Deposits and symptomatology with soft contact lens wear

Clinical Article

Deposits and Symptomatology with Soft Contact Lens Wear Noel A Brennan, PhD, and M-L Chantal Coles, OD

Techniques for eliciting the identity and amount of deposits on soft contact lenses have improved consistently; however, there remain many questions regarding the role of specific deposit components in causing ocular reactions. We review the large body of literature on soft lens deposition to define the link between deposits and symptoms. Our critique attempts to clarify areas of doubt in previous methodologies for analyzing deposits, and to focus on the aspects of deposition as relevant to inducing ocular responses. The principal features confounding previous experimentation are: variables in experimental design; methodological flaws, such as imperfect extraction of material from a lens; focus on determining the quantity of a component at the expense of considering its nature and biological activity; reporting of results from nonrepresentative wearing conditions and lenses. Despite the introduction of disposable lenses, lens surface build-up remains an important factor in determining lens-wear success. The composition of deposits has been the target of many studies that show that lysozyme is the principal soilant on the lens surface. Estimates of protein quantities found on lenses are subject to the extraction technique but provide the common finding that Group IV lenses attract the greatest level of deposit. Nonionic lens surfaces have a greater affinity for lipids. The extent to which other species such as carbohydrates and minerals, contribute to lens deposits is less well defined. There are some clues to the structural basis for deposit formation, but further research is necessary to isolate the key events leading to deposits. Address reprint requests to Noel A Brennan, Brennan Consultants Pty Ltd, 96 High St Sth, Kew 3101, Australia. E-mail: [email protected] Accepted for publication November 11, 2001. ICLC, Vol. 27, 2000 © Elsevier Science Inc. 2002 655 Avenue of the Americas, New York, NY 10010

The sheer weight of energy that has been invested into examining lens coatings suggests that surface build-up plays a role in contact lens complications, although proof linking a specific component with a specific biocompatibility issue remains lacking. Emphasis should be placed on determining the nature, as well as quantity, of lens deposit components and on the development of clinical methods that can link symptomatology with derived deposit patterns. © Elsevier Science Inc. 2002 Keywords: Soft contact lens; Deposit; Symptomology; Protein; Denaturation; Care and maintenance

Introduction In a review article on biocompatibility issues of contact lenses, Korb reminds us to keep in perspective the remarkable effectiveness of these corrective devices.1 A large proportion of the population requiring vision aid is suitable for contact lens wear, and major complications are rare. Despite this relative success, the significant number of patients who cease wear each year2 remains a major problem for the industry to rectify. Biocompatibility of the lens surface is one of the major unresolved issues in achieving problem-free contact lens wear. A survey of practitioners in 1989 revealed that the most problematic soft lens issue at that time was lens deposition.3 All contact lenses attract a surface coating to some extent arising principally from components of the tear film,4,5 and some 80% of conventional lenses, when worn in extended wear, attract visible build-up.6 It has been estimated that deposition accounts for some 30% of aftercare visits.7 Perhaps most importantly, contact lens spoilage has been implicated in a wide range of complications, 0892-8967/02/$–see front matter PII S0892-8967(01)00060-8

Clinical Article including reduced wetting of the lens surface; symptoms such as dryness, discomfort, and visual disturbance; inflammatory reactions such as papillary conjunctivitis and acute red eye; and infections. A substantial amount of information about the nature of deposits has already been derived from phenomenological, descriptive, and observational research. In particular, considerable success has been achieved in describing and identifying the components from the tear film that gather on contact lens surfaces. Publications from the laboratories of Castillo8 –11 and Tighe12–16 have provided comprehensive descriptions of the components and structures of deposits. Diverse papers have since added incrementally to this knowledge. As a result of this research, the principal components of the protein, lipid, carbohydrate, and mineral groups that adhere to lenses, at least in quantitative terms, have been identified. Other combinations of species, such as glycoproteins and lipoproteins, have also been identified. A variety of deposit formations, including discrete deposits and films, have been described. The various appearances have been given a wide range of labels and include proteinaceous, muco-lipo-proteinaceous, jelly-bump, nodular, white-spot, film, plaque, and numerous others. Despite the advances in determining the composition and structure of deposits, our knowledge of the eye–lens interaction is far from complete. Difficulties in extracting all materials on lens surfaces has led to misleading quantification of components for many years. The relative proportions of surface versus matrix accumulation and the biological activity of the deposited material also remain important areas of uncertainty. But perhaps most importantly, the link between complications and specific constituents found on lens surfaces is circumstantial and demonstration of causality remains difficult. We seek not only to know what is on the lenses, how much of it is there, and what are the mechanisms behind that build-up, but also what is the activity of the deposit in terms of ocular function and whether we can devise ways of circumventing potential complications. These questions do not appear to have been subjected to comprehensive review, and interpretation of this complex area is the subject of this article. Finally, developments in the last few years in the technology of materials, production techniques, mode of wear (disposability) of lenses, and efficacy of care and storage systems mean that many of the early concepts relating to deposition are outmoded. It is timely to provide a comprehensive update in this area.

Scope and Definitions To give context to the issues of symptomatology and soft lens deposits, other subjects of continuing debate on the topic of deposition must first be considered. To begin, we will review the experimental aspects of recovering, identifying, and quantifying components that are found on the lens surface and consider specific factors influencing surface

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build-up such as lens material, tear chemistry, and time and mode of wear. With the benefit of refinements in evaluating deposits, we will then examine estimates of the compositional and structural aspects of deposition. Finally, we will look at the role of deposits in causing symptoms and the role of care and maintenance systems in preventing these reactions. We will first set the scope of the discussion and define the term ‘deposition’. The contact lens specialty constitutes a small component of the much larger domain of biomaterial investigation, which encompasses use of synthetic substances for such purposes as intraocular lenses, artificial valves, vascular substitutes, orthopaedic prostheses, skin grafting, dental work, urinary tract implants, and cosmetic surgery. Topics of inquiry in these other fields resemble those in the contact lens industry in many ways. The study of deposition is particularly prominent,17–21 although issues such as toxicity, inflammation, infection, and degradation also have parallels. It is not surprising that many of the techniques used in these other areas of biological pursuit for studying host– biomaterial interaction,22 surface chemistry,23 analyzing deposition,24 and providing a biocompatible coating 25–28 on biomaterials are also used for contact lenses. But the contact lens field has its own peculiarities; the material is not implanted into the body cavity, the fluid bathing the material is less complex than plasma and subsequently confers a level of immune privilege, the material must be porous to oxygen, the surface of the material undergoes regular drying and rewetting, and lenses are removed periodically for cleaning and storage in nonbiological fluid. We will restrict our discussion to studies directly concerned with deposits on contact lenses. All contact lens surfaces attract material that develops into deposits. The current popularity of soft lenses, including both traditional hydrogel and silicone-hydrogel, requires that the majority of attention be directed this way. The issue of deposition on rigid gas-permeable lenses is considerably different and extensive in its own right; this article will therefore focus solely on soft lens materials. Because disposable lenses had barely made an impact worldwide at the time of the 1989 practitioner survey mentioned above,3 that study most likely revealed a problem with conventional (nondisposable) soft contact lenses. The advent of disposable lenses altered the way that practitioners consider deposits; frequent replacement implies that continued deposition over time is diminished as a problem. Certainly, frequent replacement of lenses yields better performance than conventional lenses on a range of criteria typically associated with deposit problems, such as adverse reactions, vision, comfort, symptomatology, and overall patient satisfaction.29 –36 It is assumed that the replacement schedule, rather than any characteristics of the materials or manufacturing process of these lenses, imparts this level of performance. However, deposition of contact lenses is known to begin within minutes of contact between the lens and the tears.37– 40 Recent investigations into the

Deposits and Symptomatology with Soft Lenses: Brennan and Coles acceptance of disposable lenses demonstrate that this interaction continues to be of concern in achieving successful lens wear.38,39,41– 45 Wear of silicone-hydrogel materials for periods of 30 days between lens removal is likely to place further emphasis on deposit related problems. Therefore, the need for this review is augmented in light of the popularity of disposable lenses. Deposits on soft contact lenses arise principally from the tear film4 and, to a lesser extent, from external sources.46 Extraneous sources of lens spoilage include finger dirt and cosmetics, disinfecting and cleansing techniques, environmental factors, manufacturing defects and residues, polymer impurities, mechanical stress and breakage, as well as aging and decay of the lens material.46 This review will concentrate principally on deposits that arise from tear fluid components and not, for example, fungal deposits or discoloration. The term deposit is intended to imply a deposit on a soft lens. The term will be used to describe any form of accumulation or concentration of material that is not part of the polymer structure, at the surface or within the polymer matrix of a lens. Other terms, such as coating, build-up, and accumulation, are used interchangeably to refer to the same entity. Hart and coworkers have recently urged standardization of nomenclature,47 although adoption of such a standard will likely require considerable debate and take some time to achieve.

Influence of Experimental Factors and Techniques The vast number of factors that impinge upon deposit formation and component retrieval, identification, and quantification confound the experimental investigation of deposits on soft lenses. Determining the relation between symptomatology and lens deposition requires the ability to identify and measure, among other things, total protein, individual proteins, lipid as opposed to protein species, individual lipid components, surface versus matrix deposition, structural considerations in deposition, denatured versus native protein, and the interaction between the species and the ocular tissues. The following discussion considers important limitations in experimental procedures or protocols that potentially influence outcomes in deposit-related studies. Methodology and Sensitivity of Procedures for Examining Deposits Assessment of the role of individual components in contact lens deposits is reliant upon the ability of scientists to identify and quantify these substances accurately and repeatably. A variety of procedures has been used to aid scientists in making these determinations; some of these are listed in Table 1. The breadth of different techniques that have been used is testimony to the inability of a single test to provide all of the information that is required to establish the importance of specific components in deposits.

