Silicone Hydrogel Contact Lenses and the Ocular Surface

Clinical Science GARY N. FOULKS, MD, SECTION EDITOR

Silicone Hydrogel Contact Lenses and the Ocular Surface FIONA STAPLETON, PHD, MCOPTOM, DCLP FAAO,1,2, 3 SERINA STRETTON, PHD,1,2 ERIC PAPAS, PHD, MCOPTOM, DCLP,1,2,3 CHERYL SKOTNITSKY, BSC,OD,1, 3 DEBORAH F. SWEENEY, BOPTOM, PHD, FAAO1,2,3

ABSTRACT For 30 years, contact lens research focused on the need for highly oxygen-permeable (Dk) soft lens materials. High Dk silicone hydrogel contact lenses, made available in 1999, met this need. The purpose of this review is to examine how silicone hydrogel lens wear affects the ocular surfaces and to highlight areas in which further research is needed to improve biocompatibility. Silicone hydrogel lenses have eliminated lens-induced hypoxia for the majority of wearers and have a less pronounced effect on corneal homeostasis compared to other lens types; however, mechanical interaction with ocular tissue and the effects on tear film structure and physiology are similar to that found with soft lens wear in general. Although the ocular health benefits of silicone hydrogel lenses have increased the length of time lenses can be worn overnight, the risk of infection is similar to that found with other soft lens types, and overnight wear remains a higher risk factor for infection than daily wear, regardless of lens material. Future contact lens research will focus on gaining a better understanding of the way in which contact lenses interact with the corneal surface, upper eyelid, and the tear film, and the lens-related factors contributing to infection and inflammatory responses.

Accepted for publication November 2005 From the 1Vision Cooperative Research Centre, Sydney, Australia, 2Institute for Eye Research, Sydney, Australia, and 3School of Optometry and Vision Science, University of New South Wales, Kensington, Australia All authors are supported in part by the Australian Federal Government through the Cooperative Research Centre Scheme. The authors have no commercial interest in any concept or product discussed in this article. Single copy reprint requests should be sent to: Deborah F. Sweeney (address below) Corresponding author: Deborah F. Sweeney, Vision Cooperative Research Centre, PO Box 6327, UNSW Sydney, NSW, 1466, Australia. Tel: +61 2 9385 7408. Fax: +61 2 9385 7401. Email: [email protected] Abbreviations are printed in boldface where they first appear with their definitions. ©2006 Ethis Communications, Inc. The Ocular Surface ISSN: 15420124. Stapleton F, Stretton S, Papas E, et al. Silicone hydrogel contact lenses and the ocular surface. 2006;4(1):24–43.

24

KEY WORDS biomaterials, contact lens, corneal homeostasis, corneal vascularization, giant papillary conjunctivitis, limbal hyperemia, palpebral conjunctiva, papillary conjunctivitis, silicone hydrogel, tear film

I. INTRODUCTION ilicone hydrogel contact lenses represent the most important advance in the contact lens industry since development of the first soft hydrogel lenses in the early 1970s. The high oxygen permeability of this new class of silicon-based soft lens materials has provided a distinctive platform upon which new developments and designs are conceived. Until silicone hydrogel lenses became available, soft lens wearers, particularly those who wore lenses overnight, were subject to the effects of contact lens-induced hypoxia on corneal physiology and the potential consequences of compromised corneal integrity and function. The Göteborg study, published in 1985, was one of the first studies of the physiological effects of soft contact lens wear on the cornea.1 This study compared 27 eyes that had used long-term extended wear (5 years) hydrogel lenses with their non-lens-wearing fellow eyes. The lenswearing eyes showed significantly thinner corneal epithelium and lower oxygen uptake rates, greater numbers of corneal epithelial microcysts, thinner corneal stroma, significant levels of daytime edema, and a greater degree of corneal endothelial polymegethism than the fellow eyes. It has also been shown that long-term wearers of hydrogel lenses have greater amounts of limbal hyperemia than nonlens wearers, and may have greater encroachment of limbal vessels into the cornea.2 Although the changes to the stroma and endothelium remained, many of the changes to the epithelium seen in Göteborg study were reversed over 1 month after cessation of lens wear; in particular, epithelial thickness and oxygen consumption steadily recovered to non-lens wearing levels, as did the numbers of microcysts.1 This study confirmed that chronic lens-induced hypoxia is the underlying cause of the physiological changes seen during longterm contact lens wear and provided the major impetus to

S

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al OUTLINE I. Introduction II. Characteristics of silicone hydrogel materials III. Effects of contact lenses on the corneal epithelium A. Stem cell turnover B. Corneal homeostasis 1. Rate of cell exfoliation 2. Degree of thinning 3. Formation of epithelial microcysts 4. Susceptibility to bacterial binding C. Lens-induced changes in the limbal region IV. Corneal vascularization A. Mechanisms B. Hypoxia as a stimulating factor V. Clinical assessment of epithelial integrity: sodium fluorescein staining A. Mechanical abrasion B. Excessive desiccation VI. Superior palpebral conjunctiva A. Clinical features of contact lens-induced papillary conjunctivitis B. Etiology VII. Tear film A. Pre-lens tear film B. Tear evaporation

identify the critical levels of oxygen required by the cornea during daily and overnight contact lens wear to prevent these changes.3 The main components of the ocular surface that interact with a contact lens are the corneal and conjunctival epithelia and the tear film. Soft contact lenses have diameters that are approximately 2 to 3 mm larger than the cornea; thus, their peripheries directly interact with the limbus and surrounding bulbar conjunctiva. Typically, when the eye is open, the margins of the upper and lower lids overlie the periphery of a soft contact lens. This tends to reduce the impact of the interaction between the lids and the lens edge, although some frictional forces from movement of the upper lid across the lens surface do exist. When the eye is closed, the ocular environment is in a state of subclinical inflammation, and the supply of oxygen to the cornea is limited to the conjunctival vessels. The upper palpebral conjunctiva in the closed eye is in constant physical contact with the lens surface, and the effects, if any, of rapid eye movements, reduced tear film, or decreased lens wetting on the lens-lid interaction are unknown. Although the limbal transition zone is a mere 1.5 mm wide, its importance to contact lens wear relates to its crucial role in maintaining corneal health, particularly with respect to epithelial renewal and immunological response. For optimal biocompatibility, contact lenses must allow sufficient oxygen flow to maintain aerobic metabolism and

corneal homeostasis, maintain normal tear film integrity and stability, inhibit bacterial adhesion, and prevent the accumulation of debris beneath the lens. The mechanical attributes of the lens, such as modulus of elasticity (flexibility), edge design, or lens diameter, should minimize irritation of the corneal and conjunctival epithelia and maximize movement of tears. Although most contact lens research has focused on the corneal epithelium, and more recently the tear film, all surfaces play an integral part in maintaining ocular health. II. CHARACTERISTICS OF SILICONE HYDROGEL MATERIALS

All hydrogel materials are formed by the cross-linking of chains of monomeric units into a matrix-like polymer, and the unique attributes of each polymer are defined by the interaction of chemical groups and the degree of crosslinking. The main component of hydrogel lens materials is the relatively hydrophilic poly 2–hydroxyethyl methacrylate (HEMA), and other monomers are added to alter the ionicity and water content of the material in order to improve wettability, flexibility, oxygen permeability and fluid transport. The oxygen permeability of hydrogel materials is dependent on water content; and, therefore, is limited by the solubility of oxygen in water (Figure 1). Silicone hydrogels share a similar structure with hydrogel lens materials, but differ markedly in chemical composition; in essence, they combine the positive attributes of a soft lens with the excellent solubility of oxygen in silicone. Because of the relatively hydrophobic nature of silicone, if left unmodified, silicone hydrogel lenses would be inherently incompatible with the ocular surface. Hydrophobic lens surfaces cause discomfort, as their poor surface wettability contributes to destabilization of the tear film, and they accumulate deposits. The hydrophilicity of currently available silicone hydrogel lenses is enhanced by surface treatment or by the incorporation of soluble

Figure 1. Relationship between oxygen permeability (Dk) with equilibrium water content for conventional hydrogel and silicone hydrogel materials. (Reprinted from Tighe B. Silicone hydrogels: structure, properties and behaviours, in Sweeney DF (ed). Silicone hydrogels: continuous wear contact lenses Edinburgh: Butterworth Heinemann, 2004:1-27, with permission from the authors and the publisher.)

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

25

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

Table 1. Characteristics of Various Silicone Hydrogel Contact Lenses and Conventional Hydrogel Contact Lenses Material type USAN Proprietary name Manufacturer

Balafilcon A PureVision

Lotrafilcon A Focus Night & Day

Lotrafilcon B O2Optix

Bausch & Lomb

CIBA Vision

CIBA Vision

Monomers

NVP, TPVC, NCVE, PBVC

Surface modification

Plasma oxidation producing glassy islands

Initial modulus1 (MPa) Oxygen

permeability2 (

Oxygen

transmissibility3

Water content FDA class

Conventional hydrogel

Silicone hydrogel

x

10-11 (x

)

10-9

DMA, TRIS, siloxane macromer

25 nm plasma coating with high refractive index

Galyfilcon A Acuvue Advance

Senofilcon A Acuvue OASYS

Vistakon

Vistakon

mPDMS, DMA, HEMA mPDMS, DMA, HEMA siloxane macromer, siloxane macromer, TEGDMA, PVP EGDMA, PVP

Etafilcon A Acuvue2 Vistakon HEMA, MA

None Internal wetting agent – (PVP)

None

1.1

1.4

1.2

0.4

0.6

0.35

99

175

140

60

86

28

) 110

175

138

86

147

31

36%

24%

33%

47%

38%

58%

Group III Low water content Ionic

Group I Low water content Non-ionic

Group IV High water content; Ionic

USAN United States adopted name NVP N-vinyl pyrrolidone; TPVC tris-(trimethylsiloxysilyl) propylvinyl carbamate; NCVE N-carboxyvinyl ester; PBVC poly[dimethylsiloxyl] di [silylbutanol] bis[vinyl carbamate]; DMA N,N-dimethylacrylamide; HEMA 2-hydroxyethylmethacrylate; MA methacrylic acid; PVP polyvinyl pyrrolidone; mPDMS monofunctional polydimethylsiloxane; TEGDMA tetraethyleneglycol dimethacrylate; EGDMA ethyleneglycol dimethacrylate. 1 Initial modulus data from Ross et al.; Silicone hydrogels: trends in products and properties. Presented at the 29th Clinical Conference & Exhibition of the British Contact Lens Association, Brighton, UK 3-6 June, 2005. 2 Labelled 3 Calculated using center thickness of a –3.00 D lens; units = (cm ml O )(s ml mmHg)–1 2

polymers (internal wetting agents) within the bulk material that orient to form an interface between the lens and the tear film. While the presence of silicone is a unifying feature, silicone hydrogel materials are made from a diverse group of monomers (Table 1). The current silicone hydrogel lens materials range in oxygen permeability from 60 to 175 barrer, far greater than can be provided by more conventional hydrogel lens materials, and the lenses differ in water content, stiffness and surface characteristics. At present, two silicone hydrogels (lotrafilicon A and balafilcon A) are approved by the US Food and Drug Administration (FDA) for up to 30-nights of continuous wear, with monthly replacement; they also have FDA approval and CE Mark approval for therapeutic use as bandage lenses. Lotrafilcon B is recommended for daily wear and up to 6-nights extended wear, and galyfilcon A and senofilcon A are recommended for daily wear only. III. EFFECTS OF CONTACT LENSES ON THE CORNEAL EPITHELIUM A. Stem Cell Turnover

The ability of the cornea to continually replace its epithelium and to quickly repair superficial damage depends on the capacity of limbal epithelial stem cells for essentially unlimited self-renewal and, in appropriate circum26

stances, high rates of proliferation. Loss or injury to the stem cell population, which comprises up to 10% of limbal epithelial cells,4 makes the cornea vulnerable to deficient epithelialization, leading to recurrent erosions, chronic keratitis, and vascularization.5 Contact lens wear, and lens-induced hypoxia, in particular, have been cited among the possible causes of limbal stem cell deficiency.6-9 Mechanical trauma from the lens edge may also cause stem cell damage, although stem cells are largely protected by their location at the basal level of the limbal epithelium, which is thicker and more densely compacted than its corneal counterpart.4 During corneal turnover, slow-cycling stem cells located in the limbal basal epithelium produce daughter basal epithelial cells of much greater proliferative potential in the peripheral cornea, adjacent to the limbus.10 These basal cells then differentiate vertically and migrate horizontally toward the central corneal surface11,12 before terminal differentiation, apoptosis-mediated cell death,13 and eventual exfoliation into the precorneal tear film. The success of the epithelium in maintaining the delicate balance between epithelial cell proliferation, differentiation, and exfoliation during contact lens wear is demonstrated by measures such as epithelial thickness, surface cell size, and shedding rate. Several long-term clinical studies comparing performance

