与 PPS 中 IOP 的敏感性较低和 LC 中 IOP 的敏感性较高相关。在 目标 2 我们测试年龄与 ONH 组织结构变化相关的预测 多重尺度。在目标 3 中，我们将直接测量组织的机械特性，并使用建模 检验以下假设：眼压敏感性和生物力学特性随年龄的变化可以 通过微观结构的变化来解释。该项目将回答新奇和长期存在的问题 结构、眼压和衰老对 ONH 神经组织机械损伤的作用，以及 青光眼组织损失模式的潜在原因。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有青光眼风险的眼睛。

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.