noiembrie 2005

8/10/2019 noiembrie 2005

1/20

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com24

Silicone Hydrogel Contact Lenses and the

Ocular SurfaceFIONASTAPLETON, PHD, MCOPTOM, DCLP FAAO,1,2, 3SERINASTRETTON, PHD,1,2

ERICPAPAS, PHD, MCOPTOM, DCLP,1,2,3 CHERYLSKOTNITSKY, BSC,OD,1, 3

DEBORAHF. SWEENEY, BOPTOM, PHD, FAAO1,2,3

Accepted for publication November 2005

From the 1Vision Cooperative Research Centre, Sydney, Australia, 2Insti-tute for Eye Research, Sydney, Australia, and 3School of Optometry andVision Science, Universi ty of New South Wales, Kensington, Austra lia

All authors are supported in part by the Australian Federal Governmentthrough the Cooperative Research Centre Scheme.

The authors have no commercial interest in any concept or product dis-cussed in this article.

Single copy reprint requests should be sent to: Deborah F. Sweeney (ad-dress below)

Corresponding author: Deborah F. Sweeney, Vision Cooperative ResearchCentre, PO Box 6327, UNSW Sydney, NSW, 1466, Australia. Tel: +61 29385 7408. Fax: +61 2 9385 7401. Email: [email protected]

Abbreviations are printed in boldfacewhere they first appear with theirdefinitions.

2006 Ethis Communications, Inc. The Ocular SurfaceISSN: 1542-

0124. Stapleton F, Stretton S, Papas E, et al. Silicone hydrogel con-

tact lenses and the ocular surface. 2006;4(1):2443.

Clinical Science

S

GARYN. FOULKS, MD, SECTIONEDITOR

KEY WORDS biomaterials, contact lens, corneal homeosta-

sis, corneal vascularization, giant papillary conjunctivitis,

limbal hyperemia, palpebral conjunctiva, papillary conjunctivi-

tis, silicone hydrogel, tear film

I. INTRODUCTION

ilicone hydrogel contact lenses represent the mostimportant advance in the contact lens industrysince development of the first soft hydrogel lenses

in the early 1970s. The high oxygen permeability of thisnew class of silicon-based soft lens materials has provideda distinctive platform upon which new developments anddesigns are conceived. Until silicone hydrogel lenses be-came available, soft lens wearers, particularly those whowore lenses overnight, were subject to the effects of con-tact lens-induced hypoxia on corneal physiology and the

potential consequences of compromised corneal integrityand function.

The Gteborg study, published in 1985, was one ofthe first studies of the physiological effects of soft contactlens wear on the cornea.1This study compared 27 eyesthat had used long-term extended wear (5 years) hydrogellenses with their non-lens-wearing fellow eyes. The lens-wearing eyes showed significantly thinner corneal epithe-lium and lower oxygen uptake rates, greater numbers ofcorneal epithelial microcysts, thinner corneal stroma, sig-nificant levels of daytime edema, and a greater degree ofcorneal endothelial polymegethism than the fellow eyes.It has also been shown that long-term wearers of hydrogellenses have greater amounts of limbal hyperemia than non-lens wearers, and may have greater encroachment of limbalvessels into the cornea.2

Although the changes to the stroma and endotheliumremained, many of the changes to the epithelium seen inGteborg study were reversed over 1 month after cessa-tion of lens wear; in particular, epithelial thickness andoxygen consumption steadily recovered to non-lens wear-ing levels, as did the numbers of microcysts.1This studyconfirmed that chronic lens-induced hypoxia is the under-lying cause of the physiological changes seen during long-term contact lens wear and provided the major impetus to

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 elimi-

nated 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 in-

creased 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 infec-

tion than daily wear, regardless of lens material. Future con-tact 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.

8/10/2019 noiembrie 2005

2/20

THE OCULAR SURFACE / JANUARY 2006, VOL. 4, NO. 1 / www.theocularsurface.com 25

corneal homeostasis, maintain normal tear film integrityand stability, inhibit bacterial adhesion, and prevent theaccumulation of debris beneath the lens. The mechanicalattributes of the lens, such as modulus of elasticity (flex-ibility), edge design, or lens diameter, should minimizeirritation of the corneal and conjunctival epithelia andmaximize movement of tears. Although most contact lens

research has focused on the corneal epithelium, and morerecently the tear film, all surfaces play an integral part inmaintaining ocular health.

II. CHARACTERISTICS OF

SILICONE HYDROGEL MATERIALS

All hydrogel materials are formed by the cross-linkingof chains of monomeric units into a matrix-like polymer,and the unique attributes of each polymer are defined bythe interaction of chemical groups and the degree of cross-linking. The main component of hydrogel lens materialsis the relatively hydrophilic poly 2hydroxyethyl meth-acrylate (HEMA), and other monomers are added to alterthe ionicity and water content of the material in order toimprove wettability, flexibility, oxygen permeability andfluid transport. The oxygen permeability of hydrogel ma-terials is dependent on water content; and, therefore, islimited by the solubility of oxygen in water (Figure 1).

Silicone hydrogels share a similar structure with hy-drogel lens materials, but differ markedly in chemical com-position; in essence, they combine the positive attributesof a soft lens with the excellent solubility of oxygen insilicone. Because of the relatively hydrophobic nature ofsilicone, if left unmodified, silicone hydrogel lenses wouldbe inherently incompatible with the ocular surface. Hy-

drophobic lens surfaces cause discomfort, as their poorsurface wettability contributes to destabilization of the tearfilm, and they accumulate deposits. The hydrophilicity ofcurrently available silicone hydrogel lenses is enhancedby surface treatment or by the incorporation of soluble

SILICONE HYDROGEL CONTACT LENSES / Stapleton et al

identify the critical levels of oxygen required by the cor-nea during daily and overnight contact lens wear to pre-vent these changes.3

The main components of the ocular surface that inter-act with a contact lens are the corneal and conjunctivalepithelia and the tear film. Soft contact lenses have diam-eters that are approximately 2 to 3 mm larger than thecornea; thus, their peripheries directly interact with thelimbus and surrounding bulbar conjunctiva. Typically,when the eye is open, the margins of the upper and lowerlids overlie the periphery of a soft contact lens. This tendsto reduce the impact of the interaction between the lidsand the lens edge, although some frictional forces frommovement of the upper lid across the lens surface do ex-ist. When the eye is closed, the ocular environment is in astate of subclinical inflammation, and the supply of oxy-gen to the cornea is limited to the conjunctival vessels.The upper palpebral conjunctiva in the closed eye is inconstant physical contact with the lens surface, and theeffects, if any, of rapid eye movements, reduced tear film,or decreased lens wetting on the lens-lid interaction areunknown. Although the limbal transition zone is a mere1.5 mm wide, its importance to contact lens wear relatesto its crucial role in maintaining corneal health, particu-larly with respect to epithelial renewal and immunologi-cal response.

For optimal biocompatibility, contact lenses must allowsufficient oxygen flow to maintain aerobic metabolism and

Figure 1. Relationship between oxygen permeability (Dk) with equi-

librium water content for conventional hydrogel and silicone hydro-

gel materials. (Reprinted from Tighe B. Silicone hydrogels: struc-

ture, 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.)

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: sodiumfluorescein staining

A. Mechanical abrasion

B. Excessive desiccation

VI. Superior palpebral conjunctiva

A. Clinical features of contact lens-induced papillaryconjunctivitis

B. Etiology

VII. Tear film

A. Pre-lens tear film

B. Tear evaporation

8/10/2019 noiembrie 2005

3/20


polymers (internal wetting agents) within the bulk mate-

rial that orient to form an interface between the lens andthe tear film.

While the presence of silicone is a unifying feature,silicone hydrogel materials are made from a diverse groupof monomers (Table 1). The current silicone hydrogel lensmaterials range in oxygen permeability from 60 to 175barrer, far greater than can be provided by more conven-tional hydrogel lens materials, and the lenses differ in wa-ter content, stiffness and surface characteristics.

