Patrick M. Ladage

Effects of rigid and soft contact lens daily wear on corneal epithelium, tear lactate dehydrogenase, and bacterial binding to exfoliated epithelial cells☆

OBJECTIVE To determine the effects of lens type and oxygen transmissibility on human corneal epithelium during daily lens wear (DW). DESIGN Prospective, randomized, double-masked, single-center, parallel treatment groups clinical trial. PARTICIPANTS Two hundred forty-six patients fitted with: (1) high oxygen-transmissible soft lenses (n = 36), (2) hyper oxygen-transmissible soft lenses (n = 135), and (3) hyper oxygen-transmissible rigid gas-permeable (RGP) lenses (n = 75). INTERVENTION Irrigation chamber to collect exfoliated epithelial surface cells, confocal microscopy, and tear collection at baseline, 2 weeks, and 4 weeks of DW. MAIN OUTCOME MEASURES (1) Pseudomonas aeruginosa (PA) binding to exfoliated corneal epithelial surface cells, (2) central epithelial thickness, (3) superficial epithelial cell area, (4) epithelial surface cell exfoliation, and (5) tear lactate dehydrogenase (LDH). RESULTS Four weeks of DW with the high oxygen-transmissible soft lens significantly increased PA binding from baseline 6.55 +/- 3.01 to 8.75 +/- 3.05 bacteria per epithelial cell (P < 0.01). By contrast, hyper oxygen-transmissible soft lens wear increased binding significantly less (6.13 +/- 2.45 to 7.62 +/- 3.06; P < 0.01), whereas hyper oxygen-transmissible RGP lens wear demonstrated no significant changes (5.91 +/- 2.40 to 6.13 +/- 2.17; P = 0.533). No significant change in central epithelial thickness was found after 4 weeks of DW in either soft lens; however, the epithelial thickness decreased by 9.8% (P < 0.001) with RGP lens wear. Epithelial cell surface area increased 3.3% and 4.1% with the high and hyper oxygen-transmissible soft lenses, respectively, and 10.5% with the hyper oxygen-transmissible RGP lens (P < 0.001). Epithelial desquamation significantly decreased in all groups (P < 0.001). Tear LDH levels increased for all test lenses (P < 0.001). CONCLUSIONS Increased PA binding induced by wear of a conventional soft lens material is significantly greater than that induced by the new hyper oxygen-transmissible soft silicone hydrogel lens during DW. However, both soft materials showed significant increases in PA binding as compared with baseline controls. By contrast, hyper oxygen-transmissible RGP lens DW did not increase PA binding significantly. Taken together, these findings suggest for the first time both an oxygen effect as well as a difference between soft and rigid lens types on PA binding in DW.

Adaptive effects of 30-night wear of hyper-O2 transmissible contact lenses on bacterial binding and corneal epithelium: A 1-year clinical trial☆

OBJECTIVE To determine effects of lens type and oxygen transmissibility on human corneal epithelium during extended wear (EW). DESIGN Prospective, randomized, double-masked, single-center, parallel treatment groups, 1-year clinical trial. PARTICIPANTS One hundred seventy-eight patients completed the study: (1) high-O(2) soft lens (6-night [N] EW) (n = 27); (2) hyper-O(2) soft lens (6N-EW, n = 33) or (30N-EW, n = 66); and (3) hyper-O(2) rigid gas-permeable lens (RGP) (30N-EW, n = 52). INTERVENTION Irrigation chamber to collect exfoliated corneal surface cells, confocal microscopy, and tear collection at baseline, 1, 3, 6, 9, 12 months of EW. MAIN OUTCOME MEASURES (1) Pseudomonas aeruginosa (PA) binding to exfoliated corneal surface cells; (2) central epithelial thickness; (3) superficial epithelial cell area; (4) epithelial surface cell exfoliation; and (5) tear lactate dehydrogenase. RESULTS Quantitative evidence demonstrated increased binding of PA to human exfoliated corneal epithelial cells during the first 3 months of soft lens EW; the control high-O(2) test lens showed significantly higher bacterial binding (P < 0.05). Binding activity gradually decreased thereafter and returned to baseline after 9 and 12 months. The corneal epithelium demonstrated enlargement of surface cell size, thinning of central epithelium, and a significant decrease in surface cell shedding (P < 0.05). Remarkably, there was subsequent partial adaptive recovery in cell shedding and epithelial thickness but not surface cell size. There was no significant difference between 6N and 30N continuous wear of the hyper-O(2) soft lens for all outcome measures. Importantly, hyper-O(2) RGP lens wear did not show significantly increased PA binding during 1 year. CONCLUSIONS This study establishes three important new findings: (1) hyper-O(2) soft lens EW produces significantly less PA binding than the lower O(2) soft lens with no significant difference in PA binding with 6N versus 30N EW of the hyper-O(2) soft lens; (2) there is a remarkable adaptive recovery after 6 months with all soft lens wear with gradual return to prelens PA binding levels and partial recovery of other outcome measures for all test lenses EW except surface cell size; (3) 30N EW of the hyper-O(2) RGP lens produced no significant increases in PA binding over 1 year. Taken together, these results suggest that introduction of new hyper-O(2) transmissible lens materials into clinical use may offer safer EW, and future epidemiologic studies of ulcerative infectious keratitis should consider both lens type and time in lens EW in any incidence/risk analysis.

