Advanced transepithelial corneal collagen crosslinking

项目摘要 圆锥角膜是一种眼部疾病，其中角膜机械弱化，导致 视力逐渐变薄、变形和退化。在严重的情况下， 可能需要移植来恢复视力。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 强化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 首先将其去除，以便核黄素、氧气和紫外线可以容易地进入角膜基质。通常 延迟上皮愈合的可能性这增加了角膜可能 变得模糊。它还会增加感染的风险，从而导致疤痕和视力丧失。到 为了避免这些问题，有些医生在不切除上皮的情况下进行CXL。这被称为 “经上皮CXL”与标准的“epi-off CXL”程序相反。可惜作为 目前实施的经上皮CXL在强化角膜方面效果差得多。 我们开发了一种先进的经上皮CXL技术（凯西CXL）， 克服了上皮细胞对核黄素、氧气和紫外线输送的屏障。一个计算有限的- 扩散和反应动力学的有限元模型（FEM）表明，凯西CXL可以显着 超过标准epi-off CXL的性能。我们建议验证的优点， 凯西CXL在使用兔和人眼角膜库的离体实验中： 1.建造一个氧气-紫外线输送系统，使周围空气中的氧气含量超过90%， 在紫外线照射过程中的角膜表面。 2.在CXL期间测量角膜基质中的氧浓度。我们将使用光纤 血氧测定探针，用于在UV照射期间测量前部和中间基质中的氧气。我们将 测试假设，通过使用富氧和脉冲紫外线，凯西CXL允许更大的 氧渗透到中间基质比标准epi-off CXL。FEM预测， 2-折叠优势凯西CXL，这将大大提高角膜加强的深度。 3.使用光学相干断层弹性成像技术，一种无损检测技术， 测量实验性CXL前后的角膜硬度。这将检验假设， 正如FEM预测的那样，凯西CXL可以比标准epi-off CXL更好地覆盖角膜。 这些实验将验证凯西CXL方案，包括药物配方， 手术步骤和氧气-UV输送装置，为人类患者的临床试验做准备。

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.