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Contact Lens & Anterior Eye 35 (2012) 53– 64

Contents lists available at SciVerse ScienceDirect

Contact Lens & Anterior Eye

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rotein deposition on contact lenses: The past, the present, and the future

oerte Luensmann ∗, Lyndon Jonesentre for Contact Lens Research, School of Optometry, University of Waterloo, Waterloo, Ontario, N2L 3G1, Canada

r t i c l e i n f o

eywords:rotein depositionontact lensydrogelolyHEMAilicone hydrogeliocompatibility

a b s t r a c t

Proteins are a key component in body fluids and adhere to most biomaterials within seconds of theirexposure. The tear film consists of more than 400 different proteins, ranging in size from 10 to 2360 kDa,with a net charge of pH 1–11. Protein deposition rates on poly-2-hydroxyethyl methacrylate (pHEMA)and silicone hydrogel soft contact lenses have been determined using a number of ex vivo and in vitroexperiments. Ionic, high water pHEMA-based lenses attract the highest amount of tear film protein(1300 �g/lens), due to an electrostatic attraction between the material and positively charged lysozyme.

All other types of pHEMA-based lenses deposit typically less than 100 �g/lens. Silicone hydrogel lensesattract less protein than pHEMA-based materials, with <10 �g/lens for non-ionic and up to 34 �g/lensfor ionic materials. Despite the low protein rates on silicone hydrogel lenses, the percentage of dena-tured protein is typically higher than that seen on pHEMA-based lenses. Newer approaches incorporatingphosphorylcholine, polyethers or hyaluronic acid into potential contact lens materials result in reducedprotein deposition rates compared to current lens materials.

Britis

© 2012

. Introduction

Contact lenses represent a biomaterial that is widely used andelatively easy to study, due to its ease of removal from the ocularurface. Immediately after being placed on the eye, contact lensesre coated with a protein layer and most proteins attach stronglyo the material, with typically less than 50% being removed by con-entional care regimens [1–3]. The deposition of certain proteinso contact lenses has shown to increase the risk of microbial cellttachment to the lens material [4–6], and is also associated withnflammatory complications such as giant papillary conjunctivitis7].

. Proteins in the tear film

Protein deposition on contact lenses is substantially impactedy the lens material, and also by the protein concentration, proteintructure and charge of the proteins within the tear film. Proteinsre a major component of the human tear film and perform a vari-

ty of important tasks, which include protecting the ocular surfacerom microorganisms, cell membrane transport/metabolism,egulating immune responses, protein folding, antioxidation, andct as protease inhibitors [8]. de Souza [9] identified 491 different

∗ Corresponding author at: Centre for Contact Lens Research, University of Water-oo, 200 University Ave West, Waterloo, N2l 3G1, ON, Canada.el.: +1 519 888 4567x37312; fax: +1 519 884 8769.

E-mail address: dluensma@uwaterloo.ca (D. Luensmann).

367-0484/$ – see front matter © 2012 British Contact Lens Association. Published by Elsoi:10.1016/j.clae.2011.12.005

h Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

proteins and mucins in the tear film, ranging in size from 10 kDato 2360 kDa [9]. Approximately 80% of the proteins have a size of<100 kDa [9] and they range in charge from isoelectric points (pI) ofpH 1 to 11 [10]. Examples of proteins that have received the mostattention in contact lens research include lysozyme (14.3 kDa, pIpH 11.4), lactoferrin (80 kDa, pI pH 8.7) and albumin (66 kDa, pI pH5.2). The average pH of the tear film is 7.4, which results in lysozymeand lactoferrin being positively charged and albumin being nega-tively charged. Most proteins have a pI significantly above or belowpH 7.4, which helps their solubility in the tear film, as proteins areleast soluble if the environment is close to the protein’s pI, whichwould lead to increased aggregation and deposition rates [11,12].

The total protein concentration in the tear film ranges between6.5 and 9.0 mg/mL and varies between individuals [13]. A varietyof factors are known to influence the protein concentration in thetear film, including: time of the day [14,15], contact lens wear [16],age [17] and eye diseases such as Sjögrens syndrome [18]. Signif-icant differences in concentration are also seen when tearing isstimulated, compared to that seen with unstimulated tears [19].

3. The principals of protein sorption

Proteins adsorb to most surfaces, and while hydrophobic (non-polar) amino acids are typically protected inside the proteinmolecule, the hydrophilic (polar) amino acids, with and without

charged side chains, interact freely with their environment [20].If the charged side chains come into contact with an oppositelycharged surface, the adsorption process is further reinforced. Eachprotein is typically folded in a three-dimensional structure, which

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s held together by hydrophobic forces, hydrogen bonds and vaner Waals forces [21]. However, the structure of most proteins isetastable and the exposure to water-based solutions is energet-

cally unfavorable due to an increase in Gibbs energy [22]. Whenow exposed to a solid surface – particularly hydrophobic surfaces

proteins tend to rearrange their structure and favor adsorptiono the surface in order to once again lower the Gibbs energy [23].nce proteins are unfolded and have coiled in a random manner,

hey are unable to perform their natural tasks, but instead maynteract with other proteins/cells in an undesired manner. Thesenfolded, or “denatured” proteins, may cause aggregation or canrigger immune reactions [24,25].

