Scleral Collagen Cross-Linking to Stop Myopia Progression

Aug 11, 2022
8 min read
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Myopia (nearsightedness) is a type of refractive error in which the image created by light rays entering the eye focuses in front of the retina leading to blur. This is often secondary to axial length elongation, but can also be related to refractive properties of the cornea. Myopia is a very prevalent condition in our society, and the incidence is only increasing.1 There are many theories as to why this is the case, including genetic components, decreased exposure to outdoor light, and increased near work.

Recent studies have shown that over 20% of the world population is myopic (about 1.4 billion people) and that number is expected to rise to nearly 50% by the year 2050.1 High myopia is defined by a spherical equivalent greater than -6.00 D.

Why does myopia matter?

Myopia has been associated with degenerative changes in the retina, choroidal thinning and neovascularization, increased risk of retinal detachment, and increased risk of open angle glaucoma.2 All of these can result in significant visual impairment. Aside from the individual visual complications of myopia in patients, it proves to be a significant socioeconomic issue as well.

In some areas of the world, especially rural less developed areas of Asia, older people with myopia are less likely to have enough, if any, refractive correction, which has been found to cause significant visual impairment and limit economic productivity.3 As the number of myopic patients increases, the number of high myopes may increase in parallel, leading to increased visual morbidity.

What can be done?

A variety of treatment options have been hypothesized and tested in attempts to combat this issue. It is thought that one underlying issue in the progression of myopia is aberrant scleral remodeling that leads to weakening, thinning, and expansion of the scleral tissue.4 Current noninvasive treatment options include glasses, contact lenses (soft lenses as well as rigid, scleral, piggyback lenses), topical atropine drops, and orthokeratology, among other methods.5

Collagen cross-linking naturally occurs in the body with age and UV light exposure. Cross-linking helps to enhance and strengthen the biomechanical properties of the tissue. Corneal cross-linking has been used increasingly in the past two decades in the treatment of keratoconus and other progressive ectatic states.4 Given the aberrant changes noted in the sclera of patients with progressive myopia, a similar hope for the stabilization of myopic change via cross-linking of the sclera is held in the research community.

How does scleral cross-linking work?

There are two forms of scleral cross-linking: physical and chemical. The cross-linking occurs at the level of the outer sclera which is helpful in that it potentially avoids structural change in the retina/choroid.

Physical cross-linking

The physical method requires opening the conjunctiva to expose the scleral tissue. This is followed by activation of riboflavin via UVA (370 nm) or blue light (460 nm) which leads to excitation of riboflavin to triplet state and subsequent production of reactive oxygen species.4 This cross-linking process forms new chemical bonds between collagen and other molecules or between two collagen molecules.

Chemical cross-linking

Chemical cross-linking enhances scleral stability with reagents such as glutaraldehyde or glyceraldehyde with reactive groups that can cause molecules to form new covalent bonds.4

Chemical cross-linking has been shown to improve the stiffness of the sclera more effectively than physical cross-linking.6 It is also advantageous in that it is performed via sub-Tenon’s injection which is less invasive than performing a surgical conjunctival peritomy.

One disadvantage of the chemical process includes poor control of the area affected as the reagents are liquid and may spread past the desired area of treatment. The creation of advanced glycosylation products with glyceraldehyde can decrease elasticity of the lamina cribrosa which could potentially affect the optic nerve.7

Figure 1 shows a histology section of normal rabbit sclera (A); and 0.4 M ribose-treated rabbit sclera (B) stained with Masson’s trichrome where collagen stains blue. Here, dense collagen bundles are evident in the cross-linked sclera compared to normal scleral tissue.

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Figure 1: Image obtained from: Kim, Tae Gi, et al. "Effects of scleral collagen crosslinking with different carbohydrate on chemical bond and ultrastructure of rabbit sclera: Future treatment for myopia progression." Plos one 14.5 (2019): e0216425.)

Does scleral collagen cross-linking work and is it safe?

Scleral collagen cross-linking has not been tested in humans yet; however, the data from the animal studies is promising. It is a minimally invasive procedure which reduces the risk of infection and does not involve placement of any additional material that could be rejected by the body.

Dotan et al found scleral cross-linking with riboflavin and UVA radiation to prevent occlusion-induced axial elongation in rabbits.8 Zeugolis et al found that scleral cross-linking with riboflavin-UVA irradiation increases scleral strength and prevents myopic progression in guinea pigs.9 Some of these studies showed temporary effects which could indicate that the procedure may need to be repeated.

