Corneal ectasia is a major cause of impaired vision-related quality of life in the United States and a leading indication for corneal transplantation. The lack of clinical tools for resolving biomechanical properties throughout the cornea is a critical barrier to understanding mechanisms of corneal instability and applying potentially transformative bioengineering approaches to risk screening and treatment optimization. The goal of this research program is to develop a robust OCT-based simulation platform for quantifying ectasia risk and predicting individual responses to a broad range of corneal treatments. The objective, which is aided by the sensitive link between corneal shape and visual function, is to identify the key structural predictors of ectatic disease and develop rationl approaches to customized crosslinking therapy through integrated patient- specific biomechanical measurement and modeling. The central hypothesis is that the magnitude and distribution of biomechanical properties in the cornea are key drivers of corneal shape. This hypothesis and the methods for testing it have been developed in part through the applicants'preliminary work in corneal optical coherence elastography (OCE) and in patient-specific finite element (FE) analysis studies that suggest important dependencies between material properties and shape. The hypothesis will be tested through the following specific aims: 1) Characterize the magnitude and distribution of corneal biomechanical properties across normal, surgically altered and pathologic states, 2) determine the accuracy of elastography-driven FE models for predicting outcomes of corneal interventions in donor eyes and patients, and 3) identify the key biomechanical drivers of keratoconus progression, post-refractive surgery ectasia, and crosslinking response using patient-specific simulations.
Under Aim 1, OCE will be used in donor eye and clinical studies to test the hypothesis that the human cornea has intrinsic regional differences in biomechanical properties that are altered in characteristic ways by LASIK, keratoconus and collagen crosslinking. After generating FE models using subject-specific geometry for all pre-intervention eyes in Aim 1, Aim 2 will test the hypothesis that models populated with subject-specific OCE property data better predict outcomes than those with idealized bulk property estimates. Finally, in large-scale, multifactorial FE simulations using al normal and keratoconic patients as modeling substrates, Aim 3 will determine how elastic properties, initial corneal geometry and procedure variables interact to influence ectasia risk and crosslinking responses. Expected outcomes include clinical translation of OCT-based capabilities for mapping corneal biomechanical properties and generating patient-specific computational models capable of predicting treatment responses. Simulation-based optimizations will support novel, customizable calculators for ectasia risk and new algorithms for enhancing the effects of collagen crosslinking in individual eyes. These outcomes directly address gaps identified by the NEI and will enable new simulation-based treatment strategies for existing and emerging corneal procedures.

Public Health Relevance

This research program addresses core challenges in the development and integration of tools for simulation-based surgical planning. Major clinical targets of the proposal include keratoconus and post-LASIK ectasia, corneal diseases in which visual function and emerging treatments all depend explicitly on corneal structural properties. Projected outcomes of the work include development of noninvasive methods for biomechanical property mapping and integration of such measurements into patient-specific computational models that can be used to project disease risk and facilitate rational customization of treatment.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (BNVT)
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Mckie, George Ann
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Kligman, Brad E; Baartman, Brandon J; Dupps Jr, William J (2016) Errors in Treatment of Lower-order Aberrations and Induction of Higher-order Aberrations in Laser Refractive Surgery. Int Ophthalmol Clin 56:19-45
Dupps Jr, William Joseph; Seven, Ibrahim (2016) A Large-Scale Computational Analysis of Corneal Structural Response and Ectasia Risk in Myopic Laser Refractive Surgery. Trans Am Ophthalmol Soc 114:T1
Beene, Lauren C; Traboulsi, Elias I; Seven, Ibrahim et al. (2016) Corneal Deformation Response and Ocular Geometry: A Noninvasive Diagnostic Strategy in Marfan Syndrome. Am J Ophthalmol 161:56-64.e1
Au, John; Goshe, Jeffrey; Dupps Jr, William J et al. (2015) Intraoperative Optical Coherence Tomography for Enhanced Depth Visualization in Deep Anterior Lamellar Keratoplasty From the PIONEER Study. Cornea 34:1039-43
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Shetty, Rohit; Matalia, Himanshu; Srivatsa, Purnima et al. (2015) A novel zernike application to differentiate between three-dimensional corneal thickness of normal corneas and corneas with keratoconus. Am J Ophthalmol 160:453-462.e2
Dupps Jr, William J (2015) Ectasia risk: a multifactorial conundrum. J Cataract Refract Surg 41:699-700
Hallahan, Katie M; Sinha Roy, Abhijit; Ambrosio Jr, Renato et al. (2014) Discriminant value of custom ocular response analyzer waveform derivatives in keratoconus. Ophthalmology 121:459-68
Kanellopoulos, Anastasios John; Dupps, William J; Seven, Ibrahim et al. (2014) Toric topographically customized transepithelial, pulsed, very high-fluence, higher energy and higher riboflavin concentration collagen cross-linking in keratoconus. Case Rep Ophthalmol 5:172-80

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