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

of silicone hydrogel lens wear with no lens wear,14 and hydrogel lens wear,15 have firmly established that eyes that wear silicone hydrogel lenses are clinically indistinguishable from non-lens wearing eyes. Generally, they exhibit excellent clinical performance based on indicators such as numbers of epithelial microcysts and degree of corneal epithelial staining and limbal and bulbar hyperemia. Clinical performance of silicone hydrogel lenses was the same whether they were worn for 6 or 30 consecutive nights.16,17 B. Corneal Homeostasis

Recent studies by Cavanagh et al18 showed that all contact lens wear significantly slows the turnover of the corneal epithelium to some degree by suppressing epithelial cell proliferation19 and migration20 and by decreasing the rate of exfoliation21-23; these processes are mediated in part by lens-induced hypoxia and by the physical presence of the lens per se. The lenses used in these studies were the highly oxygen transmissible rigid gas permeable (tisilfocon A) and silicone hydrogel lenses (balafilcon A and lotrafilcon A,) as well as a hydrogel lens (etafilcon A) of lower oxygen transmissibility (Table 1). 1. Rate of Cell Exfoliation Extended wear with all currently available contact lenses, including soft and rigid gas permeable lenses, is characterized by significant thinning of the central corneal epithelium, an increase in cell surface size, and a decreased rate of exfoliation (Figure 2).24,25 The rate of surface cell exfoliation decreases with all contact lens types, irrespective of lens oxygen transmissibility, material rigidity, or wear schedule,21,23-25 and occurs at levels similar to those induced by the closed eye in the absence of lens wear (suturing) in a rabbit model.26 This effect of contact lens wear on the rate of cell exfoliation is further supported by the finding that all contact lens types similarly suppress apoptosis-driven cell death in the central epithelium, as in the closed eye.27,28 In the absence of hypoxia, contact lens wear seems to mimic the conditions of the closed eye, in which surface epithelial cells are protected from the shear forces of the blinking lid. Cavanagh proposed that regulation of epithelial cell apoptosis and exfoliation is mediated by Bcl-2, an antiapoptotic protein, and suggested that contact lens-induced suppression of cell exfoliation may arise from continued expression of Bcl-2 at the corneal surface.18 The increase in cell size at the corneal surface during contact lens wear is most likely a result of longer retention times and the slower rate of exfoliation. The size of exfoliated corneal epithelial cells in eyes that wear silicone hydrogel lenses is similar to that found in non-lens-wearing eyes after 3 months of extended wear (30-consecutive-night regimen),29 but it increases above baseline levels within 6 to 9 months of wear.24,25 However preliminary studies suggest that in the longer-term (up to 3 years), cell size in silicone hydrogel lens wearers recovers to pre-lens wear levels.30

Figure 2. Effects of 6-nights or 30-nights extended wear (EW) on corneal homeostasis. Central corneal epithelial thickness and epithelial cell surface area were assessed by in vivo confocal microscopy. Dk=oxygen permeability; RGP=rigid gas permeable; 6N=6night EW; 30N=30-night EW; *=p<0.05. (Reprinted from Ren DH, Yamamoto K, Ladage PM, et al. Adaptive effects of 30-night wear of hyper-O2 transmissible contact lenses on bacterial binding and corneal epithelium. A 1-year clinical trial. Ophthalmology 2002;109:27-40, with permission from the authors and the American Academy of Ophthalmology.

2. Degree of Thinning In contrast to cell exfoliation, the degree of thinning of the central corneal epithelium is affected to varying degrees by lens type and oxygen transmissibility. Highly oxygen transmissible silicone hydrogel lenses have less pronounced effects than hydrogel lenses of lower oxygen transmissibility or rigid gas permeable lenses of equivalent oxygen transmissibility (Figure 2), and they show greater evidence of adaptive recovery during long-term extended wear. The decrease in the rate of surface cell exfoliation with contact lens wear seems at first to be inconsistent with the concomitant thinning of the corneal epithelium. During the first 48 hours of overnight wear, all contact lens types suppress proliferation of cells at the basal epithelium to some degree at levels similar to those seen in the closed eye.19,31 However, highly oxygen transmissible silicone hydrogel lenses have less effect on proliferation than other lens types. Ladage et al reported a significant reduction in proliferation of central epithelial basal cells with silicone hydrogels (–33.8%), which is less pronounced than that

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

27

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

Figure 3. Typical appearance of corneal epithelial microcysts x30 magnification

found with hydrogel lenses of lower oxygen transmissibility (–40.8%) or in the closed eye model (–47%).19 Ladage et al suggested that the reduction in epithelial thickness seen with contact lens wear may be caused by a reduced demand for new surface cells, which, in turn, may signal suppression of basal cell proliferation.19 Insufficient proliferation and movement of epithelial cells to the corneal surface, may then lead to corneal thinning. Although there is some indication that basal cell proliferation recovers with silicone hydrogels after 8 days of wear, it is not clear whether this response is a result of an adaptive response to contact lens wear or is a result of a delay in cells entering the cell cycle.19

Figure 4. Mean numbers of microcysts in subjects wearing silicone hydrogel lenses on extended wear schedules over 3 years. Subjects were classified by their previous lens wear history. Subjects who were new to lens wear or who had previously worn silicone hydrogel lenses began the study with low number of microcysts. Subjects who had previously worn hydrogel lenses began the study with higher levels of microcysts indicative of lens-induced hypoxia. Error bars represent mean ± 1 SD. BL=Baseline. (Modified from Stern J, Wong R, Naduvilath TJ, et al. Comparison of the performance of 6- or 30-night extended wear schedules with silicone hydrogel lenses over 3 years. Optom Vis Sci 2004;81:398-406, with permission from the authors and the publisher.)

28

Figure 5. Rebound effect in the microcyst response observed when a patient is refitted with silicone hydrogel lenses after 12 months extended wear with hydrogel lenses of lower oxygen transmissibility. (Reprinted from Sweeney DF, et al. Clinical performance of silicone hydrogel lenses, in Sweeney DF (ed). Silicone hydrogels: continuous wear contact lenses. Edinburgh: Butterworth Heinemann, 2004, pp 164-216, with permission from the publisher.)

3. Formation of Epithelial Microcysts Epithelial microcysts that form during contact lens wear are perhaps the most reliable clinical indicator of chronic hypoxic stress brought about by extended wear.32 With high magnification slit-lamp microscopy and marginal retroillumination, they appear as very small (10 to 50 μm diameter) translucent and irregular dots (Figure 3), usually distributed as a ring in the midperiphery of the cornea. Fewer than 10 microcysts are associated with no lens wear or daily wear,14,33,34 and more than 50 microcysts indicate severe chronic hypoxic stress.35 Wearers of hydrogel lenses usually develop microcysts within 3 months of commencing extended wear, after which a relatively steady state is reached; however, numbers do fluctuate over time.36 By comparison, the numbers of microcysts in wearers of silicone hydrogel lenses have been shown to remain consistently low (less than 10) after 18 months37 and up to 3 years of extended wear (Figure 4), irrespective of the consecutive number of nights of wear (6 versus 30).17 The reversed illumination displayed by epithelial microcysts indicates that they are comprised of degenerated cellular material,38,39 possibly arising from hypoxiainduced apoptotic processes.13,40 Microcysts are thought to form in the basal cell layer of the epithelium and move to the surface during cellular turnover. The transitory increase in microcyst numbers after sufficiently higher levels of oxygen are supplied to the eye, either by removing hydrogel lenses or by replacing them with silicone hydrogel lenses, is postulated to result from the resurgence in corneal metabolism. The transitory increase in the number of microcysts occurs in approximately 50% of subjects and slowly decreases to non-lens wearing levels over 1 to 3 months (Figure 5).1,37 4. Susceptibility to Bacterial Binding Lens-induced hypoxia affects corneal structure and function, but it is not clear how these often subtle changes

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

translate to a clinical setting. Lens-induced hypoxia is postulated to predispose lens wearers to a greater rate of infection and inflammation by contributing to impaired corneal integrity and wound healing41-43 and by increasing the susceptibility of corneal surface cells to bacterial binding.25,44-46 The ability of Pseudomonas aeruginosa, a major ocular pathogen, to bind to human exfoliated epithelial cells is significantly greater with wear of all soft contact lens types compared to rigid gas permeable lenses, irrespective of wear schedule, and significantly greater binding occurs with hydrogel lenses compared to silicone hydrogels.23-25 Bacterial binding to host cells may be mediated through lectin-binding receptors on host cell membranes, and, in animal studies, any type of contact lens wear increases expression of such receptors in a closed eye model.47 Low oxygen-transmissible lenses have a more profound effect on expression of lectin-binding receptors than more highly oxygen transmissible lenses. Results from prospective population-based studies suggest that the rate of infection with 3-4 weeks or more of continuous overnight wear of silicone hydrogel lenses is not increased over the rates reported with earlier extended-wear soft lens types typically worn for shorter periods of overnight wear. However, it is clear from these studies that the single major risk factor for corneal infection is overnight lens wear irrespective of soft lens material.48-52 C. Lens-induced Changes in the Limbal Region

The superficial blood supply of the limbal region stems from the episcleral arterial circle, which is situated 1 to 5 mm posterior to the limbus and is formed by branches from the anterior ciliary arteries.53 Blood also enters the episcleral circle from vessels communicating with the intraocular arterial circle, which is deeper within the eye and derived from the long posterior ciliary arteries.54-56 Two types of vessels emerge from the episcleral circle. Those in the first group pass anteriorly, among the palisades of Vogt, then subdivide and recombine extensively to form the peripheral corneal or limbal arcades. The second group is comprised of recurrent vessels, which partially contribute to the limbal arcades but mainly travel posteriorly to supply the anterior 3 to 6 mm of conjunctiva. Capillary vessels are confined mainly to the upper stromal levels of the conjunctiva, whereas larger vessels and nerves penetrate the lower stratum. The cornea itself is avascular, so the limbal vessels provide the nearest point of access to blood-borne defense mechanisms. Filling and engorgement of the limbal capillaries comprise one of the best-documented signs associated with both daily wear and extended wear of hydrogel contact lenses and can be detected after as little as 4 hours of lens wear (Figure 6). Although several etiologies have been proposed for lens-induced limbal hyperemia, hypoxia is now considered to be the primary cause. Using soft contact lenses of varying oxygen transmissibility, Papas has shown that hypoxia in the region immediately beneath

Figure 6. Change in limbal redness from baseline after 4 hours of lens wear (n=6). The change in limbal redness was measured using CCLRU decimalized grading scales where 0.0=absent, 1.0=very slight, 2.0=slight, 3.0=moderate, and 4.0=severe. Error bars represent mean ± 1 SD.

the lens periphery creates a hyperemic response of a magnitude that is closely related to the oxygen transmissibility of the lens in that region (Figure 7).57,58 Wearing silicone hydrogel lenses of high oxygen transmissibility would, therefore, be expected to abolish the limbal vascular response, and several recent reports confirm that this is, indeed, the case.15, 59-62 Limbal hyperemia in silicone hydrogel lens wearers is no different from that in non-lens wearers within the first 4 hours of lens wear (Figure 6) and after 9 months of extended wear,14 and it is significantly less than that found in hydrogel lens wearers.15,16,61 Although limbal hyperemia itself is not sufficient to cause corneal vascularization, it is of concern because it does seem to be a factor necessary for corneal vascularization. IV. CORNEAL VASCULARIZATION New vessel growth in the cornea is initiated in response to a stimulus that has the right character, strength, and duration to disturb the dynamic equilibrium of pro- and anti-angiogenic factors that maintain avascularity in the normal cornea.63 The effect is to up-regulate one or more of an array of molecular messengers that control new vessel

F igure 7. Relationship between peripheral lens oxygen transmissbility and change in limbal redness graded using decimalized grading scales, where 0.0=absent, 1.0=very slight, 2.0=slight, 3.0=moderate, and 4.0=severe. (Reprinted from Stretton S, Jalbert I, Sweeney DF. Corneal hypoxia secondary to contact lenses: the effect of high-Dk lenses. Ophthalmol Clin N Am 2003;16:327-40, with permission from the authors and Elsevier.)