Table 1. Methods for Evaluating Deposits on Contact Lenses Clinical Assessment Various grading systems48–52 Microscopy and Imaging Techniques Spectrophotometry/UV spectroscopy43,53,54 Staining and light microscopy38,55–58 Video image analyis41 Transmission electron microscopy59 Scanning electron microscopy12,38,60–64 Immunochemistry5,38,59,65–71 Fluorescence techniques38,43,44,58,65,69 Confocal microscopy55,72,73 Atomic force microscopy74,75 Fourier transform infra red11,76 Radiolabelling72,73,77–80 Electron spectrometry for chemical analysis40 Surface matrix assisted laser desorption/ionisation mass spectrometry81 X-ray techniques58,63,72,81 Assays General protein assay44,64,68,82–85 Amino acid analysis53,86–88 Ninhydrin assay52 Bicinchoninic acid analysis89,90 Gel electrophoresis4,38,39,66,68,69,74,84,87,91–94 High performance liquid chromatography (HPLC)89,90,92,95

The procedures can be generally grouped into clinical assessment, observational (microscopic) techniques, and assays. Each technique within these groups has its specific advantages but can not provide all of the information required about a deposit. Clinical Assessment Visual grading in a clinical setting offers the advantages of being nondestructive, requiring simple, readily available equipment, achieving rapid estimation, and being clinically based and thus symptom-oriented. It is also the important starting point for further investigation. However, visual assessment of deposits is generally regarded as inferior to laboratory-based investigation in terms of identification and quantification, and rigorous experimental design is arguably less well-enforced in clinical investigations. Both on-eye biomicroscopic and off-eye systems are used for clinical assessment, as exemplified in Figures 1 and 2, respectively. Assessment is made according to various systems such as grading scales, on-eye lens wettability assessment, and variations of the Rudko grading system.48 –50 A number of articles have compared the deposit rankings obtained in this way with laboratory analysis with poor correlation between results.52,96 In particular, the Rudko grading system has come under attack for its poor performance. However, the lack of correlation between visible typing and laboratory analysis possibly occurs because visible typing is most likely to detect denatured, surface protein and reduced wettability as a result of such build-up. To this end, Gellatly and coworkers found a relation between

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Figure 1. On-eye evaluation of lens deposits (clockwise from top left): drying of a lens surface with minor protein film accumulation; significant protein build-up with likely visual consequences; major drying in the lower half of the lens caused by lens deposition; high magnification of white-spot deposits; lower magnification showing multiple diffuse white-spot deposits; jelly-bump deposits.

Rudko grading and lens age and vision with contact lenses,97 suggesting that visible typing may be sensitive to clinically important deposition. In this way, visible typing may provide detail to which more technologically advanced analysis, at least at the current level of sophistication, is insensitive. More recently, Long and coworkers established that Rudko gradings correlated well with image analysis in the midrange.98 Despite advances in other methodologies, there have been few refinements in visual grading systems 50 and, as yet, no system is universally adopted. Microscopic and Imaging Techniques Observational systems, including microscopic and imaging techniques, are very powerful in specific aspects of deposit investigation. Importantly, they provide critical scientific information on the structure of deposits. Specificity of these procedures varies between tests. For simple initial deposit investigation, a binocular microscope with capacity for dark-field or phase contrast illumination can be enlightening. Figure 3 provides examples of deposits photographed with such systems. Simple staining procedures are more informative but generally insensitive compared with photometric assessment such as spectrophotometry44,53 or immunohistochemistry, which is by nature highly specific for identification purposes.5,38,59,65–70 The major limitation of microscopic and imaging techniques is that they are generally not suitable for accurate quantification purposes. Also, the more advanced observational techniques are de-

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structive, meaning that sequential measurements from the same lenses are not possible. Preparation of samples is important in obtaining good images. For example, sample preparation for scanning electron microscopy (SEM) can aggressively modify organic material, especially deposited lipids, causing reticulation of smooth areas of film-like deposit or damage to the lens surface.13,99,100 Most SEM studies need to be considered against the background of this potential artefact. Assays Various biochemical assays, including high performance liquid chromatography (HPLC), sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), immunochemical techniques, and enzymatic assays provide useful techniques for both identification and quantification of individual components of lens deposits. Figure 4 provides examples of the output from some of the assay procedures used in deposit analysis. Many technical aspects of these procedures, however, offer potential for inaccuracy. For example, quantification using densitometry assumes linearity between concentration and density (the Beer-Lambert law), the application of which is limited to a small range. Further, gel electrophoretic methods make the invalid assumption that the intensity of protein stain is independent of protein type and consistent between gels.16 Ho and coworkers have demon-

Deposits and Symptomatology with Soft Lenses: Brennan and Coles

Figure 2. Off-eye evaluation of lens deposits (clockwise from top left): a heavily deposited lens showing browning toward lens edge and central haze; protein accumulation on a lens surface showing a crystallization pattern; regions of organic plaque on a lens surface; multiple white-spot deposits on a tinted lens; accumulation of white-spot deposits in a ring pattern; fungal deposits in a lens.

strated the differences in the yield between some of these techniques.101 Recently, the ability of preparation techniques to extract the desired material for analysis has been a point of major interest. One of the more significant earlier works on deposit removal was conducted by Wedler.69 This work considered the removal of deposits on contact lenses by various chemical reagents including urea, guanidine hydrochloride, potassium thiocyanate, potassium perchlorate, hydroxylamine, and ethylene dithretyl acetamide (EDTA), but found that SDS and dithiothreitol (DTT) were most effective in removing material from lenses.69 Many researchers performing assays have since used these techniques, in particular SDS. Others have used sodium hydroxide to retrieve lens-bound protein. It has become apparent that these common extraction procedures may fail to remove some 75% of the total material on lenses.92 This finding has widespread ramifications for deposit analysis. The tenacity of binding of components to the surface may vary due to differences in the mode of chemical bonding of a given species. Consequently, the yield from a lens may exhibit differential recovery of components. The findings of Yan and coworkers92 thus cast doubt on the validity of all previous research that had provided quantitative values of components found on lenses, and compel researchers in the future to use procedures that essentially digest all of the lens material. Recently, Keith and coworkers have proposed using an extraction solvent consisting of trifluoroacetic acid and

acetonitrile, which they found was capable of 100% efficiency.90 Despite improvements in quantitation techniques, correlations between empirically derived figures and patient responses remain unimpressive. It is apparent that something about the nature of the deposit is important. Proteins may exist in a number of conformational states, that is, the tertiary structure can be altered by chemical and/or physical events without changing the amino acid sequence, an event commonly referred to as denaturation.8,9 Most assays will be sensitive to the amino acid sequence but not the conformational state. Future research into deposits should therefore place greater emphasis on the nature of protein above simple quantitation of components. Recently, an assay to test specifically the nature of protein in lens deposits has been employed.102,103 Further discussion on the importance of denaturation is found below. Extraction procedures can also modify the components that are being assayed. The procedure may cause breakdown of individual components with the resulting yield being composed of fragments rather than the original species. Assays, like most imaging techniques, are destructive so lenses can not be reused. Some assays, such as the ninhydrin assay, may artefactually quantify commercial enzymes used to clean lenses as well as deposits. Finally, biochemical assays fail to provide detail about topography, geography, and structure.

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Figure 3. Dark-field light microscopic evaluation of lens deposits (clockwise from top left): surface protein becomes desiccated and breaks up to form this pattern; extensive reticulated protein deposit on a lens surface; high magnification shot of an accumulation of white-spot deposits; inorganic film deposit.

Other Options Newer techniques have been developed and applied in recent years. These offer new opportunities in elucidating the composition and nature of deposits. For example, atomic force microscopy allows high resolution images to be obtained without the potential artefactual problems of SEM.74,75 Confocal microscopy has recently been used in a variety of applications,55,72 and staining for selective lysine residues with this technique has yielded impressive results.55 Van Duzee has presented a relatively simple video image analysis, which has the advantage of being nondestructive, well correlated to ninhydrin assay results, and offers potential for adaptation to clinical use.41 Accurate clinical assessment of deposits is one of the more pressing needs in our understanding of contact lens related problems. Whichever approach is adopted, deposit assessment is highly technique dependent; for example, protein extraction and assay will reveal protein quantities but provide no information about lipid types or quantities. The capacity of procedures to detect accurately the type and amount of deposits will remain a matter of continuing concern in deposit evaluation. Assessment of results should always be considered against this background of information.

