The Role of the Sclera and Orbital Tissues in the Biomechanical Deformation Response of the Cornea and Whole Eye Under Loading by Dynamic Scheimpflug Analyzer Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Boihoan Audrey Nguyen, M.S. Graduate Program in Biomedical Engineering The Ohio State University 2019 Dissertation Committee Cynthia J. Roberts, Ph.D, Advisor Matthew A. Reilly, Ph.D., Co-advisor Jun Liu, Ph.D., Committee Member Copyrighted by Boihoan Audrey Nguyen 2019 2 Abstract The biomechanical behavior of the ocular and orbital tissues are important to maintaining proper structure and function of the eye. The cornea and the sclera are the two main components of the ocular shell, which are loaded by IOP and are responsible for maintaining the structure and therefore function of the eye. This work comprises of four studies which explore the contribution of the sclera and the biomechanical response of the eye. The first study focused on the development of a finite-element model to explore the impact of varying scleral properties on the deformation response of the cornea to an air- puff. An axisymmetric model of the eye – consisting of a cornea, sclera, and vitreous humor – loaded internally by intraocular pressure (IOP) and externally by an air-puff from a noncontact tonometer was generated in COMSOL 5.2a. Our results showed that increasing scleral stiffness (with constant corneal stiffness and IOP) resulted in decreasing displacement of the corneal apex, i.e. the cornea responded to the air-puff as if it had stiffer mechanical properties. The finite-element model also showed that apical displacement decreased nonlinearly with increasing IOP, which is consistent with literature reports. This study demonstrated that the sclera has an inseparable impact on the biomechanical deformation response of the cornea, and that the corneal response to an air-puff is the result of both corneal and scleral properties, in addition to IOP. ii The second study further explores the impact of varying scleral properties on corneal deformation response in an ex vivo experiment. Our results showed that the corneal response to an air-puff is significantly impacted by scleral properties. Several dynamic corneal response (DCR) parameters exported by the CorVis ST noncontact tonometer were analyzed to compare the effect of stiffening the sclera while leaving the cornea untreated. With stiffened sclera, changes in DCRs showed that the cornea had an apparently stiffer response to air-puff loading. Additionally, we showed that the Stiffness Parameter (SP) at Highest Concavity parameter is sensitive to changes in scleral properties and changed significantly after scleral stiffening. The Stiffness Parameter at First Applanation (A1), which is known to be sensitive to corneal properties, showed no significant differences with scleral properties. The results of this study have important clinical implications, demonstrating corneal response is significantly affected by scleral properties and providing insights into potential response parameters for evaluating scleral biomechanics with a clinical device. The third study focused on the development of an analytical model to determine the contribution of ocular and orbital tissues to the motion of the cornea and the whole-eye under air-puff loading. During air-puff loading, the whole-globe experiences a rearward displacement into the orbit while the cornea undergoes its deformation response. A one- dimensional model of centerline motion was developed to evaluate the relative contributions of ocular and orbital tissues to this motion. The resultant model was validated with data from ex vivo studies and showed that (1) orbital tissues were best represented by a Kelvin-Voigt viscoelastic solid, (2) the cornea must necessarily be viscoelastic, and was iii best represented as a 3-parameter standard linear solid, and (3) that the contribution of the sclera must be considered to reproduce the timing of key events in in vivo motion, and that the sclera is accurately modeled as a nonlinear stiffening spring. The final study applied the analytical model to a clinical cohort of newly-diagnosed glaucoma subjects undergoing treatment with prostaglandin-analogs (PGA)s. While we originally hypothesized that measured whole-eye motion would increase as a result of potential atrophy of orbital fat, our results showed a significant decrease in measured whole-eye motion. The results of the analytical model showed that while there were no changes in orbital tissue properties, that the apparent paradox of decreasing whole-eye motion following PGA-treatment was the result of decreased corneal and scleral stiffness, in addition to a reduction in IOP. Calculated impulse of the cornea and globe showed that PGA-treatment resulted in a significant increase in corneal impulse and decrease in globe impulse, demonstrating that a greater proportion of the kinetic energy from the air-puff is absorbed by the cornea and less kinetic energy is used in the rearward translation of the globe. Overall, these studies have demonstrated that the biomechanical deformation response of the cornea to an air-puff is the result of the coupling of the corneal, scleral, and orbital tissue properties in addition to intraocular pressure. This work has provided insight into the relative contributions of ocular and orbital tissues to the deformation response of the cornea and globe, and may help to elucidate the changes in tissue properties in different disease states or treatment conditions. iv Dedication This document is dedicated to my parents, Tram Nguyen and Kieuhanh Ngo. v Acknowledgments I would like to thank my advisor, Dr. Cynthia Roberts, for her guidance and support of my graduate career. I will always be grateful that she took a chance on me and accepted me into her lab, helping me to develop my skills and confidence as a researcher and making all this possible. I would also like to thank my co-advisor, Dr. Matt Reilly, for being an integral part of my research career, for his near-infinite patience, and for all of our conversations. I would like to thank Dr. Jun Liu for serving on both my candidacy and dissertation committees, and for her helpful advice and insights on my research. I would also like to thank the members of the Liu lab for opening their lab space and our supportive collaborations. I would like to thank Dr. Alan Litsky, who has been an incredibly supportive mentor to me since the beginning of my graduate studies. Thank you to all of my colleagues in the Ophthalmic Engineering group for your friendship and camaraderie. Finally, I would like to thank my friends (especially Monica Okon and Isabel Fernandez), my family, my parents, and my love, Matthew Rudy. Words cannot express how much your support has meant to me, and I am forever grateful to have you in my life. vi Vita The Ohio State University ............................................................................ Columbus, OH Ph.D., Biomedical Engineering ........................................................... 2013-Present Master of Science, Biomedical Engineering ............................................ 2013-2017 Bachelor of Science, Biomedical Engineering ........................................ 2009-2013 Publications Nguyen, B. A., Roberts, C. J., & Reilly, M. A. (2018). Biomechanical impact of the sclera on corneal deformation response to an air-puff: a finite-element study. Frontiers in bioengineering and biotechnology, 6. Fields of Study Major Field: Biomedical Engineering vii Table of Contents Abstract ............................................................................................................................... ii Dedication ........................................................................................................................... v Acknowledgments.............................................................................................................. vi Vita .................................................................................................................................... vii List of Tables .................................................................................................................... xii List of Figures .................................................................................................................. xiv Chapter 1. Introduction ....................................................................................................... 1 Structure and Function of the Eye .................................................................................. 1 CorVis ST ....................................................................................................................... 4 Specific Aims .................................................................................................................. 9 Aim 1: Evaluate the biomechanical impact of the sclera on dynamic corneal deformation response to an air-puff ............................................................................ 9 Aim 2: Describe the relative contribution of ocular and orbital tissues to corneal and whole-eye motion...................................................................................................... 10 viii Aim 3: Determine the impact of prostaglandin-analog (PGA) treatment on ocular and orbital tissue properties and biomechanical response .......................................