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.
This proposal is relevant to the public health because it will elucidate the governing principles of the accommodation process and identify the mechanical properties of the crystalline lens that drive the decline of accommodation power leading to presbyopia. This is expected to inspire, develop and enable testing current and future approaches to preserve or restore accommodation. In addition, this will broadly provide mechanistic insights on lens growth and function as well as on cataract formation. Therefore, the proposed research is relevant to the NIH's mission of pursuing fundamental knowledge in order to extend healthy life.
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