Mechanochemistry of collagen network remodeling in the sclera

The primary load-bearing tissue of the eye is the sclera, the eye's white outer shell. It helps the eye maintain its shape by resisting intraocular pressure and protects the delicate intraocular structures. The sclera is able to respond to mechanical changes in its environment by adapting to its environment, a process known as remodeling. This process, which alters the microstructure and/or properties of the tissue, can occur over the normal course of aging or under physiological conditions but may also contribute to pathological diseases such as glaucoma and myopia when an imbalance in the remodeling process occurs. It is therefore important to understand the underlying mechanisms that drive the remodeling process, and how it affects tissue microstructure and its mechanical properties. This work focuses on two main parts of the connective tissue microstructure: collagen, which serves as the primary load-bearing component and dominates the anisotropic large-strain mechanical response of the tissue, and glycosaminoglycans (GAGs), which regulate the spacing between collagen fibrils and help determine tissue hydration. The objective of this work is to study the effect of remodeling on mechanical behavior of the posterior sclera. We investigate this through three case studies. The first part of this work studies the mechanical role of GAGs in the human posterior sclera. Although alterations in mechanical properties and GAG content have been reported in glaucomatous eyes, it is unknown if the change in GAG content directly contributes to the observed changes in mechanical properties. Experimental protocols and analysis methods were developed for determining the inflation response of posterior human sclera, measured before and after enzymatic GAG degradation. It was shown that GAGs play a measurable role in altering the structural response and mechanical behavior of the posterior human sclera, likely through their effects on hydration and their interactions with the collagen fibrils. The second case study investigates how cyclic preconditioning of a collagenous substrate induces material property changes and morphological changes in collagen fibrils. Experimental studies have shown that repeated cyclic loading of an acellular collagen construct increased collagen stiffness, but did not significantly change fibril anisotropy. A model for the collagen fibril substrate was developed to show that the changes in the collagen anisotropy measured in experiments were insufficient to explain the measured increase in the stiffness of the collagen constructs with cyclic loading. The findings suggest that mechanical loading can induce changes in the stiffness and failure properties of the collagen fibril network through passive chemomechanical processes. The last part of this work examines the effect of changes in the geometry of the sclera, collagen anisotropic structure, and material properties from glaucoma on the inflation response of the mouse sclera. An inverse finite element method was used to fit model parameters describing fibril properties to the average measured scleral edge displacements of glaucoma and normal mouse eyes. The findings show that changes in collagen fibril material properties were responsible for the observed stiffening effect in glaucoma mouse eyes. The observed structural changes associated with glaucoma did not meaningfully stiffen the mechanical response