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Experimental Design The evolving history of contact lenses has seen a number of trends in lens materials, wearing mode, care systems, length of usage of each lens, and local cultural factors related to contact lens wear. Because these factors all impact the nature of contact lens deposition, every clinical study is subject to sample bias related to the time and place at which studies are performed. Experimental findings are restricted to lens materials used in the study sample. In the early days of soft contact lens usage, hydroxy– ethyl–methacrylate predominated as the material of choice. More recently Group IV and, to a lesser extent, Group II lenses have enjoyed more widespread usage, particularly with the popularity of the disposable concept. As explained below, the various lens categories listed by the U.S. Food and Drug Administration (FDA) show distinctive deposition patterns. Disposable lenses currently predominate contact lens fitting worldwide, which means that studies reporting wearing time of more than several months have specific applicability. Extended wear enjoyed popularity in the early and late 1980s and, thus, a number of studies reported at this time have limited applicability to the more common mode of daily wear. The promising introduction of silicone-hydrogel ex-

Deposits and Symptomatology with Soft Lenses: Brennan and Coles

Figure 4. Examples of assays of lens deposits. Left: SDS-PAGE of protein deposits extracted from artificial tear protein deposited Group I, II, III and IV lenses. (1, Human tear; 2, Artificial tear; 3 to 6, Deposits from Group I to IV lenses, respectively; 7, Protein molecular weight markers). Center: SDS-PAGE of protein deposits extracted from human worn lenses. (A, Lysozyme; B, Human tear; C to F, Lens extracts; G, Protein molecular weight markers). Right: typical lysozyme chromatogram.

tended wear materials has added yet a further dimension to the issue of lens deposition. Care and maintenance systems will be considered later, but it is important to consider the type of cleaning systems used by the sample population when evaluating experimental design. Originally, thermal disinfection was the preferred mode, followed by chemical disinfection with thimerosal and chlorhexidine based-products, hydrogen peroxide, and more recently, multipurpose systems with more physiologically tolerable agents. The incorporation of chelating agents in the early 1980s also altered deposition patterns. The United Kingdom was slow to adopt multipurpose solutions, and chlorine-based systems were popular early in the 1990s, with concomitant effects on deposit related studies. Interpretation of the experimental procedures should also be viewed in context of the time at which a particular finding was made. It is natural that experimental procedures will improve over the years, and recently gathered data is more likely to provide an accurate scenario of the mechanisms and constituents of lens deposition. In particular, identification and quantification procedures have become highly refined in the last few years. Selection criteria for the sample group have a major impact on study outcome. For example, Tripathi and coworkers in 1980 considered deposition on 300 spoiled lenses.46 In 1991, Myers and colleagues analyzed lens build-up from heavy depositors.96 Clearly, the findings of these studies are representative of events leading to deposits judged by the criteria of heavy visible lens deposition. Application of these results cannot therefore extend beyond the realm of heavily spoiled lenses as judged by visible deposit typing. Findings should also be restricted to the particular type

of deposit being considered (for example, film or nodular). A good example is the white spot deposit. Clinical opinion suggests that such deposits are more frequent on highwater-content lenses, during extended wear, with thermal disinfection, and with longer wearing periods. They are less commonly seen with disposable lenses used for daily wear. Findings regarding structural formation are relevant specifically to such conditions. Provision of lenses according to a randomization pattern can distance study results from the real-world situation. This may produce different results from the clinical situation, where lens–patient compatibility is subjected to screening by the practitioner. Other problems arise despite adherence to traditionally accepted experimental designs.104 Recent research in other fields indicates that observers will bias their findings of treatment effects in double-masked studies based on their knowledge of whether or not the control group offers a comparable treatment or no treatment at all.105 Finally, despite being a common practice, the presentation of results by mean and standard deviation will be misleading in deposit analysis where a gaussian distribution of deposit amount is not apparent. There are many potential ramifications and pitfalls when designing experiments investigating contact lens deposits. Interpretation of findings from deposit studies should always be considered within such a framework. Source of Deposited Lenses Soft lenses are not always obtained for analysis from clinical sources. A number of studies have found artificial tear solutions an attractive option in determining the binding affinity of different components and the mechanisms

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Clinical Article involved in such binding.57,77,79,80,84,106 –110 The principal advantages are that many experimental variables are eliminated, quantitation can be enhanced by labeling the species fluorometrically or radiometrically, and simple hypotheses can be tested without having to engage in a resourceconsuming clinical trial. However, the real world provides a complex array of variables that cannot be excluded from having an influence in clinical lens spoilage. Such effects include the cycle of evaporative drying and wetting created by the blinking action, the mechanical aspect of shear forces during blinking, variability in tear film composition, structure of the tear film, replenishment rate and volume of tears, wearing times, wearing conditions (for example outdoor or air-conditioned environments and proximity to chemical agents), ultraviolet light exposure, wearing mode (extended wear versus daily wear), interactions between the items under test and other tear film components, and the influence of external contaminants. Summary As in all fields of science, procedural, experimental, and interpretative caution needs to be exercised to make accurate statements regarding lens deposition and its relation to complications with contact lens wear. In particular, older studies should be considered in this light. Clearly, opportunity remains for further developments in deposit analysis technology.

Influence of Wear Factors The previous section examined experimental factors that may be responsible for inaccuracies in examining the build-up on lens surfaces. However, several real-world factors produce genuine differences in deposition impacting the performance of contact lenses. These factors include lens materials, time of wear, and the patients being tested. Lens material The material from which a contact lens is manufactured is in many respects the most important, and thus the most frequently considered, factor influencing contact lens deposition. In the future, this is likely to continue to form the basis of most biocompatibility considerations. The FDA classifies contact lenses within four groups, based upon the water content of the material and the charge of the surface. Although not definitive, this categorization is a very useful guide to the propensity of materials to attract deposits. Keeping in mind that varying methodologies and experimental conditions will confound results, there are clear differences in deposition profiles among the four FDA contact lens groupings. High-water– content contact lenses attract more protein than low-water materials. Moreover, ionic materials show more protein accumulation.38,39,44,52,62,68,87,92,111–115 Thus, large quantities of protein are typically retrieved from Group IV lenses (FDA

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categorization for high–water, ionic contact lenses).92,114 The study of Minno and coworkers on 1058 contact lenses showed that Group II and III lenses attracted an average of 38 ␮g and 33 ␮g protein/lens, respectively, whereas Group IV materials, such as etafilcon, attracted a mean of 991 ␮g protein/lens for wearing periods of between 5 and 1675 days.52 Other studies have also shown retrieval of approximately 1000 ␮g protein/lens for Group IV lenses,96,116 with Keith and colleagues reporting a range of 900 to 1800 ␮g protein/lens by the ninth day of wear.117 Despite the advantages of the FDA classification for determining propensity to deposition, there is considerable variation between materials designated within a particular lens category.58 The electrophoretic gels reproduced in Figure 4 illustrate protein patterns derived from different lens types. Group IV lenses attract the most protein due to the ionic affinity between methacrylic acid (MAA) in the material and protonated functional groups on lysozyme, a basic tear protein. Positive charge is essentially unique to lysozyme in the tear film, rendering it the main protein retrieved from such lenses.39,87 However, the term ionic does not necessarily indicate equally enhanced deposition in all lenses so termed.58 Both in vivo and in vitro experiments suggest that individual material properties, in particular monomer constituents such as MAA or N–vinyl pyrrolidone (NVP), may play a role beyond simple electrostatic interactions.73,77,118 Lipid deposition varies with lens type but, as a general rule, is found more frequently on nonionic rather than ionic materials within the same water content.42,44,95,108 The presence of NVP as opposed, for example, to polyvinyl alcohol (PVA) enhances the attraction of lipids by the lens material.44,115 This may be explained by the known lipid solubility of pyrrolidone derivatives.44 In comparison, Prager and Quintana, by radiometric labelling, found cholesterol and phospholipid more on Group IV lenses than other lens types after exposing them to an artificial tear solution.80 Mirejovsky and colleagues57 also report this opposite effect, that is Group IV lenses have a greater predilection than Group II for lipid deposition; however, this finding has been explained as spurious due to decreased sensitivity of staining procedures compared with spectrophotofluorimetry.44 Jones and colleagues noted that individual tear characteristics may play a role over and above that of the material in respect of lipids.44 The differences between Group II and Group IV lenses in both protein and lipid deposition are generally present in single-use (oneday) lenses.119 Other material characteristics in addition to those described by the FDA categories may influence deposition. A number of manufacturers have produced materials that are claimed to be deposit resistant. Examples include the CSI lens and the Atlafilcon material. Laboratory evaluation of clinically worn lenses fails to validate the claims conclusively.64,89 A biomimetic approach has been taken by one company by coupling phosphorylcholine onto the polymer

Deposits and Symptomatology with Soft Lenses: Brennan and Coles backbone. This component is the primary natural factor responsible for cell membrane biocompatibility. Clinical results support the claim of superior deposit resistance.120 The search for increasing oxygen transmissibility of contact lens materials to meet the respiration requirements of the cornea during closed-eye wear led to the development of silicone-hydrogels. The addition of siloxane groups to traditional hydrogel contact lens materials gives rise to wettability and lipid-like deposit problems. Surface modification of these materials is required to restore hydrophilicity and counter these problems.121 The deposit performance of silicone-hydrogel lenses is largely predictable from a knowledge about their water content and surface charge, that is, their FDA classification. Lotrafilcon and balafilcon both have low water content and medium-to-low surface charge. Consistent with their low water content, there is no intramatrix protein accumulation. Thus, total lysozyme deposition for these lenses has been reported at less than 1 ␮g/lens and is of the order of a thousandfold less than etafilcon.122–125 Other proteins seem to bind to siliconehydrogels in a similarly low manner.126 Despite these low assay results, visible deposition is comparable to that observed on etafilcon,127 emphasizing the importance of intramatrix accumulation and the vagaries of visible typing. Lipid, albeit varying with subclass, is attracted more to the surface of silicone-hydrogel lenses than etafilcon in laboratory-soiled lenses, consistent with the low surface charge.125 In summary, it is evident that contact lens material factors influence total protein and lipid deposition. Lenssurface charge and water content are the principle, although not absolute, determinants of these patterns. However, it is clear that there is more to deposit-induced symptomatology than total protein. Furthermore, there are other features of wear and care that influence deposition. Patients Individuals show demonstrable variations in lens deposition in response to wear of different lens types.119 Among the factors that may influence the amount of deposition is individual patient tear constituency. Various aspects of human tears might play a role, including the quantity and quality of the tear film. Dry-eye sufferers appear more prone to deposition, probably through consistent drying out of materials on the lens surface. From this standpoint, the interaction between break-up time and blink rate becomes a critical factor in deposit development. Other factors include the concentration of individual protein, lipid, carbohydrate, and mineral species, and differences in home and work habitats. Individual influences on deposits may include high fat diets, high protein diets, increased alcohol consumption, and low tear-film potassium.128 The clinical results of Jones et al, Young et al, and Guillon et al are consistent in establishing that acceptance of different lens types varies between individuals,42,44,45