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

29

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

Figure 8. Limbal vascularization in a patient after 15 years of low Dk conventional lens wear (left). After 6 months of silicone hydrogel lens wear, a significant reduction in filling of the limbal vessels was observed (right). (Reprinted from Sweeney DF, et al. Clinical performance of silicone hydrogel lenses, in Sweeney DF (ed). Silicone hydrogels: continuous wear contact lenses. Edinburgh, Butterworth Heinemann, 2004, pp 1-27, with permission from the publisher.)

growth. Although the full range of agents and their activity have not been established, vascular endothelial growth factor (VEGF) appears to have a particular role. Found at low levels throughout the normal human cornea, the concentration of VEGF substantially increases during the vascularization process64,65 and has three key properties crucial to the process of corneal vascularization. These are the abilities to promote monocyte chemotaxis, increased local blood flow (hyperemia), and vascular endothelial cell mitosis. A. Mechanisms

Leukocytes, and in particular macrophages, are crucial to the process of corneal vascularization. Animal models show that they are capable of producing a series of effective angiogenic mediators in their own right.66,67 The chemotactic activity of VEGF draws leukocytes to the vascular bed adjacent to the injury site, from where they begin to infiltrate the cornea. This movement appears to be the first visible sign heralding the vascularization process.68 Localized hyperemia then increases blood flow to the area, aiding the process of leukocyte recruitment. Meanwhile, the action of substances like VEGF and basic fibroblast growth factor (bFGF) induces the vascular endothelium to proliferate. Increased mitotic activity in these normally quiescent endothelial cells creates a profusion of new cellular material that is then available for assembly into vessels. Because the surrounding cornea is quite dense, however, it is impossible for these cells to form tubules and penetrate a significant distance toward the injury site without additional assistance.69 This assistance is provided by a process of tissue remodeling that acts to alter the characteristics of the cornea ahead of the proliferating cells. Animal models indicate that one such mechanism appears to involve the activity of the matrix metalloproteinase MMP-2,70-72 a collagenase that is up-regulated by VEGF73 and digests the collagen matrix of the cornea. 30

Direct leukocyte activity has been proposed to have similar effects.74 Excessive corneal damage is prevented by the antagonistic action of a second series of endogenous substances known as tissue inhibitors of metalloproteinases (TIMPs), which dampen MMP activity and limit tissue changes.71 In this way, new vessels bud out from existing capillaries, penetrate the cornea and grow toward the injury. Assuming that the original stimulus is maintained, the growth of new vessels can proceed at a rate of about 0.5 mm per day, with blood cell movement occurring as soon as 72 hours after the event.68 Once the stimulus ceases, whether or not vessel regression occurs appears to depend on how far pericyte recruitment has progressed. Pericytes are cells that have features in common with smooth muscle cells and which periodically surround capillaries.75,76 They are recruited to new vessels quite rapidly after their creation, and this determines their permanency. Around 80% of vessels become associated with pericytes within their first 2 weeks and vessel regression is unlikely once this has happened.77 Hence, stimuli causing vascularization responses must be removed within about 2 weeks of onset if corneal vessels to prevent their becoming permanent. B. Hypoxia as a Stimulating Factor

Several stimulating agents can initiate corneal vascularization, and the precise mechanisms associated with contact lens wear are not fully understood. However, substantial clinical evidence suggests that hypoxia is an important factor. A compelling supporting observation is that rates of corneal vascularization found with various contact lens types differ substantially. When the entire cornea is covered, as is the case with soft lenses, the rates of corneal vascularization are generally higher than when the peripheral cornea is exposed to the atmosphere, as during rigid gas permeable lens wear. In one study, 18% of soft lens wearers had corneal vascularization compared to only

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

1% of rigid gas permeable wearers.78 It is hypothesized that this is related to the relatively greater peripheral hypoxic load induced by the larger diameter soft lenses, a view supported by the observation that in wearers of scleral lenses made from poly methyl methacrylate (PMMA), which has essentially zero oxygen transmissibility, corneal vascularization regressed after their lenses were refabricated using a rigid gas permeable polymer.79 The key point to note here is that the diameters of scleral lenses are such that they cover not only the limbus, but also the surrounding sclera. Thus, any mechanical effect would be substantially constant, irrespective of the oxygen transmissibility of the polymer, leaving increased oxygen tension at the ocular surface as the likely reason for improvement. Silicone hydrogel lenses have been reported to be effective in preventing the growth of new vessels during extended soft lens wear, providing further support for the role of hypoxia in corneal vascularization,61 as well as suggesting a clinical strategy to prevent vascularization in contact lens wear. Dumbleton et al61 reported a small but clinically significant decrease in vascularization after 9 months of extended wear among silicone hydrogel lens wearers who had moderate levels of vascularization at baseline, but not in those who had low baseline levels. Vascularization also is reduced in long-term wearers of hydrogel lenses who transfer to silicone hydrogel lenses, and is a result of the emptying of blood vessels to leave “ghost-like” vessels in the limbal vasculature (Figure 8). Although vessel growth only rarely affects vision in contact lens wearers, it has been suggested that corneal vascularization interferes with immune privilege within the anterior chamber.80 Therefore, vascularization continues to be viewed as a serious complication of contact lens wear. V. CLINICAL ASSESSMENT OF EPITHELIAL INTEGRITY: SODIUM FLUORESCEIN STAINING

As a marker of damaged epithelium, sodium fluorescein is used to assess corneal integrity during contact lens wear. In asymptomatic non-lens wearers, sodium fluorescein staining is relatively common (40-100% of eyes examined) and occurs mostly in the nasal and inferior regions of the corneal epithelium.34,81,82 Asymptomatic staining also occurs in contact lens wearers and is caused by minor abrasions from repeated rubbing against tear debris trapped beneath the lens, lens-induced effects of mechanical interaction of the lens with the corneal surface, and desiccation, toxic/hypersensitivity, and inflammatory effects. Although any compromise to the epithelial surface potentially places contact lens wearers at risk of infection, micropunctate fluorescein staining equivalent to the levels seen in non-lens wearers83-85 generally is considered clinically insignificant.

lesions. To fit well, soft contact lenses must have the appropriate design and sufficient flexibility to conform to the steeper cornea and flatter sclera and to minimize any local areas of pressure that may be intensified by the frictional forces applied by the upper lid. Silicone hydrogel lenses of relatively high elastic modulus can have a greater mechanical impact on the corneal surface, manifesting as superior epithelial arcuate lesions (SEALs)86; however, optimal lens design can minimize this occurrence. Overall, the frequency of mechanically-induced corneal staining that occurs with silicone hydrogel lenses is low and rarely exceeds micropunctate levels.15,17 B. Excessive Desiccation

Excessive desiccation is a major cause of corneal staining with mid- to high-water soft contact lenses.87,88 Hydrogel lenses can dehydrate by as much as 20% within minutes after lens insertion; thicker lenses dehydrate less than thinner lenses made from the same material, and greater effects are seen with high-water-content materials compared to low water materials.89,90 This type of staining usually manifests as localized areas of snowflake-like punctate or coalescent punctate staining in the inferior cornea and is rarely associated with silicone hydrogel lenses, which are made from relatively low water content materials. Clinically unacceptable levels of corneal staining do arise in individuals with specific combinations of silicone hydrogel materials and multipurpose lens care solutions. In such cases, diffuse punctate staining is scattered across the whole cornea and can be concentrated more in a ring around the periphery (Figure 9). Although patients are generally asymptomatic, the severity of staining is sufficient to necessitate cessation of lens wear.91 Most solution-based staining associated with silicone hydrogel lenses is caused by multipurpose solutions with polyhexamtheylene biguanide (PHMB) as the active ingredient.91-95 Although all lens care solutions with a disinfecting

A. Mechanical Abrasion

Mechanical abrasion caused by trapped debris or illfitting or defective lenses can result in characteristic patterns of staining, ranging from foreign body tracks to linear

Figure 9. Sodium fluorescein toxic staining associated with incompatibility between silicone hydrogel lenses and contact lens care solutions. X10 magnification

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

31

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

agent are to some degree toxic to the cornea, little or no solution-based staining seems to occur with solutions containing hydrogen peroxide or polyquaternium-1-based compounds.91,92.96 Moreover, the same silicone hydrogel material can interact differently with different formulations of PHMB-based solutions,92 which indicates that components other than the active ingredient may also be responsible for the incompatibility seen. The mechanism for the incompatibility observed between silicone hydrogel lenses and PHMB-based lens care solutions is unknown, although the most likely explanation is that specific component(s) within the formulation adsorb to the lens surface, or possibly to lens deposits that accumulate on the surface, and desorb after lenses are inserted in the eye.91 VI. SUPERIOR PALPEBRAL CONJUNCTIVA The superior palpebral conjunctiva is an uninterrupted extension of the bulbar conjunctiva that lines the posterior surface of the upper lid. While structurally similar to the bulbar conjunctiva, there are some key functional differences.97 The epithelium of the palpebral conjunctiva consists of a greater concentration of goblet cells, which form in the basal layers before moving to the surface and discharging their contents, and the dense stromal layer of the bulbar conjunctiva is replaced by the tarsal plate. The conjunctiva is a highly immunologically sensitive tissue, which in the noninflammatory state contains high numbers of mast cells and other inflammatory cells in the stroma but not the epithelium. Inflammatory responses of the superior palpebral conjunctiva are characterized by an influx of inflammatory cells to the epithelium and eventual formation of raised papillae, which comprise blood vessels in the center of an assembly of lymphocytes and plasma cells. Contact lens-induced papillary conjunctivitis (CLPC) is an inflammatory reaction of the upper palpebral conjunctiva that is thought to be a consequence of mechanical trauma and/or an allergic response to lens materials or deposits that accumulate on the lens surface. The condition is clinically significant, because it is an underlying cause of lens intolerance and is the major reason patients discontinue lens wear.17,98 A. Clinical Features of Contact Lens-induced Papillary Conjunctivitis

As described by Allansmith et al,99 the superior palpebral conjunctiva is divided into 5 areas: area 1 is nearest the palpebral border, area 2 is the central area, area 3 is along the lid margin of the tarsal plate, area 4 is near the nasal region and area 5 is near the temporal region. Areas 4 and 5 comprise the junctional conjunctival tissue. Clinical diagnosis of CLPC is based upon biomicroscopic signs of papillary changes across each of the palpebral areas, as seen with a slit lamp biomicroscope (X10 to X16 magnification) with diffuse white light. The area along the tarsal fold is not included in assessment of the upper eyelid. Papillary redness and roughness are graded sepa32

Figure 10. Contact lens-induced papillary conjunctivitis (CLPC) with soft contact lens wear. A=local CLPC; B=general CLPC. X10 magnification

rately, and the number of papillae and papillae of largest size are recorded for each area when lens wear begins and at each follow-up visit, so that changes caused by contact lens wear can be assessed. CLPC is diagnosed when raised papillae at the upper eyelid are 0.3 mm or greater in diameter, and when hyperemia is increased in any area. After papillae have been examined under white light, the conjunctiva can be examined using sodium fluorescein staining with a cobalt blue light and yellow fluorescein enhancement filter (Kodak Wratten #12) to allow greater differentiation in the size and definition of the papillae. The presence or absence of apical staining of the papillae is also noted with this technique. Although patients with CLPC may be asymptomatic, symptoms such as foreign body sensation, itchiness, mucous discharge, increased lens awareness, excessive lens movement and blurred vision due to lens mislocation can be of sufficient severity to cause lens intolerance. A major problem with CLPC is that even though symptoms gradually disappear with cessation of lens wear, the signs at the upper palpebral conjunctiva do not always completely resolve, predisposing the patient to recurrent CLPC when lens wear resumes. CLPC is more frequently seen with soft lens materials

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

than with rigid lens materials100 and is particularly associated with extended wear versus daily wear.101 With contact lens wear, papillae occur either as a small cluster in areas 2 and 3 (local response) or are randomly distributed across the entire region (general response).102,103 The most recent analysis indicates that although the incidence of CLPC during extended wear is similar between hydrogel (3.4 per 100 patient eye years) and silicone hydrogel lens wearers (4.7 per 100 patient eye years), a significantly greater proportion of events with silicone hydrogels are local compared to general (Figure 10).104 B. Etiology