. Analyzing protein deposits on contact lenses

A number of qualitative and quantitative techniques have beenpplied to analyze protein deposition on contact lens materials26]. These can be broadly categorized into clinical assessment,iochemical and imaging techniques, each of which provides verypecific information about the deposition on the lens material. Arief overview is outlined in this section, describing some com-only used techniques.Subjective clinical grading provides a fast, non-destructive

ethod of assessing visible deposition on contact lenses. Rudkond Proby [27] described the degree of visible deposition on softontact lenses using a slit lamp, by categorizing the deposits basedpon the level of magnification required to visualize the deposits,n a dry or wet lens. Despite some modifications of this classifi-ation system over the years, research has shown that there is aack of correlation between these so-called “Rudko scores” and theotal amount of protein deposited on lenses, as determined usinguantitative techniques [28]. Further, it is difficult to differenti-te between types of deposition (for example whether the visibleeposits are protein or other tear film components) [28,29] usingubjective clinical grading.

Biochemical laboratory-based techniques provide detailed infor-ation on the quantity and/or type of deposition present. Protein

ssays typically require extraction of the proteins from the contactens before they can be analyzed, and focus on the identificationnd/or quantification of the protein content. Chemical reagents thatre typically used to undertake the extraction include urea, guani-ine hydrochloride, potassium thiocyanate, potassium perchlorate,ydroxylamine, ethylene dithretyl acetamide, sodium dodecyl sul-

ate (SDS), dithiothreitol (DTT), and acetonitrile/trifluoroacetic acidACN/TFA) [30,31]. The efficiency of these reagents with respecto removing the protein depends on the type of protein and com-osition of the lens material, and may remove as little as 25% ofhe deposited substance [32,33]. Once extracted, general proteinssays such as the bicinchoninic acid (BCA) assay can quantifyhe total amount of protein [34–36], while amino acid analysis32] or sodium dodecyl sulfate polyacrylamide gel electrophore-is (SDS-PAGE) have been used to quantify and identify depositedroteins. Another sensitive technique for identifying different typesf proteins is high performance liquid chromatography (HPLC),hich provides semi-quantitative results [31,37]. The conforma-

ional state of deposited lysozyme has further been determinedsing the micrococcal activity assay [38–40].

Imaging techniques provide primarily qualitative results, withome techniques providing quantitative information [41,42]. Aumber of microscopy techniques, such as light and dark fieldicroscopy, phase contrast and interference microscopy have

een used to examine gross and fine morphological aspects ofeposition [41,43]. For higher resolution imaging and elemen-al analysis, scanning electron (SEM) and transmission electron

icroscopy (TEM) have successfully been adopted [44–46]. Atomic

Anterior Eye 35 (2012) 53– 64

force microscopy (AFM) provides details at the nanometer rangeand is therefore even more advanced compared to conventionalscanning microscopy techniques [47]. In contact lens research, AFMhas been used to image the interaction between surface rough-ness and tear film deposition [5,48–50]. Confocal laser scanningmicroscopy (CLSM) is a unique technique that allows the examinerto scan directly into the contact lens matrix, making it possible todetermine the penetration depth of proteins. [51,52]. In contrastto microscopy, spectroscopic techniques typically measure theenergy that is either absorbed or emitted by the deposited speciesand can, for example, identify proteins, carbohydrates or lipids byanalyzing specific absorption bands. Ultraviolet (UV) and fluores-cence spectroscopy [42], attenuated total reflectance (ATR) [53],electron spectroscopy for chemical analysis (ESCA) [54], surfacematrix assisted laser desorption/ionisation (MALDI) mass spec-trometry [55,56] and radiolabeling [57,58] are just some examplesof spectroscopic techniques used to analyze protein deposition.The conformational state of deposited proteins has further beeninvestigated using electron spin resonance (ESR) spectroscopy [59]or Fourier transform infrared-attenuated total reflectance spec-troscopy (FTIR-ATR) [53].

A number of factors need to be considered when evaluating thelevel of protein deposition on contact lenses. These include thelength of time the lenses were worn for, the use of specific con-tact lens care regimens, the extraction and quantification methodemployed, inter-subject differences and finally an acceptance thatin vitro experiments may not necessarily mimic ex vivo situations.

This review provides an overview of quantitative protein sorp-tion to soft contact lens materials that have been used in the past,materials presently in use and materials that could potentially beused in the future. Most information is currently available on thetear film proteins lysozyme, lactoferrin and albumin, therefore spe-cific information on these proteins are included in this review,where available.

5. Hydrogel contact lenses – the past

Poly-2-hydroxyethyl methacrylate (pHEMA) was invented byOtto Wichterle more than 50 years ago and has shown such accept-able biocompatibility that even today it is still used in manybiomedical fields, for blood-contacting implants, artificial organs,drug delivery devices, intraocular lenses (IOL) and contact lenses[60–62]. Hydrated pHEMA has a water content of 38%, but variousmonomers or polymers are frequently incorporated for use in con-tact lens materials, to enhance material strength and to increaseequilibrium of water content and hence oxygen permeability [63].Currently, more than 150 different types of soft contact lenses areavailable, most of which are still based on pHEMA compositions[64].

5.1. 2-Hydroxyethyl methacrylate

Contact lens materials that primarily consist of pHEMA are cat-egorized by the Food and Drug Administration (FDA) as Group I(non ionic, <50% water) materials and account today for approx-imately 10% of all newly fitted soft contact lenses worldwide[65]. The literature to-date unanimously agrees that contact lensesmade of pHEMA deposit less protein than pHEMA materials com-bined with other monomers, particularly methacrylic acid orN-vinylpyrrolidone [31,66].