At present, two silicone hydrogels (lotrafilicon A andbalafilcon A) are approved by the US Food and Drug Ad-ministration (FDA) for up to 30-nights of continuous wear,with monthly replacement; they also have FDA approvaland CE Mark approval for therapeutic use as bandagelenses. Lotrafilcon B is recommended for daily wear andup to 6-nights extended wear, and galyfilcon A andsenofilcon 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 epi-thelium and to quickly repair superficial damage dependson the capacity of limbal epithelial stem cells for essen-tially unlimited self-renewal and, in appropriate circum-

stances, high rates of proliferation. Loss or injury to the

stem cell population, which comprises up to 10% of limbalepithelial cells,4makes the cornea vulnerable to deficientepithelialization, leading to recurrent erosions, chronickeratitis, and vascularization.5

Contact lens wear, and lens-induced hypoxia, in par-ticular, have been cited among the possible causes of limbalstem cell deficiency.6-9Mechanical trauma from the lensedge may also cause stem cell damage, although stem cellsare largely protected by their location at the basal level ofthe limbal epithelium, which is thicker and more denselycompacted than its corneal counterpart.4

During corneal turnover, slow-cycling stem cells lo-cated in the limbal basal epithelium produce daughter basalepithelial cells of much greater proliferative potential inthe peripheral cornea, adjacent to the limbus.10These basalcells then differentiate vertically and migrate horizontallytoward the central corneal surface11,12before terminal dif-ferentiation, apoptosis-mediated cell death,13and even-tual exfoliation into the precorneal tear film. The successof the epithelium in maintaining the delicate balance be-tween epithelial cell proliferation, differentiation, and ex-foliation during contact lens wear is demonstrated bymeasures such as epithelial thickness, surface cell size, andshedding rate.

Several long-term clinical studies comparing performance

Table 1. Characteristics of Various Silicone Hydrogel Contact Lenses and Conventional Hydrogel Contact Lenses

Conventional

Material type Silicone hydrogel hydrogel

USAN Balafilcon A Lotrafilcon A Lotrafilcon B Galyfilcon A Senofilcon A Etafilcon A

Proprietary name PureVision Focus Night & Day O2Optix Acuvue Advance Acuvue OASYS Acuvue2

Manufacturer Bausch & Lomb CIBA Vision CIBA Vision Vistakon Vistakon Vistakon

Monomers NVP, TPVC, DMA, TRIS, siloxane macromer mPDMS, DMA, HEMA mPDMS, DMA, HEMA HEMA, MA

NCVE, PBVC siloxane macromer, siloxane macromer,

TEGDMA, PVP EGDMA, PVP

Surface modification Plasma oxidation 25 nm plasma coating with None None

producing glassy high refractive index Internal wetting agent (PVP)

islands

Initial modulus1(MPa) 1.1 1.4 1.2 0.4 0.6 0.35

Oxygen permeability2 ( x 10-11 ) 99 175 140 60 86 28

Oxygen transmissibility3( x 10-9 ) 110 175 138 86 147 31

Water content 36% 24% 33% 47% 38% 58%

FDA class Group III Group I Group IV

Low water content Low water content High water

Ionic Non-ionic 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 polyvinylpyrrolidone; 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 29thClinical Conference

& Exhibition of the British Contact Lens Association, Brighton, UK 3-6 June, 2005.2 Labelled3 Calculated using center thickness of a 3.00 D lens; units = (cm ml O2)(s ml mmHg)1


8/10/2019 noiembrie 2005

4/20


of silicone hydrogel lens wear with no lens wear,14andhydrogel lens wear,15have firmly established that eyes thatwear silicone hydrogel lenses are clinically indistinguish-able from non-lens wearing eyes. Generally, they exhibitexcellent clinical performance based on indicators such asnumbers of epithelial microcysts and degree of cornealepithelial staining and limbal and bulbar hyperemia. Clini-

cal performance of silicone hydrogel lenses was the samewhether they were worn for 6 or 30 consecutive nights.16,17

B. Corneal Homeostasis

Recent studies by Cavanagh et al18 showed that allcontact lens wear significantly slows the turnover of thecorneal epithelium to some degree by suppressing epithe-lial cell proliferation19and migration20and by decreasingthe rate of exfoliation21-23; these processes are mediatedin part by lens-induced hypoxia and by the physical pres-ence of the lens per se. The lenses used in these studieswere the highly oxygen transmissible rigid gas permeable(tisilfocon A) and silicone hydrogel lenses (balafilcon Aand lotrafilcon A,) as well as a hydrogel lens (etafilcon A)of lower oxygen transmissibility (Table 1).

1. Rate of Cell ExfoliationExtended wear with all currently available contact

lenses, including soft and rigid gas permeable lenses, ischaracterized by significant thinning of the central cor-neal epithelium, an increase in cell surface size, and a de-creased rate of exfoliation (Figure 2).24,25The rate of sur-face cell exfoliation decreases with all contact lens types,irrespective of lens oxygen transmissibility, material rigid-ity, or wear schedule,21,23-25and occurs at levels similar to

those induced by the closed eye in the absence of lenswear (suturing) in a rabbit model.26

This effect of contact lens wear on the rate of cell exfo-liation is further supported by the finding that all contactlens types similarly suppress apoptosis-driven cell deathin the central epithelium, as in the closed eye.27,28In theabsence of hypoxia, contact lens wear seems to mimic theconditions of the closed eye, in which surface epithelialcells are protected from the shear forces of the blinkinglid. Cavanagh proposed that regulation of epithelial cellapoptosis and exfoliation is mediated by Bcl-2, an anti-apoptotic protein, and suggested that contact lens-inducedsuppression of cell exfoliation may arise from continuedexpression of Bcl-2 at the corneal surface.18

The increase in cell size at the corneal surface duringcontact lens wear is most likely a result of longer retentiontimes and the slower rate of exfoliation. The size of exfoli-ated corneal epithelial cells in eyes that wear silicone hy-drogel lenses is similar to that found in non-lens-wearingeyes after 3 months of extended wear (30-consecutive-nightregimen),29but it increases above baseline levels within 6to 9 months of wear.24,25However preliminary studiessuggest that in the longer-term (up to 3 years), cell size insilicone hydrogel lens wearers recovers to pre-lens wearlevels.30

2. Degree of ThinningIn contrast to cell exfoliation, the degree of thinning of

the central corneal epithelium is affected to varying de-grees by lens type and oxygen transmissibility. Highly oxy-gen transmissible silicone hydrogel lenses have less pro-nounced effects than hydrogel lenses of lower oxygen trans-missibility or rigid gas permeable lenses of equivalent oxy-gen transmissibility (Figure 2), and they show greater evi-dence of adaptive recovery during long-term extended wear.

The decrease in the rate of surface cell exfoliation withcontact lens wear seems at first to be inconsistent with theconcomitant thinning of the corneal epithelium. Duringthe first 48 hours of overnight wear, all contact lens typessuppress proliferation of cells at the basal epithelium tosome degree at levels similar to those seen in the closedeye.19,31However, highly oxygen transmissible siliconehydrogel lenses have less effect on proliferation than otherlens types. Ladage et al reported a significant reduction inproliferation of central epithelial basal cells with siliconehydrogels (33.8%), which is less pronounced than that

Figure 2. Effects of 6-nights or 30-nights extended wear (EW) on

corneal homeostasis. Central corneal epithelial thickness and epi-

thelial cell surface area were assessed by in vivo confocal micros-

copy. Dk=oxygen permeability; RGP=rigid gas permeable; 6N=6-

night EW; 30N=30-night EW; *=p

8/10/2019 noiembrie 2005

5/20


found with hydrogel lenses of lower oxygen transmissibil-ity (40.8%) or in the closed eye model (47%).19