Several theories exist as to the etiology of CLPC, which involve immunologic and/or a mechanical components; however, the pathogenesis remains largely unresolved. Current thinking suggests that during contact lens wear, both antigenic stimuli and trauma to the conjunctival surface contribute to the release of inflammatory mediators; lens deposits that accumulate during wear may stimulate the antigenic response or may contribute further to trauma. The immunologic response of patients with CLPC is quite complex, involving both immediate hypersensitivity reactions (Type I hypersensitivity) and delayed cell-mediated responses (Type IV hypersensitivity). The condition is characterized by a mixed cellular infiltrate comprising mast cells, eosinophils, basophils, and neutrophils, as well as expression of a range of inflammatory mediators. Involvement of Type 1 hypersensitivity is indicated by the finding that patients with a history of allergy are more susceptible to CLPC105-108 and that increased levels of IgE, the antigen-recognition molecule of type I hypersensitivity reactions, is present in the tears and serum of patients with active CLPC.109-111 Degranulation of IgE-bound mast cells releases mediators into the surrounding conjunctival tissue, which causes edema, hyperemia, and itching. Degranulated and intact mast cells have been found in the conjunctival epithelium of patients with CLPC,112,113 and products of mast cell degranulation have been detected in tears.110 Delayed type IV hypersensitivity is a T-cell-mediated reaction in response to persistent antigenic stimuli that results in tissue injury via cytokine-induced inflammation or direct cell lysis. Involvement of type IV hypersensitivity in CLPC is suggested by the presence of helper T cells (CD4+) and CD45RO+ memory cells, as well as epithelial cells expressing major histocompatibility complex in conjunctiva of patients with CLPC.114,115 Moreover, increased expression of a range of cytokines that recruit and activate T cells in conjunctival epithelial cells in patients with CLPC further supports a role for type IV hypersensitivity in this condition.114,116 The profile of T cell cytokine expression in patients with CLPC is indicative of a TH2 cell-driven response, which is responsible for the further release of inflammatory mediators and an accelerated immune response after successive exposure to antigen. More frequent replacement of contact lenses107 or regular use of enzymatic cleaners to remove accumulated de-

posits from the surfaces of worn lenses are the most effective strategies used in the treatment of CLPC; however, it is not yet understood how contact lens deposits contribute to the etiology of this condition. There is no correlation between the amount of protein on lenses and CLPC, and deposits on lenses of patients with CLPC appear to be very similar to those on lenses of asymptomatic wearers,117119 which supports the hypothesis that CLPC is more likely related to individual responses to lens deposits rather than to differences in type of deposits per se. Ballow et al examined contact lens deposits in three groups of monkeys, who wore contact lenses taken from human patients with and without CLPC, as well as unworn lenses.120 Monkeys with worn lenses from subjects with CLPC developed a cellular response similar to CLPC and elevated levels of IgE were detected in the tears. No effect was evident in monkeys that received worn lenses from asymptomatic subjects, and the level of IgE in tears was similar to that of monkeys that had received unworn lenses. This study strongly implicates accumulated lens deposits in the type I hypersensitivity response seen in CLPC. Evidence for a mechanical component to CLPC is provided by the palpebral response to contact with raised foreign objects, such as exposed sutures, ocular prostheses, and epithelialized corneal bodies.121-125 Although the papillary response in these instances is severe, it remains localized to the area of contact and resolves rapidly once the object is removed. Moreover, the tarsal conjunctiva of these patients are characterized by a preponderance of polymorphonuclear leukocytes with no eosinophils,126 and elevated levels of neutrophil chemotactic factors, associated with conjunctival injury, can be detected in tears.127 The local response with silicone hydrogel lenses is far less severe than that which occurs with raised foreign objects but is similar in that papillae remain localized to one or two areas of the conjunctiva.102 It is postulated that repeated rubbing of worn lenses against the upper palpebral conjunctiva may stimulate inflammatory mediators associated with mechanical trauma at the superficial epithelium. Factors that may contribute to local CLPC with silicone hydrogel lenses include the modulus of elasticity, peripheral lens fit, or edge shape, as well as patients inadvertently wearing inverted lenses. VII. TEAR FILM Successful lens wear requires a stable tear film to maintain normal optical, lubrication, and defense functions. Contact lens wear has the potential to destabilize and impact each of these functions by: 1) affecting the structure and function of the tear film; 2) altering the normal lidcornea-tear resurfacing mechanism; 3) causing compartmentalization of the tear film; 4) altering pre- and postlens tear exchange characteristics; or 5) increasing tear instability. Moreover, accumulation of debris, metabolic by-products, and inflammatory cells, as well as lens-induced changes in tear film components, contribute to adverse responses that are both inflammatory and mechani-

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

33

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

cal in nature. In general, contact lens wear of any type appears to have a negative effect on tear physiology, specifically by causing an increase in tear evaporation, an increase in the rate of tear thinning, and a reduction in tear break-up time, all of which are most likely due to a reduced thickness in the lipid layer. Closed-eye tear defense mechanisms are relevant to contact lens wear because lenses worn in the closed eye present a higher risk of infection than lenses worn in the open-eye.128-130 When the eye is closed, the tear film stagnates and takes on the characteristics of subclinical inflammation,131-134 which is intensified during contact lens wear. Specifically, there is a reduction in the levels of total and specific secretory immunoglobulin A (sIgA);135-139 an increase in tear fibronectin;139,140increases in the concentration of the cytokines interleukin (IL)-6141 and IL-8142; and lower polymorphonuclear leucocyte (PMN) recruitment.143 The implications of altered tear components in overnight contact lens wear have not been fully elucidated; however, it is generally thought that these changes may alter normal defense functions, such as phagocytosis and microbial killing, and could prolong the retention time of microorganisms at the ocular surface. The limited information available suggests that the effect of silicone hydrogel lenses on closed-eye tear defense mechanisms is similar to that of hydrogel lenses. sIgA is similarly reduced with overnight wear of silicone hydrogel lenses and with hydrogels,144 and the levels of tear IL-8 are elevated with silicone hydrogel lens wear, but to a lesser extent than with hydrogel lens wear.144

a transient hypo-osmolar tear film and thick pre-lens tear film. However, during the initial settling period following contact lens insertion, the pre-lens tear film over the center of the contact lens thins148,149 to an average of 2.31±82 μm.150 The average published thickness of the pre-lens tear film measured by interferometric techniques is about 3 μm.151 Good concordance exists between studies, despite the use of different methodologies, with pre-lens tear film thicknesses of up to 6.4 μm reported.146,151-153 Although the average thickness of the pre-lens and precorneal tear films is similar,146,151 there is greater variation in the thickness of the pre-corneal tear film compared to the pre-lens tear film. The pre-lens tear film is less stable than the pre-corneal tear film,153,154 and this instability is closely associated with thinner tear films.144 Tear film stability may be relevant in contact lens dehydration,90,155 lens deposition,156,157 corneal staining,158 and patient symptoms.159 Localized thinning of the pre-contact lens tear film also occurs at the lens edge, which may align well with a proposed model of tear film break up,151 where thinning occurs due to a discontinuity at the ocular surface and is driven initially by surface tension and later by evaporation. Despite the slight variation in tear break-up time between different hydrogel materials,153,160 it is generally agreed that differences in hydrogel lens types have little overall effect on the quality of the pre-lens tear film. There is some evidence that thick hydrogel lenses are associated with a thicker pre-lens tear film compared to thin hydrogel lenses153 and that high water content hydrogel lenses are associated with a thicker pre-lens tear film160 but lower tear thinning time.161 However, the effect of lens water content on the pre-lens tear film is somewhat controversial, and other studies have found that water content and lens type are not relevant to pre-lens tear stability.154 One study examined the effects of differences in material hydrophilicity and coating thickness, using a range of gas plasma and wet chemistry surface attachment methods; it was determined that the drying time over the lens surface on-eye was no different between lens surface chemistries.156 Although silicone hydrogel lens materials are markedly different from their hydrogel counterparts, the thickness of the pre-lens tear film between these lens types is remarkably similar,162 further supporting the view that the thickness of the pre-lens tear film is independent of lens type.

A. Pre-lens Tear Film

B. Tear Evaporation

The pre-lens tear film (Figure 11) is a dynamic structure, which may be affected by environmental conditions,145 time of day, individual patient tear characteristics,146 and position on the cornea and lid position as the lid travels upward following the blink.147 It can also be affected by a range of lens-related factors, including lens wear schedule, lens diameter, lens fitting relationship and, to a lesser extent, lens type and surface chemistry. Contact lens insertion produces an initial disturbance to tear film thickness and structure. Reflex tearing can cause

The rate of tear evaporation is greater in eyes wearing any contact lens than in non-lens wearing eyes.163-167 However, as regards the pre-lens tear film, no relationship appears to exist between lens water content or material type and the degree of evaporation. Additionally no consistent differences in tear evaporation between hydrogel and silicone hydrogel lens materials164,165 have been shown, despite the greater resistance of silicone hydrogel lenses to dehydration in vitro.168 Dehydration of hydrogel lenses on-eye may affect lens fitting, comfort, and oxygen

Figure 11. Tear break up over a silicone hydrogel contact lens. X10 magnification.

34

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

transmissibility, and may cause epithelial desiccation. Material properties, and not solely water content, can influence the dehydration of hydrogel lenses,169 but the influence of these properties on dehydration is less clear with silicone hydrogel lenses. One study has suggested that silicone hydrogel lenses dehydrate more slowly oneye than hydrogel lenses.170 This may be consistent with preliminary analysis of a small group of hydrogel lens wearers that transferred to silicone hydrogel lens wear for 12 months.171 These subjects reported significantly more sensations of dryness with hydrogel lenses than with silicone hydrogels and no lens wear, and they reported that end-of-day comfort during silicone hydrogel lens wear was no different than with no lens wear.171 However, in vivo studies have previously not demonstrated a link between hydrogel lens dehydration and subjective dryness symptoms,172 and in vitro contact lens dehydration is perceived to be a poor predictor of on-eye dehydration.173 Tear film stability is affected by the thickness of the lipid layer of the tear film, with reduced tear film stability being associated with a thinner lipid layer.153,165,174,175 Thinner lipid layers, either for the pre-ocular or pre-lens tear film,176,177 are more prone to contamination and may promote tear evaporation and lens dehydration. Tear breakup time is inversely related to the rate of tear evaporation and to lipid layer thickness,178 and there is some evidence that a thicker aqueous layer may encourage development of a thicker and more stable lipid layer.174 Compared with the pre-corneal tear film, the pre-lens lipid layer is thin or absent.153,160,179 Large scleral lenses are associated with thicker lipid layers, possibly because the barrier effect of the lens edge is reduced.174 Hydrogel contact lens wear affects tear lipid composition; lens wearers show lower levels of polar lipids and higher levels of non-polar cholesterol based lipids.180 Conceivably, this shift disrupts lipid spreading and negatively affects the outer hydrophobic lipid layer, causing a thinner and less robust pre-lens lipid layer. Although the thickness and appearance of the lipid layer do not predict tolerance to contact lens wear, higher levels of degraded tear lipids (MDA and 4-HNE), secretory phospholipase A2 and the lipid carrying protein, lipocalin, are found in the tears of subjects intolerant to lens wear.175 Such changes in tear film components can disturb the nature and dynamics of the tear film; specifically, we believe that lipid degradation plays a major role in destabilization of the pre-lens tear film. C. Lens Wettability and Deposits

Lens wettability is a measure of the quality of the prelens tear film over the anterior surface of a contact lens. It is assessed in vitro using the dynamic contact angle technique or clinically using subjective scales of tear break-up over a lens. Subjective scales range from a totally hydrophobic, non-wetting surface to wettability of a healthy cornea. Typically, hydrogel lenses are used as a mid-way benchmark for comparing lens performance.