Chemical cross-linking has only been found to work with certain reagents. Wang et al reported genipin sub-Tenon’s injections to effectively block myopia progression.10 No known complications have been reported in animal models.

What’s next?

Further studies are needed with both physical and chemical scleral cross-linking to determine treatment parameters, safety, and efficacy in human subjects. Given the limitations of the current treatments for progressive myopia, scleral collagen cross-linking stands apart in that it offers a treatment that could arrest the underlying pathology of the disease.

References

  1. Holden, B. A., Fricke, T. R., Wilson, D. A., Jong, M., Naidoo, K. S., Sankaridurg, P., Wong, T. Y., Naduvilath, T. J., & Resnikoff, S. (2016). Global Prevalence of Myopia and High Myopia and Temporal Trends from 2000 through 2050. Ophthalmology, 123(5), 1036–1042. https://doi.org/10.1016/j.ophtha.2016.01.006
  2. Haarman AEG, Enthoven CA, Tideman JWL, Tedja MS, Verhoeven VJM, Klaver CCW. The Complications of Myopia: A Review and Meta-Analysis. Invest Ophthalmol Vis Sci. 2020 Apr 9;61(4):49. doi: 10.1167/iovs.61.4.49. PMID: 32347918; PMCID: PMC7401976.
  3. Naidoo, K. S., Fricke, T. R., Frick, K. D., Jong, M., Naduvilath, T. J., Resnikoff, S., & Sankaridurg, P. (2019). Potential Lost Productivity Resulting from the Global Burden of Myopia: Systematic Review, Meta-analysis, and Modeling. Ophthalmology, 126(3), 338–346. https://doi.org/10.1016/j.ophtha.2018.10.029
  4. Zhang, Fengju MD, PhD; Lai, Lingbo MD Advanced Research in Scleral Cross-Linking to Prevent From Progressive Myopia, Asia-Pacific Journal of Ophthalmology: March-April 2021 - Volume 10 - Issue 2 - p 161-166. doi: 10.1097/APO.0000000000000340
  5. Gwiazda J. Treatment options for myopia. Optom Vis Sci. 2009 Jun;86(6):624-8. doi: 10.1097/OPX.0b013e3181a6a225. Erratum in: Optom Vis Sci. 2009 Jul;86(7):915. PMID: 19390466; PMCID: PMC2729053.
  6. Wollensak, G., & Spoerl, E. (2004). Collagen crosslinking of human and porcine sclera. Journal of cataract and refractive surgery, 30(3), 689–695. https://doi.org/10.1016/j.jcrs.2003.11.032
  7. Kimball EC, Nguyen C, Steinhart MR, Nguyen TD, Pease ME, Oglesby EN, Oveson BC, Quigley HA. Experimental scleral cross-linking increases glaucoma damage in a mouse model. Exp Eye Res. 2014 Nov;128:129-40. doi: 10.1016/j.exer.2014.08.016. Epub 2014 Oct 5. PMID: 25285424; PMCID: PMC4254118.
  8. Dotan A, Kremer I, Livnat T, et al. Scleral cross-linking using riboflavin and ultraviolet-a radiation for prevention of progressive myopia in a rabbit model. Exp Eye Res 2014; 127:190–195.
  9. Zeugolis D, Liu S, Li S, et al. 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. Plos One 2016; 11:
  10. Wang M, Corpuz CCC. Effects of scleral cross-linking using genipin on the process of form-deprivation myopia in the guinea pig: a randomized controlled experimental study. BMC Ophthalmol 2015; 15:89.
  11. Kim, Tae Gi, et al. "Effects of scleral collagen crosslinking with different carbohydrate on chemical bond and ultrastructure of rabbit sclera: Future treatment for myopia progression." Plos one 14.5 (2019): e0216425.
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About Alanna James, MD

Alanna James, MD is a PGY-4 resident at Loma Linda University Eye Institute. She has a Bachelor's of Science in Biochemistry from Andrews University in Michigan. She attended medical school at Loma Linda University School of Medicine in California. She …

About Robin K. Kuriakose, MD

Dr. Robin Kuriakose is a resident physician completing his surgical residency in Ophthalmology at Loma Linda University Health in Southern California. Prior to this, he attended a combined BS/MD program at Virginia Commonwealth University in Richmond, Virginia. He is passionate …

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