Ladage et al suggested that the reduction in epithelialthickness seen with contact lens wear may be caused by areduced demand for new surface cells, which, in turn, maysignal suppression of basal cell proliferation.19Insufficient prolif-eration and movement of epithelial cells to the corneal surface,may then lead to corneal thinning. Although there is some indi-cation that basal cell proliferation recovers with silicone hydrogelsafter 8 days of wear, it is not clear whether this response is aresult of an adaptive response to contact lens wear or is a

result of a delay in cells entering the cell cycle.19

3. Formation of Epithelial MicrocystsEpithelial microcysts that form during contact lens wear

are perhaps the most reliable clinical indicator of chronichypoxic stress brought about by extended wear.32Withhigh magnification slit-lamp microscopy and marginalretroillumination, they appear as very small (10 to 50 mdiameter) translucent and irregular dots (Figure 3), usu-ally distributed as a ring in the midperiphery of the cor-nea. Fewer than 10 microcysts are associated with no lenswear or daily wear,14,33,34and more than 50 microcystsindicate severe chronic hypoxic stress.35Wearers of hy-drogel lenses usually develop microcysts within 3 months

of commencing extended wear, after which a relativelysteady state is reached; however, numbers do fluctuate overtime.36By comparison, the numbers of microcysts in wear-ers of silicone hydrogel lenses have been shown to remainconsistently low (less than 10) after 18 months37and upto 3 years of extended wear (Figure 4), irrespective of theconsecutive number of nights of wear (6 versus 30).17

The reversed illumination displayed by epithelialmicrocysts indicates that they are comprised of degener-ated cellular material,38,39possibly arising from hypoxia-induced apoptotic processes.13,40Microcysts are thoughtto form in the basal cell layer of the epithelium and moveto the surface during cellular turnover. The transitory in-crease in microcyst numbers after sufficiently higher lev-els of oxygen are supplied to the eye, either by removinghydrogel lenses or by replacing them with silicone hydro-gel lenses, is postulated to result from the resurgence incorneal metabolism. The transitory increase in the num-ber of microcysts occurs in approximately 50% of sub-

jects and slowly decreases to non-lens wearing levels over1 to 3 months (Figure 5).1,37

4. Susceptibility to Bacterial BindingLens-induced hypoxia affects corneal structure and

function, but it is not clear how these often subtle changes

Figure 3. Typical appearance of corneal epithelial microcystsx30

magnification

Figure 4. Mean numbers of microcysts in subjects wearing sili-

cone hydrogel lenses on extended wear schedules over 3 years.

Subjects were classified by their previous lens wear history. Sub-

jects who were new to lens wear or who had previously worn sili-

cone 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 perfor-

mance of 6- or 30-night extended wear schedules with silicone hy-

drogel lenses over 3 years. Optom Vis Sci 2004;81:398-406, with

permission from the authors and the publisher.)

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 transmissibil-

ity. (Reprinted from Sweeney DF, et al. Clinical performance of sili-

cone hydrogel lenses, in Sweeney DF (ed). Silicone hydrogels: con-

tinuous wear contact lenses. Edinburgh: Butterworth Heinemann,

2004, pp 164-216, with permission from the publisher.)


8/10/2019 noiembrie 2005

6/20


translate to a clinical setting. Lens-induced hypoxia is pos-tulated to predispose lens wearers to a greater rate of in-fection and inflammation by contributing to impaired cor-neal integrity and wound healing41-43and by increasingthe susceptibility of corneal surface cells to bacterial bind-ing.25,44-46The ability of Pseudomonas aeruginosa, a majorocular pathogen, to bind to human exfoliated epithelial

cells is significantly greater with wear of all soft contactlens types compared to rigid gas permeable lenses, irre-spective of wear schedule, and significantly greater bind-ing occurs with hydrogel lenses compared to siliconehydrogels.23-25

Bacterial binding to host cells may be mediated throughlectin-binding receptors on host cell membranes, and, inanimal studies, any type of contact lens wear increasesexpression of such receptors in a closed eye model.47Lowoxygen-transmissible lenses have a more profound effecton expression of lectin-binding receptors than more highlyoxygen transmissible lenses. Results from prospectivepopulation-based studies suggest that the rate of infectionwith 3-4 weeks or more of continuous overnight wear ofsilicone hydrogel lenses is not increased over the rates re-ported with earlier extended-wear soft lens types typicallyworn for shorter periods of overnight wear. However, it isclear from these studies that the single major risk factorfor corneal infection is overnight lens wear irrespective ofsoft lens material.48-52

C. Lens-induced Changes in the Limbal Region

The superficial blood supply of the limbal region stemsfrom the episcleral arterial circle, which is situated 1 to 5mm posterior to the limbus and is formed by branches

from the anterior ciliary arteries.53Blood also enters theepiscleral circle from vessels communicating with the in-traocular arterial circle, which is deeper within the eyeand derived from the long posterior ciliary arteries.54-56

Two types of vessels emerge from the episcleral circle. Thosein the first group pass anteriorly, among the palisades of

Vogt, then subdivide and recombine extensively to formthe peripheral corneal or limbal arcades. The second groupis comprised of recurrent vessels, which partially contrib-ute to the limbal arcades but mainly travel posteriorly tosupply the anterior 3 to 6 mm of conjunctiva. Capillaryvessels are confined mainly to the upper stromal levels ofthe conjunctiva, whereas larger vessels and nerves pen-etrate the lower stratum. The cornea itself is avascular, sothe limbal vessels provide the nearest point of access toblood-borne defense mechanisms.

Filling and engorgement of the limbal capillaries com-prise one of the best-documented signs associated withboth daily wear and extended wear of hydrogel contactlenses and can be detected after as little as 4 hours of lenswear (Figure 6). Although several etiologies have beenproposed for lens-induced limbal hyperemia, hypoxia isnow considered to be the primary cause. Using soft con-tact lenses of varying oxygen transmissibility, Papas hasshown that hypoxia in the region immediately beneath

the lens periphery creates a hyperemic response of a mag-nitude that is closely related to the oxygen transmissibilityof the lens in that region (Figure 7).57,58Wearing siliconehydrogel lenses of high oxygen transmissibility would,therefore, be expected to abolish the limbal vascular re-sponse, and several recent reports confirm that this is, in-deed, the case.15, 59-62Limbal hyperemia in silicone hy-drogel lens wearers is no different from that in non-lenswearers within the first 4 hours of lens wear (Figure 6)and after 9 months of extended wear,14and it is signifi-cantly less than that found in hydrogel lens wearers.15,16,61

Although limbal hyperemia itself is not sufficient to causecorneal vascularization, it is of concern because it doesseem to be a factor necessary for corneal vascularization.

IV. CORNEAL VASCULARIZATION

New vessel growth in the cornea is initiated in responseto a stimulus that has the right character, strength, andduration to disturb the dynamic equilibrium of pro- andanti-angiogenic factors that maintain avascularity in thenormal cornea.63The effect is to up-regulate one or more ofan array of molecular messengers that control new vessel

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 repre-

sent mean 1 SD.

Figure 7. Relat ionship between peripheral lens oxygen

transmissbility and change in limbal redness graded using decimal-

ized 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.)


8/10/2019 noiembrie 2005

7/20


growth. Although the full range of agents and their activ-ity have not been established, vascular endothelial growthfactor (VEGF) appears to have a particular role. Found atlow levels throughout the normal human cornea, the con-centration of VEGF substantially increases during the vas-cularization process64,65and has three key properties cru-cial to the process of corneal vascularization. These arethe abilities to promote monocyte chemotaxis, increasedlocal blood flow (hyperemia), and vascular endothelial cellmitosis.

A. Mechanisms

Leukocytes, and in particular macrophages, are cru-cial to the process of corneal vascularization. Animal mod-els show that they are capable of producing a series ofeffective angiogenic mediators in their own right.66,67 Thechemotactic activity of VEGF draws leukocytes to the vas-cular bed adjacent to the injury site, from where they be-gin to infiltrate the cornea. This movement appears to bethe 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 andbasic fibroblast growth factor (bFGF) induces the vascu-lar endothelium to proliferate. Increased mitotic activityin these normally quiescent endothelial cells creates a pro-fusion of new cellular material that is then available forassembly into vessels. Because the surrounding cornea isquite dense, however, it is impossible for these cells toform tubules and penetrate a significant distance towardthe injury site without additional assistance.69This assistanceis provided by a process of tissue remodeling that acts to alterthe characteristics of the cornea ahead of the proliferatingcells. Animal models indicate that one such mechanism ap-pears to involve the activity of the matrix metalloproteinaseMMP-2,70-72a collagenase that is up-regulated by VEGF73

and digests the collagen matrix of the cornea.