Despite the low deposition level of this material, proteins can be

detected after as little as 1 min of lens wear [67,68]. Highly abun-dant proteins in the tear film (e.g. lysozyme; lactoferrin) depositonto pHEMA lenses at quantities that are similar or even lowerthan less abundant proteins such as albumin or Immunoglobulin

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[58,66]. The amount of protein deposition is further impactedy lens manufacturing technique as suggested in a previous study.hese data showed that lysozyme and albumin levels on EGDMA-rosslinked pHEMA materials are 1.5–2× higher on lenses that wereanufactured using a lathe-cut technique as compared to those

hat were spun cast [69,70].The total amount of protein depositing on worn pHEMA lenses

anges between 4 and 75 �g/lens [28,30,32,34,71], while in vitroxperiments have detected 16–23 �g of lysozyme [72] and 4.5 �g73] to 41 �g [4] of albumin per lens. The overall protein sur-ace coating on pHEMA lenses worn for 2 h is approximately0–30 ng/cm2, as determined by X-ray photoelectron spectroscopyXPS) [56].

.2. Methacrylic acid

Methacrylic acid (MAA) is the most commonly employedydrophilic monomer that is used in combination with pHEMAaterials. It is found in some FDA Group III materials (ionic,

50% water) and is almost always present in FDA Group IV (ionic,50% water) lens materials [63]. Copolymerization with this highlyegatively charged (anionic) monomer increases the water con-ent of pHEMA, which results in higher oxygen permeability.owever, the negatively charged carboxyl groups of MAA attractositively charged proteins such as lysozyme, and both ex vivond in vitro studies have shown that with increasing amountsf MAA the amount of lysozyme accumulation increases [58,74],hile negatively charged proteins such as albumin decrease

58].Although several contact lens materials are categorized within

DA Group IV, the amount of MAA varies greatly. The impactf this is shown by the fact that materials containing “low”mounts of MAA such as vifilcon A [58] (which also includeinyl pyrrolidone), typically deposit less than half the amountf total protein compared to etafilcon A [32,74], which containsore MAA. Ex vivo results have determined 82–488 �g total

rotein on vifilcon A lenses, which is similar to in vitro experi-ents investigating lysozyme alone [72]. The amount of lysozyme

epositing on worn etafilcon A (Group IV) lenses accounts for5% [75] to 92% [31] of the total protein. The average amount ofeposited lysozyme is approximately 1300 �g/lens, ranging from09 to 3700 �g/lens [28,34,37,38,71,76,77] as determined by var-

ous extraction/quantification methods. Slightly lower amounts ofotal protein are typically found when using spectroscopy methods75,78]. In vitro studies are in reasonable agreement with ex vivoesults, reporting on 428–2200 �g of lysozyme [31,35,39,72,73],–11 �g of lactoferrin [79] and <1–4 �g of albumin [3,73] per lens.

In vitro CLSM experiments have determined that etafilcon Aeposits both lysozyme and albumin throughout the lens material,hen exposed for >24 h [3,52]. However, vifilcon A lenses accumu-

ate lysozyme at slightly higher concentrations in the outer surfaceegion, but significant amounts are still detected within the lensatrix [80]. After 2 h of lens wear, the protein surface coating on

tafilcon A lenses is approximately 70–220 ng/cm2, as determinedy XPS analysis [56].

Comparisons between pHEMA-MAA and crosslinked pHEMAenses have determined that albumin deposited on pHEMA exhibitsonformational changes earlier than pHEMA-MAA lenses [69]. ESRpectroscopy has further shown that albumin binds irreversiblynd denatures within 1 h of exposure to vifilcon A, which is fasterhan that measured on etafilcon A [59]. These findings suggest that

he amount of MAA in the material impacts the stability of theeposited protein. Finally, the amount of active lysozyme on etafil-on A lenses is typically >75%, as determined by the micrococcalctivity assay [39,76].

Anterior Eye 35 (2012) 53– 64 55

5.3. N-vinylpyrrolidone

N-vinylpyrrolidone (NVP) is another hydrophilic monomer thatis used to increase the water content of either pHEMA or poly-methyl methacrylate (pMMA) [63]. NVP or PVP, which is thepolymer of NVP [11], can either be incorporated into the bulk mate-rial or is grafted onto the material’s surface. NVP is present in mostFDA Group II lenses (non ionic, >50% water), but is also seen in com-bination with MAA in certain FDA Group IV materials (e.g. vifilconA). PVP is a component that is often incorporated in biomaterialsto increase surface hydrophilicity and to reduce protein deposition[81].

The incorporation of NVP into pHEMA materials impacts theoverall charge of the material, to a small but noticeable degree:with an increasing NVP content, less positively charged lysozymeand more negatively charged albumin deposits on HEMA-basedlenses [58,66]. A study using synthesized hydrogels containing 80%HEMA, 1% MAA and 19% NVP found similar amounts of albumin andlysozyme on these lenses, but surprisingly more than twice as muchof the larger protein lactoferrin, after incubation in an artificial tearsolution (ATS) containing various proteins [82].

