Biomechanical understanding of accommodation mechanism with Brillouin microscopy

描述（由申请人提供）：每个超过50岁的人都会经历严重的适应性下降，导致老花眼，对生活质量和工作表现产生负面影响。与年龄相关的透镜硬化被认为是 在调节力的降低中起主要作用。然而，目前关于透镜的弹性模量、其老化进展以及重要的是透镜内的弹性模量的空间分布的可用实验数据是高度可变的。因此，仍然缺少指导透镜调节的生物物理原理的明确解释，这阻碍了延迟/减缓老花眼发作或恢复调节能力的有效方法的开发。为了克服这种限制，申请人已经开发了一种光学技术，布里渊显微术，其可以非微扰地并且以3D微米分辨率映射透镜弹性模量的空间分布。利用这种新技术，本提案的目的是测量老化透镜的3D生物力学特性，并了解调节的生物物理原理。该建议的中心假设是，由于透镜内局部模量的空间分布中的与年龄相关的变化，导致透镜刚度的总体增加，从而丧失了调节能力。这一假设源于用离体人透镜样本收集的初步数据。在目标1中，将通过系统比较不同年龄晶状体的基于弹性的指标及其相应的调节力来检验假设。对这些数据的统计分析将验证说明空间分布的指标 模量的分布比透镜内的弹性模量的局部值更好地预测调节。在目标2中，将通过实验验证申请人开发的生物物理透镜模型的预测来测试该假设，其中透镜表现为具有从周边到核增加的粘弹性模量的复合椭圆体。随着年龄的增长，空间弹性梯度和透镜内较硬组分的贡献增加。这导致增加的透镜“等效”模量和刚度，引起调节能力的下降。由于布里渊技术可以转化为临床应用，因此这项研究的结果可以在体内验证。该方法是创新性的，因为它引入了透镜弹性特性的非侵入性3D分辨测量和超出特定模拟的第一原理生物物理建模。这项研究意义重大，因为通过揭示透镜内部弹性模量空间分布的关键作用，有望在纵向上推进对调节过程以及更广泛地对透镜生长和功能的机械理解。最终，从这项研究中获得的知识可能会激励，促进和加速正在进行的努力，以开发药理学或外科干预措施，以保持或恢复调节能力。

DESCRIPTION (provided by applicant): Every person beyond the age of 50 experiences severe decline of accommodation, leading to presbyopia, with negative consequences in terms of quality of life and work performance. The age-related stiffening of the lens is believed to play a primary role in the decrease of accommodation power. However, currently available experimental data on lens's elastic modulus, its age progression and, importantly, the spatial distribution of elastic modulus inside the lens are highly variable. As a result, a definitive explanation of the biophysical principles guiding lens accommodation is still missing, which hinders the development of effective approaches to delay/slow down presbyopia onset or restore accommodation power. To overcome this limitation, the applicants have developed an optical technology, Brillouin microscopy, which can map the spatial distribution of the lens elastic modulus non-perturbatively and with 3D micron resolution. Leveraging on this novel technology, the objective of this proposal is to measure the 3D biomechanical properties of the aging lens and understand the biophysical principles governing accommodation. The central hypothesis of this proposal is that the accommodation power is lost as a result of an age-related variation in the spatial distribution of the local modulus inside the lens, which results in overal increase of lens stiffness. This hypothesis stems from preliminary data collected with ex vivo human lens samples. In Aim 1, the hypothesis will be tested through a systematic comparison of elasticity-based metrics of lenses of different ages and their corresponding accommodation power. The statistical analysis of these data will verify that metrics that account for the spatial distribution of modulus are better predictors of accommodation than the local values of elastic moduli inside the lens. In Aim 2, the hypothesis will be tested by experimentally validating the predictions of a biophysical lens model, developed by the applicants, where the lens behaves as a composite ellipsoid with increasing viscoelastic modulus from periphery to nucleus. With age, the spatial elasticity gradient and the contribution of the harder components inside the lens increase. This results in increased lens "equivalent" modulus and stiffness causing the decline of accommodation power. As Brillouin technology can be translated to clinical use, the results of this research can be validated in vivo. The approach is innovative because it introduces non- invasive 3D-resolved measurements of lens elastic properties and first-principle biophysical modeling beyond ad hoc simulations. The research is significant because, by unveiling the crucial role of the spatial distribution of elastic modulus inside the lens, it is expected to vertcally advance the mechanistic understanding of the accommodation process as well as, more broadly, of lens growth and function. Ultimately, the knowledge gained from this research is likely to inspire, facilitate and accelerate the on-going effort to develop pharmacological or surgical interventions to preserve or restore accommodation power.