Effects of daily and overnight wear of a novel hyper oxygen-transmissible soft contact lens on bacterial binding and corneal epithelium: A 13-month clinical trial

OBJECTIVE To test prospectively a new biologic rationale for an advanced hyper oxygen-transmissible lens (HOTL) providing prospects for safer daily (DW) or extended (EW) contact lens wear. DESIGN Prospective, randomized, double-masked, single-center, 13-month clinical trial. PARTICIPANTS One hundred sixty-eight patients completed the DW study (1 month): control lens (n = 70); HOTL (n = 98). One hundred thirty-six patients finished 1 year of EW: controls (n = 56), HOTL (n = 25, 6 nights; n = 55, 30 nights). TESTING Irrigation chamber to collect corneal surface cells, confocal microscopy, tear collection at baseline, 2, and 4, weeks of DW, and 24 hours, 1, 3, 6, 9, and 12 months of EW. MAIN OUTCOME MEASURES (1) Pseudomonas aeruginosa (PA) binding to exfoliated corneal surface cells; (2) central epithelial thickness (CET); (3) superficial cell area (SCA); (4) epithelial surface cell exfoliation (DESQ); and (5) tear lactate dehydrogenase (LDH). RESULTS Daily wear with control lens increased PA binding from 5.90 +/- 2.60 to 7.81 +/- 3.04 bacteria per cell (P < 0.01); HOTL wear increased PA binding significantly less (5.31 +/- 1.87-5.98 +/- 2.26; P < 0.01). Daily wear produced no significant changes in CET or SCA. Significant decreases in DESQ were seen with both lenses with no significant intergroup differences. Tear LDH increased significantly in DW with HOTL wear versus control (P = 0.0017), but not after 1 month of subsequent EW (P = 0.533). One to 3 months of EW with control lens showed significantly higher PA binding than HOTL wear (P < 0.01); binding adaptively decreased thereafter, returning to baseline at 9 to 12 months. Lens EW produced significantly enlarged SCA, thinning of CET (except 6-night HOTL wear), and decreased DESQ (P < 0.01). Some adaptive recovery was seen with CET and DESQ, but not SCA; importantly, the data indicated no significant difference between 6- or 30-night EW for all outcomes. CONCLUSIONS Hyper oxygen-transmissible lens wear (DW or EW) produced significantly decreased PA binding compared with control lens wear, with no significant difference in wearing schedule (6 nights vs. 30 nights); additionally, there was a remarkable and unexpected adaptive recovery in the first 6 months of all soft lens wear, with a return to baseline PA binding levels and partial recovery for the other outcomes except SCA at 1 year. These results suggest that HOTL use should result in a decrease in the incidence of and risk(s) for lens-related microbial keratitis and that further epidemiologic studies should consider time in adapted EW in future risk and incidence analyses.

Effect of eyelid closure and overnight contact lens wear on viability of surface epithelial cells in rabbit cornea.

Purpose. To determine the effects of open, closed eye, and overnight contact lens wear on homeostatic epithelial surface cell death in the rabbit cornea. Methods. One eye of each rabbit was either closed by eyelid suture or fitted with one of the following test contact lenses: (1) low Dk/t rigid gas permeable (RGP) lens, (2) hyper Dk/t RGP lens, (3) hyper Dk/t soft lens. The other eye served as a control. After 24 hours, whole corneas were carefully excised and immediately stained with a calcein-acetoxymethyl ester–ethidium homodimer viability assay to quantify the number of nonviable surface epithelial cells. In addition, exfoliated corneal epithelial cells were collected with an eye irrigation chamber to determine cell viability. Results. In the normal cornea, open-eye conditions showed significantly more nonviable surface cells in the central cornea than in the periphery (p < 0.05). Overnight wear of all test lenses and eyelid closure induced significant decreases in the number of nonviable cells on the central corneal surface compared with controls (p < 0.05). All exfoliated corneal epithelial cells collected by eye irrigation were nonviable. Conclusion. In the rabbit model, overnight contact lens wear significantly down-regulated spontaneous epithelial surface cell death independent of lens rigidity or material oxygen transmissibility. These effects were similar to eyelid closure without lens wear. Taken together, these results suggest that eyelid closure and the physical presence of the contact lens may protect against the shear stress forces exerted by eyelid blinking, which are believed to cause central surface cell death and subsequent exfoliation.