although the precise mechanism is uncertain. It appears that individual characteristics most strongly determine the lipid deposition, while lens material type most strongly influences protein deposition in the early stages.44 Despite this, various authors have failed to correlate tear components with deposition profiles.106,129 –131 Intuitively, specific patient factors should be responsible for the different deposition profiles observed when the same type of lens is worn under similar circumstances. However, there is not currently a measure of human tears that allows accurate prediction of an individual’s deposition characteristics. Time and Replacement Frequency Because deposition is a time-dependent process, empirically derived values will be highly dependent upon the age of lenses tested. Lenses recovered within the first few minutes of wear demonstrate coatings of some degree.38 – 40,128 The process continues over time. Sack and coworkers found a constant rate of lysozyme deposition on Group IV lenses of 2.2 ␮g/min in the early part of open-eye wear, which later levelled to a steady state.93 Accumulation of components is not consistent, with some entities showing faster binding rates.39 Keith and coworkers have accurately plotted the medium term build-up of lysozyme on Group IV lenses.117 They found a mean concentration of 55 ␮g/lens after 15 min of wear, which reached a maximum at around 1300␮g/ lens after 6 days of wear.132 The time to steady-state varies from day 4 to 11 between people. Consistent with this picture, Jones et al determined that surface deposition on Group IV lenses plateaus on day 1, with intramatrix deposition continuing to increase up to 7 days.133 Surface protein on Group II lenses also peaked within 1 day, but total protein accumulation continued for up to 30 days.133 The concept of plateauing is supported by Richards and Tripathi.5,68 Other work suggests that deposition is ongoing. In comparing the deposition on Group II lenses, Jones and coworkers found an increase in lipid by 80% and of protein by 152% at 3 months compared with 1 month of wear.43 Gellatly and coworkers noted that only 3% of patients whose lenses had been worn for an estimated total of 2600 h or less showed a Rudko deposit classification of ⬎2, whereas 80% of patients whose lenses were older than 2600 h showed this degree of deposition.97 Maissa et al observed more surface proteins on ionic materials after 3 months compared with 1 month of wear, but no change over this time for nonionic materials.115 Lipid accumulation has been found to cease by the end of day 1 on Group IV lenses but continues unabated for at least 4 weeks for Group II lenses.133 The kinetics of material build-up on lenses has ramifications for both lens replacement frequency and the regularity of care and maintenance. Long-term clinical studies of nondisposable lenses suggests that build-up of lens surface material continues over a period of years. Elucidating

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Clinical Article the apparent differences between studies that do and do not show plateauing may be an important feature in relating deposition to symptomatology. Examination of methodology, differences in lens materials, denaturation of protein, and changes of the inflammatory state of the eye over longer wearing periods may explain these findings. In the context of this review, all results analyzing the role of deposition in successful contact lens wear should be viewed against the background of lens age.

way as to leave polishing or lathe marks.61 However, Kaplan achieved equivocal deposit ratings for polished and unpolished lenses.60 Prevention of deposit-related complications in this regard relies on improvement in manufacturing techniques so as to prevent defects. Moreover, the need to consider differences in potential deposition by manufacturing method (eg cast molding, lathing, spin casting) is highlighted by these works. Summary

Open Versus Closed-Eye Wear Considerable clinical evidence suggests that extended contact lens wear induces more serious deposit-related problems than daily wear, in particular with regard to white-spot formation. While this proposition has been subjected to little laboratory based consideration, the study of Sack and coworkers would suggest the opposite. They found that deposition of lysozyme occurred in a linear fashion during the early stages of lens wear, and was considerably higher during open-eye wear (2.2 ␮g/min) than closed-eye wear (0.2 ␮g/min) before reaching a steady-state.93 The difference between this finding and clinical impression may result from the influences of regular cleaning, which occurs with daily but not extended wear; the overall percentage of time for which an extended wear lens is in the eye, affording greater opportunity for deposition; a difference in the manner in which the deposits bind to the surface between wear conditions; or the use of different materials for extended wear in field trials. The considerable differences between the immunological and inflammatory state of the closed eye may also prove to be a defining factor in inciting clinically significant reactions.66 The importance of considering wearing mode in deposit analysis is highlighted by the rebirth of extended wear afforded by silicone-hydrogel lenses. Care and Maintenance The proportion of build-up of various components on lenses is clearly related to a range of factors, not the least of which are lens type, and care and maintenance systems. Confounding the influence of the care and maintenance regime is the issue of compliance. Poor compliance, in the form of diminished rubbing and rinsing and enzyme cleaning, is likely to enhance the build-up on the surface of a lens. Further details of studies considering the cleaning systems are presented below in the section entitled Care systems and deposition. Quality of Lens Surface It is predictable that the quality of the lens surface would play a role in determining the degree of build-up. Hosaka et al found deposits to be centred around defects in the lens surface.76 Similarly, Fowler and Gaertner found deposits “heaped-up” on the lens surfaces manufactured in such a

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These results emphasize the complexity of analyzing the impact of lens deposits. A wide range of commonly encountered variables in wear conditions can influence the ultimate deposition rate. Perhaps most importantly, these factors can be distinguished from the experimental factors presented above by the need to develop models of deposition that allow for variation by the specific parameter.

Composition of Soft Lens Deposits Given the wide range of factors that influence yields of deposits, both from an experimental and clinical standpoint, the following review of the composition and amount of deposits found on lenses should be interpreted with caution. We have attempted to provide these details in context. Table 2 summarizes the individual constituents that have been identified on contact lenses. Proteins Protein has been the major focus of both identification and quantitation studies of contact lens deposits. Estimates of the total amounts vary but fall within a reasonably well-defined range, providing the various experimental factors mentioned above are considered. Group I lenses typically attract less than 10 ␮g of protein, Groups II and III lenses approximately 30 ␮g, and Group IV lenses 1000 ␮g or more.38,39,44,52,62,68,69,83,87,92,96,111–114,116 Karageozian first reported that the principal component of deposits that presented problems with contact lens wear was lysozyme, which may be selectively adsorbed and denatured on the lens surface.86 Many others have since confirmed the predominance of lysozyme in lens deposition.39,68,69,76,87,91,92 It appears to be found in various forms on lenses, whether loosely or tightly bound, and active or denatured. Sack and coworkers reported that nonionic polymers generally have a thin and largely insoluble protein layer, devoid of active lysozyme.87 On anionic polyHEMA lenses, the protein coat was much thicker and composed of loosely bound protein, principally lysozyme. As mentioned above, not only is the type of protein found on a lens of importance, but also the condition in which that protein exists. Castillo’s group reported that lysozyme adsorbs to surfaces in both reversible and irreversible fashions.8,9 Reversible binding is accompanied by minimal change in protein structure, while irreversibly ad-

Deposits and Symptomatology with Soft Lenses: Brennan and Coles Table 2. Tear Film Constituents Found on Contact Lenses Proteins lysozyme albumin lactoferrin immunoglobulins (sIgA, IgE, IgG, IgM) complement prealbumin PMFA (proteins migrating faster than albumin) tear lipocalin alpha1-lipoprotein other glycoproteins and degraded peptides lysozyme dimer Lipids cholesterol cholesterol esters monoglycerides diglycerides triglycerides unsaturated fatty acids arachadonic linolenic linoleic oleic palmitoleic saturated fatty acids arachidic stearic palmitic fatty alcohols phospholipids Carbohydrates including mucins Minerals calcium potassium ions chloride ions silicon sulfur sodium nitrogen zinc aluminium iron

sorbed lysozyme undergoes a transformation from its native alpha-helical state to a beta-sheet conformation and constitutes an important denaturation effect. Protein that is able to migrate into the matrix of the lens is less likely to denature. Although the state of protein in deposits is not well researched, several workers have noted that the activity of lysozyme on soft lenses may be retained,87,102 suggesting retention of conformational structure. This is attributable to the stable nature of lysozyme under extreme conditions. Other proteins found on the lens surface include albumin, lactoferrin, the immunoglobulins (sIgA, IgE, IgG, IgM), complement and other inflammatory mediators, prealbumin, proteins migrating faster than albumin (PMFA), tear lipocalin, alpha1-lipoprotein, other glycoproteins, and