The total amount of protein detected on patient-worn lensesranges from 7 to 87 �g/lens [28,32,42,75,78,83], with most stud-ies reporting 30–40 �g/lens [28,42,78,83]. In vitro studies thatdetermined the amount of individual proteins on NVP-containinghydrogels have reported on 35–68 �g/lens for lysozyme [39,72],4–7 �g/lens for lactoferrin [79] and approximately 2–7 �g/lens foralbumin [73,84].

Similar to other pHEMA-based materials, lysozyme can bedetected throughout the NVP-containing lens material alphafilconA after only 1 day of exposure to a single protein solution, as deter-mined by CLSM using fluorescently conjugated lysozyme [80].

Clearly, MAA and NVP have a strong impact on protein sorptionto pHEMA-based materials. However, other principal componentsnot reviewed in this paper may also play important roles in mod-ifying or controlling protein deposition. Some examples includemethyl methacrylate and other di- or trifunctional methacry-lates (which are mainly hydrophobic), allyl methacrylate, divinylbenzene diacetone acrylamide, isobutyl methacrylate, vinylacetate, hydrophilic 2,3-dihydroxypropyl methacrylate, diacetoneacrylamide (which is ionic), phosphorylcholine, the crosslinkerEGDMA, polyvinyl alcohol (which is nonionic) and others [63].

In summary, hydrogel lenses are made of a number of differ-ent hydrophobic or hydrophilic, negatively or positively chargedmonomers, which have a significant impact on the amount ofprotein deposition. Group I (non-ionic; <50% water) lenses typ-ically deposit the lowest amount of protein, followed by similaramounts on Group II (non-ionic; >50% water) and Group III (ionic;<50% water), with the most being found on Group IV (ionic; >50%water) lenses, which deposit approximately 10 times more pro-tein than Group I lenses (Table 1a). The amount of protein foundon worn Group I, II and III lenses is typically less than 100 �g/lens,while most Group IV lenses deposit between 400 and 2000 �g/lens,depending on the quantification method and degree of ionicity ofthe material. Comparisons between hydrogel materials have shownthat the percentage of active lysozyme is typically >2× higher onionic materials, compared to non-ionic materials, as shown in bothin vitro [39] and ex vivo studies [85].

6. Silicone hydrogel contact lenses – the present

Pure silicone is a highly gas permeable material, but due to itshydrophobic character silicone-based contact lenses are poorlywettable [86] and show high rates of lipid deposition [76,87].

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Table 1aQuantitative data on protein deposition to pHEMA-based contact lens materials.

Material Total protein(�g/lens)

Lysozyme(�g/lens)

Lactoferrin(�g/lens)

Albumin(�g/lens)

In vitro/ex vivo

Sol type/extraction method/quantificationmethod

Exposuretime (days)

Group I[28] All 13.6 ± 16.8 Ex vivo Ninhydrin assay/spectrophotometry Open[34] N/A 74.5 ± 5.7 Ex vivo Alcohol, urea, acetic acid/Bio-Rad assay Open[34] N/A 86.9 ± 12 In vitro ATS/Alcohol, urea, acetic acid/Bio-Rad assay 1[73] N/A 4.5 ± 2.0 In vitro Single sol/ACN-TFA extraction/Coomassie

brilliant blue1

[71] Polymacon 30 ± 60 Ex vivo ACN-TFA extraction/BCA analysis 14[30] Polymacon 3.9 ± 2.2 Ex vivo Heat, SDS/Lowry colorimetric test Open[72] Polymacon 16 ± 8 In vitro Single sol/radiolabeling 14[72] Polymacon 23.2 ± 9 In vitro Single sol/radiolabeling 28[31] Polymacon 3.2 ± 0.7 In vitro ATS/ACN-TFA extraction/HPLC, BCA analysis,

SDS-PAGE14

[4] Polymacon 41.1 In vitro Urea, acetic acid/Bradford assay 2[32] Tefilcon A 20.4 ± 17 Ex vivo SDS extraction/amino acid analysis Open

Group II[28] All 37.7 ± 135 Ex vivo Ninhydrin assay/spectrophotometer Open[34] N/A 234.3 ± 19 In vitro ATS Alcohol + urea + acetic acid/Bio-Rad assay 1[73] N/A 6.8 ± 4.1 In vitro Single sol/ACN-TFA extraction/Coomassie

brilliant blue1

[78] Alphafilcon A 26 ± 7 Ex vivo UV spectrophotometry 14[78] Alphafilcon A 40 ± 7 Ex vivo UV spectrophotometry 28[72] Alphafilcon A 44.5 ± 13 In vitro Single sol/radiolabeling 14[72] Alphafilcon A 53.3 ± 11 In vitro Single sol/radiolabeling 28[32] Atlafilcon A 6.8 ± 5.6 Ex vivo SDS extraction/amino acid analysis Open[31] Lidofilcon A 14.8 ± 1.4 In vitro ATS/ACN-TFA extraction/HPLC, BCA analysis,