Deposition and denaturation of tear film components to a contact lens surface is an inevitable consequence of lens wear that contributes to poor wettability, reduced biocompatibility,181 adverse responses such as CLPC, increased contact lens dehydration, and reduced comfort, and may conceivably influence ocular surface defense through effects on microbial binding to the lens or through an antigenic response. The surfaces of all silicone hydrogel lens materials are modified in some way to enhance hydrophilicity (see Table 1) with the intent of improving wettability and preventing tear film deposits from accumulating. Atomic force microscopy of the surfaces of balafilcon A and lotrafilcon A silicone hydrogel lenses reveals that, although both lenses have been surface-modified, significant differences exist in the uniformity of the surface coating. Balafilcon A lenses are characterized by glassy hydrophilic islands, leaving areas of hydrophobic substrate, whereas lotrafilcon A lenses are more uniformly coated.182,183 In vitro assessment indicates that the wettability of silicone hydrogels is similar to that of hydrogel lenses182; this is confirmed by clinical measures that demonstrate little overall difference between silicone hydrogel and hydrogel lens wear.15 17,184 Despite these similarities, the in vitro wettabilities between balafilcon A and lotrafilcon A silicone hydrogel lenses are different and may reflect the differences in surface treatment.183 More hydrophobic lens surfaces have greater affinity for accumulation of lipid deposits, and this is borne out by studies comparing lens spoilation between lens types.185 Lens spoilation is dependent on the individual wearer’s tear chemistry, on the material type, and the length of lens wear. Group IV hydrogel materials (high water content, ionic) such as etafilcon A are negatively charged and attract both surface- and matrix-associated lysozyme from the tear film.186,187 Conversely, Group II materials (high water content, non-ionic) containing N-vinyl pyrrolidone (NVP) absorb more lipid than do other hydrogel lens materials.188 Compared with ionic hydrogel lens materials, silicone hydrogel lenses absorb considerably less lysozyme, but they also deposit far more lipid, especially oleic acid and oleic acid methyl ester, regardless of the type of silicone hydrogel lens material.184 However, the authors concede the limitation of the non-cross-over study design and acknowledge that lipid deposition is highly wearer-specific. Greater hydrophobicity may arise from nonuniform surface treatment,183 but other factors may also affect lipid deposition, e.g., the presence of lipid-attracting bulk material components, including NVP which is present in balafilcon A. With increased wear time, the surface lipid may progressively diffuse into the lens matrix; both surface and bulk lipid appear to be higher for balafilcon A silicone hydrogel lenses compared with lotrafilcon B silicone hydrogels.183 D. Post–lens Tear Film and Tear Exchange

In the non-contact lens-wearing eye, blinking and normal tear turn-over effectively remove debris, toxins, antigens,

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

35

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

and microorganisms from the ocular surface. Contact lens wear disrupts this process and slows tear exchange in the post-lens tear film. Prolonged retention of debris, cells, and microorganisms behind the contact lens has been implicated in the development of inflammatory and infectious adverse responses. Rigid gas permeable lenses have much faster rates of tear exchange and retain far less debris after eye opening compared to soft lenses, which most likely contributes to the low rate of inflammatory complications associated with extended wear of these lenses.189,190 Although optimizing post-lens tear exchange appears to be important in limiting lens-related complications and maintaining normal ocular surface homeostasis, it is not clear at this stage what the optimal value is. With hydrogel lens use, the average thickness of the post-lens tear film measured by interferometric techniques is estimated to be between 2 and 5 μm,150,162,191,192 with no apparent depletion during the initial settling period.148 The thickness of the post-lens tear film appears to be more variable than the that of the pre-lens tear film, possibly because of factors such as lid pressure, the relationship between the back surface of the lens and corneal curvature.151 Subtractive pachometry has also been used to estimate post-lens tear film thickness193,194; this technique yields somewhat thicker measurements than interferometry, possibly because of some systematic errors compounded by inherent large variability.150 Notwithstanding such potential limitations, pachometric measurements have demonstrated that the thickness of the post-lens tear film varies significantly with lens modulus, optic zone radius, palpebral aperture size, and race (post-lens tear thickness is estimated to be higher in non-Asian eyes than in Asian eyes).193,194 Fluorexon photography shows that post-lens tear film thickness varies considerably and nonuniformly from the center to the periphery of the lens.195 The rate of tear exchange can be estimated using fluorophotometry with high molecular weight fluorescent tracers instilled onto the back surface of the lens before insertion. The kinetics of the rate of tear elimination appears to be best described by a double exponential curve, and elimination may be described as either percent elimination rate per minute (ER%: 8-10% for hydrogel lenses), tear replenishment rate (TRR), the percentage volume of tears replaced per blink (0.4-0.6% per blink), or T95, the time taken for removal of 95% of the dye (20-35 minutes with hydrogel lenses). Although the values obtained by different methods are related, one value may be preferred over another in certain instances.196 The rate of tear exchange is influenced by wearer characteristics, such as palpebral aperture size197 or race (non-Asian versus Asian),197 and it can be greater with smaller lens diameters198 and when lens fenestrations are used.195 Clinically, however, the improvements in tear exchange achieved by decreasing lens diameter or adding fenestrations are not substantial, and efforts to improve tear exchange can compromise some aspects of lens fit. The peripheries of small-diameter contact lenses, for example, are 36

Figure 12. Mucin balls associated with soft contact lens wear. X30 magnification

more likely to interact with the lid margins during wear and may reduce wearer comfort. Dispersive mixing modeling has suggested that tear mixing and exchange behind a contact lens is controlled by a combination of vertical lens movement and transverse (in-out) movement.199 Clinically, however, a large change in vertical lens movement has limited effect on tear replenishment.197 Silicone hydrogel lenses are consistently associated with greater tear exchange than hydrogel lenses,196,197 and elimination rate appears to improve with increased lens modulus,197 which has been attributed to the increased transverse movement with these lenses. Tear exchange on blinking with silicone hydrogel lenses has also been demonstrated to contribute an additional 8% to corneal oxygenation above that achieved through lens transmissibility alone.200 Most studies of tear exchange and tear thickness with silicone hydrogel lenses have been performed or modeled under open-eye conditions with blinking. During eye closure, the tear film behind a silicone hydrogel contact lens thins to <1 μm,201 and during sleep, tear production is downregulated131; hence, the kinetics of tear elimination during and following eye closure with contact lens wear are quite different. VIII. MUCIN BALLS One feature of soft contact lens wear that has become more common since silicone hydrogel lenses have become available is the phenomenon of mucin balls. These small, opalescent spheroids form in the space between the posterior lens surface and the corneal epithelium (Figure 12). Usually their diameters are around 50 μm,202 although they can be as small as 5 μm 203 or as large as 200 μm.204,205 Because the post-lens space generally is much narrower than this,150,193 mucin balls often become effectively trapped between the lens and cornea, making both surfaces markedly indented.203,206 Confocal microscopy studies have shown that in the epithelium, the depth of these

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

indentations can be substantial. Some examples extend through the full epithelial thickness, to at least the level of the basal lamina.202,203,207 When the lens is removed, the action of blinking sweeps mucin balls from their epithelial cradles and into the general tear film. From there, they follow the normal elimination route for tears via the lacrimal duct. Subsequent instillation of sodium fluorescein allows the small, hemispherical corneal depressions created by the mucin balls to be easily seen. The dye does not penetrate the cells but simply pools in the corneal depressions, indicating that epithelial barrier function is maintained throughout. After lens removal, the normal, regular corneal contour returns spontaneously over 2-24 hours.203 This remarkable ability of the corneal epithelium to mold itself to, and then recover from, the local presence of a mucin ball appears similar to the behavior seen during orthokeratology and hints at viscoelastic properties that are reminiscent of high viscosity fluids. The numbers of mucin balls vary widely both within and between individuals. While 10-20 are fairly typical, some individuals may have 100 or more. Approximately equal numbers of wearers of hydrogel and silicone hydrogel lenses have exhibited mucin ball formation, and the proportion in both groups increases with the overall length of wear.208 After 12 months, about 70% of all wearers may have observable mucin balls, although the actual number per eye appears to be greater and to fluctuate more widely with silicone hydrogel lenses. This differential has been linked to the higher elastic modulus typical of first-generation silicone hydrogel materials, as compared to hydrogel materials, and may not occur with the second-generation silicone hydrogel lenses that have lower elastic modulus. Notwithstanding the influence of lens material, some individual predisposition to mucin ball production also seems likely. While it has not, so far, been possible to identify all the factors that influence the response in a given person, evidence suggests that steeper corneal curvature,204,208 better lens front surface wettability, and greater amounts of post-lens debris208 are associated with a tendency to produce mucin balls. The term “mucin ball” became commonly used among clinicians over the last decade based on biomicroscopic appearance rather than analytical evidence of composition. Direct analysis has been hampered by the inability to obtain identifiable samples or mucin balls from human subjects.203 Recently, however, capillary collection techniques have allowed examples to be cryo-sectioned and examined immunohistochemically.202 Although no measurable signs of lipid, cells, or bacteria were found, the samples were positive to periodic acid Schiff (PAS) stain. This indicated the presence of a major polysaccharide component, a finding consistent with what would be expected from a primarily mucin-based structure. Not all the samples observed in this study were composed of entirely PASpositive material, however, suggesting that two alterna-

tive mucin ball configurations exist. Whereas the first type is composed almost entirely of mucinous material, the second has a non-mucin core surrounded by a mucinous outer shell. The latter alternative appears consistent with mucin ball images derived from in-vivo confocal microscopy, where highly reflective centers appear surrounded by more poorly reflective, translucent outer layers.203 Further support for this type of internal structure comes from electron microscope images of whole mucin balls, which show a relatively dense, fibrous core surrounded by a more gelatinous outer layer or coating.202 The mechanism by which mucin balls form is not precisely known. However, the proposal that they result from the relative motion between the corneal and lens surfaces204 seems reasonable. The effect of this movement would be to produce a “rolling–up” of, presumably, epithelial surface mucus. Debris residing within the tear film may act as a seed point for this activity and, in the process, become encapsulated within the mucus shell. Additionally, it may be that formation is aided by the collapse of the mucin matrix due to withdrawal of water as the post-lens tear film dehydrates.202 Significant clinical sequelae have not been reported associated with mucin balls, although there have been occasional reports of visual complaints when large numbers are present in a given individual,204 and there may be a slightly increased risk of sterile, contact lens-related peripheral ulcer (CLPU) in the presence of large numbers of mucin balls.209 The clinical consequences of mucin ball formation, thus, appear to be rather slight. IX. SUMMARY AND CONCLUSIONS All contact lens wear affects the ocular surfaces; corneal homeostasis is slowed, close interaction occurs between ocular tissue and contact lens material, and tear film structure and physiology are altered. Many of the effects are intensified by overnight wear, when the eye is in a pro-inflammatory state, is prone to lens-induced hypoxia, and has closer interaction with the palpebral conjunctiva. Silicone hydrogel lenses have combined the benefits of a soft lens material with high oxygen transmissibility, giving wearers greater flexibility and longer wear times with excellent clinical outcomes. Many of these lenses have sufficient oxygen transmissibility to eliminate the clinical markers traditionally associated with chronic hypoxia, and they have a less pronounced effect on corneal homeostasis than other lens types. However, extended wear with silicone hydrogels still has the potential to irreversibly affect corneal homeostasis, particularly in the subset of wearers with higher than average requirements for oxygen and in those with higher refractive errors, who require thicker and, hence, lower oxygen transmissibility lenses. The short-term effect of silicone hydrogel lenses on the tear film is little different from that of hydrogel lenses, and individual differences between wearers must be overcome. Future studies may evaluate the effects of longer durations of wear on tear film characteristics with different lens types and elucidate individual

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

37

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

differences that influence wearer success. A major goal in contact lens design is to produce a contact lens that interacts with the ocular environment with the biocompatibility of a healthy cornea. Improving oxygen transmissibility has been a major achievement, yet further improvements with regard to lens movement, tear exchange, and mechanical interaction with the ocular surfaces are needed. Although acknowledging the increased average continuous wear time with silicone hydrogel lenses, early studies indicate that during extended wear, silicone hydrogel lenses and hydrogel lenses have a similar risk of infection48-52 and corneal infiltrates98,210, such as contact lens-induced peripheral ulcer, confirming that hypoxia is not a major contributor to the etiology of these events. To further improve biocompatibility of contact lenses with the ocular surfaces, we need a better understanding of the way in which contact lenses interact with the corneal surface, upper eyelid, and the tear film, and of the lens-related factors contributing to infection and inflammatory responses. The quality of the tear film during longterm lens wear is particularly important, as it relates to symptoms of dryness and discomfort, lens adherence and deposition, and frictional forces from the blinking lid. Future strategies to limit adverse responses associated with prolonged retention of microorganisms at the ocular surface include incorporation of antimicrobial compounds into lens surfaces or bulk materials and, although unproven, increasing post-lens tear exchange. Given the recent revival in interest in compatibility of lens care solutions with newer lens materials, there is perhaps an opportunity for the development of solutions that can improve the stability of the pre-lens tear film. Furthermore, the higher modulus of silicone hydrogel materials compared with hydrogel lens materials may allow innovative lens designs that would provide greater opportunity to modulate tear exchange and reduce the mechanical interaction of lens wear with the ocular surfaces. Ultimate biocompatibility will be achieved through future advances in polymer and surface chemistry aimed at developing softer lens materials with optimized surface characteristics. REFERENCES 1. Holden BA, Sweeney DF, Vannas A, et al. Effects of long-term extended contact lens wear on the human cornea. Invest Ophthalmol Vis Sci 1985;26:1489-501 2. Holden BA, Sweeney DF, Swarbick HA, et al. The vascular response to long-term extended contact lens wear. Clin Exp Optom 1986;69:112-19 3. Holden BA, Mertz GW. Critical oxygen levels to avoid corneal edema for daily and extended wear contact lenses. Invest Ophthalmol Vis Sci 1984;25:1161-67 4. Wolosin J, Xiong X, Schutte M, et al. Stem cells and differentiation stages in the limbo-corneal epithelium. Prog Retinal Eye Res 2000;19:223-55 5. Huang A, Tseng S, Kenyon K. Paracellular permeability of corneal and conjunctival epithelia. Invest Ophthalmol Vis Sci 1989;30:684-9

