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First introduced over 20 years ago as a treatment for progressive keratoconus, the original "Dresden" corneal cross-linking (CXL) protocol involved riboflavin saturation of the stroma, followed by 30 min of 3 mW/cm 2 -intensity ultraviolet-A (UV-A) irradiation. This procedure generates reactive oxygen species (ROS) that cross-link stromal molecules, thereby stiffening the cornea and counteracting the ectasia-induced weakening. Due to their large size, riboflavin molecules cannot readily pass through the corneal epithelial cell tight junctions; thus, epithelial debridement was performed. Moreover, the Dresden protocol necessitates a minimal corneal thickness of 400 μm to protect the endothelium from UV-induced damage. While the Dresden protocol is highly effective at enhancing corneal biomechanical strength, there was a strong desire for CXL procedures that would deliver Dresden-like strengthening in a shorter time, in corneas thinner than 400 μm, and without requiring epithelial debridement. This review explores the advancements and scientific discoveries that have enabled such improvements. Accelerated CXL protocols, utilizing our increased knowledge about the role of oxygen and photochemical reactions in the cornea have shortened and simplified the procedure duration while maintaining efficacy and safety, improving clinical workflow and patient compliance. CXL is not confined to improving biomechanics in corneal ectasia, but rather represents a technique that modulates corneal physiology and biochemistry on multiple levels. Accordingly, CXL indications have expanded to include treating other corneal ectasias, corneal neovascularization, corneal sterile melting, inflammatory dry eye and importantly, infectious keratitis in a procedure termed photoactivated chromophore for keratitis-CXL (PACK-CXL). In PACK-CXL, ROS have a direct pathogen-killing effect, and cross-linking enhances the cornea's resistance to pathogen-produced protease digestion through steric hindrance. The distinct requirements of PACK-CXL compared to ectasia treatment have led to the development of different CXL protocols, including higher UV fluences and other chromophore/light combinations, specifically rose bengal and green light. Additionally, combining CXL with vision-enhancing procedures like individualized wavefront- or topographically-guided excimer ablation can regularize a biomechanically stable cornea, improve visual acuity, and potentially eliminate the need for corneal transplantation, leading to long-term improvements in quality of life., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: To determine whether corneal cross-linking (CXL) with individualized fluence ("sub400 protocol") is able to stop keratoconus (KC) progression in ultrathin corneas with 12-month follow-up., Design: Retrospective, interventional case series., Methods: Thirty-nine eyes with progressive KC and corneal stromal thicknesses from 214 to 398 μm at the time of ultraviolet irradiation were enrolled. After epithelium removal, ultraviolet irradiation was performed at 3 mW/cm 2 with irradiation times individually adapted to stromal thickness. Pre- and postoperative examinations included corrected distance visual acuity (CDVA), refraction, Scheimpflug, and anterior segment optical coherence tomography imaging up to 12 months after CXL. Outcome measures were arrest of KC progression at 12 months postoperatively and stromal demarcation line (DL) depth., Results: Thirty-five eyes (90%) showed tomographical stability at 12 months after surgery. No eyes showed signs of endothelial decompensation. A significant correlation was found between DL depth and irradiation time (r = +0.448, P = .004) but not between DL depth and change in K max (r = -0.215, P = .189). On average, there was a significant change (P < .05) in thinnest stromal thickness (-14.5 ± 21.7 μm), K max (-2.06 ± 3.66 D) and densitometry (+2.00 ± 2.07 GSU). No significant changes were found in CDVA (P = .611), sphere (P = .077), or cylinder (P = .915)., Conclusions: The "sub400" individualized fluence CXL protocol standardizes the treatment in ultrathin corneas and halted KC progression with a success rate of 90% at 12 months. The sub400 protocol allows for the treatment of corneas as thin as 214 μm of corneal stroma, markedly extending the treatment range. The DL depth did not predict treatment outcome. Hence, the depth is unlikely related to the extent of CXL-induced corneal stiffening but rather to the extent of CXL-induced microstructural changes and wound healing., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Photoactivated chromophore for keratitis cross-linking (PACK-CXL) is used as an adjunct therapy to antibiotic medication in infectious keratitis. This experimental study aimed at quantifying the PACK-CXL efficacy as a function of UV fluence using several bacterial strains and irradiated volumes., Methods: Six distinct bacterial strains, including standardized strains and clinically isolated strains from patients with keratitis, were analyzed. Bacterial concentrations between 10 and 10 cells/mL were used (simulating small corneal ulcers). Volumes of either 11 μL (≈285 μm stromal thickness) or 40 μL (≈1000 μm stromal thickness) were irradiated within a microtiter plate at different fluences (5.4-27 J/cm) and irradiances (3, 9 and 18 mW/cm). The ratio of bacterial killing (B†) was determined to evaluate the antimicrobial efficacy of PACK-CXL., Results: B† was similar (51 ± 11%) in bacterial concentrations between 10 and 10 per ml. In 11 μL volume, Staphylococcus aureus (SA) 8325-4 ATCC 29213, Bacillus subtilis (BS) 212901, and Pseudomonas aeruginosa (PA) 2016-866624 were most sensitive to PACK-CXL at 5.4 J/cm (on average B† = 49 ± 8%), whereas Klebsiella oxytoca (KO) 2016-86624 (B† = 25%) was least sensitive. When irradiating a larger volume, B† was on average lower in 40 μL (19 ± 18%), compared with 11 μL (45 ± 17%, P < 0.001). By contrast, applying a higher UV fluence increased B† of SA ATCC 29213, from 50% at 5.4 J/cm to 92% at 10.8 J/cm, to 100% at 16.2 J/cm and above., Conclusions: Applying higher UV fluences substantially increases the bacterial killing rates. Safety limits for clinical application require further investigation.

