Advanced transepithelial corneal collagen crosslinking

项目总结 圆锥角膜是一种眼科疾病，角膜受到机械性削弱，导致 渐进性视力减薄、变形和退化。在严重情况下，角膜 可能需要移植才能恢复视力。角膜胶原交联(CXL)是一种 利用核黄素、氧气和紫外线(UV)产生化学反应的过程 这会加强角膜基质中的胶原纤维。CXL已被证明可以阻止圆锥角膜 长期的进步。 标准CXL程序的一个问题是表面上皮细胞必须是 首先去除，以便核黄素、氧气和紫外线可以很容易地进入角膜基质。这是很常见的 CXL后上皮愈合延迟。这增加了角膜可能 变得模糊不清。它还增加了感染的风险，可能导致疤痕和失明。至 为了避免这些问题，一些医生在不切除上皮的情况下进行CXL。这叫做 “跨皮细胞CXL”与标准的“外膜CXL”程序不同。不幸的是，由于 目前的实践中，跨上皮CXL在加强角膜方面的效果要差得多。 我们已经开发出一种先进的跨上皮CXL技术(Casey CXL)， 克服上皮细胞对核黄素、氧气和紫外线传递的障碍。一种计算有限元- 扩散和反应动力学的有限元模型表明，Casey CXL可以显著 超过标准EPI-OFF CXL的性能。我们建议验证以下优势： Casey CXL在使用兔和人眼库角膜进行的体外实验中： 1.构建氧气-紫外光输送系统，使环境空气中的氧气含量达到90% 紫外线照射过程中的角膜表面。 2.测量准分子激光原位角膜磨镶术中角膜基质中氧浓度。我们将使用光纤 血氧饱和度探头测量紫外线照射过程中间质前部和中部的氧含量。我们会 测试假设，通过使用富氧和脉冲紫外线，Casey CXL允许更多 氧气穿透到基质中部比标准的外切CXL。有限元预测超过 Casey CXL的2倍优势，将大大提高角膜强化的深度。 3.使用光学相干层析弹性成像这一无损检测技术， 测量实验性CXL手术前后的角膜硬度。这将检验这样一个假设： 正如有限元预测的那样，Casey CXL可以比标准的Epioff CXL更能使角膜僵硬。 这些实验将验证Casey CXL方案，包括药物配方， 程序步骤和氧气-紫外线输送装置，为在人类患者身上进行临床试验做准备。

PROJECT SUMMARY Keratoconus is an eye disease where the cornea is mechanically weakened, leading to progressive thinning, distortion, and degradation of vision. In severe cases, corneal transplantation may be required to restore vision. Corneal collagen crosslinking (CXL) is a procedure that uses riboflavin, oxygen and ultraviolet (UV) light to produce a chemical reaction that strengthens collagen fibers in the cornea stroma. CXL has been shown to halt keratoconus progression over the long term. A problem with the standard CXL procedure is that the surface epithelial cells must be removed first so that riboflavin, oxygen, and UV can easily enter the corneal stroma. It is common for epithelial healing to be delayed after CXL. This increases the chance that the cornea may become hazy. It also increases the risk of infections that can lead to scarring and loss of vision. To avoid these problems, some doctors perform CXL without removing the epithelium. This is called “transepithelial CXL” in contrast to the standard “epi-off CXL” procedure. Unfortunately, as currently practiced, transepithelial CXL is far less effective in strengthening the cornea. We have developed an advanced transepithelial CXL technology (Casey CXL) that overcomes the epithelial barrier to riboflavin, oxygen, and UV delivery. A computational finite- element model (FEM) of diffusion and reaction kinetics showed that Casey CXL can significantly exceed the performance of standard epi-off CXL. We propose to validate the advantages of Casey CXL in ex vivo experiments using both rabbit and human eye bank corneas: 1. Construct an oxygen-UV delivery system to enrich oxygen to >90% in the ambient air over the corneal surface during UV irradiation. 2. Measure oxygen concentration in the corneal stroma during CXL. We will use a fiber-optics oximetry probe to measure oxygen in the anterior and mid-stroma during UV irradiation. We will test the hypothesis that by using oxygen enrichment and pulsed UV, Casey CXL allows greater oxygen penetration to the mid-stroma than standard epi-off CXL. The FEM predicts a more than 2-fold advantage for Casey CXL, which would greatly improve the depth of corneal strengthening. 3. Use optical coherence tomographic elastography, a nondestructive testing technology, to measure cornea stiffness before and after experimental CXL. This would test the hypothesis that Casey CXL can stiffen the cornea more than standard epi-off CXL, as predicted by the FEM. These experiments would validate the Casey CXL protocol, including the drug formulation, procedure steps, and oxygen-UV delivery device, to prepare for clinical trials in human patients.