Direct leukocyte activity has been proposed to havesimilar effects.74Excessive corneal damage is preventedby the antagonistic action of a second series of endogenoussubstances known as tissue inhibitors of metalloproteinases(TIMPs), which dampen MMP activity and limit tissuechanges.71In this way, new vessels bud out from existingcapillaries, penetrate the cornea and grow toward the in-

jury. Assuming that the original stimulus is maintained,the growth of new vessels can proceed at a rate of about0.5 mm per day, with blood cell movement occurring assoon as 72 hours after the event.68

Once the stimulus ceases, whether or not vessel re-

gression occurs appears to depend on how far pericyterecruitment has progressed. Pericytes are cells that havefeatures in common with smooth muscle cells and whichperiodically surround capillaries.75,76They are recruitedto new vessels quite rapidly after their creation, and thisdetermines their permanency. Around 80% of vessels be-come associated with pericytes within their first 2 weeksand vessel regression is unlikely once this has happened.77

Hence, stimuli causing vascularization responses must beremoved within about 2 weeks of onset if corneal vesselsto prevent their becoming permanent.

B. Hypoxia as a Stimulating Factor

Several stimulating agents can initiate corneal vascu-larization, and the precise mechanisms associated withcontact lens wear are not fully understood. However, sub-stantial clinical evidence suggests that hypoxia is an im-portant factor. A compelling supporting observation is thatrates of corneal vascularization found with various con-tact lens types differ substantially. When the entire corneais covered, as is the case with soft lenses, the rates of cor-neal vascularization are generally higher than when theperipheral cornea is exposed to the atmosphere, as duringrigid gas permeable lens wear. In one study, 18% of softlens wearers had corneal vascularization compared to only

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 perfor-

mance 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.)


8/10/2019 noiembrie 2005

8/20


1% of rigid gas permeable wearers.78It is hypothesizedthat this is related to the relatively greater peripheral hy-poxic load induced by the larger diameter soft lenses, aview supported by the observation that in wearers of sclerallenses made from poly methyl methacrylate (PMMA),which has essentially zero oxygen transmissibility, cornealvascularization regressed after their lenses were refabricated

using a rigid gas permeable polymer.79The key point tonote here is that the diameters of scleral lenses are suchthat they cover not only the limbus, but also the surround-ing sclera. Thus, any mechanical effect would be substan-tially constant, irrespective of the oxygen transmissibilityof the polymer, leaving increased oxygen tension at theocular surface as the likely reason for improvement.

Silicone hydrogel lenses have been reported to be ef-fective in preventing the growth of new vessels duringextended soft lens wear, providing further support for therole of hypoxia in corneal vascularization,61as well as sug-gesting a clinical strategy to prevent vascularization in con-tact lens wear. Dumbleton et al61reported a small but clini-cally significant decrease in vascularization after 9 monthsof extended wear among silicone hydrogel lens wearerswho had moderate levels of vascularization at baseline,but not in those who had low baseline levels. Vasculariza-tion also is reduced in long-term wearers of hydrogel lenseswho transfer to silicone hydrogel lenses, and is a result ofthe emptying of blood vessels to leave ghost-like vesselsin the limbal vasculature (Figure 8).

Although vessel growth only rarely affects vision incontact lens wearers, it has been suggested that corneal vas-cularization interferes with immune privilege within the an-terior chamber.80Therefore, 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 fluores-cein is used to assess corneal integrity during contact lenswear. In asymptomatic non-lens wearers, sodium fluores-cein staining is relatively common (40-100% of eyes ex-amined) and occurs mostly in the nasal and inferior re-gions of the corneal epithelium.34,81,82Asymptomaticstaining also occurs in contact lens wearers and is causedby minor abrasions from repeated rubbing against teardebris trapped beneath the lens, lens-induced effects ofmechanical interaction of the lens with the corneal sur-face, and desiccation, toxic/hypersensitivity, and inflam-matory effects. Although any compromise to the epithe-lial surface potentially places contact lens wearers at riskof infection, micropunctate fluorescein staining equivalentto the levels seen in non-lens wearers83-85generally is con-sidered clinically insignificant.

A. Mechanical Abrasion

Mechanical abrasion caused by trapped debris or ill-fitting or defective lenses can result in characteristic pat-terns of staining, ranging from foreign body tracks to linear

lesions. To fit well, soft contact lenses must have the ap-propriate design and sufficient flexibility to conform tothe steeper cornea and flatter sclera and to minimize anylocal areas of pressure that may be intensified by the fric-tional forces applied by the upper lid. Silicone hydrogellenses of relatively high elastic modulus can have a greatermechanical impact on the corneal surface, manifesting as

superior epithelial arcuate lesions (SEALs)86; however,optimal lens design can minimize this occurrence. Over-all, the frequency of mechanically-induced corneal stain-ing that occurs with silicone hydrogel lenses is low andrarely exceeds micropunctate levels.15,17

B. Excessive Desiccation

Excessive desiccation is a major cause of corneal stain-ing with mid- to high-water soft contact lenses.87,88Hy-drogel lenses can dehydrate by as much as 20% withinminutes after lens insertion; thicker lenses dehydrate lessthan thinner lenses made from the same material, andgreater effects are seen with high-water-content materialscompared to low water materials.89,90This type of stain-ing usually manifests as localized areas of snowflake-likepunctate or coalescent punctate staining in the inferiorcornea and is rarely associated with silicone hydrogellenses, which are made from relatively low water contentmaterials.

Clinically unacceptable levels of corneal staining doarise in individuals with specific combinations of siliconehydrogel materials and multipurpose lens care solutions.In such cases, diffuse punctate staining is scattered acrossthe whole cornea and can be concentrated more in a ringaround the periphery (Figure 9). Although patients are

generally asymptomatic, the severity of staining is suffi-cient to necessitate cessation of lens wear.91

Most solution-based staining associated with silicone hy-drogel lenses is caused by multipurpose solutions with poly-hexamtheylene biguanide (PHMB) as the active ingredi-ent.91-95Although all lens care solutions with a disinfecting

Figure 9. Sodium fluorescein toxic staining associated with in-

compatibility between silicone hydrogel lenses and contact lens

care solutions. X10 magnification


8/10/2019 noiembrie 2005

9/20


agent are to some degree toxic to the cornea, little or nosolution-based staining seems to occur with solutions con-taining hydrogen peroxide or polyquaternium-1-basedcompounds.91,92.96Moreover, the same silicone hydrogelmaterial can interact differently with different formulationsof PHMB-based solutions,92which indicates that compo-nents other than the active ingredient may also be respon-

sible for the incompatibility seen. The mechanism for theincompatibility observed between silicone hydrogel lensesand PHMB-based lens care solutions is unknown, althoughthe most likely explanation is that specific component(s)within the formulation adsorb to the lens surface, or possi-bly to lens deposits that accumulate on the surface, anddesorb after lenses are inserted in the eye.91

VI. SUPERIOR PALPEBRAL CONJUNCTIVA

The superior palpebral conjunctiva is an uninterruptedextension of the bulbar conjunctiva that lines the poste-rior surface of the upper lid. While structurally similar tothe bulbar conjunctiva, there are some key functional dif-ferences.97The epithelium of the palpebral conjunctivaconsists of a greater concentration of goblet cells, whichform in the basal layers before moving to the surface anddischarging their contents, and the dense stromal layer ofthe bulbar conjunctiva is replaced by the tarsal plate.

The conjunctiva is a highly immunologically sensitivetissue, which in the noninflammatory state contains highnumbers of mast cells and other inflammatory cells in thestroma but not the epithelium. Inflammatory responses ofthe superior palpebral conjunctiva are characterized byan influx of inflammatory cells to the epithelium and even-tual formation of raised papillae, which comprise blood

vessels in the center of an assembly of lymphocytes andplasma cells.

