Critical Analysis of Corneal Cross-linking (Part-II): Resolving the Controversial Issues (Theory versus Measurements)
Ophthalmology Research: An International Journal,
Aims: To resolve the controversial issues of UV-light-initiated corneal collagen cross-linking (CXL) by theoretical formulas and measured clinical outcomes.
Study Design: Analysis and measured data of CXL.
Place and Duration of Study: New Vision Inc, Taipei, between June 2021 and August 2021.
Methodology: The controversial issues are addressed and resolved by analytical formulas including: the validation of Bunsen Roscoe law (BRL), the cutoff light intensity, the minimum corneal thickness, the demarcation line depth, the role of oxygen and riboflavin concentration. The overall CXL efficacy is governed by UV-A light intensity, dose, exposure time, mode of exposure (pulsed or CW), the riboflavin concentration, diffusion and drops pre-operation and interoperation administration, the concentration of oxygen in the stromal tissue (pre-op and inter-op), and environmental conditions. The length of the riboflavin presoaking time and viscosity of the riboflavin film also affect the crosslink depth. Analytic formulas are derived for the scaling laws for type-I and type-II efficacy, given by the square root of light intensity, and light dose, respectively.
Conclusion: The controversial issues of CXL may be partially resolved via analytic formulas, and compared with measurements. The scaling laws of type-I and type-II efficacy are different and given by analytic formulas. Our formulas also predict the maximum light intensity and the minimum corneal thickness, which are consistent with measurements.
- Corneal collagen crosslinking
- safety dose
- ultraviolet light
How to Cite
Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res. 1998;66:97–103.
Wollensak G, Spoerl E, Seiler T. Riboflavin/ ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620–7.
Choi M, Kim J, Kim EK, Seo KY, Kim TI. Comparison of the conventional Dresden protocol and accelerated protocol with higher ultraviolet intensity in corneal collagen cross-linking for keratoconus. Cornea. 2017;36(5):523– 9.
Lang PZ, Hafezi NL, Khandelwal SS et al. Comparative Functional Outcomes After Corneal Crosslinking Using Standard, Accelerated, and Accelerated With Higher Total Fluence Protocols. Cornea 2019;38: 433-441.
Bunsen RW, Roscoe HE. Photochemical researches-Part V. On the measurement of the chemical action of direct and diffuse sunlight. Proc R Soc Lond. 1862;12:306–12.
Lin JT. Analytic formulas on factors determining the safety and efficacy in UV-light sensitized corneal cross-linking. Invest Ophthalmol Vis Sci 2015;56:5740-5741.
Lin JT. On the dynamic safety for cross linking in thin corneas (350-398 um) with extra protection under a contact lens. J Refract Sur. 2015:31(7):495-496.
Lin JT, Cheng DC, Chang C, Yong Zhang. The new protocol and dynamic safety of UV-light activated corneal collagen cross-linking. Chinese J Optom Ophthalmol Vis. Sci. 2015;17:140-147.
Lin JT. Combined analysis of safety and optimal efficacy in UV-light-activated corneal collagen crosslinking. Ophthalmo-logy Research. 2016;6(2):1-14.
Lin JT, Cheng DC. Modeling the efficacy profiles of UV-light activated corneal collagen crosslinking. PloS One. 2017;12: e0175002.
Lin JT. Efficacy and Z* formula for minimum corneal thickness in UV-light crosslinking. Cornea, 2017;36:30-31.
Lin JT. Photochemical Kinetic modeling for oxygen-enhanced UV-light-activated corneal collagen crosslinking. Ophthalmo-logy Research. 2017;7:1-8.
Lin JT. Efficacy S-formula and kinetics of oxygen-mediated (type-II) and non-oxygen-mediated (type-I) corneal cross-linking. Ophthalmology Research. 2018; 8(1):1-11.
Lin JT. A critical review on the kinetics, efficacy, safety, nonlinear law and optimal protocols of corneal cross-linking. J Ophthalmology & Visual Neuroscinece. 2018;3:017.
Lin JT. A proposed concentration-controlled new protocol for optimal corneal crosslinking efficacy in the anterior stroma. Invest. Ophthalmol Vis Sci. 2018;59:431–432.
Lin JT. The role of stroma riboflavin concentration in the efficacy and depth of corneal crosslinking. Invest. Ophthalmol Vis Sci. 2018;59:4449-4450.
Lin JT. Influencing factors relating the demarcation line depth and efficacy of corneal crosslinking. Invest Ophthalmol Vis Sci. 2018;59:5125-5126.
Lin JT, HW Liu, Chen KT, Cheng DC. Modeling the optimal conditions for improved efficacy and crosslink depth of photo-initiated polymerization. Polymers. 2019;11:217.
Lin JT. Modeling a new strategy and influencing factors for improved efficacy of accelerated corneal crosslinking. J Cataract Refract Surg. 2019;45:527–529.
Lin JT, Chen KT, Cheng DC, Liu HW. Modeling the efficacy of radical-mediated photopolymerization: The role of oxygen inhibition, viscosity and induction time. Front. Chem. 2019;7:760.
Lin JT. Up-dated the Critical Issues of Corneal Cross-linking (type-I and II): Safety dose for ultra-thin cornea, demarcation line depth and the role of oxygen. Ophthalmology Res. 2021;4(1);1-7.
