TABLE 2.

The advantages and limitations of the chemical compounds to promote the penetration of CXL agents.

Chemical enhancer	Advantages	Limitations	Mechanisms	References
BAC	Capable to promote the penetration of riboflavin into the cornea without epithelial removal	Inferior biomechanical effect and potential toxicity	Loosen the tight junctions among corneal epithelial cells	Wollensak and Iomdina (2009), Kissner et al. (2010), Koppen et al. (2012), Raiskup et al. (2012), Stojanovic et al. (2012), Armstrong et al. (2013), Torricelli et al. (2014), Gatzioufas et al. (2016a), Akbar et al. (2017), Heikal et al. (2017), Hill et al. (2020)
Tetracaine	Potentially capable to promote the penetration of riboflavin into the cornea without epithelial removal	Undetermined penetration enhancing effect and potential toxicity	Loosen the tight junctions among corneal epithelial cells	Hayes et al. (2008), Armstrong et al. (2013), Wen et al. (2013), Gatzioufas et al. (2016b), Chen et al. (2016)
Ethanol	Potentially capable to promote the penetration of riboflavin into the cornea without epithelial removal	Insufficient penetration enhancing effect and potential toxicity	Loosen the tight junctions among corneal epithelial cells	Samaras et al. (2009), Ozmen et al. (2014), Bilgihan et al. (2022)
Glutaraldehyde	Capable to promote the penetration of riboflavin into the cornea without epithelial removal	Decreased corneal hysteresis and potential toxicity	Form Schiff bases (-N=C-)	Knox Cartwright et al. (2012), Kim et al. (2014), Labate et al. (2015)
NaI	Capable to promote the penetration of riboflavin into the cornea without epithelial removal	Small sample size and uncertain long-term efficacy and safety	Reduce riboflavin photodegradation	Rubinfeld et al. (2018), Rubinfeld et al. (2021), Epstein et al. (2022), Vaidya et al. (2022)
Calcium chelating agents	Capable to promote the penetration of riboflavin into the cornea without epithelial removal	Uncertain stability especially for pediatric patients	Undermine the integrity of tight junctions by binding with Ca2+ in the corneal epithelium	Alhamad et al. (2012), Caporossi et al. (2012), Filippello et al. (2012), Spadea and Mencucci (2012), Caporossi et al. (2013), Morrison and Khutoryanskiy (2014), Rossi et al. (2015), Morrison et al. (2017), Cifariello et al. (2018)
VE-TPGS	Capable to promote the penetration of riboflavin into the cornea without epithelial removal	Small sample size	Enhance drug permeability as a specific riboflavin transporter	Ostacolo et al. (2013), Caruso et al. (2016), Palazzo et al. (2020), Caruso et al. (2021)
CDs	Capable to promote the penetration of riboflavin into the cornea without epithelial removal	Only two studies on bovine corneas in vitro	Encapsulate multiple molecules due to their structure of hydrophilic rim and hydrophobic cavity	Morrison et al. (2013), Conde Penedo et al. (2021)