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Updated: Aug 5, 2026
Three Different Protocols of Corneal Collagen Crosslinking in Keratoconus: Conventional, Accelerated and Iontophoresis
Published on: November 12, 2015
Evaluating the rationale and outcomes of crosslinking corneal stromal lenticules: a systematic review with
Raluca Bievel Radulescu1,2, Stefano Ferrari3, Antonia-Elena Ranetti4
1Fondazione Banca Degli Occhi del Veneto, Via Paccagnella, 11, Venice, 30174, Italy. raluca.bievel@fbov.it.
Purpose:
To systematically evaluate the biomechanical, optical, and clinical outcomes of crosslinking (CXL) applied to corneal stromal lenticules derived from keratorefractive lenticular extraction, and to assess the rationale and efficacy of this approach for therapeutic re-implantation in corneal disease.
Methods:
A systematic review with exploratory pooled analysis was conducted following PRISMA and MOOSE guidelines. Literature searches across five databases identified studies reporting outcomes following crosslinking of SMILE-derived lenticules. Risk of bias was assessed using appropriate tools for study design. Random-effects pooled analyses were performed for clinical outcomes where appropriate, with careful consideration of study heterogeneity.
Results:
Nine studies met inclusion criteria (5 in vitro, 4 clinical). In vitro studies consistently demonstrated that both ultraviolet A (UVA)-riboflavin and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) chemical CXL enhanced lenticule stiffness, enzymatic resistance, and transparency, with chemical CXL showing superior mechanical performance. Because of the limited sample size and substantial between-study heterogeneity, pooled estimates should be interpreted as exploratory and hypothesis-generating rather than definitive evidence. Clinical data from 26 eyes across three heterogeneous studies showed variable outcomes. Maximum keratometry showed a non-significant trend toward improvement (random-effects weighted mean difference: -2.94 D; 95% CI: -6.24 to 0.35 D; P = 0.08), though this finding was limited by substantial heterogeneity (I² = 87.7%). No serious complications were reported in the limited follow-up periods available.
Conclusions:
In vitro experimental studies consistently demonstrate that crosslinking enhances the structural resilience and therapeutic potential of SMILE-derived lenticules. Chemical CXL, particularly EDC/NHS protocols, provides superior biomechanical reinforcement while preserving transparency in experimental settings. Preliminary clinical data suggest possible benefit in selected advanced keratoconus cases. However, current evidence remains insufficient to establish efficacy. Controlled trials are warranted to standardize protocols and validate long-term safety and efficacy.