degraded peptides.4,5,39,69,70,87,91,134 The propensity for binding of these proteins appears to be related principally to the type of lenses being worn.39,87 Of additional interest is a 30-kD protein that has been isolated repeatedly in recent studies, especially in association with disposable lenses.68,74,92,135 Scott and MowreyMcKee have identified this protein, previously thought to be sub-units of protein G,39,136 as a homologous dimer of lysozyme, which suggests that it is a conformationally altered form of this protein on the lens surface.137 Lipids A number of investigators have confirmed the presence of lipids in deposits on the surface of hydrogel lenses.63,76,88,138 –141 The quantities of lipid species on contact lenses tend to be quite small, and so sensitivity of the procedures for detecting and quantifying is critical to interpretation.14 The approximate amount of lipid on contact lens surfaces was found to be 0.01– 0.05 ␮mole/lens by Wedler and coworkers.69 All the major lipid groups that occur in tears, such as cholesterol, cholesterol esters, monoglycerides, diglycerides, triglycerides, fatty acids, fatty alcohols, and phospholipids, are expected to occur in lens deposits. Although Rapp and Broich138 did not find triglycerides, cholesterol, and cholesterol esters and Hart et al140 did not find fatty acids, these components have since been found on worn lenses. Tighe’s group has found all of the lipid groups on contact lens surfaces.141 While cholesterol and cholesterol esters are not widespread on the surface of lenses, they do occur in much larger quantities in discrete, elevated spots.139 Fatty acids isolated from lenses include arachadonic (U-unsaturated), arachidic (S-saturated), linolenic (U), linoleic (U), oleic (U), stearic (S), palmitoleic (U), and palmitic (S).14 Jones et al report varying amounts of lipid types on lenses ranging from 2 ␮g of cholesterol on etafilcon to 40 ␮g of oleic acid on a silicone-hydrogel lens.125 It is suggested that unsaturated fatty acids may play an important role in deposit formation, and this is considered more closely below. Carbohydrates Mucin is a mixture of glycoproteins that, on decomposition, yields a combination of protein and carbohydrate. Most models of tear-film formation and breakdown consider mucin to be crucial in constructing a basal layer upon which the aqueous component forms. Carbohydrate derivatives, likely indicating a mucin layer, have been found to form part of the accumulation on lens surfaces.11,63,69 Castillo reported that mucin was only present to a considerable extent on heavily deposited lenses.11 Minerals Select studies have isolated particular mineral species on contact lens surfaces, including calcium, potassium and

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Clinical Article chloride ions, silicon, sulfur, sodium, nitrogen, zinc, aluminium, and iron.40,63,76 Many of these may arise from preparation of the lens or other environmental contamination.40,76 Of these components, calcium appears to have special significance in deposit formation. Begley and coworkers noted that all but 3 of 72 nodular deposits contained calcium.63 The specific role is uncertain but Tighe’s group suggests that it provides a structural integrity to the deposit.13 (See below for more discussion on this topic.) Summary It’s clear that most tear components have been found in surface deposits on soft contact lenses. In terms of creating symptomatology, the amount, distribution, and pattern of deposition and conformational effects therefore become key factors. However, experimental procedures for establishing this information are subject to variable influences that can alter the derived perceptions.

Structural Considerations in Deposit Formation The pathway to the formation of deposits that lead to clinical symptoms is not immediately apparent. One of the key processes in determining this mechanism is to consider the structural aspect of deposition. Structural formation appears to be complex and dependent on a range of factors other than the simple presence of particular species in the tear film. Light microscopy and other forms of microscopy are typically employed to assess structural formation of deposits. While a large range of appearances have been described, the most common differentiation is between two distinct structural classifications: films and spots. From the instant a contact lens is placed within the tear film, accumulation of material on the lens surface is evident.37– 40 It has been suggested that the initial coating arises from mucin,4,37 which forms the basal layer of the tear film, and it would follow that the same process that induces the formation of this layer on the ocular surface might also operate on the surface of a contact lens. The initial film formation may be beneficial in achieving biocompatibility of the contact lens by allowing surface interactions which promote an aqueous layer to form.4,37 The concept of a physiologically normal film is widely supported. Hart and coworkers term this coating the pellicle to differentiate it from a deposit that is considered a rigidly adherent moeity and may lead to pathological events.47 They have measured the normal coating to be 0.1 ␮m to 8.6 ␮m thick and noted that, while thicker on Group IV lenses, it continued to thicken with time on Group I lenses. Wedler and coworkers propose that a complex 3-layered structure of mucin arises at the surface some time after insertion.4 Mucin may therefore provide the base layer on which deposits form. Begley and Waggoner found that polysaccharides (which include mucins) were more evident

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in newer nodular deposits, suggesting that these are involved in the formation of this type of deposit.63 The interaction between lipids and proteins is of considerable interest as these both are thought to play a role in deposit formation. Bontempo and Rapp have recently used artificial tear solutions on various lens types to investigate the effects.142 The presence of protein influenced lipid binding profoundly on all lens types, while lipid only affected protein binding to Group IV lenses. They concluded that the interaction of protein and lipid on a lens surface most prone to a particular contaminant apparently makes it less likely for that contaminant to bind. SEM micrographs have played an important role in investigating the initial surface coating. Hart reports that the early coatings show a reticulation pattern consisting mainly of mucins and proteins with little lipid present.140,143 However, interpretation of such micrographs should be made cautiously, because preparative protocols are very aggressive in modifying deposited lipoidal material. The high vacuum involved may be responsible for reticulation of smooth areas of film-like deposit.13 It is believed that protein and other tear film components are attracted to the lens surface and form an equilibrium with such substances in the tear film. When denaturation occurs (whether due to surface phenomena, drying, care procedures, or other causes), a concentration gradient exists to drive protein to the lens surface. To a point, the initial build-up should not be viewed as an adverse state, an interstitial layer between contact lens and tear aqueous being necessary for formation of a functional tear film. Certain circumstances arise that lead to structural entities that are associated with negative consequences in terms of lens performance. Tighe and colleagues have provided considerable detail on structural considerations from their observations of both patient-worn and laboratory-soiled lenses. Much of the following discussion summarizes that work.12–16,58,139,141,144 –146 The kinetics of soft lens deposition is also discussed to some extent in the section Time and Replacement Frequency above.

Protein Films Protein films form a distinct group of surface deposits, characterized by a thin, semi-opaque superficial layered appearance.16 Despite the apparent importance of this type of film, the structural formation is not well described. Lin and coworkers were unable to observe a pattern of order of accumulation of protein in the first minute, providing no evidence as to the basis for attachment.39 Protein films appear to be an exaggerated manifestation of the normal coating that occurs soon after lens insertion, with denaturation playing an important role. Differences between the laying down of lysozyme on the front and back surface of contact lenses147 suggest that evaporative drying from the

Deposits and Symptomatology with Soft Lenses: Brennan and Coles lens front surface may play a key role in the initiation of lens spoilage. Lipid does not appear to be present in these deposits,99 and there is no evidence to suggest that it forms a base layer, as with the other forms of deposit listed below. Mucin features in heavy deposition, but not so much in lighter deposits.4 The chemical nature of attachment may be of value in determining structural factors involved in deposition. Wedler et al 69 and later Yan et al 92 have considered the issue of dissociating the material from the lens, producing initial concepts of the types of bonds that form during deposition. Further work in this area is recommended.16 Analytical studies of protein that show lysozyme as the major component on the surface may reflect stronger adherence of other proteins to the surface. Tighe’s group also reports identification of surface films and plaques on contact lenses that are different from the protein films.15,16 These include organic and inorganic plaques. Organic Plaques The organic plaques form a complex multilayered coating over a significant area of the lens surface.15 The primary layer of such plaques appears to be strongly lipoidal in nature. Proteins and carbohydrates form a complex covering. While present, protein is not involved in the interfacial conversion process that eventually leads to the formation of these plaques. A common factor associated with these plaques is the use of thermal disinfection, although this is believed to be an accelerating rather than formative process. Inorganic Plaques Inorganic plaques are structurally heterogeneous and composed of discrete elevated crystalline structures overlaid by a transparent film.15 This characteristic appearance is independent of patient identity and lens chemistry. Deposit structures are particularly rich in calcium and phosphorus, particularly at the lens-deposit interface. The overlying film is composed of an organic coating, including protein and lipids. Morphology and chemical composition of deposits developed in vitro correspond with that of lenses worn by patients, suggesting that the basis for deposit formation is simple and that the bulk and surface properties of lenses are of little importance. White-Spot Deposits One of the principal formations considered by Tighe and colleagues is the white-spot deposit.13,14,139,146 These are also known as nodular, jelly-bump, calciferous, and calculi deposits. Their studies reveal that these discrete elevated deposits consist of three distinctive layers. The primary layer is a flattened rounded plateau, composed primarily of unsaturated lipoidal material. Hart confirms the impor-

tance of lipid as the nidus for further deposition.99 Immobilization of this material appears to be due to polymerization of the lipid. Once attached, the free fatty acid groups are available for interaction with calcium. The second layer is an ellipsoidal dome-shaped structure with numerous lobular subunits. The most anterior layer is composed of a complex, multinodulated, transparent film-like coating. All tear components, including lipid, protein, calcium, potassium, and chloride ions, appear to be present in these deposits. Calcium appears to be an essential stabilizing component of these deposits,13,63 although lipid penetration into the lens matrix appears to be an integral part of their formation. The structure of white-spot deposits is the same regardless of patient factors, lens chemistry, and wearing mode or time. Such factors, however, affect the rate of deposit formation. Silicon is present at the hydrogel– deposit interface, suggesting that media in the lens-polishing procedure may also be involved in the initial formation of these deposits. Intramatrix Deposition Deposition is an interfacial phenomenon, but certain species penetrate into the polymer matrix. While an early electron microscopic cross section of a lens that had become opaque showed the deposit to be at the lens surface and not within the matrix,76 various studies since have clearly demonstrated the presence of tear components within the lens matrix. Proteinaceous material can be isolated within the lens matrix,14,55 and the quantities, particularly where the pore size is large, may be greater than that at the surface. Meadows and Paugh showed that large amounts of lysozyme enter the matrix of Group IV lenses.55 Molecular size relative to hydrogel lens pore size is obviously important. Lysozyme, but not larger proteins, are small enough to penetrate the matrix of high-water-content materials, but no proteins are small enough to enter the matrix of low-water-content materials, including siliconehydrogels. Most lenses also show an appreciable amount of within-matrix lipid. Because it is colorless (no light absorbing or chromophoric groups), it clinically remains undetected. Lipids are quite soluble in some hydrogel materials. Summary Of equal importance to the composition of material that gathers at the surface of a contact lens are the processes behind the formation of the solid structures that lead to observed clinical symptoms. As our understanding of the processes behind structural features unfolds, so do opportunities for devising methods of avoiding such clinical complications.