SDS-PAGE14

[84] Lidofilcon A 2.2 ± 0.1 In vitro Single sol/radiolabeling 3[75] Netrafilcon A 87 Ex vivo UV spectrophotometry 90[72] Omafilcon A 35.3 ± 8 In vitro Single sol/radiolabeling 14[72] Omafilcon A 43.8 ± 13 In vitro Single sol/radiolabeling 28[79] Omafilcon A 4.1 ± 1.1 In vitro Single sol/radiolabeling 14[79] Omafilcon A 6.8 ± 2.0 In vitro Single sol/radiolabeling 28[39] Omafilcon A 68 ± 28 In vitro Single sol/ACN-TFA extraction/Western

blotting17

[83] Vasurfilcon A 42 ± 7 Ex vivo SDS extraction/spectrophotometry 30[42] Vasurfilcon A 28 ± 20 Ex vivo SDS extraction/spectrophotometry 30

Group III[28] All 33.2 ± 73.6 Ex vivo Ninhydrin assay/spectrophotometer Open[34] N/A 78.5 ± 2.1 2 samples

only!!!Ex vivo ATS/Alcohol, urea, acetic acid/Bio-Rad assay N/A

[34] N/A 151.4 ± 10.6 In vitro ATS/Alcohol, urea, acetic acid/Bio-Rad assay 1[73] N/A 5.8 ± 0.8 In vitro Single sol/ACN-TFA extraction/Coomassie

brilliant blue1

[31] Phemfilcon A 12.2 ± 2.3 In vitro ATS/ACN-TFA extraction/HPLC, BCA analysis,SDS-PAGE

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57

Table 1a (Continued)

Material Total protein(�g/lens)

Lysozyme(�g/lens)

Lactoferrin(�g/lens)

Albumin(�g/lens)

In vitro/ex vivo

Sol type/extraction method/quantificationmethod

Exposuretime (days)

Group IV[28] All 991.2 ± 472.7 Ex vivo Ninhydrin assay/spectrophotometer Open[34] N/A 208.7 ± 137.8 Ex vivo Alcohol, urea, acetic acid/Bio-Rad assay Open[34] N/A 322.6 ± 10.3 In vitro ATS/Alcohol, urea, acetic acid/Bio-Rad assay 1[73] N/A 4.0 ± 1.8 In vitro Single sol/ACN-TFA extraction/Coomassie

brilliant blue1

[78] Etafilcon A 482 ± 67 Ex vivo UV spectrophotometry 14

[78] Etafilcon A 493 ± 101 Ex vivo UV spectrophotometry 28

[77] Etafilcon A 1341.7 ± 175.5 Ex vivo ACN-TFA/Lowry method, spectrophotometry 14[76] Etafilcon A 985 ± 241 Ex vivo ACN-TFA extraction/SDS-PAGE, Western

blotting14

[75] Etafilcon A 707 Ex vivo UV spectrophotometry 14

[37] Etafilcon A 600 Ex vivo ACN-TFA extraction/HPLC 1[37] Etafilcon A 1300 Ex vivo ACN-TFA extraction/HPLC 11[71] Etafilcon A 3700 ± 700 Ex vivo ACN-TFA extraction/BCA 14

[38] Etafilcon A 1413 ± 2472005 ± 252

935 ± 271 OFE1551 ± 371 Renu MP

Ex vivo ACN-TFA extraction/Western blotting 30

[72] Etafilcon A 1433.5 ± 76 In vitro Single sol/radiolabeling 14[72] Etafilcon A 1434.5 ± 56 In vitro Single sol/radiolabeling 28[79] Etafilcon A 5.7 ± 0.9 In vitro Single sol/radiolabeling 14[79] Etafilcon A 11.3 ± 1.9 In vitro Single sol/radiolabeling 28[35] Etafilcon A 427.5 ± 6.4 In vitro Single sol/ACN-TFA extraction/BCA assay 1[4] Etafilcon A 30.1 In vitro Single sol/Urea + acetic acid/Bradford assay 2[39] Etafilcon A 1800 ± 600 In vitro Single sol/ACN-TFA extraction/Western

blotting17

[3] Etafilcon A 2200.3 ± 15.6 0.2 ± 0.04 In vitro Single sol/radiolabeling 14[31] Etafilcon A 554.9 ± 18.3 In vitro ATS/ACN-TFA extraction/HPLC, BCA analysis,

SDS-PAGE14

[75] Vifilcon A 82 Ex vivo UV spectrophotometry 30

[32] Vifilcon A 376 ± 216 Ex vivo SDS extraction/amino acid analysis Open

[42] Vifilcon A 488 ± 40 Ex vivo SDS extraction/spectrophotometry 30

[72] Vifilcon A 356 ± 48 In vitro Single sol/radiolabeling 14[72] Vifilcon A 512.3 ± 51 In vitro Single sol/radiolabeling 28[128] Vifilcon A 598 ± 184 In vitro ATS/Ninhydrin assay/spectrophotometer 16 h

[84] Perfilicon A 3.0 ± 0.05 In vitro Single sol/radiolabeling 3[84] Bufilcon A 0.2 ± 0.02 In vitro Single sol/radiolabeling 3[129] Phemfilcon A 905 OFE

1025 RenuEx vivo ACN-TFA extraction/HPLC 90

ACN-TFA: acetonitrile/trifluoroacetic acid, ATS: artificial tear solution, BCA: bicinchoninic acid, DTT: dithiothreitol, FTIR: Fourier transform infrared, HPLC: high performance liquid chromatography, OFE: Optifree Express, OFR:Optifree Replenish, SDS: sodium dodecyl suphate, SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis, sol: solution, UV: ultraviolet.

