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      Scleral Cross-Linking Using Riboflavin UVA Irradiation for the Prevention of Myopia Progression in a Guinea Pig Model: Blocked Axial Extension and Altered Scleral Microstructure

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          Abstract

          Purpose

          To develop methods of collagen cross-linking (CXL) in the sclera for the treatment of progressive myopia and to investigate the biomechanical and histological changes that occur in as a result.

          Methods

          Twenty 14-day-old guinea pigs were divided into 3 groups: the cross-linking group (CL, n = 8), non cross-linking group (NCL, n = 8), and control group (n = 4). The scleras of the right eyes of the guinea pigs in the CL group were surgically exposed and riboflavin was dropped onto the irradiation zone for 20 seconds prior to ultraviolet-A (UVA) irradiation. The same procedure was conducted on the NCL group but without UVA irradiation. No procedure was conducted on the control group. The right eyes of the guinea pigs in the CL and NCL groups were then fitted with -10.00DS optics for six weeks. Retinoscopy and the axial lengths (AXL) were measured at baseline, and at the second, fourth and sixth weeks post-treatment in all three groups. All animal subjects were euthanized after the sixth week and then biomechanical and histopathological examinations of the scleras were conducted.

          Results

          The mean AXL of the NCL group was longer than both the control and CL groups at six weeks (P = 0.001). The mean refractive error in the NCL group was statistically significantly more negative than both the control and the CL groups at six weeks (P = 0.001). The scleral collagen fiber arrangements of the CL and control groups were denser and more regularly distributed than the NCL group. Ultimate stress of the sclera was lowest in the NCL group, followed by the CL then the control group (P<0.05). Ultimate strain (%) of the sclera was lowest in the CL group followed by the NCL and then the control group (P<0.05).

          Conclusion

          Our study demonstrates that scleral CXL using riboflavin UVA irradiation effectively prevents the progression of myopia by increasing scleral biomechanical strength in a guinea pig model.

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          Most cited references23

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          Increased resistance of crosslinked cornea against enzymatic digestion.

          Eberhard Spoerl, Gregor Wollensak, Theo Seiler (2004)
          Collagen-crosslinking using combined riboflavin/ UVA treatment has been developed by us as a new treatment for keratoconus by stiffening the collagenous matrix. Recently, we have started to use the same method for the treatment of corneal ulcers. The aim of the present study was to evaluate the influence of the crosslinking treatment on the resistance of the cornea against enzymatic degradation. 60 enucleated porcine eyes were treated with the photosensitizer riboflavin and UVA-irradiation (370 nm; irradiance of 1, 2 or 3 mW/cm2) for 30 minutes and compared with 20 untreated control eyes. After crosslinking treatment, the corneal buttons were trephined and exposed to pepsin, trypsin and collagenase solutions. The extent of the corneal digestion was monitored daily. Selected cases were examined by light microscopy. The corneal buttons crosslinked with riboflavin/ UVA at 3 mW/cm2 were dissolved only by day 13 following pepsin digestion and by day 14 following collagenase treatment versus 6 days in the untreated control corneas. Digestion by trypsin was observed on day 5 in buttons crosslinked at 3 mW/cm2 compared to day 2 in the control corneas. Microscopically, a prolonged preservation especially of the anterior portion of the crosslinked corneas could be demonstrated. Photochemical crosslinking of the cornea using riboflavin and UVA results in a markedly increased resistance versus collagen digesting enzymes. The findings support the use of the new method in the treatment of corneal ulcers.
          Article 0 comments Cited 142 times – based on 0 reviews     Review now
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            Role of the sclera in the development and pathological complications of myopia.

            N McBrien (2003)
            Myopia is one of the most prevalent ocular conditions and is the result of a mismatch between the power of the eye and axial length of the eye. As a result images of distant objects are brought to a focus in front of the retina resulting in blurred vision. In the vast majority of cases the structural cause of myopia is an excessive axial length of the eye, or more specifically the vitreous chamber depth. In about 2% of the general population, the degree of myopia is above 6 dioptres (D) and is termed high myopia. The prevalence of sight-threatening ocular pathology is markedly increased in eyes with high degrees of myopia ( > -6 D). This results from the excessive axial elongation of the eye which, by necessity, must involve the outer coat of the eye, the sclera. Consequently, high myopia is reported as a leading cause of registered blindness and partial sight. Current theories of refractive development acknowledge the pivotal role of the sclera in the control of eye size and the development of myopia. This review considers the major biochemical mechanisms that underlie the normal development of the mammalian sclera and how the scleral structure influences the rate of eye growth during development. The review will characterise the aberrant mechanisms of scleral remodelling which underlie the development of myopia. In describing these mechanisms we highlight how certain critical events in both the early and later stages of myopia development lead to scleral thinning, the loss of scleral tissue, the weakening of the scleral mechanical properties and, ultimately, to the development of posterior staphyloma. This review aims to build on existing models to illustrate that the prevention of aberrant scleral remodelling must be the goal of any long-term therapy for the amelioration of the permanent vision loss associated with high myopia.
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              The sclera and myopia.

