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

摘要： 圆锥角膜和相关的角膜扩张性疾病导致的生活质量明显下降，是主要的 在美国，全厚角膜移植的原因，而且比之前认为的要普遍得多。 角膜交联术(CXL)已经成为一种通过硬化来阻止圆锥角膜进展的临床技术 角膜基质。尽管已经在临床上使用了十多年，但目前还不可能对其进行评估 CXL方案的疗效或预测长期稳定性，因为我们缺乏定量的生物力学措施 为预测模型提供信息。目前可用来表征CXL反应的指标是形态和 还没有被证明可以预测临床结果。主要的差距是缺乏能够 用三维(3-D)分辨率精确和非摄动地表征角膜力学 活着。为了满足这一需求，在过去的十年里，我们开创了布里渊显微镜，一种高分辨率的光学 这项技术可以在不接触或干扰眼睛的情况下，在3D中原位测量角膜纵向模数。 布里渊显微镜提供了第一个也是唯一一个直接的力学证据 活体圆锥角膜和CXL诱导的角膜硬化的唯一三维地图。这个项目的总体目标是 研究计划是将三维布里渊角膜地图和有限元(FE)建模相结合，以定量 预测CXL手术后的角膜形态结果。在强劲的初步数据中，我们通过 考虑到组织的水合作用，我们可以建立布里渊测量之间的定量关系 纵向模数和杨氏模数。因此，我们的中心假设是角膜杨氏空间图 从定量布里渊显微镜获得的模数将使准确预测角膜形状行为成为可能 通过有限元建模。这种非侵入性角膜硬度测量的发展也使我们能够使用 首次在纵向研究中评估形态和力学演变的兔模型 活体，通过使用不能在人类身上执行的实验方案的直接力学分析进行验证 研究对象。我们将通过三个具体目标来验证我们的中心假设：1)在体内验证布里渊 CXL后的机械测量；2)量化新的CXL方案的体内机械结果；以及 3)通过布里渊成像和有限元模拟将CXL的生物力学影响与形态学结果联系起来。这 研究具有重要意义，因为准确的无损、非扰动的基于弹性的指标将推动 CXL方案在临床和最终评估、开发和执行方式的范式转变 允许我们开发个性化的CXL治疗方案。

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.