Purpose: To evaluate the biomechanical effect of corneal cross-linking (CXL) in paired human corneas following small incision lenticule extraction (SMILE) or photorefractive keratectomy (PRK) in an ex vivo model for postoperative ectasia., Methods: Twenty-six paired human corneas preserved in tissue culture medium were equally divided into two groups: right and left corneas were treated with PRK and SMILE, respectively. Corneal thickness was measured in all eyes before surgery. Corneas were stretched using an extensometer with two cycles of up to 9 N (570 kPA stress), followed by accelerated CXL with irradiance of 9 mW/cm 2 for 10 minutes (fluence 5.4 J/cm 2 ) in both groups. The elastic modulus was evaluated using two-dimensional stress-strain extensometry., Results: Following accelerated CXL, the ectatic cornea model showed a mean effective elastic modulus of 17.2 ± 5.3 MPa after PRK and 14.1 ± 5.0 MPa after SMILE. Although the elastic modulus in corneas previously subjected to PRK was higher, there was no significant biomechanical difference between the two groups (P = .093)., Conclusions: Under similar conditions, both experimental groups (PRK followed by CXL and SMILE followed by CXL) were characterized by similar biomechanical stability as measured experimentally on ex vivo human fellow corneas. The data suggest that, in the event of postoperative ectasia, the biomechanical improvement achieved by CXL may be similar after PRK and SMILE. [J Refract Surg. 2020;36(1):49-54]., (Copyright 2020, SLACK Incorporated.)

Corneal cross-linking (CXL), introduced by Wollensak et al. in 2003, is a minimally invasive procedure to halt the progression of keratoconus. Conventional CXL is recommended in eyes with corneal thickness of at least 400 microns after de-epithelialization to prevent endothelial toxicity. However, most of the keratoconic corneas requiring CXL may not fulfill this preoperative inclusion criterion. Moderate-to-advanced cases are often found to have a pachymetry less than this threshold. There are various modifications to the conventional method to circumvent this issue of CXL thin corneas while avoiding the possible complications. This review is an update on the modifications of conventional CXL for thin corneas., Competing Interests: None

Purpose: To evaluate the impact of varying treatment time on the efficacy of iontophoresis-assisted transepithelial corneal cross-linking (I-CXL) in ex vivo porcine corneas., Methods: One hundred twelve porcine corneas with intact epithelium were divided into 7 groups and analyzed. Groups 1, 2, and 3 received standard epitheliumoff CXL (S-CXL) with hypo-osmolaric 0.1% riboflavin and 30 minutes of ultraviolet-A (UV-A) irradiation at 3 mW/cm 2 , 10 minutes at 9 mW/cm 2 , or were not irradiated (controls). Groups 4, 5, 6, and 7 received I-CXL for either 60 minutes at 1.5 mW/cm 2 , 30 minutes at 3 mW/cm 2 , 10 minutes at 9 mW/cm 2 , or were not irradiated (controls). Elastic modulus and stress after relaxation of 5-mm wide corneal strips were analyzed., Results: In the S-CXL groups, significant differences (P ≤ .05) in stress-strain extensometry were found between controls and 3 mW/cm 2 for 30 minutes (group 1) and between controls and 9 mW/cm 2 for 10 minutes (group 2). In the I-CXL groups, only the 1.5 mW/cm 2 for 60 minutes setting (group 4) showed a significant stiffening effect. All epithelium-off groups provided a stiffening effect significantly stronger than I-CXL: with a stiffening effect of 149% and 112%, groups 1 and 4 were the groups with greater elastic modulus between the S-CXL and I-CXL groups, respectively., Conclusions: The biomechanical effect of I-CXL increased significantly when using a low irradiance/long irradiation setting. Oxygen diffusion thus represents a limiting factor even when riboflavin penetration is improved via iontophoresis. Still less effective than S-CXL, this modification may help establish transepithelial CXL as a treatment option in selected cases. [J Refract Surg. 2018;34(11):768-774.]., (Copyright 2018, SLACK Incorporated.)