The Link Between Symptoms and Deposits Most articles dealing with contact lens deposits begin by stating that deposits on contact lenses are associated with

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Clinical Article Table 3. Complications and Symptoms of Soft Lens Wear Attributed to Deposits Visual disturbance Contact-lens-related papillary conjunctivitis Contact-lens-related acute red eye Contact-lens-related peripheral ulcers Tear film disruption Discomfort (various subjective descriptors) Decreased wearing time, lens intolerance Corneal staining Conjunctival hyperemia Bacterial adhesion Decreased lens life Release of inflammatory mediators

an increased frequency of a wide range of signs and symptoms. Table 3 provides a detailed list of the complications and symptoms that have been attributed to lens deposits. Figure 5 presents a series of photographs of different slitlamp signs that might be attributable at least in part to deposit problems. The association between lens surface build-up and signs and symptoms is implicated with circumstantial rather than incontrovertible evidence. Methods for establishing a link are difficult and most reported connections are casual, inasmuch as a particular symptom increases concomitantly with increased deposition. Another circumstance that points toward involvement of deposits in causing symptoms is a decrease in a specific symptom with the introduction of a cleaning step or product aimed at removing a specific component, or with the use of disposable lenses. This link is, again, not direct proof but strong supportive evidence. Thus, the issues surrounding symptomatology and deposits are complex. Clinicians will testify to overwhelming experience with symptoms associated with visible deposition in certain individuals, and to resolution of symptoms on treating the deposit problem. An overwhelming example of this link is the association between lens deposition and papillary conjunctivitis, which is discussed in more detail below. Other reports linking signs and symptoms tend to be based on incidents of extreme deposits or anecdotal evidence. For example, Hart and coworkers noted that maximal nitrogen/carbon ratios on lens surfaces (indicative of the highest amounts of organic matter on the lens surface) occurred on a pair of pathologically deposited lenses and on the lens with the longest wearing time of their study.40 Also, Wedler and coworkers noticed that mucin components form on top of lens aggregates in heavy deposits when such lenses are reported to be irritating.4 Few investigators have managed to describe an association between symptoms and subtle variations in deposits. Using tools specifically targeted to linking symptoms and deposits, van Duzee claims that it is possible to detect significant differences in comfort from low levels of deposits.41 Equally true is that some lenses with high grades of deposition will

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not cause symptoms in some patients,148 and that there are multifactorial reasons for lens intolerance.149,150 As well as involvement in adsorption, the nature of the protein also plays an important role in biological activity and the ability of care systems to clean the lenses. Denaturation of protein may lead to loss of antibacterial activity, changes in the protein in terms of antigenic or immunogenic properties, alteration of the optical clarity of the lens, or undesirable mechanical properties of the lens surface. These features may play a major role in lens intolerance or occur in addition to effects caused by binding of native protein to the lens surface. To date, there is insufficient evidence to relate the specific effects of denaturation of protein to signs and symptoms, so the comments below are for the greater part nonspecific with regard to the nature of the deposits. The following discussion focuses almost uniquely on the protein lysozyme, because this species is most often implicated. The importance of variation in lipid deposition between hydrogel materials remains unclear. Certainly, Guillon and coworkers consider it to be of no clinical relevance in the use of daily disposable contact lenses.42 Comfort Discomfort is possibly the major cause of contact lens dropouts. In large scale studies looking at contact lens discontinuations, Fonn’s group found approximately onethird of all long-term dropouts were due to discomfort.2,151 Binder reported in 1983 that, of 1099 patients entered into the first FDA extended-wear studies, 14.5% of 566 discontinuations found lens comfort inadequate.152 Despite the intuitive link of tear–lens-surface interactions in producing discomfort, the proportion of these dropouts that can be attributed to deposits is unknown. Indeed, the difficulties in associating clinical measures with symptomatology is well documented.153 A range of clinical studies make the casual association between the tear–lens interface and comfort of the wearer. In studies by Nilsson and coworkers, use of enzyme tablets periodically was associated with improved comfort and less deposition as determined by visual assessment.154 Further, lens-surface desiccation, protein deposits on the lens, and discomfort were found to be correlated in a second study.155 Similarly, van Duzee reported a correlation between video image analysis of deposits and discomfort as reported by anchored visual analog scales.41 Brennan and Efron found that 31% of patients with lenses older than 6 months reported the symptom of dryness often, compared with only 12% of patients whose lenses were less than 6 months old.156 This finding can be considered with the study of Gellatly and coworkers, who noted significantly greater visible deposition in lenses greater than 6 months old.97 The evidence, however, is not conclusive in this regard. In an important study surveying 50 comfortable and uncomfortable wearers, Bruce and coworkers were unable to

Deposits and Symptomatology with Soft Lenses: Brennan and Coles

Figure 5. Ocular signs related to deposits (clockwise from top left): focal leucocytic infiltration into corneal epithelium; contact-lensrelated papillary conjunctivitis; bulbar hyperemia; corneal desiccation pattern, potentially caused by lack of wettability associated with lens surface build-up; toxic corneal reaction to care system used in maintaining lens cleanliness; superior limbic keratoconjunctivitis.

show a difference in the amount of visible deposition on the lenses between the two groups.148 This finding was evident despite a link between deposits and both tear break-up and lens age. Further evidence suggests that total assayed protein is not the sole factor in determining lens comfort.157 There is, however, the possibility that individual species that adhere to lenses, the way in which surface roughness occurs in deposits, the individual susceptibility to irritation, or the nature of the bound protein are the prime determinants of lens comfort. Important bridges between comfort responses and lens cleanliness may be the wettability of the lens surface and the quality of the patient’s tears. Indeed, the four features are potentially so interlinked that a fault in any one feature may induce deficiencies with another, and the identity of the initiating factor may be unclear. Anecdotal reports suggest that problems in all four properties are often simultaneously observed. With disposable lenses, initial comfort levels do not appear to be related to different lens types39,42,44,45 or time of replacement,43 despite different deposition profiles on lenses used in such studies.39,43,44 However, these generalizations are derived from mean results and do not preclude patients preferring the comfort levels attainable with a specific lens type. Efron and coworkers have determined that comfort differences can occur with different lens types initially.158 Improved investigative techniques, such as the use of anchored analog grading scales159 or sensitive clinical tools for obtaining information about deposits and symptoms,41 should improve our understanding of the influence of lens build-up on discomfort.

Vision As with many of the symptoms listed here, the link between vision and deposits is intuitively strong. Build-up of matter in any fashion other than that which produces a refractively smooth surface will influence the optics of the lens. However, as with other symptoms, proof of an effect of deposits on vision remains elusive. McClure and coworkers reported a decrease of 2 to 3 lines of Snellen acuity over several months of lens wear, ostensibly caused by lens deposition.160 However, their results were not analyzed statistically. Jones et al found a demonstrable decrease in subjective visual appreciation within 1 month of use of disposable lenses, a finding paralleled by measured build-up on the lens surfaces.161 However, we are aware of only one paper that has numerically linked lens deposits to visual disturbance. Gellatly and colleagues measured high and low contrast visual acuity as well as Rudko deposit grades in a group of 51 wearers of Group I lenses.97 They found statistical verification that lenses with Grade III or IV deposits provided worse vision. In contrast, Elliott and colleagues found that stray light scatter does not correlate with Rudko grading.162 Recent studies looking at the initial acceptance of disposable lenses fail to demonstrate a clear link between surface characteristics and vision.39,42,43,45 One Group IV lens shows consistently better vision, but there is inadequate evidence to confirm that this is related to tear–lenssurface interactions.42,45 A reasonable explanation for the findings is that vision is only degraded when considerable deposition has occurred or denaturation of attached protein is significant.

