Optic nerve head microstructure, biomechanics and susceptibility to glaucoma

总结 青光眼的检测和治疗将大大受益于对机制的深入了解 导致神经组织变性，以及评估眼睛特异性易感性的技术的发展 在它发生之前就破坏。我们的长期目标是开发这种技术。神经组织 早期青光眼中的变性通常局限于视神经头（ONH）的特定区域， 和升高的眼内压（IOP）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），决定了局部的 鲁棒性和对IOP的敏感性，以及由此引起的对早期神经组织损伤的区域敏感性。 青光眼，在所有IOP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），以获得ONH组织的微米级信息，包括胶原纤维图 排列和纤维的拉伸或松弛程度，称为卷曲。我们发现了 ONH内和地球仪周围的卷曲，以及与年龄相关的卷曲减少。然而，由于缺乏 由于采用了适当的技术，对IOP敏感性的分析仅限于比较固定在不同IOP下的眼睛。 我们使用建模来预测结构对组织特性和对IOP的敏感性的影响，但是， 由于缺乏实验工具，无法实际测试这种关系。我们开发了两个国家- 最先进的成像技术，SPLM和IPOL。SPLM提供来自新鲜厚ONH组织的PLM样数据。 结合光学相干断层扫描，它提供了ONH对IOP敏感性的极好细节， 通胀IPOL提高了速度、分辨率和灵敏度，能够真实的实时分辨，不仅是胶原蛋白束， 形成纤维束的纤维的细节。在一种新型的微机械测试系统中使用IPOL， 组织的细节，同时在受控的负荷，从而允许直接测量局部机械性能。 最后，我们已经开发了一种基于纤维的模拟技术，该技术允许在一个高度 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的生物力学敏感性， 测试已知对早期青光眼损伤敏感的区域对IOP更敏感的假设。 我们检验了年龄与PPS中IOP敏感性较低和LC中IOP敏感性较高相关的假设。在 目的2：我们验证年龄与ONH组织结构变化相关的预测， 多尺度在目标3中，我们将直接测量组织的力学特性，并使用建模 为了检验这一假设，即随着年龄的增长，对IOP的敏感性和生物力学特性的变化可能是 微观结构的变化。这个项目将回答新的和长期存在的问题 对ONH神经组织机械损伤的结构、IOP和老化的作用，以及ONH神经组织机械损伤的机制进行了研究。 青光眼组织缺损的潜在原因。这是朝着最终目标迈出的重要一步， 在所有年龄和IOP水平下诊断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.