Contact lens-induced papillary conjunctivitis (CLPC)is an inflammatory reaction of the upper palpebral con-

junctiva that is thought to be a consequence of mechani-cal trauma and/or an allergic response to lens materials ordeposits that accumulate on the lens surface. The condi-tion is clinically significant, because it is an underlyingcause of lens intolerance and is the major reason patientsdiscontinue lens wear.17,98

A. Clinical Features of Contact Lens-induced

Papillary Conjunctivitis

As described by Allansmith et al,99the superior palpe-bral conjunctiva is divided into 5 areas: area 1 is nearestthe palpebral border, area 2 is the central area, area 3 isalong the lid margin of the tarsal plate, area 4 is near thenasal region and area 5 is near the temporal region. Areas4 and 5 comprise the junctional conjunctival tissue.

Clinical diagnosis of CLPC is based upon biomicro-scopic signs of papillary changes across each of the palpe-bral areas, as seen with a slit lamp biomicroscope (X10 toX16 magnification) with diffuse white light. The area alongthe tarsal fold is not included in assessment of the uppereyelid. Papillary redness and roughness are graded sepa-

rately, and the number of papillae and papillae of largestsize are recorded for each area when lens wear begins andat each follow-up visit, so that changes caused by contactlens wear can be assessed. CLPC is diagnosed when raisedpapillae at the upper eyelid are 0.3 mm or greater in di-ameter, and when hyperemia is increased in any area.

After papillae have been examined under white light,the conjunctiva can be examined using sodium fluores-cein staining with a cobalt blue light and yellow fluores-cein enhancement filter (Kodak Wratten #12) to allowgreater differentiation in the size and definition of the pa-pillae. The presence or absence of apical staining of thepapillae is also noted with this technique.

Although patients with CLPC may be asymptomatic,symptoms such as foreign body sensation, itchiness, mu-cous discharge, increased lens awareness, excessive lensmovement and blurred vision due to lens mislocation canbe of sufficient severity to cause lens intolerance. A majorproblem with CLPC is that even though symptoms gradu-ally disappear with cessation of lens wear, the signs at theupper palpebral conjunctiva do not always completely re-solve, predisposing the patient to recurrent CLPC whenlens wear resumes.

CLPC is more frequently seen with soft lens materials

Figure 10. Contact lens-induced papillary conjunctivitis (CLPC)

with soft contact lens wear. A=local CLPC; B=general CLPC. X10

magnification


8/10/2019 noiembrie 2005

10/20


than with rigid lens materials100 and is particularly associ-ated with extended wear versus daily wear.101With con-tact lens wear, papillae occur either as a small cluster inareas 2 and 3 (local response) or are randomly distributedacross the entire region (general response).102,103The mostrecent analysis indicates that although the incidence ofCLPC during extended wear is similar between hydrogel

(3.4 per 100 patient eye years) and silicone hydrogel lenswearers (4.7 per 100 patient eye years), a significantlygreater proportion of events with silicone hydrogels arelocal compared to general (Figure 10).104

B. Etiology

Several theories exist as to the etiology of CLPC, whichinvolve 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 sur-face contribute to the release of inflammatory mediators;lens deposits that accumulate during wear may stimulatethe antigenic response or may contribute further to trauma.

The immunologic response of patients with CLPC isquite complex, involving both immediate hypersensitiv-ity reactions (Type I hypersensitivity) and delayed cell-me-diated responses (Type IV hypersensitivity). The condition ischaracterized by a mixed cellular infiltrate comprising mastcells, eosinophils, basophils, and neutrophils, as well asexpression of a range of inflammatory mediators.

Involvement of Type 1 hypersensitivity is indicated bythe finding that patients with a history of allergy are moresusceptible to CLPC105-108and that increased levels of IgE,the antigen-recognition molecule of type I hypersensitivity

reactions, is present in the tears and serum of patients withactive CLPC.109-111Degranulation of IgE-bound mast cellsreleases mediators into the surrounding conjunctival tissue,which causes edema, hyperemia, and itching. Degranulatedand intact mast cells have been found in the conjunctivalepithelium of patients with CLPC,112,113and products of mastcell degranulation have been detected in tears.110

Delayed type IV hypersensitivity is a T-cell-mediatedreaction in response to persistent antigenic stimuli thatresults in tissue injury via cytokine-induced inflammationor direct cell lysis. Involvement of type IV hypersensitiv-ity in CLPC is suggested by the presence of helper T cells(CD4+) and CD45RO+ memory cells, as well as epithelialcells expressing major histocompatibility complex in con-

junctiva of patients with CLPC.114,115Moreover, increasedexpression of a range of cytokines that recruit and activateT cells in conjunctival epithelial cells in patients with CLPCfurther supports a role for type IV hypersensitivity in thiscondition.114,116The profile of T cell cytokine expressionin patients with CLPC is indicative of a TH2 cell-drivenresponse, which is responsible for the further release ofinflammatory mediators and an accelerated immune re-sponse after successive exposure to antigen.

More frequent replacement of contact lenses107or regu-lar use of enzymatic cleaners to remove accumulated de-

posits from the surfaces of worn lenses are the most effec-tive strategies used in the treatment of CLPC; however, itis not yet understood how contact lens deposits contrib-ute to the etiology of this condition. There is no correla-tion between the amount of protein on lenses and CLPC,and deposits on lenses of patients with CLPC appear to bevery similar to those on lenses of asymptomatic wearers,117-

119which supports the hypothesis that CLPC is more likelyrelated to individual responses to lens deposits rather thanto differences in type of deposits per se. Ballow et al exam-ined contact lens deposits in three groups of monkeys,who wore contact lenses taken from human patients withand without CLPC, as well as unworn lenses.120Monkeyswith worn lenses from subjects with CLPC developed acellular response similar to CLPC and elevated levels ofIgE were detected in the tears. No effect was evident inmonkeys that received worn lenses from asymptomaticsubjects, and the level of IgE in tears was similar to that ofmonkeys that had received unworn lenses. This studystrongly implicates accumulated lens deposits in the typeI hypersensitivity response seen in CLPC.

Evidence for a mechanical component to CLPC is pro-vided by the palpebral response to contact with raised for-eign objects, such as exposed sutures, ocular prostheses,and epithelialized corneal bodies.121-125Although the pap-illary response in these instances is severe, it remains lo-calized to the area of contact and resolves rapidly once theobject is removed. Moreover, the tarsal conjunctiva of thesepatients are characterized by a preponderance of polymor-phonuclear leukocytes with no eosinophils,126and elevatedlevels of neutrophil chemotactic factors, associated withconjunctival injury, can be detected in tears.127

The local response with silicone hydrogel lenses is farless severe than that which occurs with raised foreign ob-

jects but is similar in that papillae remain localized to oneor two areas of the conjunctiva.102 It is postulated thatrepeated rubbing of worn lenses against the upper palpe-bral conjunctiva may stimulate inflammatory mediatorsassociated with mechanical trauma at the superficial epi-thelium. Factors that may contribute to local CLPC withsilicone hydrogel lenses include the modulus of elasticity,peripheral lens fit, or edge shape, as well as patients inad-vertently wearing inverted lenses.

VII. TEAR FILM

Successful lens wear requires a stable tear film to main-tain normal optical, lubrication, and defense functions.Contact lens wear has the potential to destabilize and im-pact each of these functions by: 1) affecting the structureand function of the tear film; 2) altering the normal lid-cornea-tear resurfacing mechanism; 3) causing compart-mentalization of the tear film; 4) altering pre- and post-lens tear exchange characteristics; or 5) increasing tearinstability. Moreover, accumulation of debris, metabolicby-products, and inflammatory cells, as well as lens-in-duced changes in tear film components, contribute to ad-verse responses that are both inflammatory and mechani-


8/10/2019 noiembrie 2005

11/20


cal in nature. In general, contact lens wear of any typeappears to have a negative effect on tear physiology, spe-cifically by causing an increase in tear evaporation, an in-crease in the rate of tear thinning, and a reduction in tearbreak-up time, all of which are most likely due to a re-duced thickness in the lipid layer.