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ilicone hydrogel lenses, which became commercially availablen 1999 combine the benefits of the hydrophilic, ion-transportingroperty of pHEMA and the high oxygen permeability of siloxane-roups [88,89]. To-date, a dozen silicone hydrogel materials arearketed worldwide, with oxygen transmissibilities (Dk/t) ranging

rom 65 to 175 × 10−9 units. These lenses account for approxi-ately 39% of all newly fitted soft contact lenses worldwide [65].Most silicone hydrogel lens materials require surface mod-

fication to overcome the hydrophobic nature of the siliconeomponents, which impacts the distribution of the protein on theurface and within the lens matrix [80]. Various plasma treatmentsave been used to improve the surface wettability of certain sili-one hydrogel lenses [64,90].

Silicone hydrogel lenses have a more complex monomer compo-ition than pHEMA-based materials [63,64]. Components that areommonly seen are DMA (N,N-dimethylacrylamide), PDMS (poly-imethylsiloxane), TPVC (tris-(trimethylsiloxysilyl) propylvinylarbamate), TRIS (trimethylsiloxy silane), proplvinyl carbamate,VP and other siloxane macromers [64]. Due to the complex-ty of these materials, the following protein sorption profiles areeviewed by lens type rather than material groups.

.1. Balafilcon A

A reactive gas plasma process transforms the hydrophobiciloxane components on the surface of balafilcon A lenses intoydrophilic silicate compounds (‘glassy islands’) [64,91]. However,his surface modification is no barrier for lysozyme and albumino penetrate into the matrix, as demonstrated by CLSM [3,80]. Bal-filcon A is the only silicone hydrogel material considered ionicFDA Group III) due to the incorporation of an ionic group (N-vinylminobutyric acid), and it attracts more protein than all other sil-cone hydrogel lenses currently available [39,72,92]. Patient wornenses deposit 5–34 �g of total protein [36,92,93], while lysozymeccounts for approximately 32% [36] to 50% [93] of the totalmount of deposited protein. The amounts of individual proteinsepositing on balafilcon A have been determined using in vitroxperiments, and indicate 10–50 �g of lysozyme [3,35,39,72,76],–17 �g of lactoferrin [35,79] and less than 2 �g of albumin [3]er lens. Lysozyme activity on worn lenses and in vitro models

s approximately 50% [38,39,76,93]. Choice of care regimen maylso impact protein activity on these lenses: higher levels of dena-ured lysozyme have been found when lenses were cleaned with aolyhexanide-based system compared to a polyquaternium-basedystem [38,76].

.2. Lotrafilcon A, lotrafilcon B and sifilcon A

The contact lens materials lotrafilcon A and B are permanentlyodified by a gas plasma treatment using a mixture of trimethylsi-

ane, oxygen and methane to form a 25 nm thin hydrophilic coatingver the surface [63,88,94]. This lens surface minimizes albuminnd lysozyme penetration into the materials, with higher accumu-ations seen on the surface as determined by CLSM [3,52]. Despitehe similarity between both materials, lotrafilcon B, which has aower Dk/t and a higher water content compared to lotrafilcon A,eems to deposit slightly more protein. Quantitative analysis onorn lenses detected 5–7 �g/lens of total protein on lotrafilcon A

36,93], while <1–19 �g/lens has been reported for lotrafilcon B,ith the majority of studies reporting >7 �g per lens [92,93,95–97].

x vivo studies have further determined that lysozyme accountsor <25% of the total protein deposited on worn lotrafilcon A and B

36,93].

In vitro studies on both lotrafilcon materials have confirmed theesults from ex vivo lenses, showing that slightly higher amountsf deposited protein are typically found on lotrafilcon B compared

Anterior Eye 35 (2012) 53– 64

to lotrafilcon A lenses: lotrafilcon A deposited 2–4 �g lysozyme[39,72,76] and 1–2 �g lactoferrin [79], while lotrafilcon B accu-mulated 4–10 �g of lysozyme [3,39,72] and 2–3 �g of lactoferrin[79]. Lysozyme activity on both lens types have been determinedto be ≤25%, while results typically show marginally, but statisti-cally insignificant, higher levels of active lysozyme on lotrafilcon Blenses [38,39,76,93].

Sifilcon A is manufactured using a lathe-cutting process and rep-resents the newest member of this “family” of materials. Ex vivoresults confirmed that the amount of protein depositing on thislens is similar to lotrafilcon A and lotrafilcon B, with 5 �g of totalprotein and 2 �g of lysozyme/lens being found after 90 days of wear[98]. The level of protein denaturation is also similar to the othertwo lens types, with 20% lysozyme activity for patient-worn lenses[98].

6.3. Asmofilcon A

The surface of asmofilcon A lenses is modified based on “Nano-glass” technology using a new plasma treatment, which combinesplasma coating and surface oxidation [99]. Although these lenseshave been available since 2007, no data on protein sorption havebeen reported as of to date.

6.4. Galyfilcon A and senofilcon A

High molecular weight chains of PVP are incorporated into galy-filcon A and senofilcon A lenses to enhance surface wettability ofthe lens on eye [100–104]. Both lens types are manufactured usingsimilar material components.