38

6. Jenkins C, Tuft S, Liu C, et al. Limbal transplantation in the management of chronic contact lens-asociated epitheliopathy. Eye 1993;7(Pt 5):629-33 7. Lim L, Wei R. Laser in situ keratomileusis treatment for myopia in a patient with partial limbal stem cell deficiency. Eye Contact Lens 2005;31:67-9 8. Tseng S, Prabhasawat P, Barton K, et al. Amniotic membrane transplantation with or without limbal allografts for corneal surface reconstruction in patients with limbal stem cell deficiency. Arch Ophthalmol 1998;116:431-41 9. Puangsricharern V, Tseng S. Cytologic evidence of corneal diseases with limbal stem cell deficiency. Ophthalmology 1995;102:1476-85 10. Lavker R, Tseng S, Sun T-T. Corneal epithelial stem cells at the limbus: looking at some old problems from a new angle. Exp Eye Res 2004;78:433-46 11. Thoft RA, Friend J. The X, Y, Z hypothesis of corneal epithelial maintenance. Invest Ophthalmol Vis Sci 1983;24:1442-3 12. Auran J, Koester C, Kleiman N, et al. Scanning slit confocal microscopic observation of cell morphology and movement within the normal human anterior cornea. Ophthalmology 1995;102:33-41 13. Ren H, Wilson G. Apoptosis in the corneal epithelium. Invest Ophthalmol Vis Sci 1996;37:1017-25 14. Covey M, Sweeney DF, Terry RL, et al. Hypoxic effects on the anterior eye of high Dk soft contact lens wearers are negligible. Optom Vis Sci 2001;78:95-9 15. Brennan NA, Chantal Coles ML, Comstock TL, et al. A 1-year prospective clinical trial of Balafilcon A (PureVision) siliconehydrogel contact lenses used on a 30-day continuous wear schedule. Ophthalmology 2002;109:1172-7 16. Nilsson SE. Seven-day extended wear and 30-day continuous wear of high oxygen transmissibility soft silicone hydrogel contact lenses: a randomized 1-year study of 504 patients. CLAO J 2001;27:125-36 17. Stern J, Wong R, Naduvilath TJ, et al. Comparison of the performance of 6- or 30-night extended wear schedules with silicone hydrogel lenses over 3 years. Optom Vis Sci 2004;81:398406 18. Cavanagh HD. The effects of low- and hyper-Dk contact lenses on corneal epithelial homoeostasis. Ophthalmol Clin N Am 2003;16:311-25 19. Ladage PM, Ren DH, Petroll WM, et al. Effects of eyelid closure and disposable and silicone hydrogel extended contact lens wear on rabbit corneal epithelial proliferation. Invest Ophthalmol Vis Sci 2003;44:1843-9 20. Ladage PM, Jester JV, Petroll WM, et al. Vertical movement of epithelial basal cells toward the corneal surface during use of extended-wear contact lenses. Invest Ophthalmol Vis Sci 2003;44:1056-63 21. O’Leary DJ, Madgewick R, Wallace J, et al. Size and number of epithelial cells washed from the cornea after contact lens wear. Optom Vis Sci 1998;75:692-3 22. Ren DH, Petroll WM, Jester JV, et al. The relationship between contact lens oxygen permeability and binding of Pseudomonas aeruginosa to human corneal epithelial cells after overnight and extended wear. CLAO J 1999;25:80-100

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al 23. Ladage PM, Yamamoto K, Ren DH, et al. Effects of rigid and soft contact lens daily wear on corneal epithelium, tear lactate dehydrogenase, and bacterial binding to exfoliated epithelial cells. Ophthalmology 2001;108:1279-88 24. Ren DH, Yamamoto K, Ladage PM, et al. Adaptive effects of 30-night wear of hyper-O2 transmissible contact lenses on bacterial binding and corneal epithelium: a 1-year clinical trial. Ophthalmology 2002;109:27-40 25. Cavanagh HD, Ladage PM, Li SL, et al. Effects of daily and overnight wear of a novel hyper oxygen-transmissible soft contact lens on bacterial binding and corneal epithelium: a 13month clinical trial. Ophthalmology 2002;109:1957-69 26. Yamamoto K, Ladage PM, Ren DH, et al. Effect of eyelid closure and overnight contact lens wear on viability of surface epithelial cells in rabbit cornea. Cornea 2002;21:85-90 27. Yamamoto K, Ladage PM, Ren DH, et al. Effects of low and hyper Dk rigid gas permeable contact lenses on Bcl-2 expression and apoptosis in the rabbit corneal epithelium. CLAO J 2001;27:137-43 28. Li L, Ren DH, Ladage PM, et al. Annexin V binding to rabbit corneal epithelial cells following overnight contact lens wear or eyelid closure. CLAO J 2002;28:48-54 29. Stapleton F, Kasses S, Bolis S, Kaey L. Short term wear of high Dk soft contact lenses does not alter corneal epithelial cell size or viability. Br J Ophthalmol 2001;85:143-6 30. Stapleton F, Kasses J, Kasses S, et al. Effect of long term wear of highly oxygen permeable contact lenses on corneal epithelial cells [ARVO Abstract]. Invest Ophthalmol Vis Sci 2002;43:Abstract # 1657 31. Ladage PM, Yamamoto K, Ren DH, et al. Proliferation rate of rabbit corneal epithelium during overnight rigid contact lens wear. Invest Ophthalmol Vis Sci 2001;42:2804-12 32. Holden BA, Sweeney DF. The significance of the microcyst response: a review. Optom Vis Sci 1991;68:703-7 33. Terry RL, Schnider CM, Holden BA, et al. CCLRU standard for success of daily and extended wear contact lenses. Optom Vis Sci 1993;70:234-43 34. Hickson S, Papas E. Prevalence of idiopathic corneal anomalies in a non contact lens-wearing population. Optom Vis Sci 1997;74:293-7 35. Zantos SG. Cystic formations in the corneal epithelium during extended wear of contact lenses. Int Contact Lens Clin 1983;10:128-46 36. Keay L, Jalbert I, Sweeney DF, et al. Microcysts: clinical significance and differential diagnosis. Optometry 2001;72:452-60 37. Keay L, Sweeney DF, Jalbert I, et al. Microcyst response to high Dk/t silicone hydrogel contact lenses. Optom Vis Sci 2000;77:582-5 38. Tripathi RC, Bron AJ. Ultrastructural study of non-traumatic recurrent corneal erosion. Br J Ophthalmol 1972;56:73-85 39. Bergmanson JP. Histopathological analysis of the corneal epithelium after contact lens wear. J Am Optom Assoc 1987;58:812-8 40. Madigan MC. Cat and monkey as models for extended hydrogel contact lens wear in humans. PhD thesis, The University of New South Wales, Sydney, Australia, 1989 41. Millodot M. Effect of soft lenses on corneal sensitivity. Acta

Ophthalmol 1974;52:603-8 42. Madigan MC, Holden BA, Kwok LS. Extended wear of contact lenses can compomise corneal epithelial adhesion. Curr Eye Res 1987;6:1257-9 43. Mauger TF, Hill RM. Corneal epithelial healing under contact lenses: quantitative analysis in the rabbit. Acta Ophthalmol 1992;70:361-5 44. Imayasu M, Petroll WM, Jester JV, et al. The relation between contact lens transmissibility and binding of Pseudomonas aeruginosa to the cornea after overnight wear. Ophthalmology 1994;101:371-88 45. Cavanagh HD, Ladage PM, Yamamoto K, et al. 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. Eye Contact Lens 2003;29(1 suppl):S14-S16 46. Ladage PM, Jester JV, Petroll WM, et al. Role of oxygen in corneal epithelial homeostasis during extended contact lens wear. Eye Contact Lens 2003;29(1 suppl):S2-S5 47. Latkovic S, Nilsson S. The effect of high and low Dk/L soft contact lenses on the glycocalyx layer of the corneal epithelium and on the membrane associated receptors for lectins. CLAO J 1997;23:185-91 48. Radford C, Stapleton F, Minassian D, et al. Risk factors for contact lens related microbial keratitis: Interim analysis of case control study [ARVO Abstract]. Invest Ophthalmol Vis Sci 2005;46:Abstract# 5026 49. Stapleton F, Edwards K, Keay L, et al. Incidence of contact lens related microbial keratitis [ARVO Abstract]. Invest Ophthalmol Vis Sci 2005;46:Abstract# 5025 50. Schein O, McNally J, Katz J, et al. The incidence of microbial keratitis among wearers of a 30-day silicone hydrogel extended wear contact lens. Ophthalmology 2005;112:2172-9 51. Morgan P, Efron N, Brennan NA, et al. Risk factors for the development of corneal infiltrative events associated with contact lens wear. Invest Ophthalmol Vis Sci 2005;46:3136-43 52. Morgan PB, Efron N, Hill EA, et al. Incidence of keratitis of varying severity among contact lens wearers. Br J Ophthalmol 2005; 89:430-6 53. Leber T. Die Cirkulations und Ernahrungsverhaltnisse des Auges. Graefe-Saemisch Handbuch der Gesamten Augenheilkunde. Leipzig, Engelmann, 2nd ed, 1903:Ch 1 54. Morrison J, van Buskirk E. Anterior collateral circulation in the primate eye. Am Acad Ophthalmol 1983;90:707-15 55. van Buskirk E. The anatomy of the limbus. Eye 1989;3:101-8 56. Ashton N, Smith R. Anatomical study of Schlemm’s canal and aqueous veins by means of Neoprene casts. Part III: arterial relations of Schlemm’s canal. Br J Ophthalmol 1953;37:577-86 57. Papas E. On the relationship between soft contact lens oxygen transmissibility and induced limbal hyperaemia. Exp Eye Res 1998;67:125-31 58. Papas E. The role of hypoxia in the limbal vascular response to soft contact lens wear. Eye Contact Lens 2003;29 (1 suppl):S72-S74 59. Papas EB, Vajdic CM, Austen R, et al. High-oxygen-transmissibility soft contact lenses do not induce limbal hyperaemia. Curr Eye Res 1997;16:942-8