              Jody A. Summers Rada, Setareh Shelton, Thomas T. Norton (2006)
              Myopia is a very common ocular problem, affecting perhaps one billion people worldwide. Most myopia is produced by lengthening of the vitreous chamber of the ocular globe. High myopia is characterized by scleral thinning and localized ectasia of the posterior sclera. The sclera is a dense, fibrous, viscoelastic connective tissue that forms the outer coat of the eye and consists of irregularly arranged lamellae of collagen fibrils interspersed with proteoglycans and non-collagenous glycoproteins. Scleral fibroblasts are located between scleral lamellae, and are responsible for synthesizing the extracellular matrix in which they reside. Research highlighted in this review clearly demonstrates that the sclera is not a static container of the eye, but rather is a dynamic tissue, capable of altering extracellular matrix composition and its biomechanical properties in response to changes in the visual environment to regulate ocular size and refraction. Based on these studies, a strategy directed at reversing myopia-associated scleral extracellular matrix remodeling events would be warranted, particularly in cases of high myopia in humans.
              Article 0 comments Cited 129 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Dimitrios Zeugolis: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 9 November 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 11
                Electronic Location Identifier: e0165792
                Affiliations
                [1 ]Department of Ophthalmology & Visual Science, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
                [2 ]The Department of Pre-hospital Emergency, the First People's Hospital of Hefei, Anhui, China
                [3 ]Key Laboratory of Myopia, Ministry of Health, Fudan University, Shanghai, China
                [4 ]Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
                [5 ]Department of Clinical Laboratory, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
                [6 ]Infections department, the People's Hospital of Fuyang, Anhui Medical University, Anhui, China
                National University of Ireland—Galway, IRELAND
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: HZ S. Liu S. Li BW XL YW HL XQ JD XZ.

                • Data curation: HZ S. Liu S. Li.

                • Formal analysis: HZ S. Liu S. Li.

                • Funding acquisition: HZ.

                • Investigation: S. Liu S. Li BW XL YW.

                • Methodology: HZ S. Liu S. Li HL XQ JD XZ.

                • Project administration: HZ S. Liu S. Li.

                • Resources: HZ S. Liu S. Li BW XL YW HL XQ JD XZ.

                • Software: HZ S. Liu S. Li BW XL.

                • Supervision: HZ S. Liu S. Li BW XL.

                • Validation: YW HL XQ JD XZ.

                • Writing – original draft: S. Liu S. Li.

                • Writing – review & editing: HZ S. Liu S. Li HL XQ JD XZ.

                Article
                Publisher ID: PONE-D-16-07421
                DOI: 10.1371/journal.pone.0165792
                PMC ID: 5102452
                PubMed ID: 27829051
                SO-VID: 75d78a96-0fdd-4293-a68d-2c0c44eacf3f
                Copyright © © 2016 Liu et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 4 March 2016
                Date accepted : 18 October 2016
                Page count
                Figures: 10, Tables: 3, Pages: 16
                Funding
                Funded by: Shanghai Science and Technology Committee
                Award ID: 134119a5100
                Award Recipient :
                This research project was supported by Shanghai Science and Technology Committee (134119a5100).
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Collagens
                Subject: Research and Analysis Methods
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Guinea Pigs
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Animals
                Subject: Vertebrates
                Subject: Amniotes
                Subject: Mammals
                Subject: Rodents
                Subject: Guinea Pigs
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Physical Chemistry
                Subject: Chemical Bonding
                Subject: Cross-Linking
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Eyes
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Eyes
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Eyes
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Eyes
                Subject: Medicine and Health Sciences
                Subject: Ophthalmology
                Subject: Visual Impairments
                Subject: Myopia
                Subject: Physical sciences
                Subject: Physics
                Subject: Electromagnetic radiation
                Subject: Light
                Subject: Ultraviolet radiation
                Subject: Ultraviolet A
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Compounds
                Subject: Organic Compounds
                Subject: Vitamins
                Subject: B Vitamins
                Subject: Riboflavin
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Organic Chemistry
                Subject: Organic Compounds
                Subject: Vitamins
                Subject: B Vitamins
                Subject: Riboflavin
                Subject: Engineering and Technology
                Subject: Equipment
                Subject: Optical Equipment
                Subject: Optical Lenses
                Custom metadata
                Data Availability All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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