In vitro experiments have shown that lysozyme can penetrateinto the matrix of both lens materials after 24 h of incubationwith fluorescently conjugated protein [80]. Both lens types tendto deposit similar amounts of tear film proteins after wear. Thevalues reported range from <1 to 9 �g/lens, while slightly higheramounts are typically found on galyfilcon A lenses [36,40,92,93].The majority of studies report approximately 7 �g/lens of total pro-tein, of which lysozyme contributes <2 �g (∼25%) [36,93]. In vitrostudies have also confirmed that galyfilcon A, which has a lowerDk/t and a higher water content compared to senofilcon A, accumu-lates slightly more protein than senofilcon A [39,72,79]. Incubationin single protein solutions generally resulted in a higher proteinuptake in comparison to ex vivo studies, which can be explainedby the missing tear film components, which typically competewith proteins during the sorption process. In vitro studies of galy-filcon A and senofilcon A determined 8–17 �g and 6–13 �g oflysozyme/lens [39,72], respectively, while lactoferrin was found insimilar quantities on both lens types, at 3–5 �g/lens [79]. The activ-ity of deposited lysozyme on galyfilcon A lenses was 42–60%, whilea slightly lower percentage of 28–51% has been found for senofil-con A lenses [36,39,40,93]. However, so far none of these ex vivoand in vitro studies have shown a statistically significant differencebetween the two materials [36,39,40,93].

6.5. Narafilcon A and narafilcon B

These materials are modified using an internal PVP-based wet-ting agent (Hydraclear 1) and are used as single-use daily disposablelenses. Narafilcon A and B have been introduced fairly recently andas a result, no scientific data on protein deposition are available todate.

6.6. Comfilcon A and enfilcon A

These materials incorporate silicone which is based on siloxy-macromers instead of the commonly used TRIS-derivates [105].

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L. Jones

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Eye 35 (2012) 53– 64

59

Table 1bQuantitative data on protein deposition to silicone hydrogel contact lens materials.

Material Total protein(�g/lens)

Lysozyme(�g/lens)

Lactoferrin(�g/lens)

Albumin(�g/lens)

In vitro/ex vivo

Sol type/extraction method/quantificationmethod

Exposuretime (days)

SiHy[130] All 5.2 ± 10 Ex vivo Urea, SDS, DTT/BCA, Nano Orange assay 14 and 30[36] Balafilcon A 33.5 ± 6.1 10.9 ± 2.9 Ex vivo ACN-TFA extraction/Bradford assay, SDS-PAGE 14[76] Balafilcon A 10 ± 3 Ex vivo ACN-TFA extraction/SDS-PAGE, Western

blotting30

[38] Balafilcon A 10 ± 5.0 OFE10 ± 3.5 Renu MP

Ex vivo ACN-TFA extraction/Western blotting 30

[93] Balafilcon A 26.9 ± 2.2 13.3 ± 9.0 Ex vivo ACN-TFA extraction/Western blotting,Bradford assay

14

[131] Balafilcon A 110.1 ± 26.1 Ex vivo ACN-TFA extraction/BCA assay 14[92] Balafilcon A 23.1 ± 5.8 OFE

5.4 ± 6.7 Aquify23.2 ± 10.7 ClearCare17.6 ± 6.1 OFR

Ex vivo Urea, SDS, DTT/BCA, Nano Orange assay 30

[35] Balafilcon A 17 ± 1.4 In vitro Single sol/ACN-TFA extraction/BCA assay 4 h[72] Balafilcon A 10.6 ± 1.6 In vitro Single sol/radiolabeling 14[72] Balafilcon A 19.4 ± 2.9 In vitro Single sol/radiolabeling 28[79] Balafilcon A 6.3 ± 1.1 In vitro Single sol/radiolabeling 14[79] Balafilcon A 11.8 ± 2.9 In vitro Single sol/radiolabeling 28[35] Balafilcon A 17 ± 1.4 In vitro Single sol/ACN-TFA extraction/BCA assay 1[39] Balafilcon A 44 ± 10 In vitro Single sol/ACN-TFA extraction, Western

blotting17

[3] Balafilcon A 50 ± 0.1 1.9 ± 0.4 In vitro Single sol/radiolabeling 14[36] Lotrafilcon A 6.7 ± 2.7 0.7 ± 0.5 Ex vivo ACN-TFA extraction/Bradford assay, SDS-PAGE 14[132] Lotrafilcon A 0.07 0.21 0.17 Ex vivo ELISA/peroxidase conjugated antibodies 30[76] Lotrafilcon A 3 ± 1 Ex vivo ACN-TFA extraction/SDS-PAGE, Western

blotting30

[93] Lotrafilcon A 5.2 ± 2.2 1.1 ± 0.8 Ex vivo ACN-TFA extraction/Western blotting,Bradford assay

14

[133] Lotrafilcon A 0.7 rub Complete2.0 no rub OFE

Ex vivo Tert-butyl-methyl ether/FTIR 30

[72] Lotrafilcon A 2.7 ± 0.7 In vitro Single sol/radiolabeling 14[72] Lotrafilcon A 4.2 ± 0.9 In vitro Single sol/radiolabeling 28[79] Lotrafilcon A 0.7 ± 0.7 In vitro Single sol/radiolabeling 14[79] Lotrafilcon A 2.1 ± 0.9 In vitro Single sol/radiolabeling 28[39] Lotrafilcon A 2 ± 1 In vitro Single sol/ACN-TFA extraction/Western

blotting17

[95] Lotrafilcon B 9.8 ± 1.4 Aquify9.8 ± 1.0 Renu ML

Ex vivo Acetone/Bradford assay 14–17

[93] Lotrafilcon B 6.6 ± 3.4 1.4 ± 1.1 Ex vivo ACN-TFA extraction/Western blotting,Bradford assay