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

39

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al 60. du Toit R, Simpson T, Fonn D, et al. Recovery from hyperemia after overnight wear of low and high transmissibility hydrogel lenses. Curr Eye Res 2001;22:68-73 61. Dumbleton KA, Chalmers RL, Richter DB, et al. Vascular response to extended wear of hydrogel lenses with high and low oxygen permeability. Optom Vis Sci 2001;78:147-51 62. Morgan PB, Efron N. Comparative clinical performance of two silicone hydrogel contact lenses for continuous wear. Clin Exp Optom 2002;85:183-92 63. Polverini P. The pathophysiology of angiogenesis. Crit Rev Oral Biol Med 1995;6:230-47 64. Philipp W, Speicher L, Humpel C. Expression of vascular endothelial growth factor and its receptors in inflamed and vascularized human corneas. Invest Ophthalmol Vis Sci 2000;41:2514-22 65. Cursiefen C, Rummelt C, Kuchle M. Immunohistochemical localization of vascular endothelial growth factor, transforming growth factor alpha, and transforming growth factor beta1 in human corneas with vascularization. Cornea 2000;19:526-33 66. Becker M, Kruse F, Assam L, et al. In vivo significance of ICAM1-dependent leukocyte adhesion in early corneal angiogenesis. Invest Ophthalmol Vis Sci 1999;40:612-8 67. Zhu S, Dana M. Expression of cell adhesion molecules on limbal and neovascular endothelium in corneal inflammatory neovascularization. Invest Ophthalmol Vis Sci 1999;40:1427-34 68. Yaylali V, Ohta T, Kaufmann S, et al. In vivo confocal imaging of corneal neovascularization. Cornea 1998;17:646-53 69. Daxer A, Ettl A. Corneal vascularisation and its relation to the physical properties of the tissue: a fractal analysis. Curr Eye Res 1995;14:263-8 70. Kvanta A, Sarman S, Fagerholm P, et al. Expression of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in inflammation-associated corneal neovascularization. Exp Eye Res 2000;70:419-28 71. Ma D, Chen J, Kim W, et al. Expression of matrix metalloproteinases 2 and 9 and tissue inhibitors of metalloproteinase 1 and 2 in inflammation-induced corneal neovascularization. OphthalmicRes 2001;33:353-62 72. Kato T, Kure T, Chang J, et al. Diminished corneal angiogenesis in gelatinase A-deficient mice. FEBS Letts 2001;508:18790 73. Wang H, Keiser JA. Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells. Circ Res 1998;83:832-40 74. Gan L, Fagerholm P. Leukocytes in the early events of corneal neovascularization. Cornea 2001;20:96-9 75. Sims D. The pericyte - a review. Tissue Cell 1986;18:153-74 76. Allt G, Lawrenson JG. Pericytes: cell biology and pathology. Cells Tissues Organs 2001;169:1-11 77. Cursiefen C, Hofmann-Rummelt C, Küchle M, et al. Pericyte recruitment in human corneal angiogenesis: an ultrastructural study with clinicopathological correlation. Br J Ophthalmol 2003;87:101-6 78. Keeche P, Ichikawa L, Barlow W. A prospective study of contact lens complications in a managed care setting. Optom Vis Sci 1996;73:653-8 79. Tan D, Pullum K, Buckley R. Medical applications of scleral

40

contact lenses 2: gas permeable scleral contact lenses. Cornea 1995;14:130-7 80. Dana M, Streilein J. Loss and restoration of immune privilege in eyes with corneal neovascularization. Invest Ophthalmol Vis Sci 1996;37:2485-94 81. Schwallie JD, McKenney CD, Long WD, et al. Corneal staining patterns in normal non-contact lens wearers. Optom Vis Sci 1997;74:92-8 82. Josephson JE, Caffery BE. Corneal staining afer instillation of topical anesthetic (SSII). Invest Ophthalmol Vis Sci 1988;29:1096-9 83. Begley C, Barr J, Edrington T, et al. Characteristics of corneal staining in hydrogel contact lens wearers. Optom Vis Sci 1996;73:193-200 84. Nichols K, Mitchell G, Simon KM, et al. Corneal staining in hydrogel lens wearers. Optom Vis Sci 2002;79:20-30 85. Jalbert I, Sweeney DF, Holden BA. The characteristics of corneal staining in successful daily and extended disposable contact lens wearers. Clin Exp Optom 1999;82:4-10 86. Jalbert I, Sweeney DF, Holden BA. Epithelial split associated with wear of a silicone hydrogel contact lens. CLAO J 2001;27:231-3 87. Guillon J, Guillon M, Malgouyres S. Corneal desiccation staining with hydrogel lenses: tear film and contact lens factors. Ophthal Physiol Opt 1990;10:343-50 88. Orsborn GN, Zantos SG. Corneal desiccation staining with thin high water content contact lenses. CLAO J 1988;14:81-5 89. Andrasko G. Hydrogel dehydration in various environments. Int Contact Lens Clin 1983;10:22-8 90. Efron N, Brennan NA, Bruce AS, et al. Dehydration of hydrogel lenses under normal wearing conditions. CLAO J 1987;13:152-6 91. Jones L, MacDougall N, Sorbara LG. Asymptomatic corneal staining associated with the use of balafilcon silicone-hydrogel contact lenses disinfected with a polyaminopropyl biguanide-preserved care regimen. Optom Vis Sci 2002;79:753-61 92. Amos C. A clinical comparison of two soft lens care systems used with silicone hydrogel contact lenses. Optician 2004;227:16-20 93. Epstein A. SPK with daily wear of silicone hydrogel lenses and MPS. Contact Lens Spectrum 2002;17:30 94. Fonn D. Observations of corneal staining with MPS and silicone hydrogel lenses. Contact Lens Spectrum 2002;17:32 95. Sentell K, Beaullieu E. Comparison of preservative uptake and release profiles of PHMB from soft conact lens care products by silicone hydrogel contact lenses [ARVO Abstract]. Invest Ophthalmol Vis Sci 2004;45:Abstract# 1573 96. Jones L. Understanding incompatibilities. Contact Lens Spectrum 2004;18:4-7 97. Bergmanson J. Clinical anatomy of the external eye. J Am Optom Assoc 1990 (6 suppl);61:S7-S15 98. Sankaridurg PR, Sweeney DS, Sharma S, et al. Adverse events with extended wear of disposable hydrogels: results for the first 13 months of lens wear. Ophthalmology 1999;106:1671-80 99. Allansmith MR, Korb DR, Greiner JV, et al. Giant papillary conjunctivitis in contact lens wearers. Am J Ophthalmol 1977;83:697-708

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al 100. Alemany AL, Redal P. Giant papillary conjunctivitis in soft and rigid lens wear. Contactologica 1991;13:14-7 101. Levy B, McNamara N, Corzine J, et al. Prospective trial of daily and extended wear disposable contact lenses. Cornea 1997;16:274-6 102. Skotnitsky CC, Naduvilath TJ, Sweeney DF, et al. Two presentations of contact lens induced papillary conjunctivitis (CLPC) in hydrogel lens wear: local and general. Optom Vis Sci 2005, In press 103. Korb D, Allansmith M, Greiner J, et al. Prevalence of conjunctival changes in wearers of hard contact lenses. Am J Ophthalmol 1980;90:336-41 104. Skotnitsky C, Sweeney DF, Naduvilath T, et al. The incidence of local and general contact lens induced papillary conjunctivitis in silicone hydrogel contact lenses [ARVO Abstract]. Invest Ophthalmol Vis Sci 2005;46:Abstract # 2064 105. Molinari JF. The clinical management of giant papillary conjunctivitis. Am J Optom 1981;58:886-91 106. Skotnitsky C, Naduvilath T, Sweeney DF, et al. Contact lens papillary conjunctivitis(CLPC): A case control study. [AAO Abstract]. Optom Vis Sci 2000;77:S257 107. Porazinski AD, Donshik PC. Giant papillary conjunctivitis in frequent replacement contact lens wearers: a retrospective study. CLAO J 1999;25:142-7 108. Buckley R. Pathology and treatment of giant papillary conjunctivitis. The British perspective. Clin Ther 1987;9:451-7 109. Donshik PC, Ballow M. Tear immunoglobulins in giant papillary conjunctivitis induced by contact lenses. Am J Ophthalmol 1983;96:460-6 110. Barishak Y, Zavaro A, Samra Z, et al. An immunological study of papillary conjunctivitis due to contact lenses. Curr Eye Res 1984;3:1161-8 111. Buckley RJ. Allergic eye disease - a clinical challenge. Clin Exp Allergy 1998;6:39-43 112. Allansmith MR, Korb DR, Greiner JV. Giant papillary conjunctivitis induced by hard or soft contact lens wear: quantitative histology. Ophthalmology 1978;85:766-78 113. Allansmith M, Baird R. Percentage of degranulated mast cells in vernal conjunctivitis and giant papillary conjunctivitis associated with contact lens-wear. Am J Ophthalmol 1981;91:71-5 114. Hingorani M, Calder V, Buckley R, et al. The role of conjunctival epithelial cells in chronic ocular allergic disease. Exp Eye Res 1998;67:497-500 115. Metz DP, Bacon AS, Holgate S, et al. Phenotypic characterization of T cells infiltrating the conjunctiva in chronic allergic eye disease. J Allergy Clin Immunol 1996;98:686-96 116. Metz DP, Hingorani M, Calder VL, et al. T-cell cytokines in chronic allergic eye disease. J Allergy Clin Immunol 1997;100(Pt 1):817-24 117. Fowler SA, Greiner JV, Allansmith MR. Soft contact lenses from patients with giant papillary conjunctivitis. Am J Ophthalmol 1979;88:1056-61 118. Tripathi PC, Tripathi RC. Analysis of glycoprotein deposits on disposable soft contact lenses. Invest Ophthalmol Vis Sci 1992;33:121-5 119. Hart DE, Schkolnick JA, Bernstein S, et al. Contact lens induced giant papillary conjunctivitis: A retrospective study. J

Am Optom Assoc 1989;60:195-204 120. Ballow M, Donshik PC, Rapacz P, et al. Immune responses in monkeys to lenses from patients with contact lens induced giant papillary conjunctivitis. CLAO J 1989;15:64-70 121. Stenson S. Focal giant papillary conjunctivitis from retained contact lenses. Ann Ophthalmol 1982;14:881-5 122. Skrypuch OW, Willis NR. Giant papillary conjunctivitis from an exposed prolene suture. Can J Ophthalmol 1986;21:189-92 123. Greiner JV. Papillary conjunctivitis induced by an epithelialized corneal foreign body. Ophthalmologica 1988;196:82-6 124. Meisler DM, Krachmer J, Goeken J. An immunopathologic study of giant papillary conjunctivitis associated with an ocular prosthesis. Am J Ophthalmol 1981;92:368-71 125. Dunn Jr JP, Weissman BA, Mondino BJ, et al. Giant papillary conjunctivitis associated with elevated corneal deposits. Cornea 1990;9:357-8 126. Reynolds RM. Giant papillary conjunctivitis: A mechanical aetiology. Aust J Optom 1978;61:320-3 127. Elgebaly SA, Donshik PC, Rahhal F, et al. Neutrophil chemotactic factors in the tears of giant papillary conjunctivitis patients. Invest Ophthalmol Vis Sci 1991;32:208-13 128. Cheng KH, Leung SL, Hoekman HW, et al. Incidence of contact-lens associated microbial keratitis and its related morbidity. Lancet 1999;354:181-5 129. Dart JK, Stapleton F, Minassian D. Contact lenses and other risk factors in microbial keratitis. Lancet 1991;338:651-3 130. Schein OD, Glynn RJ, Seddon JM, et al. The relative risk of ulcerative keratitis among users of daily-wear and extendedwear soft contact lenses. N Engl J Med 1989;321:773-8 131. Sack RA, Tan KO, Tan A. Diurnal tear cycle: evidence for a nocturnal inflammatory constitutive tear fluid. Invest Ophthalmol Vis Sci 1992;33:626-40 132. Sack R, Sathe S, Hackworth L, et al. The effect of eye closure on protein and complement deposition on Group IV hydrogel contact lenses: relationship to tear flow dynamics. Curr Eye Res 1996;15:1092-100 133. Willcox M, Morris C, Sack R. Complement and complement regulatory proteins in human tears. Invest Ophthalmol Vis Sci 1997;38:1-8 134. Thakur A, Willcox MD. Cytokine and lipid inflammatory mediator profile of human tears during contact lens associated inflammatory diseases. Exp Eye Res 1998;67:9-19 135. Cheng KH, Spanjaard L, Rutten H, et al. Immunoglobulin A antibodies against Pseudomonas aeruginosa in the tears of contact lens wearers. Invest Ophthalmol Vis Sci 1996;37:2081-8 136. Vinding T, Eriksen JS, Nielsen NV. The concentration of lysozyme and secretory IgA in tears from healthy persons with and without contact lens use. Acta Ophthalmologica 1987;65:23-6 137. Pearce DJ, Demerci G, Willcox MD. Secretory IgA epitopes in basal tears of extended wear soft contact lens wearers and nonlens wearers. Aust NZ J Ophthalmol 1999;27:221-3 138. Kijlstra A, Polak BC, Luyendijk L. Transient decrease of secretory IgA in tears during rigid gas permeable contact lens wear. Curr Eye Res 1992;11:123-6 139. Willcox MD, Pearce DJ, Tan ME, et al. Contact lenses and tear film interactions. Adv Exp Med Biol 2002;506:879-84

