Castroviejo Lecture 2009: 40 years in search of the perfect contact lens

Abstract

Purpose: To identify the pathophysiological changes produced by contact lens wear that predispose the cornea to infection and search for prospective modifiable risk factors that could reduce the incidence of this critical complication in millions of patients worldwide.

Methods: Significant experimental and clinical publications are reviewed, and the results of ongoing studies are presented.

Results: Pseudomonas aeruginosa (PA) is the most common pathogen causing lens-related infectious keratitis over 3 decades. Contact lens wear can increase the risk of infection by increasing surface cell PA binding, thereby promoting invasion between broken tight junctions and initiating direct intracellular invasion mediated by lens-induced membrane lipid rafts. Prevention of upregulation of specific surface-binding receptors for PA with concomitant increase in infection risk is a zero damage game where independent interactions among lens type, mode of wear, oxygen transmissibility, polymer, and toxic effects of associated care solutions ideally should collectively produce no increased ability for PA to attach and/or to invade, thus minimizing the risk for lens-associated infections. The specific hypothesis tested is, "no increased epithelial surface damage... no increased PA binding or invasion... no increased risk for infection." Testing of this new paradigm has been performed in vitro and in animal and human clinical trials and correlated clinically with relative risk results from robust current epidemiological studies. Results to date clearly support the use of lens-related increases in PA binding (bench) as a noninvasive clinical predictor of risk for lens-related infection in subsequent large-scale population studies (bedside). Currently, results suggest that use of common commercial multipurpose lens care solutions with soft lenses may alone significantly increase infection risk by enhancing lens-related PA binding as compared with use of nonpreserved solutions (hydrogen peroxide). Clinical testing also shows that only peroxide solutions show significant disinfection capability against amoebic cysts. Further case-control studies to examine relative risk for infection by lens type and lens care solution are urgently needed.

Conclusions: Millions of patients are dependent on contact lenses for vision worldwide; over 3 decades, lens use has increased, although risk for lens-related infection has remained stubbornly unchanged. Unfortunately, recent introduction of a new generation of hyper-oxygen transmissible lenses used with traditional multipurpose lens care solutions has not lowered overall risks for lens-related infections; however, similar lenses used with nonpreserved care solutions (peroxide) recently demonstrated no significant increases in PA binding in a 1-year clinical trial. Collectively, these findings along with the urgent need for amoebic cysticidal disinfection have led to a current recommendation to patients to use nonpreserved (hydrogen peroxide) care solutions in soft lens wear.

Figure 1

Prevention of microbial keratitis: a zero damage game. Figure adapted from Robertson DM, Petroll WM, Cavanagh HD. The effects of nonpreserved care solutions on 12 months of daily and extended silicone hydrogel contact lens wear. Invest Ophthalmol Vis Sci 2008;49:7–15 (Copyright © Association for Research in Vision and Ophthalmology).

Figure 2

Propidium Iodide (PI) staining of corneal epithelial nuclei (red) and PA (red), FITC-conjugated beta cholera toxin staining of lipid rafts (green). A: Normal rabbit cornea (no lens); B: 24 hours of PMMA lens wear, no PA; C: 24 hours of PMMA lens wear, 30 minutes after PA infection; D: 24 hours of PMMA lens wear; 1 hour after PA infection. Figure adapted from Yamamoto N, Yamamoto N, Petroll WM, Cavanagh HD, Jester JV. Internalization of Pseudomonas aeruginonsa is mediated by lipid rafts in contact lens-wearing rabbit and cultured human corneal epithelial cells. Invest Ophthalmol Vis Sci 2005;46:1348–1355 (Copyright © Association for Research in Vision and Ophthalmology).

Figure 3

PI staining of corneal epithelial nuclei (red) and FITC-conjugated beta cholera toxin staining of lipid rafts (green). A: Note the presence of rafts in the conjunctival and limbal epithelium in the control eye, no rafts were noted in the central or peripheral corneal epithelium in the non-lens wearing condition. B: Following 24 hours of PMMA lens wear, rafts appeared in the peripheral and central corneal epithelium; PA preferentially localized to these rafts. No PA adherence was seen with rafts localized to the conjunctival or limbal epithelium (arrows). Figure adapted from Yamamoto N, Yamamoto N, Petroll WM, Cavanagh HD, Jester JV. Internalization of Pseudomonas aeruginonsa is mediated by lipid rafts in contact lens-wearing rabbit and cultured human corneal epithelial cells. Invest Ophthalmol Vis Sci 2005;46:1348–1355 (Copyright © Association for Research in Vision and Ophthalmology).