Closed-eye tear defense mechanisms are relevant tocontact lens wear because lenses worn in the closed eyepresent a higher risk of infection than lenses worn in theopen-eye.128-130When the eye is closed, the tear film stag-nates and takes on the characteristics of subclinical inflam-mation,131-134which is intensified during contact lens wear.Specifically, there is a reduction in the levels of total and spe-cific secretory immunoglobulin A (sIgA);135-139an increasein tear fibronectin;139,140increases in the concentration of thecytokines interleukin (IL)-6141and IL-8142; and lower poly-morphonuclear leucocyte (PMN) recruitment.143

The implications of altered tear components in over-night contact lens wear have not been fully elucidated;however, it is generally thought that these changes mayalter normal defense functions, such as phagocytosis andmicrobial killing, and could prolong the retention time ofmicroorganisms at the ocular surface. The limited infor-mation available suggests that the effect of silicone hydro-gel lenses on closed-eye tear defense mechanisms is simi-lar to that of hydrogel lenses. sIgA is similarly reducedwith overnight wear of silicone hydrogel lenses and withhydrogels,144and the levels of tear IL-8 are elevated withsilicone hydrogel lens wear, but to a lesser extent than withhydrogel lens wear.144

A. Pre-lens Tear Film

The pre-lens tear film (Figure 11) is a dynamic struc-ture, which may be affected by environmental condi-tions,145 time of day, individual patient tear characteris-tics,146and position on the cornea and lid position as thelid travels upward following the blink.147It can also beaffected by a range of lens-related factors, including lenswear schedule, lens diameter, lens fitting relationship and,to a lesser extent, lens type and surface chemistry.

Contact lens insertion produces an initial disturbanceto tear film thickness and structure. Reflex tearing can cause

a transient hypo-osmolar tear film and thick pre-lens tearfilm. However, during the initial settling period followingcontact lens insertion, the pre-lens tear film over the cen-ter of the contact lens thins148,149to an average of 2.3182m.150The average published thickness of the pre-lenstear film measured by interferometric techniques is about3 m.151Good concordance exists between studies, de-

spite the use of different methodologies, with pre-lens tearfilm thicknesses of up to 6.4 m reported.146,151-153

Although the average thickness of the pre-lens and pre-corneal tear films is similar,146,151there is greater varia-tion in the thickness of the pre-corneal tear film comparedto the pre-lens tear film. The pre-lens tear film is less stablethan the pre-corneal tear film,153,154and this instability isclosely associated with thinner tear films.144Tear film sta-bility may be relevant in contact lens dehydration,90,155

lens deposition,156,157 corneal staining,158 and patientsymptoms.159Localized thinning of the pre-contact lenstear film also occurs at the lens edge, which may alignwell with a proposed model of tear film break up,151wherethinning occurs due to a discontinuity at the ocular sur-face and is driven initially by surface tension and later byevaporation.

Despite the slight variation in tear break-up time be-tween different hydrogel materials,153,160 it is generallyagreed that differences in hydrogel lens types have littleoverall effect on the quality of the pre-lens tear film. Thereis some evidence that thick hydrogel lenses are associatedwith a thicker pre-lens tear film compared to thin hydro-gel lenses153and that high water content hydrogel lensesare associated with a thicker pre-lens tear film160but lowertear thinning time.161 However, the effect of lens water

content on the pre-lens tear film is somewhat controver-sial, and other studies have found that water content andlens type are not relevant to pre-lens tear stability.154Onestudy examined the effects of differences in material hydro-philicity and coating thickness, using a range of gas plasmaand wet chemistry surface attachment methods; it was deter-mined that the drying time over the lens surface on-eye wasno different between lens surface chemistries.156

Although silicone hydrogel lens materials are markedlydifferent from their hydrogel counterparts, the thickness ofthe pre-lens tear film between these lens types is remarkablysimilar,162further supporting the view that the thickness ofthe pre-lens tear film is independent of lens type.

B. Tear Evaporation

The rate of tear evaporation is greater in eyes wearingany contact lens than in non-lens wearing eyes.163-167

However, as regards the pre-lens tear film, no relationshipappears to exist between lens water content or materialtype and the degree of evaporation. Additionally no con-sistent differences in tear evaporation between hydrogeland silicone hydrogel lens materials164,165 have beenshown, despite the greater resistance of silicone hydrogellenses to dehydration in vitro.168Dehydration of hydrogellenses on-eye may affect lens fitting, comfort, and oxygen

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

X10 magnification.


8/10/2019 noiembrie 2005

12/20


transmissibility, and may cause epithelial desiccation.Material properties, and not solely water content, can

influence the dehydration of hydrogel lenses,169but theinfluence of these properties on dehydration is less clearwith silicone hydrogel lenses. One study has suggestedthat silicone hydrogel lenses dehydrate more slowly on-eye than hydrogel lenses.170This may be consistent with

preliminary analysis of a small group of hydrogel lenswearers that transferred to silicone hydrogel lens wear for12 months.171These subjects reported significantly moresensations of dryness with hydrogel lenses than with sili-cone hydrogels and no lens wear, and they reported thatend-of-day comfort during silicone hydrogel lens wear wasno different than with no lens wear.171However, in vivostudies have previously not demonstrated a link betweenhydrogel lens dehydration and subjective dryness symp-toms,172and in vitro contact lens dehydration is perceivedto be a poor predictor of on-eye dehydration.173

Tear film stability is affected by the thickness of thelipid layer of the tear film, with reduced tear film stabilitybeing associated with a thinner lipid layer.153,165,174,175

Thinner lipid layers, either for the pre-ocular or pre-lenstear film,176,177are more prone to contamination and maypromote tear evaporation and lens dehydration. Tear break-up time is inversely related to the rate of tear evaporationand to lipid layer thickness,178and there is some evidencethat a thicker aqueous layer may encourage developmentof a thicker and more stable lipid layer.174Compared withthe pre-corneal tear film, the pre-lens lipid layer is thin orabsent.153,160,179

Large scleral lenses are associated with thicker lipidlayers, possibly because the barrier effect of the lens edge

is reduced.174Hydrogel contact lens wear affects tear lipidcomposition; lens wearers show lower levels of polar lip-ids and higher levels of non-polar cholesterol based lip-ids.180Conceivably, this shift disrupts lipid spreading andnegatively affects the outer hydrophobic lipid layer, caus-ing a thinner and less robust pre-lens lipid layer. Althoughthe thickness and appearance of the lipid layer do not pre-dict tolerance to contact lens wear, higher levels of de-graded tear lipids (MDA and 4-HNE), secretory phospho-lipase A2 and the lipid carrying protein, lipocalin, are foundin the tears of subjects intolerant to lens wear.175Suchchanges in tear film components can disturb the natureand dynamics of the tear film; specifically, we believe thatlipid degradation plays a major role in destabilization ofthe pre-lens tear film.

C. Lens Wettability and Deposits

Lens wettability is a measure of the quality of the pre-lens tear film over the anterior surface of a contact lens. Itis assessed in vitro using the dynamic contact angle tech-nique or clinically using subjective scales of tear break-upover a lens. Subjective scales range from a totally hydro-phobic, non-wetting surface to wettability of a healthycornea. Typically, hydrogel lenses are used as a mid-waybenchmark for comparing lens performance.

