Biomechanical understanding of accommodation mechanism with Brillouin microscopy

描述(申请人提供)：每个50岁以上的人都会经历严重的住宿能力下降，导致老花眼，对生活质量和工作表现造成负面影响。与年龄相关的晶状体僵硬被认为起了作用 在住宿能力下降中起主要作用。然而，目前可获得的关于晶状体弹性模数、年龄进程以及更重要的是晶状体内弹性模数的空间分布的实验数据是高度可变的。因此，指导晶状体调节的生物物理学原理仍然缺乏明确的解释，这阻碍了有效方法的发展，以延迟/减缓老花眼的发病或恢复调节能力。为了克服这一限制，申请人开发了一种名为布里渊显微镜的光学技术，它可以以非微扰的方式绘制透镜弹性模数的空间分布，并具有3D微米的分辨率。利用这项新技术，这项建议的目标是测量老化晶状体的3D生物力学特性，并了解调节的生物物理原理。这一建议的中心假设是，调节力的丧失是由于晶状体内部局部模数的空间分布随年龄的变化而导致的，从而导致晶状体硬度的整体增加。这一假说源于通过体外人类晶状体样本收集的初步数据。在目标1中，将通过系统地比较不同年龄的镜片的弹性指标及其相应的调节能力来检验这一假设。对这些数据统计分析将验证解释空间的度量 与晶状体内部弹性模量值相比，弹性模量值的分布能更好地预测调节情况。在目标2中，将通过实验验证申请者开发的生物物理透镜模型的预测来检验这一假设，在该模型中，透镜表现为从外围到原子核的粘弹性模数增加的复合椭球体。随着年龄的增长，晶状体的空间弹性梯度和晶状体内部较硬成分的贡献增加。这会导致透镜的“等效”模数和硬度增加，从而导致调节能力下降。由于布里渊技术可以转化为临床使用，这项研究的结果可以在体内得到验证。这种方法是创新的，因为它引入了非侵入性的3D分辨率的晶状体弹性特性测量，以及超越特殊模拟的第一原理生物物理建模。这项研究意义重大，因为通过揭示晶状体内部弹性模数的空间分布的关键作用，有望垂直推进对调节过程以及更广泛地说对晶状体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，开发药物或外科干预措施来保存或恢复调节能力。

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.