Figure 4

Results from animal studies show that at the same level of oxygen transmissibility, rigid lenses produce inherently greater epithelial surface damage but induce significantly less PA adhesion than their soft lens counterparts. (p<0.05). Figure adapted from Imayasu et al, 1994, with permission.

Figure 5

An eye irrigation chamber was used to wash exfoliated epithelial cells from the corneal surface using warmed sterile saline. Following epithelial cell collection, cells were stained with acridine orange and visualized under an epifluorescent microscope, allowing for quantitation of the number of cells collected and the number of adherent PA per cell. Figure adapted from Ren et al, 1997, with permission.

Figure 6

The clinical relationship between lens oxygen parameters and increased PA binding to exfoliated corneal cells. Adapted from Ren et al, 1999, with permission.

Figure 7

Summary table detailing MPS components: preservative, surfactant, and buffer, utilized by three commercially available MPS solutions. Note that both Renu MP and Optifree P. contain Boric acid as a buffering agent. Table adapted from Imayasu et al, 2008, with permission.

Figure 8

Quantitative analysis of PA adhesion to corneal epithelial cells following treatment with the three MPS outlined in Figure 7. Importantly, both solutions containing Boric acid showed the largest increase in PA adhesion compared to the control (p<0.05). Figure adapted from Imayasu et al, 2009, with permission

Figure 9

Scanning electron micrograph showing PA selectively adhering and migrating toward areas of tight junction breakdown in monolayer epithelial cell cultures treated with boric acid containing MPS. Figure adapted from Imayasu et al, 2009, with permission.

Figure 10

Study outline for a clinical trial investigating the effects of chemically preserved care solutions on the surface of the eye in the absence of a contact lens. PA adhesion rates and surface epithelial exfoliation rates were assessed as previously described.

Figure 11

Study outline for a clinical trial investigating the effect of topically applied chemically preserved care products in the absence of a contact lens. Figure adapted from Li et al, 2003, with permission.

Figure 12

All four chemically preserved solutions demonstrated an increase in PA adhesion when applied directly to the eye in the absence of a contact lens (p<0.02). Figure adapted from Li et al, 2003, with permission.

Figure 13

All four solutions concomitantly decreased epithelial surface cell shedding in the absence of a confounding lens effect (p<0.004). Figure adapted from Li et al, 2003, with permission.

Figure 14

Results from a one year clinical trial demonstrate that silicone hydrogel lenses, worn daily or extended wear over a one month period, failed to increase PA adhesion when used in conjunction with a preservative free (peroxide) solution. Acuvue 2 data shown here as an historical control for comparison. Figure adapted from Robertson DM, Petroll WM, Cavanagh HD. The effects of nonpreserved care solutions on 12 months of daily and extended silicone hydrogel contact lens wear. Invest Ophthalmol Vis Sci 2008;49:7–15 (Copyright © Association for Research in Vision and Ophthalmology).

Figure 15

Results from a one year clinical trial showing an increase in PA binding associated with lens wear and use of a chemically preserved MPS (Renu MP). PA rates were stratified by lens type and showed an adaptive return to baseline during the first 6 months of lens wear. Figure adapted from Ren et al, 2002.

Figure 16

In contrast to Figure 15, silicone hydrogel lenses in combination with a preservative free solution (peroxide) failed to show an increase in PA adhesion when followed over one year. Acuvue 2 data shown here as an historical control for comparison. Figure adapted from Robertson DM, Petroll WM, Cavanagh HD. The effects of nonpreserved care solutions on 12 months of daily and extended silicone hydrogel contact lens wear. Invest Ophthalmol Vis Sci 2008;49:7–15 (Copyright © Association for Research in Vision and Ophthalmology).