title: Quantification of the efficacy of collagen cross-linking agents to induce stiffening of rat sclera.
abstract: The concept of scleral stiffening therapies has emerged as a novel theoretical approach for treating the ocular disorders glaucoma and myopia. Deformation of specific regions of the posterior eye is innately involved in the pathophysiology of these diseases, and thus targeted scleral stiffening could resist these changes and slow or prevent progression of these diseases. Here, we present the first systematic screen and direct comparison of the stiffening effect of small molecule collagen cross-linking agents in the posterior globe, namely using glyceraldehyde, genipin and methylglyoxal (also called pyruvaldehyde). To establish a dose-response relationship, we used inflation testing to simulate the effects of increasing intraocular pressure in freshly harvested rat eyes stiffened with multiple concentrations of each agent. We used digital image correlation to compute the mechanical strain in the tissue as a metric of stiffness, using a novel treatment paradigm for screening relative stiffening by incubating half of each eye in cross-linker and using the opposite half as an internal control. We identified the doses necessary to increase stiffness by approximately 100%, namely 30 mM for glyceraldehyde, 1 mM for genipin and 7 mM for methylglyoxal, and we also identified the range of stiffening it was possible to achieve with such agents. Such findings will inform development ofin vivostudies of scleral stiffening to treat glaucoma and myopia.
authors.affiliation: Center for Visual and Neurocognitive Rehabilitation, Rehabilitation Research and Development, Atlanta VA Medical Center, Decatur, GA 30033, USA.|Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.|Exponent, Inc., Biomechanics Practice, Atlanta, GA 30326, USA.
authors.forename: Ian C
authors.identifier: 0000-0002-4640-2692
authors.initials: IC
authors.lastname: Campbell
authors.affiliation: Center for Visual and Neurocognitive Rehabilitation, Rehabilitation Research and Development, Atlanta VA Medical Center, Decatur, GA 30033, USA.|George W. Woodruff Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Bailey G
authors.initials: BG
authors.lastname: Hannon
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Read
authors.affiliation: Department of Bioengineering, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Sherwood
authors.affiliation: George W. Woodruff Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Schwaner
authors.affiliation: Center for Visual and Neurocognitive Rehabilitation, Rehabilitation Research and Development, Atlanta VA Medical Center, Decatur, GA 30033, USA ross.ethier@bme.gatech.edu.|Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.|George W. Woodruff Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: C Ross
authors.identifier: 0000-0001-6110-3052
authors.initials: CR
authors.lastname: Ethier
mesh_terms: D000818:Animals; D003094:Collagen / Q000737:chemistry / Q000187:drug effects*; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005985:Glyceraldehyde / Q000494:pharmacology; D007429:Intraocular Pressure / Q000187:drug effects; D039823:Iridoids / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000494:pharmacology; D051381:Rats; D012590:Sclera / Q000187:drug effects* / Q000473:pathology
chemical_list: D003432:Cross-Linking Reagents; D039823:Iridoids; D005985:Glyceraldehyde; D011765:Pyruvaldehyde; D003094:Collagen; C007834:genipin
keywords: biomechanics; collagen; cross-linking; digital image correlation; rat; sclera