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

41

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al 140. Baleriola-Lucas C, Fukuda M, Willcox MD, et al. Fibronectin concentration in tears of contact lens wearers. Exp Eye Res 1997;64:37-43 141. Schultz CL, Kunert KS. Interleukin-6 levels in tears of contact lens wearers. J Interferon Cytokine Res 2000;20:309-10 142. Thakur A, Willcox MD. Contact lens wear alters the production of certain inflammatory mediators in tears. Exp Eye Res 2000;70:255-9 143. Stapleton F, Willcox MD, Sansey N, et al. Ocular microbiota and polymorphonuclear leucocyte recruitment during overnight contact lens wear. Aust NZ J Ophthalmol 1997;25:33-5 144. Willcox MD, Sankaridurg PR, Zhu H, et al. Inflammation and infection and the effects of the closed eye, in Sweeney DF (ed). Silicone hydrogels: continuous wear contact lenses. Edinburgh, Butterworth Heinemann, 2nd ed, 2004:90-125 145. Maruyama K, Yokoi N, Takamata A, et al. Effect of environmental conditions on tear dynamics in soft contact lens wearers. Invest Ophthalmol Vis Sci 2004;45:2563-8 146. Creech JL, Do L, Fatt I, Radke CJ. In vivo tear-film thickness determination and implications for tear-film stability. Curr Eye Res 1998;17:1058-66 147. Wong H, Fatt I, Radke C. Deposition and thinning of the human tear film. J Coll Int Sci 1996;184:44-51 148. Nichols JJ, King-Smith PE. The impact of hydrogel lens settling on the thickness of the tears and contact lens. Invest Ophthalmol Vis Sci 2004;45:2549-54 149. Wang J, Fonn D, Simpson T, et al. Topographical thickness of the epithelium and total cornea after overnight wear of reverse-geometry rigid contact lenses for myopia reduction. Invest Ophthalmol Vis Sci 2003;44:4742-6 150. Nichols J, King-Smith P. Thickness of the pre- and post-contact lens tear film measured in vivo by interferometry. Invest Ophthalmol Vis Sci 2003;44:68-77 151. King-Smith PE, Fink BA, Hill RM, et al. The thickness of the tear film. Curr Eye Res 2004;29:357-68 152. Fogt N, King-Smith PE, Tuell G. Interferometric measurement of tear film thickness by use of spectral oscillations. J Opt Soc Am A Opt Image Sci Vis 1998;15:268-75 153. Guillon JP. Tear film structure and contact lenses, in Holly FJ (ed). The preocular tear film in health, disease and contact lens wear. Lubbock, TX, Dry Eye Institute Inc, 1986:914-35 154. Faber E, Golding TR, Lowe R, et al. Effect of hydrogel lens wear on tear film stability. Optom Vis Sci 1991;68:380-4 155. Andrasko G, Schloessler J. The effect of humidity on dehydration of soft contact lenses on the eye. Int Contact Lens Clin 1980;7:210-2 156. Morris CA, Holden BA, Papas EB, et al. The ocular surface, the tear film and the wettability of contact lenses. Adv Exp Med Biol 1998:717-22 157. Jones LW. Contact lens deposits: their causes and control. Contact Lens J 1992;20:6-13 158. Holden BA, Sweeney DF, Seger RG. Epithelial erosions caused by thin high water content lenses. Clin Exp Optom 1986;69:103-7 159. Glasson M, Stapleton F, Keay L, et al. Differences in clinical parameters and tear film of tolerant and intolerant contact lens wearers. Invest Ophthalmol Vis Sci 2003;44:5116-24

42

160. Young G, Efron N. Characteristics of the pre-lens tear film during hydrogel lens wear. Ophthalmic Physiol Opt 1991;11:53-8 161. Patel S. Hydrogel lens water content and the stability of the pre-lens tear film. Optom Vis Sci 1991;68:783-5 162. Wang J, Fonn D, Simpson TL, et al. Pre-corneal and pre and postlens tear film thickness measured indirectly with optical coherence tomography. Invest Ophthalmol Vis Sci 2003;44:2524-8 163. Hamano H, Hori M, Mitsunaga S. Measurement of evaporation rate of water from the pre-corneal film and contact lenses. Contactologica 1981;25:7-14 164. Cedarstaff TH, Tomlinson A. A comparative study of tear evaporation rates and water content of soft contact lenses. Am J Optom Physiol Opt 1983;60:167-74 165. Thai L, Tomlinson A, Doane MG. Effect of contact lens materials on tear physiology. Optom Vis Sci 2004;81:194-204 166. Farris RL. The dry eye: Its mechanisms and therapy, with evidence that contact lens is a cause. CLAO J 1986;12:234-46 167. Tomlinson A, Cedarstaff TH. Tear evaporation from the human eye: the effects of contact lens wear. J Br Contact Lens Assoc 1982;5:141-50 168. Jones LW, May C, et al. In vitro evaluation of the dehydration characteristics of silicone hydrogel and conventional hydrogel contact lens materials. Contact Lens Ant Eye 2002;25:147-56 169. Efron N, Morgan PB. Hydrogel contact lens dehydration and oxygen transmissibility. CLAO J 1999;25:148-51 170. Morgan PB, Efron N. In vivo dehydration of silicone hydrogel contact lenses. Eye Contact Lens 2003;29:173-6 171. Golebiowski B, Papas E, Begley C, et al. Symptoms in low and high Dk/t contact lens wear [AAO Abstract]. Optom Vis Sci 2005; Accepted 172. Fonn D, Situ P, Simpson T. Hydrogel lens dehydration and subjective comfort and dryness ratings in symptomatic and asymptomatic contact lens wearers. Optom Vis Sci 1999;76:700-4 173. McConville P, Pope JM, Huff JW. Limitations of in vitro contact lens dehydration/rehydration data in predicting on-eye dehydration. CLAO J 1997;23:117-21 174. Korb DR, Greiner JV, Glonek T. Tear film lipid formation: implications for contact lens wear. Optom Vis Sci 1996;73:189-92 175. Glasson MJ, Stapleton F, Willcox MD. Lipid, lipase and lipocalin differences between tolerant and intolerant contact lens wearers. Curr Eye Res 2002;25:227-35 176. Guillon JP. Abnormal lipid layers: observation, differential diagnosis, and classification. Adv Exp Med Biol 1998;438:309-13 177. Guillon M, Styles E, Guillon JP, et al. Preocular tear film characteristics of nonwearers and soft contact lens wearers. Optom Vis Sci 1997;74:273-9 178. Craig JP, Tomlinson A. Importance of the lipid layer in human tear film stability and evaporation. Optom Vis Sci 1997;74:8-13 179. Glasson M, Keay L, Ball M, et al. Effect of contact lenses on the pre corneal tear film, in Zierhut M, Stern M, Sullivan D (eds). Immunology of the lacrimal gland, tear film and ocular surface. UK, Taylor & Francis, 2005:239-54 180. Maissa C, Guillon M, Giraud-Claudon K, et al. Tear lipid composition of hydrogel contact lens wearers. Adv Exp Med Biol

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al 2002;506:935-8 181. Castillo EJ, Koenig JL, Anderson JM. Characterisation of protein adsorption of soft contact lenses. IV. Comparison of in vivo spoilage with the in vitro adsorption of tear proteins. Biomaterials 1986;7:89-96 182. Cheng L, Muller S, Radke CJ. Wettability of silicone-hydrogel contact lenses in the presence of tear-film components. Curr Eye Res 2004;28:93-108 183. Tighe B. Silicone hydrogels: structure, properties and behaviour, in Sweeney DF (ed). Silicone hydrogels: continuous-wear contact lenses. Edinburgh, Butterworth Heinemann, 2nd ed, 2004:1-27 184. Maldonado-Codina C, Morgan P, Schnider C, et al. Short-term physiologic response in neophyte subjects fitted with hydrogel and silicone hydrogel contact lenses. Optom Vis Sci 2004;81:911-21 185. Jones L, Senchyna M, Glasier M-A, et al. Lysozyme and lipid deposition on silicone hydrogel contact lens materials. Eye Contact Lens 2003;29(1 suppl):S75-S79 186. Tighe BJ, Jones LW, Evans K, et al. Patient dependent and material dependent factors in contact lens deposition processes. Adv Exp Med Biol 1998:745-52 187. Sack RA, Jones B, Antignani A, et al. Specificity and biological activity of the protein deposits on the hydrogel lens. Invest Ophthalmol Vis Sci 1987;28:842-9 188. Maissa C, Franklin V, Guillon M, et al. Influence of contact lens material surface characteristics and replacement frequency on protein and lipid deposition. Optom Vis Sci 1998;75:697-705 189. Gleason W, Tanaka H, Albright RA, Cavanagh HD. A 1-year prospective clinical trial of Menicon Z (tisilfocon A) rigid gaspermeable contact lenses worn on a 30-day continuous wear schedule. Eye Contact Lens 2003;29:2-9 190. Young G, Port M. Rigid gas-permeable extended wear: a comparative clinical study. Am J Optom 1992;69:214-26 191. Little SA, Bruce AS. Postlens tear film morphology, lens movement and symptoms in hydrogel lens wearers. Ophthalmic Physiol Opt 1994;14:65-9 192. Bruce AS, Brennan NA. Clinical observations of the post-lens tear film during the first hour of hydrogel lens wear. Int Contact Lens Clin 1988;15:304-10 193. Lin M, Graham A, Polse K, et al. Measurement of post-lens tear thickness. Invest Ophthalmol Vis Sci 1999;40:2833-9 194. Lin MC, Chen YQ, Polse KA. The effects of ocular and lens parameters on the post lens tear thickness. Eye Contact Lens 2003;29(1 suppl):S33-S36 195. Miller KL, Polse KA, Radke CJ. Fenestrations enhance tear

mixing under soft contact lenses. Invest Ophthalmol Vis Sci 2003;44:60-7 196. Paugh J, Stapleton F, Keay L, et al. Tear exchange under hydrogel lenses. Invest Ophthalmol Vis Sci 2001;42:2813-20 197. Miller KL, Lin MC, Radke CJ, et al. Tear mixing under soft contact lenses, in Sweeney DF (ed). Silicone hydrogels: continuous wear contact lenses. Oxford, Butterworth Heinemann, 2004:57-89 198. McNamara NA, Polse KA, Brandt RJ, et al. Tear mixing under a soft contact lens: effect of lens diameter. Am J Ophthalmol 1999;127:659-65 199. Creech JL, Chauhan A, Radke CJ. Dispersive mixing in the posterior tear film under a soft contact lens. Ind Eng Chem Res 2001;40:3015-26 200. Florkey L, Fink BA, Mitchell GL, Hill RM. Tear exchange and oxygen reservoir effects in silicone hydrogel systems. Eye Contact Lens 2003;29(1 suppl):S90-S92 201. Nichols JJ, King-Smith PE. The effect of eye closure on the post-lens tear thickness during silicone hydrogel contact lens wear. Cornea 2003;22:539-44 202. Millar TJ, Papas EB, Ozkan J, et al. Clinical appearance and microscopic analysis of mucin balls associated with contact lens wear. Cornea 2003;22:740-5 203. Craig JP, Sherwin T, Grupcheva C, et al. An evaluation of mucin balls associated with high- Dk silicone hydrogel contact lens wear. Adv Exp Med Biol 2002;506(Pt B):917-23 204. Dumbleton K, Jones L, Chalmers R, et al. Clinical characterization of spherical post-lens debris associated with lotrafilcon high-Dk silicone lenses. CLAO J 2000;26:186-92 205. Pritchard N, Jones L, Dumbleton K, et al. Epithelial inclusions in association with mucin ball development in high-oxygen permeability hydrogel lenses. Optom Vis Sci 2000;77:68-72 206. Jalbert I, Stapleton F, Papas E, et al. In vivo confocal microscopy of the human cornea. Br J Ophthalmol 2003;87:225-36 207. Ladage PM, Petroll WM, Jester JV, et al. Spherical indentations of human and rabbit corneal epithelium following extended contact lens wear. CLAO J 2002;28:177-80 208. Tan J, Keay L, Jalbert I, et al. Mucin balls with wear of conventional and silicone hydrogel contact lenses. Optom Vis Sci 2003;80:291-7 209. Naduvilath T. Statistical modelling of risk factors associated with soft contact lens related corneal infiltrative events. PhD thesis, University of Newcastle, Newcastle, Australia, 2003 210. Sweeney DF, Stern J, Naduvilath T, et al. Inflammatory adverse event rates over 3 years with silicone hydrogel lenses [ARVO Abstract]. Invest Ophthalmol Vis Sci 2002;43:Abstract # 976

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com

43