Corneal epithelial homeostasis following daily and overnight contact lens wear

This report reviews and integrates our recent clinical and laboratory findings of the effects of daily (DW)/overnight (EW) contact lens wear on corneal epithelial homeostasis. In a prospective, double-masked human clinical study, three lens types (high and hyper Dk/t soft; hyper Dk/t RGP) were used to assess the effects of daily and overnight lens wear on corneal epithelial thickness, cell surface size, Pseudomonas aeruginosa (PA) binding to exfoliated epithelial cells and exfoliation rates. Concomitantly, we studied in a rabbit model, the effects of overnight lens wear on corneal epithelial surface cell viability (live/dead assay, TUNEL-labeling, Annexin-V staining, Bcl-2 expression), basal cell proliferation and migration patterns. The comprehensive results obtained yield important new insights on both the normal homeostasis of the corneal epithelium and the biological changes induced by contact lens wear.

Pseudomonas aeruginosa corneal binding after 24-hour orthokeratology lens wear

Purpose. To examine the effect of short-term 24-hr orthokeratology lens (OKL) wear on Pseudomonas aeruginosa binding, epithelial surface cell morphology, epithelial sheet thickness, and stromal thickness in a rabbit model. Methods. Seventeen New Zealand white rabbits were treated according to the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research. Partial membranectomy was performed on all rabbits 1 week before the experiments. Baseline values for epithelial and stromal thickness and epithelial surface cell size were determined by in vivo confocal microscopy in one randomly chosen eye (n = 6). One week later, rabbits were fitted in the same eye with a hyper oxygen-transmissible OKL. Twenty-four hours later, confocal microscopy was repeated. The second group of rabbits (n = 6) was fitted with an OKL in one randomly chosen eye for 24 hr. P. aeruginosa binding to the corneal epithelium was assessed for the control corneas and those exposed to the test lens. Scanning electron microscopy was performed on a third group of rabbits to assess epithelial surface damage (n = 5). Results. There was a statistically significant difference (P<0.001) in P. aeruginosa binding between the control (1.11 ± 0.74 × 105 colony-forming units per cornea) and the OKL-wearing eyes (2.74 ± 0.69 × 105 colony-forming units per cornea). The central epithelium thinned by 6.5% after lens wear (48.2 ± 1.9 μm to 45 ± 1.7 μm, P=0.005); however, central stromal thickness increased by 7.3% (322 ± 22 μm to 345 ± 29 μm, P=0.006). Compared with the baseline value, central epithelial cell size increased significantly from 1,253 ± 140 mm2 to 1,627 ± 393 mm2 (29.4%, P=0.02). Scanning electron microscopy showed increased surface epithelial damage associated with OKL wear. Conclusions. This prospective, masked, pilot study showed that 24-hr hyper oxygen-transmissible OKL wear induced a statistically significant increase in P. aeruginosa binding to the epithelium of the rabbit cornea, accompanied by central epithelial thinning, stromal thickening, and surface cell damage assessed by scanning electron microscopy. Collectively, the data suggest that despite adequate lens oxygen transmissibility, the mechanical pressure inherent in the OKL design exerted on the corneal surface appears to be associated with increased adherence of P. aeruginosa to surface corneal epithelial cells, which may pose an increased risk for lens-related microbial keratitis, especially in overnight (i.e., closed-eye) wearing conditions. Future studies are needed to determine whether these results are similar in human wear and how P. aeruginosa binding during OKL wear compares with other lens-wearing modalities, such as daily or continuous soft lens wear.

Effects of daily and overnight wear of hyper-oxygen transmissible rigid and silicone hydrogel lenses on bacterial binding to the corneal epithelium: 13-month clinical trials.

