Impact of Corneal Cross-linking on Drug Penetration in an Ex Vivo Porcine Eye Model

Abstract Hyperviscosity agents are commonly used in ophthalmic formulations for improving corneal drug penetration by increasing tissue contact time. One such viscosity agent is hydroxypropyl methylcellulose (HPMC). HPMC has been used in riboflavin solutions for photochemical UVA cross-linking (CXL). Sodium hydroxymethylglycinate (SMG) is a small molecule formaldehyde releaser that can function as a therapeutic tissue cross-linker for corneal and scleral applications. The present study was undertaken in order to study formulation factors using HPMC and SMG that could positively influence the cross-linking effect in these ocular tissues. Formulations containing 10 mM SMG and 100 mM sodium bicarbonate were prepared with varying HPMC concentrations from 0 to 4.4%. Their cross-linking effects on porcine and rabbit eyes were measured using differential scanning calorimetry (DSC), expressed as the change/difference in melting temperature (ΔTm) compared with the control. SMG in 4.4% HPMC solution resulted in ΔTm of 6.3 ± 1.21, while other concentration showed no differences in Tm shift on porcine cornea. In ex vivo rabbit cornea, there was a trend toward an increasing cross-linking effect with higher viscosity albeit mild differences. While a significant Tm shift was observed in porcine and rabbit sclera, there was no difference in effect of cross-linking between four HPMC concentrations. Increasing the HPMC concentration does not negatively affect the cross-linking efficacy attributed by SMG and could still be a positive cross-linking enhancer by virtue of increasing tissue contact time in a dynamic biological system. This information will be useful for planning further animal and human studies.

Download Full-text

Potential Effects of Corneal Cross-Linking upon the Limbus

BioMed Research International ◽

10.1155/2016/5062064 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Johnny E. Moore ◽

Davide Schiroli ◽

C. B. Tara Moore

Keyword(s):

Stem Cells ◽

Potential Risk ◽

Ocular Surface ◽

Ex Vivo ◽

Uv Exposure ◽

Cross Linking ◽

Clinical Complications ◽

Cellular Dna ◽

Pathological Consequence

Corneal cross-linking is nowadays the most used strategy for the treatment of keratoconus and recently it has been exploited for an increasing number of different corneal pathologies, from other ectatic disorders to keratitis. The safety of this technique has been widely assessed, but clinical complications still occur. The potential effects of cross-linking treatment upon the limbus are incompletely understood; it is important therefore to investigate the effect of UV exposure upon the limbal niche, particularly as UV is known to be mutagenic to cellular DNA and the limbus is where ocular surface tumors can develop. The risk of early induction of ocular surface cancer is undoubtedly rare and has to date not been published other than in one case after cross-linking. Nevertheless it is important to further assess, understand, and reduce where possible any potential risk. The aim of this review is to summarize all the reported cases of a pathological consequence for the limbal cells, possibly induced by cross-linking UV exposure, the studies donein vitroorex vivo, the theoretical bases for the risks due to UV exposure, and which aspects of the clinical treatment may produce higher risk, along with what possible mechanisms could be utilized to protect the limbus and the delicate stem cells present within it.

Download Full-text

Comparison of waveform-derived corneal stiffness and stress-strain extensometry-derived corneal stiffness using different cross-linking irradiances: an experimental study with air-puff applanation of ex vivo porcine eyes

Graefe s Archive for Clinical and Experimental Ophthalmology ◽

10.1007/s00417-020-04792-8 ◽

2020 ◽

Vol 258 (10) ◽

pp. 2173-2184 ◽

Cited By ~ 1

Author(s):

Robert Herber ◽

Mathew Francis ◽

Eberhard Spoerl ◽

Lutz E. Pillunat ◽

Frederik Raiskup ◽

...

Keyword(s):

Experimental Study ◽

Ex Vivo ◽

Cross Linking ◽

Displacement Curve ◽

Stress Strain ◽

Strain Measurements ◽

Deflection Amplitude ◽

Force Displacement ◽

Stiffening Effect ◽

Porcine Eyes

Abstract Purpose To assess corneal stiffening of standard (S-CXL) and accelerated (A-CXL) cross-linking protocols by dynamic corneal response parameters and corneal bending stiffness (Kc[mean/linear]) derived from Corvis (CVS) Scheimpflug-based tonometry. These investigations were validated by corneal tensile stiffness (K[ts]), derived from stress-strain extensometry in ex vivo porcine eyes. Methods Seventy-two fresh-enucleated and de-epithelized porcine eyes were soaked in 0.1% riboflavin solution including 10% dextran for 10 min. The eyes were separated into four groups: controls (n = 18), S-CXL (intensity in mW/cm2*time in min; 3*30) (n = 18), A-CXL (9*10) (n = 18), and A-CXL (18*5) (n = 18), respectively. CXL was performed using CCL Vario. CVS measurements were performed on all eyes. Subsequently, corneal strips were extracted by a double-bladed scalpel and used for stress-strain measurements. K[ts] was calculated from a force-displacement curve. Mean corneal stiffness (Kc[mean]) and constant corneal stiffness (Kc[linear]) were calculated from raw CVS data. Results In CVS, biomechanical effects of cross-linking were shown to have a significantly decreased deflection amplitude as well as integrated radius, an increased IOP, and SP A1 (P < 0.05). Kc[mean]/Kc[linear] were significantly increased after CXL (P < 0.05). In the range from 2 to 6% strain, K[ts] was significantly higher in S-CXL (3*30) compared to A-CXL (9*10), A-CXL (18*5), and controls (P < 0.05). At 8% to 10% strain, all protocols induced a higher stiffness than controls (P < 0.05). Conclusion Several CVS parameters and Kc[mean] as well as Kc[linear] verify corneal stiffening effect after CXL on porcine eyes. S-CXL seems to have a higher tendency of stiffening than A-CXL protocols have, which was demonstrated by Scheimpflug-based tonometry and stress-strain extensometry.

Download Full-text