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Clinical Article Inflammatory A range of immunologically based adverse reactions occur during contact lens wear, particularly extended wear. Those of most immediate concern are giant papillary conjunctivitis (GPC) and acute red eye, and may represent the major contraindications to wear in this mode.163–168 Papillary conjunctivitis has been strongly linked with surface build-up during lens wear.147,163,164,168 Both an immunologic and mechanical basis are presumed in setting up this reaction, and deposition is consistent with both mechanisms. The inflammatory event may be associated with modified secretions, which may induce a cycle of increased deposition, furthering the reaction. Richard and coworkers studied subjects with and without GPC and found that they were able to extract similar amounts of the common tear proteins, with the exception of IgMs, from the contact lenses of both groups. This was greater in those with GPC in short-term wear comparisons, leading the authors to propose that GPC depends solely on the level of deposited IgM and not on the amount of normal tear proteins IgA, IgG, IgE, lactoferrin, or lysozyme. Of course, the deposition of IgM may be part of the inflammatory response rather than the cause of it. While lens disposability reduces deposit-related problems, uninterrupted wear of silicone-hydrogels for 30 days promises to revitalize the deposit debate. Recent reports place the incidence of papillary conjunctivitis at 2 to 7% per annum for silicone-hydrogel lenses worn in continuous wear,169,170 which is a level that constitutes a significant problem for patients and practitioners. Although Stern et al report no difference between 7-day and 30-day continuous wear in their sample of 85 subjects,170 there is a clear opportunity to minimize the papillary inflammatory response by developing a more effective lens maintenance program. The inflammatory response of the cornea is manifested as corneal infiltrates, which are presumed to be migration of leucocytes into the tissue. Acute red-eye reaction is one particular expression of this inflammatory response and is classically observed during extended wear.165,167 The precise mechanism of the response is not yet fully understood. Accumulation of debris under the lens, the presence of Gram-negative organisms, and lens deposition have all been suggested as pathways.165–167,171–174 Increasing the frequency of replacement of contact lenses appears to minimize the incidence of this condition, supporting the proposition that it may be related to deposit formation.165–167,173 Because the rate of corneal inflammatory responses is approximately 15% per annum with 30 day silicone-hydrogel continuous wear,169 investigation of the role of lens deposition is highly recommended. However, frequent replacement of contact lenses does not completely eliminate sterile infiltration, suggesting that deposits may be one of a number of contributing factors in a complex mechanism.175–178 Certainly, eye closure is accompanied by initiation of a

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complex array of immunological pathways, and so may be considered a state of subclinical inflammation.66,179 –182 Studies of immunoglobulin levels may be enlightening in linking deposition to inflammatory responses. As mentioned above, Richard and coworkers found increased IgM levels on lenses from patients with GPC.5 Jones and colleagues report a higher ratio of IgG to IgA with high-water content extended-wear lenses, noting that this is typical of inflammatory states of the anterior eye.67 Leahy et al propose evidence for slow development of antigenic activity at the lens surface, comparing their result which found insignificant amounts of IgA on lenses worn for up to 8 h 38 with earlier work showing IgA and some IgG on 2-month-old lenses,65 and citing the presence of IgA, IgG, IgE, and C1q complement fraction in greater amounts on lenses worn for 8 to 12 months.59 In summary, both mechanical and immune components may be responsible for contact-lens-related papillary conjunctivitis, but infiltrative keratitis would appear to be directly mediated by an immunological response. Denatured protein on the lens surface recognized as foreign by the body’s immune system is one likely trigger of this response. Studies of species involved in the immune mechanisms support such a proposal. Infection For many years, it was believed that corneal infection associated with contact lens wear might be a result of lens spoilage. Instinctively, the proposal has merit; accumulation of material on the lens surface could provide an enhanced vehicle for entry, nutrition, and protection against the antimicrobial components of the tears for microorganisms. Tripathi et al noted that oligosaccharide side chains on the proteins attract microbes and facilitate their adherence.68 Microorganisms and their biofilm may constitute the deposit itself. The presence of microorganisms on the surface of worn lenses has certainly been demonstrated, although numbers are generally small.76,83,183,184 Furthermore, inadequate care and maintenance procedures have also been implicated in the development of infection,185–189 and it is reasonable to hypothesize that the common factor is deposition. This potential tie between infection and deposition provided impetus to the widespread adoption of disposable contact lenses, in the belief that replacing lenses regularly would prevent excessive soiling. Despite the success of disposable lenses in reducing lens surface deposition,190 the similarity between infection rates with disposables and conventional lenses191–194 can be extrapolated to suggest that deposits per se are relatively unimportant in promoting infection. A wide range of studies have compared the adherence of bacteria to contact lenses,195–201 but have failed to unequivocally support the notion that the material that coats a lens during wear induces greater attachment of bacteria than to unworn lenses. Mowrey-McKee and coworkers found no significant

Deposits and Symptomatology with Soft Lenses: Brennan and Coles relationship between bacterial bioburden and any of their study parameters, including total protein, lens age, or subjective evaluation of lens cleanliness.83 Finally, it appears that the activity of components of the deposit may well be retained, raising the possibility that the lens coating is bacteriocidal.87 A converse relationship has been proposed. An early report suggests that, rather than deposits being a vehicle for bacterial contamination, bacteria facilitate the deposition of material onto a lens.202 This proposal has not received widespread support. Summary Most symptoms that are experienced by contact lens wearers have been attributed at one time or another to lens-surface interactions. A significant amount of circumstantial evidence supports a role for deposition in many of these complications and, in particular, for the protein lysozyme as being the major culprit. Contrary to this notion is the high acceptability of Group IV lenses by the patient population despite the high affinity for lysozyme. Presumably, the conformation of the protein is critical. Studies that have considered symptoms in terms of deposition have tended to be clinical in nature and, therefore, assessment of deposit types is largely limited to visible grading. As a result, the identity, quantity, and state of constituents of deposits that produce symptoms are poorly understood.

Care Systems and Deposition Relief of deposit-induced problems is targeted to mechanisms that minimize interaction between the host defences and denatured protein on the lens. Frequent lens replacement, advances in cleaning systems, increased cleaning frequency, and lens-surface treatment offer promise for relieving deposit-induced problems. Of these, frequent lens replacement is the most attractive, with clinical and SEM studies demonstrating the value of this strategy.166,190 However, as discussed above, this does not eliminate lens deposition but reintroduces the problem in a different manifestation. As a consequence, other strategies for achieving compatibility between the lens and ocular surfaces need to be considered. Both clinical185–187,203 and epidemiological stud188,189,192,194,204 ies support the concept that improper care and maintenance can lead to lens contamination, thereby increasing the risk of infectious keratitis. It is possible to theorize a role for deposition in the process, although the evidence is limited. As mentioned above, denatured protein in deposits has an important effect on lens performance. This applies equally to the ability of care systems to clean the lenses. Information regarding the effectiveness of systems against denatured protein is scant. Despite the findings of several researchers suggesting that the biological activity of most of

the lysozyme that adheres to lenses is maintained,87,102 Christensen and coworkers suggest that more than half of the protein remaining on lenses is denatured and that cleaning systems can directly influence this amount.205 Therefore, the following discussion necessarily relates to general protein quantities because the issue of denaturation has been largely overlooked in previous studies. The role of care systems in relieving deposit-related symptomatology is uncertain. In some circumstances, the care system may be a cause of adverse reactions. The improvement in care systems during the 1980s and 1990s saw the elimination of most of the toxic and allergic responses associated with their use. This has led to a growing perception that the choice of care system matters little in the overall performance of a contact lens. It may also reflect poorly designed studies or lack of effective tools to study deposits and symptomatology.116 Christensen et al found that it is possible to demonstrate distinct performance differences in lens cleanliness and ocular awareness.116 Certainly, Jones and colleagues reported that different lens– solution combinations produced different deposition patterns.161 The following discussion looks at the role of care systems in alleviating deposit-related problems. Digital and Surfactant Cleaners One of the steps that has been a feature of contact lens care over the years is a rub and rinse before storage. The mechanical action is thought to be the key point of this procedure. Commonly, cleaning agents containing surfactants have been used to aid the rubbing effect, and may have been considered the most important aspect of this step in some circumstances. There have been anecdotal reports linking omission of mechanical cleaning with infection,206 although this has not been confirmed in epidemiological studies.189 Mechanical cleaning may well be a critical component in keeping lenses clean and disinfected. Koetting observed clinically that rubbing and rinsing delayed the onset of visible protein deposition.207 Franklin and Tighe support the concept noting that the long-term value of the ruband-rinse step may be more important than the short-term effect58 and that cleaners will vary in efficiency and possibly produce a partially modified lens surface.14 For example, Wedler and coworkers noted that mucin was present in the most irritating deposits and suggested that an agent to remove mucin would be of benefit.4 The introduction of an alcohol in some cleaners has provided such an effect. The value of a dedicated cleaner as opposed to using a multiaction solution is unclear. Lebow and Christensen provide indirect evidence that a dedicated cleaner may provide benefits in addition to rubbing and rinsing.208 Louie and coworkers demonstrated that surfactant cleaning reduced deposited lysozyme on silicone-hydrogels by approximately 25%.209 Despite the above evidence, the FDA recently approved use of multipurpose solutions for contact lens

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Clinical Article storage in the absence of an accompanying rub-and-rinse step. Clinical reports suggest that cleanliness of the lenses remains very good for up to a month with no reduction in lens comfort, vision, or ocular health.210,211 Storage Contact lenses spend a considerable time in storage solutions, and it is natural that these may influence the way in which lens deposition occurs. Among procedures that have enjoyed periods of popularity are thermal disinfection and hydrogen peroxide disinfection. The elimination of thermal disinfection in most countries is, in part, evidence that it is associated with an unacceptable rate of depositrelated complications. The preference for thermal disinfection in unique markets such as Japan has led to the application of heat-compatible enzymes; these may be more effective at maintaining lens cleanliness than, say, a multipurpose solution without enzyme.102 Hydrogen peroxide has been identified as a possible cleaning agent, and one study has found that it provides a reduction of soiling by an artificial tear solution.82 However, the benefits of such a cleaning action do not appear to outweigh the risk of ocular toxicity due to peroxide nor the added complexity involved with neutralization of this agent. Cold chemical storage solutions have also been available for many years. Many of the components in systems developed before the mid-1980s induced toxic and allergic reactions, and even interacted with deposits on the surface of lenses. As a result, these antimicrobial agents were superseded by compounds that are more compatible with ocular health.172 Because details of the earlier agents are of little relevance to current contact lens practice, the reader is invited to look elsewhere for details of such systems. Multipurpose Solutions The recent developments in cold chemical contact lens care systems, as mentioned above, have been accompanied by the rise in popularity of multipurpose solutions, in which the functions of cleaning, rinsing, and disinfecting are all served by a single solution. This evolution has led to increased simplicity of care with attendant benefits in terms of patient compliance and satisfaction. Both positive and negative cleaning influences may eventuate from combining functions in multiaction solutions. The increased compliance derived from the simplicity of the systems may produce a more consistently clean lens. However, the following potential negative effects of using multiaction solutions should be kept in mind: a specific purpose surfactant cleaner may achieve better cleanliness208,212; the cost of the storage solution is greater than, say, a saline solution, and so less liberal cleaning and rinsing may occur; and placement direct from the solution to the eye may introduce low levels of chemical agents to the eye, which may induce subtle ocular reactions that involve increased lens deposition. Nonetheless, most critics would agree that the benefits of