Purpose. For 14 years, the U. S. Food and Drug Administration (FDA) and eye care practitioners have strongly discouraged patients from sleeping in contact lenses. In the past 9 months however, the FDA has approved three new hyper-oxygen transmissible lenses for up to 30-night extended wear. Is this a great advance or another clinical triumph of hope over experience? What should the public know? What should patients do? Methods. Our research group has studied all three new lenses in prospective, randomized, masked, parallel clinical trials in a single center. As an outcome measure, we looked at whether lens wear caused more bacterial binding to surface corneal cells. Results. Compared with conventional lens use, the new lenses caused no or only small increases in bacterial binding in either daily or extended wear. Furthermore, the increases seen stratified with known infection risks by both lens type (hard or soft) and wearing schedule. Indeed, early epidemiologic reports indicate that this new generation of lenses may reduce lens-related microbial infection risks by 10- to 40-fold. Conclusion. This represents a true clinical paradigm shift of the first magnitude in safety of contact lens wear. Taken together, this data suggest that patients will soon replace their current, conventional lenses with this new generation of materials for any schedule of wear.

Effects of contact lens care solutions on surface exfoliation and bacterial binding to corneal epithelial cells.

Purpose. The purpose of this study is to assess the effects of commercially available contact lens wetting solutions on bacterial binding and cell exfoliation rates in human corneal epithelium. Methods. The effects of four contact lens care solutions were tested: ReNu Multi Plus (Bausch & Lomb, Rochester, NY) multipurpose solution; OPTI-FREE Express (Alcon, Ft. Worth, TX) multipurpose solution; Complete Blink-N-Clean (Allergan, Irvine, CA) lens drops; and Lens Plus (Allergan) rewetting drops. Study Design. Prospective, double-masked, randomized crossover clinical trial (N = 20 subjects). Outcome Measures. Measures of outcome included binding of Pseudomonas aeruginosa (PA) to exfoliated corneal epithelial cells, and the rate of surface cell exfoliation. Cells were collected at the baseline (pretreatment) examination and 4 days later, after subjects used the assigned solution six times daily and once again immediately before cell collection (posttreatment). Following cell collection, patients underwent 1 week of recovery, during which no drops were used, and random cross-over assignment to the next test solution. Results. Use of test solutions increased PA binding, with a range of + 11.9% to + 58.2%. Analyzed together, PA binding increased significantly (+ 29%;P = 0.02, paired t- test); Lens Plus solution alone raised PA binding levels significantly (P = 0.022, 2-way ANOVA, Student-Newman-Keuls [SNK] test). Exfoliation rates were decreased from −7% to −52.7%. Analyzed together, cell exfoliation decreased significantly (P = 0.004; Wilcoxon signed rank test). Individual use of OPTI-FREE decreased exfoliation significantly (P = 0.019; 2-way ANOVA, SNK test). Conclusions. Topical application of common commercial contact lens care solutions increases PA binding and reduces corneal surface cell exfoliation. Similar effects have also been reported with contact lens wear. Taken together, the data suggest that the use of lens solution itself may play a role in increasing PA binding to corneal epithelial cells and, hence, might potentially contribute inadvertently to increased risk for lens-related microbial keratitis.

Spherical indentations of human and rabbit corneal epithelium following extended contact lens wear.

PURPOSE Mucin balls appear to cause spherical indentations in the corneal epithelium during silicone hydrogel extended contact lens wear. The purpose of this report is to describe and quantify these spherical indentations, as examined in the human cornea by in vivo confocal microscopy and by in vitro immunocytochemistry in the rabbit cornea. METHODS Confocal images of full-thickness corneal epithelium were taken from three human patients participating in a 1-year extended contact lens-wear trial. Diameter and depth of the indentations were determined and measured. Two rabbit corneas showing identical indentations were stained with propidium iodide (nuclear stain) and Ki-67 (proliferation marker) and were examined using a laser scanning confocal microscope. RESULTS The diameter of the spherical indentations is largest on the epithelial surface, ranging from 33.9 to 78.8 microm. Indentations form spherical sections whose depth variably extends into the corneal epithelium, reaching as far as the basal lamina. The rabbit model showed no epithelial nuclei within the indentation. Furthermore, stromal cells localized immediately beneath the indentations were positive for Ki-67 (proliferation). DISCUSSION Spherical indentations of the corneal epithelium induced by mucin balls appear to be gaps or holes that can extend deep into the corneal epithelium. Indentations may potentially open a pathway for infectious microorganisms to penetrate the cornea. Surprisingly, stromal cells immediately beneath the holes were stimulated to proliferate, and there seemed to be an increase in localized cell density.

What does overnight lens wear do to the corneal epithelium?: is corneal refractive therapy different?

The corneal epithelium plays a central role in preventing infectious keratitis. It is a layer that functions both as a physical barrier and as an active component of the ocular surface defense system. Contact lens wear is capable of altering the structure and physiology of the corneal epithelium, potentially increasing the risk of infectious keratitis. This brief review summarizes the effects of continuous contact lens wear and corneal refractive therapy on the physiology and structure of the corneal epithelium.