Purpose: To evaluate the effect of accelerated corneal cross-linking with photoactivated chromophore (PACK-CXL) as additional treatment for therapy-resistant infectious keratitis., Methods: In this interventional cohort study, 20 patients (11 men and 9 women), aged 65.5 (interquartile range = 21.5-78.5) years, who were hospitalized for moderate-sized therapy-resistant bacterial corneal ulcers (11/20 microbiologically confirmed) were treated with hypoosmolar 0.1% riboflavin solution and Ultraviolet A (UVA) irradiation for 3 minutes at 30 mW/cm (5.4 J/cm) as additional therapy to standard antimicrobial treatment., Results: We did not observe any adverse effects of accelerated PACK-CXL on the corneal stroma or limbus. The median ulcer size was 3.00 (2.63-4.50) mm, the median time to reepithelialization was 6.50 (5.00-18.0) days, and the mean hospitalization period was 8.5 ± 4.5 days. Tectonic keratoplasty became necessary in 1 patient (5%)., Conclusions: Our results suggest that accelerated PACK-CXL may provide an antimicrobial effect similar to the 1 low-intensity, slow setting (30 minutes at 3 mW/cm) and may be used as additional treatment in moderate-sized therapy-resistant infectious keratitis.

Purpose: To determine the corneal weakening induced by different re-treatment options after small incision lenticule extraction (SMILE) and investigate the potential of corneal cross-linking (CXL) to reestablish the original corneal stress resistance., Methods: A total of 96 freshly enucleated porcine corneas were used. The initial refractive correction was defined to be -11.00 diopters (D) and the required enhancement to be -3.00 D. Three different re-treatment options were analyzed: -3D Re-SMILE, -3D photorefractive keratectomy (PRK) on top of the SMILE cap, and cap-to-flap conversion and -3D excimer ablation on the stromal bed (LASIK). The control condition did not receive any treatment. Subsequently, accelerated CXL (9 mW/cm 2 , 10 min) was performed in two groups with currently common enhancement techniques: following cap-to-flap conversion (-3D LASIK enhancement) and in controls. Biomechanical properties were measured with stress-strain extensometry ranging from 1.27 to 12.5 N., Results: The Re-SMILE and PRK enhancement did not significantly reduce the overall elastic modulus of the cornea compared to controls (24.7 ± 2.23 and 22.7 ± 2.61 versus 23.8 ± 3.35 MPa, P ≥ .176), whereas LASIK enhancement did (22.2 ± 3.37 MPa, P = .048). CXL treatment significantly increased the elastic modulus compared to all non-cross-linked conditions (P ≤.001). Refractive surgery decreased the overall elastic modulus by 7%, whereas CXL increased it by 20%., Conclusions: In enhancement, the corneal biomechanical integrity is less affected with both Re-SMILE and PRK enhancement. Corneal weakening through laser refractive surgery is small compared to the stiffening effect after CXL. [J Refract Surg. 2017;33(3):193-198.]., (Copyright 2017, SLACK Incorporated.)

Purpose: To compare the currently available ultraviolet-A (UV-A) corneal cross-linking (CXL) treatment protocols for thin corneas with respect to oxygen, UV fluence, and osmotic pressure., Methods: Freshly enucleated murine (n = 16) and porcine (n = 16) eyes were used. The dependency on oxygen and the amount of UV absorption were evaluated using different CXL protocols, including standard CXL, contact lens-assisted CXL (caCXL), and CXL after corneal swelling. The CXL protocol was adapted from the treatment parameters of the human cornea to fit the thickness of murine and porcine corneas. Immediately after CXL, the corneas were subjected to biomechanical testing, including preconditioning, stress relaxation at 0.6 MPa, and stress-strain extensiometry. A two-element Prony series was fitted to the relaxation curves for viscoelastic characterization., Results: Standard CXL was most efficient; prior corneal swelling reduced the long-term modulus by 6% and caCXL by 15% to 20%. Oxygen reduction decreased the long-term modulus G∞ by 14% to 15% and the instantaneous modulus G0 by 2% to 5%, and increased the short-term modulus G2 by 22% to 31%. Reducing the amount of absorbed UV energy decreased the long-term modulus G∞ by 5% to 34%, the instantaneous modulus G0 by 7% to 29%, and the short-term modulus G2 by 17% to 20%. The amount of absorbed UV light was more important in porcine than in murine corneas., Conclusions: The higher oxygen availability in thin corneas potentially increases the overall efficacy of riboflavin UV-A CXL compared to corneas of standard thickness. Clinical protocols for thin corneas should be revised to implement these findings., (Copyright 2015, SLACK Incorporated.)