Although fixation of tissues using glutaraldehyde and formaldehyde have been a mainstay of numerous processes and procedures (i.e. histologic processing, etc.) related to medical practice in the past and present, inducing tissue cross-linking in the patient [Therapeutic Tissue Cross-linking (TXL)], for treating human disease, is novel. The rapid growth throughout the world of CXL (riboflavin photochemistry) in treating keratoconus (KC) and post-LASIK keratectasias (LASIK=Laser-Assisted in situ Keratomileusis) is proving that in vivo tissue cross-linking is possible and can be beneficial from a patient care standpoint. As good as it is, CXL has limitations, especially the need for debridement of the corneal epithelium (painful, infection risk, delayed healing, haze) and the use of ultraviolet (UV) light (with potential damage to the lens and retina, and even cancer risk). Our long-term goal is to develop therapies for human diseases through the use of in vivo therapeutic tissue cross-linking and to understand how enzymatic cross-linking contributes to the development of disease, specifically in KC. The overall objective of this particular application is to develop a nw treatment for corneal thinning diseases that will serve as a springboard for the development of similar treatments in other diseases (such as sclera in myopia, etc.). Formaldehyde releasing agents (FARs) are a promising group of chemical compounds, used widespread by the cosmetics industry as chemical preservatives in personal care products (PCPs). These FARs can be used for an alternative purpose, namely as therapeutic tissue cross-linking agents. The following aims will be pursued: 1. Using an ex vivo corneal cross-linking simulation set up that evaluates both cell toxicity and tissue fixation, establish optimal conditions for therapeutic corneal tissue cross-linking using FARs. 2. To test the hypothesis that topically applied FARs can induce corneal cross-linking in a safe and effective manner in the living eye. 3. To utilize analytical chemical methods (LC/MS and MALDI-TOF) to quantitate enzymatic collagen cross-links in keratoconus corneas and identify biomarkers of the induced cross-linking reactions (CXL and FARs). It is anticipated that these aims will yield: 1) A safe and effective method for inducing tissue cross- linking as a therapy for KC that leaves the epithelium intact and does not require use of UV light. 2) A deeper understanding of the role of enzymatic cross-linking in the pathogenesis of keratoconus as well as the development of new biomarkers for the therapeutic cross-linking reactions. Having the ability to cross-link the cornea using a topical cross-linking agent will open the door to applying this method to the treatment of other diseases in which mechanical tissue failure plays a role, including the sclera in progressive myopia.

Public Health Relevance

The rapid growth of treated patients who have undergone corneal cross-linking using riboflavin photochemistry (CXL) is proving that intentionally stiffenin tissue in living people through cross-linking technology is possible and can be beneficial from a patient care standpoint. The results of this work will provide a better way to mechanically strengthen corneal tissue, one that is topical and does not require either painful epithelial removal or hazardous exposure to ultraviolet light. This new treatment for corneal thinning diseases (i.e. keratoconus and post-LASIK keratectasia) will serve as a 'springboard' for the development of similar treatments in other diseases (such as sclera in myopia, etc.).

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY020495-08
Application #
9428445
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
2010-04-01
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Zyablitskaya, Mariya; Takaoka, Anna; Munteanu, Emilia L et al. (2017) Evaluation of Therapeutic Tissue Crosslinking (TXL) for Myopia Using Second Harmonic Generation Signal Microscopy in Rabbit Sclera. Invest Ophthalmol Vis Sci 58:21-29
Takaoka, Anna; Babar, Natasha; Hogan, Julia et al. (2016) An Evaluation of Lysyl Oxidase-Derived Cross-Linking in Keratoconus by Liquid Chromatography/Mass Spectrometry. Invest Ophthalmol Vis Sci 57:126-36
Kim, Su-Young; Babar, Natasha; Munteanu, Emilia Laura et al. (2016) Evaluating the Toxicity/Fixation Balance for Corneal Cross-Linking With Sodium Hydroxymethylglycinate (SMG) and Riboflavin-UVA (CXL) in an Ex Vivo Rabbit Model Using Confocal Laser Scanning Fluorescence Microscopy. Cornea 35:550-6
Babar, Natasha; Kim, MiJung; Cao, Kerry et al. (2015) Cosmetic preservatives as therapeutic corneal and scleral tissue cross-linking agents. Invest Ophthalmol Vis Sci 56:1274-82
Li, Xia; Li, Yongjun; Kim, Mijung et al. (2014) Aliphatic ?-nitroalcohols for therapeutic corneoscleral cross-linking: chemical stability studies using 1H-NMR spectroscopy. Photochem Photobiol 90:338-43
Kim, MiJung; Takaoka, Anna; Hoang, Quan V et al. (2014) Pharmacologic alternatives to riboflavin photochemical corneal cross-linking: a comparison study of cell toxicity thresholds. Invest Ophthalmol Vis Sci 55:3247-57
Wen, Quan; Trokel, Stephen L; Kim, MiJung et al. (2013) Aliphatic ýý-nitroalcohols for therapeutic corneoscleral cross-linking: corneal permeability considerations. Cornea 32:179-84
Li, Xia; Li, Yongjun; Rao, Yi et al. (2013) Mechanistic and Catalytic Studies of ?-Nitroalcohol Crosslinking with Polyamine. J Appl Polym Sci 128:3696-3701
Wen, Quan; Paik, David C (2012) Using the Griess colorimetric nitrite assay for measuring aliphatic ?-nitroalcohols. Exp Eye Res 98:52-7
Solomon, Marissa R; O'Connor, Naphtali A; Paik, David C et al. (2010) Nitroalcohol Induced Hydrogel Formation in Amine-Functionalized Polymers. J Appl Polym Sci 117:1193-1196

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