The Impact of Photorefractive Keratectomy and Mitomycin C on Corneal Nerves and Their Regeneration

Abstract

Purpose: To determine how PRK and MMC impact corneal nerves and their regeneration over time after surgery. Methods: Twenty-eight New Zealand rabbits had: corneal epithelial scrape with MMC 0.02% (n=3) and without MMC (n=3), −9.0 diopter PRK with MMC (n=6) and without MMC (n=16). Corneas were removed after euthanasia and corneal nerve morphology was evaluated using acetylcholinesterase immunohistochemistry and β-III tubulin staining after 1 day for all the groups, after 1 month for PRK with and without MMC, and 2, 3 and 6 months after PRK without MMC. Image-Pro was used to quantitate the area of nerve loss after the procedures and, consequently, regeneration of the nerves overtime. Opposite eyes were used as controls. Result: Epithelial scrape with MMC treatment did not show a statistically significant difference in nerve loss compared to epithelial scrape without MMC (p=0.4). PRK with MMC was significantly different from PRK without MMC at 1 day after surgery (p=0.0009) but not different at one month after surgery (p=0.9). In the PRK without MMC group, nerves regenerated at two months (p=<0.0001) but did not return to the normal preoperative level of innervation until three months after surgery (p=0.05). However, the morphology of the regenerating nerves was abnormal—with more tortuosity and aberrant innervation compared to the preoperative controls—even at six months after surgery. Conclusion: PRK damages the corneal nerves but they are partially regenerated by three months after surgery in rabbits. Nerve loss after PRK extended peripheral to the excimer laser ablated zone, indicating that there was retrograde degeneration of nerves after PRK. MMC had a small additive toxic effect on the corneal nerves when combined with PRK that was only significant prior to one month after surgery.

Transient Mitomycin C-treatment of human corneal epithelial cells and fibroblasts alters cell migration, cytokine secretion, and matrix accumulation

“…Here we show that MMC appears to suppress fibrosis by reducing collagen deposition by corneal fibroblasts and by enhancing deposition of epithelial basement membrane proteins by corneal epithelial cells as shown by the increase in LN332 deposition observed when HLCE cells were induced by direct and indirect treatment with MMC. This knowledge contributes to our understanding of why failure of the epithelial basement membrane to reassemble after refractive surgery and other corneal injuries and pathologies can lead to fibrosis 47–49 . Also, studies by Saikia and colleagues 50 show that IL1β increases expression of the epithelial basement membrane proteins perlecan and nidogen by corneal stromal cells.…”

Effect of Transepithelial Photorefractive Keratectomy without Mitomycin C in the Treatment of Femtosecond Laser In Situ Keratomileusis Corneal Flap Complications

“…However, Gharaee [ 14 ] found that MMC can damage the corneal endothelium, especially in patients with a thin cornea or high myopia who have a thinner corneal stroma after laser ablation. Medeiros [ 15 ] also found that when PRK was used with MMC, the toxic effect on corneal nerves was reduced, but this effect was only significant one month after the operation. Hence, in PRK surgery [ 16 ], some scholars have found that there is no difference in the uncorrected visual acuity and occurrence and degree of postoperative haze with and without MMC.…”

Biological effects of mitomycin C on late corneal haze stromal fibrosis following PRK

“…During surface ablation procedures, epithelial removal and PRK ablation removes all nerves in the epithelium and sub-basal layer of the central cornea, as well as deeper stromal nerve fibers depending on the ablation depth. The recovery to preoperative densities and morphology typically takes 6 to 12 months (Erie et al, 2005;Gambato et al, 2011;Medeiros et al, 2018a). It has been proposed that MMC could actually facilitate nerve regeneration after PRK since myofibroblasts have been shown to interfere directly with reinnervation of the epithelium (Jeon et al, 2018).…”