Sheng SF, Lin JT. Critical analysis of corneal cross-linking(Part-I): Formulas for efficacy, safety dose, minimum thickness, demarcation line depth, maximum light intensity, and the role of oxygen. Ophthalmology Research, An International Journal. 2021.14:29-41.
Kamaev P, Friedman MD, Sherr E, Muller D. Cornea photochemical kinetics of corneal cross-linking with riboflavin. Vis. Sci. 2012;53:2360-2367.
Schumacher S, Mrochen M, Wernli J, Bueeler M, Seiler T. Optimization model for UV-riboflavin corneal cross-linking. Invest Opthamol Vis Sci. 2012;53:762-769.
Semchishen A, Mrochen A, Semchishen V. Model for optimization of the UV-A/Riboflavin strengthening (cross-linking) of the cornea: Percolation threshold. Photochemistry and Photobiology. 2015;91: 1403-1411.
Kling S, Hafezi F. An algorithm to predict the biomechanical stiffening effect in corneal cross-linking. J Refract Surg. 2017; 32:128-136.
Wollensak G, Spoerl E, Wilsch M, Seiler T. Endothelial cell damage after riboflavin-ultraviolet-A treatment in the rabbit. J Cataract Refract Surg. 2003;29:1786-90.
Mooren P, Gobin L, Bostan N et al. Evaluation of UVA cytotoxicity for human endothelium in an ex vivo corneal cross-linking experimental setting. J Refract Surg. 2016;32:4-46.
Wernli J, Schumacher S, Spoerl E, Mrochen M. The efficacy of corneal cross-linking shows a sudden decrease with very high intensity UV light and short treatment time. Invest Ophthalmol Vis Sci. 2013; 54:1176–80.
Mazzotta C, Sgheri A, Bagaglia SA, et al. Customized corneal crosslinking for treatment of progressive keratoconus: Clinical and OCT outcomes using a transepithelial approach with supplemental oxygen. J Surg. 2020;46(12):1582-1587.
Sachdev GS, Ramamurthy S, Dandapani R. Photorefractive intrastromal corneal crosslinking for treatment of low myopia: clinical outcomes using the transepithelial approach with supplemental oxygen. J Cataract Refract Surg. 2020;46:428–433.
Kling S, Richoz O, Hammer A, et al. Increased biomechanical efficacy of corneal cross-linking in thin corneas due to higher oxygen availability. J Refract Surg. 2015;31:840-6.
Torres-Netto EA, Kling S, Hafezi N et al. Oxygen diffusion may limit the biome-chanical effectiveness of iontophoresis-assisted transepithelial corneal cross-linking. J Refract Surg 2018;34:768- 774.
Mazzotta C, Traversi C, Caragiuli S, Rechichi M. Pulsed vs. continuous light accelerated corneal collagen crosslinking: In vivo qualitative investigation by confocal microscopy and corneal OCT. Eye (Lond). 2014;28:1179–83.
Mazzotta C, Bagaglia SA, Vinciguerra R, Ferrise M, Vinciguerra P. Enhanced-fluence pulsed-light iontophoresis corneal cross-linking: 1-year morphological and clinical results. J Refract Surg. 2018;34: 438–444
Mazzotta C, Bagaglia SA, Sgheri A et al. Iontophoresis corneal cross-linking with enhanced fluence and pulsed UV-A light: 3-year clinical results. J Refract Surg. 2020; 36:286–292.
Kanellopoulos AJ, Dupps WJ, Seven I, Asimellis G. Toric topographically customized transepithelial, pulsed, very high-fluence, higher energy and higher riboflavin concentration collagen cross-linking in Keratoconus. Case Report Ophthalmol. 2014;5:172-180.
Seiler TG, Batista A, Frueh BE, Koenig K. Riboflavin concentrations at the endothelium during corneal cross-linking in humans. Invest Ophthalmol Vis Sci. 2019; 60:2140-2145.
Seiler T, Batista, Frueh BE, Koenig K. Riboflavin concentrations at the endothelium during corneal cross- linking in humans. Invest. Ophthalmol Vis Sci. 2019;60:2140-2145.
O’Brart NAL, O’Brart DPS, Aldahlawi et al, An Investigation of the effects of riboflavin concentration on the efficacy of corneal cross-Linking using an enzymatic resistance model in porcine corneas. Invest. Ophthalmol Vis Sci. 2018;59: 1058-1065.
Kling S, Hafezi F. Biomechanical stiffening: Slow low-irradiance corneal crosslinking versus the standard Dresden protocol. J Cataract Refract Surg. 2017;43:975–979.
Mazzotta C, Traversi C, Caragiuli S, Rechichi M. Pulsed vs. continuous light accelerated corneal collagen crosslinking: In vivo qualitative investigation by confocal microscopy and corneal OCT. Eye (Lond) 2014;28:1179–83.
Hafezi F, Kling S, Gilardoni F, et al. Individualized corneal cross-linking with riboflavin and UV-A in ultra-thin corneas: the sub400 protocol. Am J Ophthalmol. 2021;224:133-142.
Mazzotta C, Riomani A, Burroni A. Pachymetry-based accelerated cross-linking: The “M Nomogram” for Standardized Treatment of All-thickness Progressive Ectatic Corneas. Int K Kerat Ect Corn Dis. 2019;7(2):137-144.
Abstract View: 131 times
PDF Download: 34 times