Deposition and denaturation of tear film componentsto a contact lens surface is an inevitable consequence oflens wear that contributes to poor wettability, reducedbiocompatibility,181 adverse responses such as CLPC, in-creased contact lens dehydration, and reduced comfort,and may conceivably influence ocular surface defensethrough 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 Table1) with the intent of improving wettability and preventingtear film deposits from accumulating. Atomic force mi-croscopy of the surfaces of balafilcon A and lotrafilcon Asilicone hydrogel lenses reveals that, although both lenseshave been surface-modified, significant differences existin the uniformity of the surface coating. Balafilcon A lensesare characterized by glassy hydrophilic islands, leavingareas of hydrophobic substrate, whereas lotrafilcon A lensesare more uniformly coated.182,183In vitro assessment in-dicates that the wettability of silicone hydrogels is similarto that of hydrogel lenses182; this is confirmed by clinicalmeasures that demonstrate little overall difference betweensilicone hydrogel and hydrogel lens wear.15 17,184Despitethese similarities, the in vitro wettabilities betweenbalafilcon A and lotrafilcon A silicone hydrogel lenses aredifferent and may reflect the differences in surface treat-ment.183More hydrophobic lens surfaces have greater af-finity for accumulation of lipid deposits, and this is borneout by studies comparing lens spoilation between lenstypes.185

Lens spoilation is dependent on the individual wearerstear 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 at-tract both surface- and matrix-associated lysozyme fromthe tear film.186,187Conversely, Group II materials (highwater content, non-ionic) containing N-vinyl pyrrolidone(NVP) absorb more lipid than do other hydrogel lens mate-rials.188Compared with ionic hydrogel lens materials, sili-cone hydrogel lenses absorb considerably less lysozyme, butthey also deposit far more lipid, especially oleic acid and oleicacid methyl ester, regardless of the type of silicone hydrogellens material.184However, the authors concede the limita-tion of the non-cross-over study design and acknowledge thatlipid deposition is highly wearer-specific.

Greater hydrophobicity may arise from nonuniform sur-face treatment,183but other factors may also affect lipid depo-sition, e.g., the presence of lipid-attracting bulk material com-ponents, including NVP which is present in balafilcon A.

With increased wear time, the surface lipid may progres-sively diffuse into the lens matrix; both surface and bulklipid appear to be higher for balafilcon A silicone hydrogellenses compared with lotrafilcon B silicone hydrogels.183

D. Postlens Tear Film and Tear Exchange

In the non-contact lens-wearing eye, blinking and nor-mal tear turn-over effectively remove debris, toxins, antigens,


8/10/2019 noiembrie 2005

13/20


and microorganisms from the ocular surface. Contact lenswear disrupts this process and slows tear exchange in thepost-lens tear film. Prolonged retention of debris, cells,and microorganisms behind the contact lens has beenimplicated in the development of inflammatory and infec-tious adverse responses. Rigid gas permeable lenses havemuch faster rates of tear exchange and retain far less de-

bris after eye opening compared to soft lenses, which mostlikely contributes to the low rate of inflammatory compli-cations associated with extended wear of theselenses.189,190Although optimizing post-lens tear exchangeappears to be important in limiting lens-related complica-tions 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 thepost-lens tear film measured by interferometric techniquesis estimated to be between 2 and 5 m,150,162,191,192withno apparent depletion during the initial settling period.148

The thickness of the post-lens tear film appears to be morevariable than the that of the pre-lens tear film, possibly be-cause of factors such as lid pressure, the relationship be-tween the back surface of the lens and corneal curvature.151

Subtractive pachometry has also been used to estimatepost-lens tear film thickness193,194; this technique yieldssomewhat thicker measurements than interferometry, pos-sibly because of some systematic errors compounded byinherent large variability.150Notwithstanding such poten-tial limitations, pachometric measurements have demon-strated that the thickness of the post-lens tear film variessignificantly with lens modulus, optic zone radius, palpe-bral aperture size, and race (post-lens tear thickness is es-timated to be higher in non-Asian eyes than in Asian

eyes).193,194Fluorexon photography shows that post-lenstear film thickness varies considerably and nonuniformlyfrom the center to the periphery of the lens.195

The rate of tear exchange can be estimated usingfluorophotometry with high molecular weight fluorescenttracers instilled onto the back surface of the lens beforeinsertion. The kinetics of the rate of tear elimination ap-pears to be best described by a double exponential curve,and elimination may be described as either percent elimi-nation rate per minute (ER%: 8-10% for hydrogel lenses),tear replenishment rate (TRR), the percentage volume oftears replaced per blink (0.4-0.6% per blink), or T95, thetime taken for removal of 95% of the dye (20-35 minuteswith hydrogel lenses).

Although the values obtained by different methods arerelated, one value may be preferred over another in cer-tain instances.196The rate of tear exchange is influencedby wearer characteristics, such as palpebral aperture size197

or race (non-Asian versus Asian),197and it can be greaterwith smaller lens diameters198and when lens fenestrationsare used.195Clinically, however, the improvements in tearexchange achieved by decreasing lens diameter or addingfenestrations are not substantial, and efforts to improve tearexchange can compromise some aspects of lens fit. The pe-ripheries of small-diameter contact lenses, for example, are

more likely to interact with the lid margins during wearand may reduce wearer comfort.

Dispersive mixing modeling has suggested that tearmixing and exchange behind a contact lens is controlledby a combination of vertical lens movement and trans-verse (in-out) movement.199Clinically, however, a largechange in vertical lens movement has limited effect on tearreplenishment.197Silicone hydrogel lenses are consistentlyassociated with greater tear exchange than hydrogellenses,196,197and elimination rate appears to improve withincreased lens modulus,197which has been attributed tothe increased transverse movement with these lenses. Tearexchange on blinking with silicone hydrogel lenses has

also been demonstrated to contribute an additional 8% tocorneal oxygenation above that achieved through lenstransmissibility alone.200

Most studies of tear exchange and tear thickness withsilicone hydrogel lenses have been performed or modeledunder open-eye conditions with blinking. During eye clo-sure, the tear film behind a silicone hydrogel contact lensthins to

8/10/2019 noiembrie 2005

14/20


indentations can be substantial. Some examples extendthrough the full epithelial thickness, to at least the level ofthe basal lamina.202,203,207

When the lens is removed, the action of blinkingsweeps mucin balls from their epithelial cradles and intothe general tear film. From there, they follow the normalelimination route for tears via the lacrimal duct. Subse-

quent instillation of sodium fluorescein allows the small,hemispherical corneal depressions created by the mucinballs to be easily seen. The dye does not penetrate the cellsbut simply pools in the corneal depressions, indicatingthat epithelial barrier function is maintained throughout.

After lens removal, the normal, regular corneal con-tour returns spontaneously over 2-24 hours.203This re-markable ability of the corneal epithelium to mold itselfto, and then recover from, the local presence of a mucinball appears similar to the behavior seen duringorthokeratology and hints at viscoelastic properties thatare reminiscent of high viscosity fluids.

The numbers of mucin balls vary widely both withinand between individuals. While 10-20 are fairly typical,some individuals may have 100 or more. Approximatelyequal numbers of wearers of hydrogel and silicone hydro-gel lenses have exhibited mucin ball formation, and theproportion in both groups increases with the overall lengthof wear.208After 12 months, about 70% of all wearers mayhave observable mucin balls, although the actual numberper eye appears to be greater and to fluctuate more widelywith silicone hydrogel lenses. This differential has beenlinked to the higher elastic modulus typical of first-gen-eration silicone hydrogel materials, as compared to hy-drogel materials, and may not occur with the second-gen-

eration silicone hydrogel lenses that have lower elasticmodulus.

Notwithstanding the influence of lens material, someindividual predisposition to mucin ball production alsoseems likely. While it has not, so far, been possible to iden-tify all the factors that influence the response in a givenperson, evidence suggests that steeper corneal curva-ture,204,208better lens front surface wettability, and greateramounts of post-lens debris208are associated with a ten-dency to produce mucin balls.