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multiaction solutions have outweighed any perceived disadvantages. Manufacturers have added various components to their multiaction solutions to enhance the cleaning capacity of the system. Citrates, used as a buffering agent, may participate in the cleaning process. A range of mechanisms for this effect are proposed— citrates render certain organic molecules more water soluble, alter the electrostatic interaction between soilant and substrate, interact with cationic biological molecules, displace polymer-bound lysozyme, serve as a chelating agent, disrupt the intermolecular bridging effect of calcium, and block the uptake of quaternary ammonium disinfectants by Group IV polymers.212 The addition of citrate to a storage solution has been found to have a beneficial effect on lens cleaning in laboratory based107,212 and clinical studies.205,213,214 This effect has been termed passive, in that it occurs in the absence of mechanical cleaning. Some manufacturers use surfactants, including the high molecular weight poloxamine (or poloxamer) or the lower molecular weight tyloxapol. Theory suggests that surfactants would alter the interfacial chemistry at the molecular layer between the contaminant and lens. Polar micelles would form, entrapping the debris and enabling it to be rinsed away. Clinically, solutions containing a surfactant have been reported to promote mechanical cleaning as well as provide ongoing cleaning during wear.85,215,216 However, the presence of the surfactant or differences between surfactants may have an impact on tear quality and lens comfort in some wearers.215,217–219 As mentioned above, the FDA has recently approved contact lens storage in multipurpose solutions without a prior rub-and-rinse step.210,211 The move in this direction means that the enhancement of passive cleaning aids, such as citrates, within the storage solution and demonstration of their clinical effect may become a critical factor in the competitive development of new lens storage products. Hydranate, a sequestering agent, has also been included in a storage solution to aid in cleaning and in an attempt to deliver a single all-purpose solution.220 In vitro tests by an independent party suggest that use of this solution gave comparable cleaning performance to that achieved with regular storage solution and an enzyme cleaner.220 Another addition to multiaction solutions, hydroxy-propyl methyl cellulose (HPMC), has been shown to produce favorable results across a range of attributes, such as lens wettability and tear structure, compared with a non-HPMCcontaining solution.221,222 For the reasons mentioned above in the section ‘the link between symptom and deposits’, these findings may have implications regarding deposit formation. The question remains whether a multiaction solution used to rub and rinse can clean lenses as well as a dedicated cleaner.212 In a study by House and coworkers, a multiaction solution was found to be as effective as a dedicated cleaning solution for maintaining lens cleanliness.216 Un-

Deposits and Symptomatology with Soft Lenses: Brennan and Coles fortunately there was no control (rub and rinse with saline), begging the question as to whether surfactant cleaners offer anything over and above the simple act of rubbing and rinsing. The absence of a statistically significant difference is not the same as demonstrating equivalence.

Enzyme The use of enzymes to target deposit-related problems has been pursued avidly by contact lens companies since Karageozian’s initial work.86,223 More than any other care component, enzymes are specifically targeted to address this problem. Clinical interpretation would suggest that enzymes are at least partially effective in addressing the deposit-related problem. Currently available enzyme cleaning provides some, but not total, relief. Baines and coworkers estimated a reduction of some 75% of protein from artificial tear solutions with enzyme usage, but this was quickly reabsorbed on exposure to the protein solution.113 In their study, Jung and Rapp found enzymic activity reduced lysozyme alone but was not effective against lactoferrin, albumin, or glycoprotein.84 Clinically, Nilsson and Lindh reported clear variations in visible differences in deposit levels, lens wetting, and patient comfort when enzyme tablets were used with conventional lenses and hydrogen peroxide disinfection.155 It may be concluded that available systems are designed specifically to target lysozyme, or that the dynamics of binding favor the release of lysozyme. To this end, a cocktail of enzymes is not the answer because they may digest each other. Furthermore, partial digestion of proteins by enzymes may paradoxically contribute to the problem. Differences between enzymatic cleaners in inherent toxicity and sensitization potential may also be important. Breen and coworkers were able to detect distinctions in comfort ratings of patients using different enzyme cleaners.224 They also noted that soaking times interacted with both the patient comfort response and the ability to achieve visual cleanliness of lenses. A recent novel concept has been the introduction of a liquid formulation containing an enzyme cleaner that is intended to be used daily. Clinical studies have suggested that this product has low inherent toxicity, is safe to use, provides good comfort and lens cleanliness, and is found convenient by patients.225 In combination with a citratebased multipurpose solution, it performed in a superior fashion with respect to lens deposition in comparison with a panel of other storage systems.213 With regard to antibacterial effects of enzyme usage, Butrus et al found that, while soft contact lens surface deposits are a major determinant in the adhesion of Pseudomonas aeruginosa to the worn lens surface, enzyme cleaning of worn lenses does not significantly reduce bacterial adhesion.197

System Assessment of individual components of care systems may not provide a realistic appreciation of the influence of the total system against deposits. For example, Aswad and coworkers found that three different systems, each considered in their entirety rather than by single components, were of comparable efficacy in reducing the infectivity of contaminated contact lenses.201 Other A range of potential anti-deposit components has been proposed that might be added to contact lens care systems. These include nonsteroidal anti-inflammatory drugs,226 such as bendazac lysine227,228 and sodium salicylate,78 and other antidenaturant drugs.109 Summary While cleaning systems perform an important role in removing the build-up that occurs on lens surfaces, they are not effective in removing all deposits. It is equally clear that this is not the desired result. A certain conditioning coating seems to be necessary to facilitate biocompatibility of a lens in the eye. The partial effect that care systems have on removing surface build-up may be beneficial in some cases or may contribute to the problem by partially modifying lens coatings.

Conclusion The principal conclusion from this review of the literature is that we have only begun to understand the issues of biocompatibility in contact lens wear. More by inference than science, we suspect that minor-to-moderate levels of deposition do play a role in producing signs and symptoms in contact lens wearers, and that the protein lysozyme is the principal culprit. Only recently have techniques for accurate compositional and quantitative evaluation of deposits on lens surfaces been employed. Even so, the large differences in recovered protein amounts between lenses with basically the same on-eye performance clearly demonstrate that it is the way in which material gathers on a lens surface, rather than the quantity of individual components, that dictates the clinical outcome. Until the precise roles of individual species on the lens surface in causing contactlens-related problems are known it is unlikely that effective prevention strategies can be formulated.

Acknowledgment This paper was commissioned by Alcon Laboratories, Sydney Australia. The authors thank Drs. Jerry Stein, Ralph Stone, Bergson DeSousa, David Keith, Kelly Higgins, Horst Zacharias, Ron Quintana, Leslie Napier, Masood Chowhan, Barry Van Duzee, and Mike Christensen

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Clinical Article for comments on the manuscript; Drs. David Keith, Russell Lowe, Kenneth Gellatly, and Timothy Golding for providing illustrations; and Dr. Haydn Scott for administration of the project.

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Clinical Implications Contact lens clinicians are often faced with the challenge of managing patients’ symptoms and complications due to soft contact lens wear. The authors of this article provide an in-depth review of soft lens deposition to analyze the link between contact lens deposits and these ocular reactions. Several factors are involved with the sources and components of these deposits and although technology has improved with regard to the methodology of structural analysis for these compounds, we have yet to discover solid, scientific methods to link symptoms with deposit pattern.

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Clinical Article This is certainly a clinically valuable topic to be investigated, as this relationship may assist in determining soft contact lens wearing success of future patients. Adverse effects and discomfort due to contact lens wear from excessive deposits may lead to discontinuation of contact lens wear. If we are able to better classify and specify the biological nature of the deposits, we may gain a better understanding of the association between symptoms and soilant from a clinical perspective. Once determined, the association between deposits and symptomatology could eventually elucidate the issues of biocompatibility of contact lenses in the eye and possibly provide a baseline rationale for ocular discomfort. Moreover, with the advent of new types of soft lenses and cleaning systems, the deposit– symptom link is of even more significance. This article reinforces the necessity to further investigate the specific roles of lens coatings in causing contact lens problems and provide a foundation for prevention strategies and an improvement in overall patient care. Jennie Y. Kageyama, OD, FAAO Jules Stein Eye Institute UCLA School of Medicine Los Angeles, CA

Dr Noel Brennan co-directs a Melbourne-based private research company. This consultancy specialises in pre-clinical assessment and development of contact lenses and ocular testing procedures, clinical trials and scientific writing. He has a Master’s degree in Optometry, a PhD, is a Fellow of the American Academy of Optometry, and a councillor of the International Society of Contact Lens Research. He was formerly a Reader and Associate Professor at the University of Melbourne. He also co-owns an optometry practice with a principal patient base of specialist contact lens fittings.

Dr Chantal Coles graduated from the New England College of Optometry in 1987. She has worked as a private practitioner in Canada and Australia and held a position as a Research Optometrist at the Centre for Conact Lens research of the University of Waterloo for a period of three years. She moved to Australia in 1994 and co-founded two companies which specialize in vision research, clinical trials and industrial consulting. She is also co-owner of a private optometry practice in Melbourne.

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