Determining the Efficacy of Corneal Cross-Linking Protocols using Brillouin Microscopy

使用布里渊显微镜确定角膜交联方案的功效

基本信息

批准号：
10443488
负责人：
William Joseph Dupps
金额：
$ 40.26万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443488
关键词：
3-Dimensional Ablation Accounting Address Affect Animals Behavior Biomechanics Clinic Clinical Clinical Research Cornea Corneal Stroma Data Development Diffusion Disease Elasticity Elements Epithelial Evaluation Evolution Excision Eye FDA approved Future Goals Human Hydration status Image In Situ Keratoconus Keratoplasty Lasers Longitudinal Studies Maps Measurement Measures Mechanical Stress Mechanics Methods Microscopy Modeling Modulus Morphology Optics Oryctolagus cuniculus Outcome Patients Photorefractive Keratectomy Photosensitizing Agents Procedures Process Protocols documentation Public Health Quality of life Recovery Research Resistance Resolution Riboflavin Safety Shapes Spatial Distribution Speed Techniques Technology Testing Thick Time Tissues Translating Treatment Protocols Ultraviolet A radiation Vision Visual Visual Acuity Work base clinical translation cohort crosslink experimental study human subject improved in vivo individualized medicine novel patient tolerability predict clinical outcome predictive modeling programs protocol development public health relevance rational design research clinical testing response time use tomography treatment planning

项目摘要

ABSTRACT: Keratoconus and related corneal ectatic diseases cause significantly decreased quality of life, are the leading cause for full thickness corneal transplant in the US, and are significantly more prevalent than previously thought. Corneal cross-linking (CXL) has emerged as a clinical technique to halt keratoconus progression by stiffening the corneal stroma. Despite being used clinically for more than a decade, it is currently impossible to assess CXL protocol efficacy or predict the long-term stability and because we lack quantitative biomechanical measures to inform predictive models. Currently available metrics to characterize CXL responses are morphologic and have not proven predictive of clinical outcomes. The major gap is the lack of measurement techniques that can accurately and non-perturbatively characterize corneal mechanics with three-dimensional (3-D) resolution in vivo. To address this need, in the past decade we have pioneered Brillouin microscopy, a high-resolution optical technology that can measure corneal longitudinal modulus in situ in 3-D without contacting or perturbing the eye. Brillouin microscopy has provided the first and only direct mechanical evidence of decreased modulus in keratoconus corneas in vivo and the only 3-D maps of CXL-induced corneal stiffening. The overall goal of this research program is to combine 3-D Brillouin corneal maps and finite element (FE) modeling to quantitatively predict corneal shape outcomes after CXL protocols. In strong preliminary data, we demonstrated that, by accounting for tissue hydration, we can establish the quantitative relationship between Brillouin-measured longitudinal modulus and Young’s modulus. Thus, our central hypothesis is that spatial maps of corneal Young’s modulus derived from quantitative Brillouin microscopy will enable accurate prediction of corneal shape behavior via FE modeling. The development of this noninvasive measure of corneal stiffness also enables us to use a rabbit model to evaluate, for the first time, both morphologic and mechanical evolution in longitudinal studies in vivo, validated by direct mechanical analysis using experimental protocols that cannot be performed in human subjects. We will test our central hypothesis through the three specific aims: 1) Validate in vivo Brillouin mechanical measurements after CXL; 2) Quantify the in vivo mechanical outcomes of novel CXL protocols; and 3) Link CXL biomechanical impact to morphologic outcome with Brillouin imaging and FE modeling. This research is significant because accurate nondestructive, nonperturbative elasticity-based metrics will drive a paradigm shift in how CXL protocols are evaluated, developed, and performed clinically as well as ultimately allow us to develop individualized CXL treatment protocols.

抽象的：圆锥角膜和相关的角膜扩张性疾病导致生活质量显着下降，是导致生活质量显着下降的主要原因这是美国进行全层角膜移植的原因，并且比之前想象的要普遍得多。角膜交联 (CXL) 已成为一种通过硬化来阻止圆锥角膜进展的临床技术尽管在临床上使用了十多年，但目前还无法对其进行评估。 CXL 方案功效或预测长期稳定性，因为我们缺乏定量的生物力学测量目前可用的表征 CXL 反应的指标包括形态学和尚未证明可以预测临床结果，主要差距是缺乏可以预测的测量技术。准确且无扰动地表征具有三维 (3-D) 分辨率的角膜力学为了满足这一需求，在过去的十年中，我们率先推出了布里渊显微镜，这是一种高分辨率光学显微镜。该技术可以在不接触或干扰眼睛的情况下原位测量 3D 角膜纵向模量。布里渊显微镜提供了第一个也是唯一一个模量降低的直接机械证据体内圆锥角膜和 CXL 引起的角膜硬化的唯一 3D 图。研究计划是将 3-D 布里渊角膜图和有限元 (FE) 建模相结合来定量通过强有力的初步数据，我们证明了预测 CXL 方案后的角膜形状结果。考虑到组织水合作用，我们可以建立布里渊测量之间的定量关系因此，我们的中心假设是角膜杨氏空间图来自定量布里渊显微镜的模量将能够准确预测角膜形状行为通过有限元建模，这种非侵入性角膜硬度测量方法的发展也使我们能够使用兔子模型首次在纵向研究中评估形态和机械进化体内，使用无法在人体中进行的实验方案通过直接机械分析进行验证我们将通过三个具体目标来检验我们的中心假设：1）验证体内布里渊。 CXL 后的机械测量；2) 量化新型 CXL 方案的体内机械结果； 3) 通过布里渊成像和有限元建模将 CXL 生物力学影响与形态结果联系起来。研究意义重大，因为准确的非破坏性、非微扰的基于弹性的指标将推动 CXL 方案在临床以及最终的评估、开发和执行方式的范式转变让我们能够制定个性化的 CXL 治疗方案。