The term mucin ball became commonly used amongclinicians over the last decade based on biomicroscopicappearance rather than analytical evidence of composi-tion. Direct analysis has been hampered by the inability toobtain identifiable samples or mucin balls from humansubjects.203Recently, however, capillary collection tech-niques have allowed examples to be cryo-sectioned andexamined immunohistochemically.202Although no mea-surable signs of lipid, cells, or bacteria were found, thesamples were positive to periodic acid Schiff (PAS) stain.This indicated the presence of a major polysaccharide com-ponent, a finding consistent with what would be expectedfrom a primarily mucin-based structure. Not all the samplesobserved in this study were composed of entirely PAS-positive material, however, suggesting that two alterna-

tive mucin ball configurations exist. Whereas the first typeis composed almost entirely of mucinous material, the sec-ond has a non-mucin core surrounded by a mucinous outershell. The latter alternative appears consistent with mucinball images derived from in-vivo confocal microscopy,where highly reflective centers appear surrounded by morepoorly reflective, translucent outer layers.203Further sup-

port for this type of internal structure comes from elec-tron microscope images of whole mucin balls, which showa relatively dense, fibrous core surrounded by a more ge-latinous outer layer or coating.202

The mechanism by which mucin balls form is not pre-cisely known. However, the proposal that they result fromthe relative motion between the corneal and lens sur-faces204 seems reasonable. The effect of this movementwould be to produce a rollingup of, presumably, epi-thelial surface mucus. Debris residing within the tear filmmay act as a seed point for this activity and, in the pro-cess, become encapsulated within the mucus shell. Addi-tionally, it may be that formation is aided by the collapseof the mucin matrix due to withdrawal of water as thepost-lens tear film dehydrates.202

Significant clinical sequelae have not been reportedassociated with mucin balls, although there have beenoccasional reports of visual complaints when large num-bers are present in a given individual,204and there may bea slightly increased risk of sterile, contact lens-related pe-ripheral ulcer (CLPU) in the presence of large numbers ofmucin balls.209The clinical consequences of mucin ballformation, thus, appear to be rather slight.

IX. SUMMARY AND CONCLUSIONS

All contact lens wear affects the ocular surfaces; cor-neal homeostasis is slowed, close interaction occurs be-tween ocular tissue and contact lens material, and tear filmstructure and physiology are altered. Many of the effectsare intensified by overnight wear, when the eye is in apro-inflammatory state, is prone to lens-induced hypoxia,and has closer interaction with the palpebral conjunctiva.

Silicone hydrogel lenses have combined the benefitsof a soft lens material with high oxygen transmissibility,giving wearers greater flexibility and longer wear timeswith excellent clinical outcomes. Many of these lenses havesufficient oxygen transmissibility to eliminate the clinicalmarkers traditionally associated with chronic hypoxia, andthey have a less pronounced effect on corneal homeostasisthan other lens types. However, extended wear with sili-cone hydrogels still has the potential to irreversibly affectcorneal homeostasis, particularly in the subset of wearers withhigher than average requirements for oxygen and in thosewith higher refractive errors, who require thicker and, hence,lower oxygen transmissibility lenses. The short-term effect ofsilicone hydrogel lenses on the tear film is little different fromthat of hydrogel lenses, and individual differences betweenwearers must be overcome. Future studies may evaluatethe effects of longer durations of wear on tear film charac-teristics with different lens types and elucidate individual


8/10/2019 noiembrie 2005

15/20


differences that influence wearer success.A major goal in contact lens design is to produce a

contact lens that interacts with the ocular environmentwith the biocompatibility of a healthy cornea. Improvingoxygen transmissibility has been a major achievement, yetfurther improvements with regard to lens movement, tearexchange, and mechanical interaction with the ocular sur-

faces are needed. Although acknowledging the increasedaverage continuous wear time with silicone hydrogel lenses,early studies indicate that during extended wear, siliconehydrogel lenses and hydrogel lenses have a similar risk ofinfection48-52 and corneal infiltrates98,210, such as contactlens-induced peripheral ulcer, confirming that hypoxia isnot a major contributor to the etiology of these events.

To further improve biocompatibility of contact lenseswith the ocular surfaces, we need a better understandingof the way in which contact lenses interact with the cor-neal surface, upper eyelid, and the tear film, and of thelens-related factors contributing to infection and inflam-matory responses. The quality of the tear film during long-term lens wear is particularly important, as it relates tosymptoms of dryness and discomfort, lens adherence anddeposition, and frictional forces from the blinking lid.Future strategies to limit adverse responses associated withprolonged retention of microorganisms at the ocular sur-face include incorporation of antimicrobial compoundsinto lens surfaces or bulk materials and, although un-proven, increasing post-lens tear exchange.

Given the recent revival in interest in compatibility oflens care solutions with newer lens materials, there is per-haps an opportunity for the development of solutions thatcan improve the stability of the pre-lens tear film. Fur-

thermore, the higher modulus of silicone hydrogel materi-als compared with hydrogel lens materials may allow inno-vative lens designs that would provide greater opportunity tomodulate tear exchange and reduce the mechanical interac-tion of lens wear with the ocular surfaces. Ultimatebiocompatibility will be achieved through future advances inpolymer and surface chemistry aimed at developing softerlens materials with optimized surface characteristics.

REFERENCES1. 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 re-

sponse 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


4. Wolosin J, Xiong X, Schutte M, et al. Stem cells and differen-

tiation stages in the limbo-corneal epithelium. Prog Retinal

Eye Res 2000;19:223-55

5. Huang A, Tseng S, Kenyon K. Paracellular permeability of cor-

neal and conjunctival epithelia. Invest Ophthalmol Vis Sci

1989;30:684-9

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 myo-

pia 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 cornealsurface reconstruction in patients with limbal stem cell defi-

ciency. Arch Ophthalmol 1998;116:431-41

9. Puangsricharern V, Tseng S. Cytologic evidence of corneal dis-

eases 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 epithe-

lial 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


14. Covey M, Sweeney DF, Terry RL, et al. Hypoxic effects on the

anterior eye of high Dk soft contact lens wearers are negli-

gible. 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) silicone-

hydrogel 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 hydrogelcontact 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 per-

formance of 6- or 30-night extended wear schedules with sili-

cone hydrogel lenses over 3 years. Optom Vis Sci 2004;81:398-

406

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 clo-

sure and disposable and silicone hydrogel extended contact

lens wear on rabbit corneal epithelial proliferation. Invest


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. OLeary 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

aeruginosato human corneal epithelial cells after overnight

and extended wear. CLAO J 1999;25:80-100


8/10/2019 noiembrie 2005

16/20


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-O2transmissible contact lenses on bac-

terial binding and corneal epithelium: a 1-year clinical trial.

Ophthalmology 2002;109:27-4025. Cavanagh HD, Ladage PM, Li SL, et al. Effects of daily and

overnight wear of a novel hyper oxygen-transmissible soft con-

tact lens on bacterial binding and corneal epithelium: a 13-

month clinical trial. Ophthalmology 2002;109:1957-69

26. Yamamoto K, Ladage PM, Ren DH, et al. Effect of eyelid clo-

sure 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 expres-

sion 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:Ab-

stract # 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 re-sponse: 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 anoma-

lies in a non contact lens-wearing population. Optom Vis Sci

1997;74:293-7

35. Zantos SG. Cystic formations in the corneal epithelium dur-

ing extended wear of contact lenses. Int Contact Lens Clin

1983;10:128-46

36. Keay L, Jalbert I, Sweeney DF, et al. Microcysts: clinical signifi-

cance 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 epi-

thelium after contact lens wear. J Am Optom Assoc

1987;58:812-8

40. Madigan MC. Cat and monkey as models for extended hydro-

gel 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 betweencontact lens transmissibility and binding of Pseudomonas

aeruginosato 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 cor-

neal 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 epithe-

lium 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;112:2172-951. Morgan P, Efron N, Brennan NA, et al. Risk factors for the

development of corneal infiltrative events associated with con-

tact 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 Schlemms canal and aque-

ous veins by means of Neoprene casts. Part III: arterial relations of

Schlemms 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-transmis-

sibility soft contact lenses do not induce limbal hyperaemia.

Curr Eye Res 1997;16:942-8


8/10/2019 noiembrie 2005

17/20


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 re-

sponse 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 ExpOptom 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 en-

dothelial growth factor and its receptors in inflamed and vas-

cularized human corneas. Invest Ophthalmol Vis Sci

2000;41:2514-22

65. Cursiefen C, Rummelt C, Kuchle M. Immunohistochemical lo-

calization of vascular endothelial growth factor, transforming

growth factor alpha, and transforming growth factor beta1 in hu-

man corneas with vascularization. Cornea 2000;19:526-33

66. Becker M, Kruse F, Assam L, et al. In vivo significance of ICAM-

1-dependent leukocyte adhesion in early corneal angiogen-

esis. 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 cornealneovascularization. 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 angiogen-

esis in gelatinase A-defici

Documents

noiembrie 2005