14

[92] Lotrafilcon B 3.6 ± 1.0 OFE0.3 ± 0.9 Aquify0.5 ± 0.4 ClearCare1.7 ± 2.3 OFR

Ex vivo Urea, SDS, DTT/BCA, Nano Orange assay 30

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35 (2012) 53– 64

Table 1b (Continued)

Material Total protein(�g/lens)

Lysozyme(�g/lens)

Lactoferrin(�g/lens)

Albumin(�g/lens)

In vitro/ex vivo

Sol type/extraction method/quantificationmethod

Exposuretime (days)

[96] Lotrafilcon B 19 no rinse7 with rinse

Ex vivo ACN-TFA extraction/Bradford assay 5

[97] Lotrafilcon B 12.1 ± 11.5 Ex vivo ACN-TFA extraction/Bradford assay 14[72] Lotrafilcon B 3.7 ± 0.6 In vitro Single sol/radiolabeling 14[72] Lotrafilcon B 6.1 ± 1.3 In vitro Single sol/radiolabeling 28[79] Lotrafilcon B 1.7 ± 0.6 In vitro Single sol/radiolabeling 14[79] Lotrafilcon B 3.1 ± 1.0 In vitro Single sol/radiolabeling 28[39] Lotrafilcon B 6 ± 3 In vitro Single sol/ACN-TFA extraction/Western

blotting17

[3] Lotrafilcon B 9.7 ± 1.5 1.8 ± 0.2 In vitro Single sol/radiolabeling 14[131] Lotrafilcon B 2.6 ± 3.8 Ex vivo ACN-TFA extraction/BCA assay 14[98] Sifilcon A 5.3 ± 2.3 2.4 ± 1.2 Ex vivo ACN-TFA extraction/Bradford assay, SDS-PAGE,

Western blotting90

[36] Galyfilcon A 7.6 ± 1.8 1.6 ± 0.8 Ex vivo ACN-TFA extraction/Bradford assay, SDS-PAGE 14[95] Galyfilcon A 8.8 ± 1.5 Aquify

7.3 ± 0.9 Renu MLEx vivo Acetone/Bradford assay 14–17

[93] Galyfilcon A 6.3 ± 3.4 1.9 ± 1.4 Ex vivo ACN-TFA extraction/Western blotting,Bradford assay

14

[92] Galyfilcon A 1.2 ± 1.2 OFE1.1 ± 2.8 Aquify0.1 ± 0.2 ClearCare0.3 ± 1.1 OFR

Ex vivo Urea, SDS, DTT/BCA, Nano Orange assay 30

[40] Galyfilcon A 8.5 ± 4.7 2.3 ± 1.4 Ex vivo ACN-TFA extraction/Bradford assay, Westernblotting

14

[131] Galyfilcon A 8.7 ± 8.1 Ex vivo ACN-TFA extraction/BCA assay 14[72] Galyfilcon A 8 ± 3.4 In vitro Single sol/radiolabeling 14[72] Galyfilcon A 16.8 ± 4 In vitro Single sol/radiolabeling 28[79] Galyfilcon A 2.9 ± 1.1 In vitro Single sol/radiolabeling 14[79] Galyfilcon A 5.4 ± 1.1 In vitro Single sol/radiolabeling 28[39] Galyfilcon A 9 ± 2 In vitro Single sol/ACN-TFA extraction/Western

blotting17

[93] Senofilcon A 4.6 ± 2.5 0.9 ± 0.6 Ex vivo ACN-TFA extraction/Western blotting,Bradford assay

14

[92] Senofilcon A 0.1 ± 0.1 OFE0.7 ± 0.5 Aquify0.0 ± 0.1 ClearCare0.3 ± 0.2 OFR

Ex vivo Urea, SDS, DTT/BCA, Nano Orange assay 30

[40] Senofilcon A 6.6 ± 2.6 1.6 ± 0.5 Ex vivo ACN-TFA extraction/Bradford assay, Westernblotting

14

[36] Senofilcon A 8.2 ± 3.7 1.6 ± 1.6 Ex vivo ACN-TFA extraction/Bradford assay, SDS-PAGE 14[131] Senofilcon A 8.3 ± 10.1 Ex vivo ACN-TFA extraction/BCA assay 14[72] Senofilcon A 6.1 ± 3.2 In vitro Single sol/radiolabeling 14[72] Senofilcon A 13.4 ± 4.1 In vitro Single sol/radiolabeling 28[79] Senofilcon A 3.4 ± 1.1 In vitro Single sol/radiolabeling 14[79] Senofilcon A 5.6 ± 0.6 In vitro Single sol/radiolabeling 28[39] Senofilcon A 6 ± 5 In vitro Single sol/ACN-TFA extraction, Western

blotting17

[134] Senofilcon A 1.8 ± 0.2 In vitro Single sol/radiolabeling 7[106] Comfilcon A 7.7 ± 3.8 1.7 ± 1.2 Ex vivo ACN-TFA extraction/Bradford assay, Western

blotting25

ACN-TFA: acetonitrile/trifluoroacetic acid, ATS: artificial tear solution, BCA: bicinchoninic acid, DTT: dithiothreitol, FTIR: Fourier transform infrared, HPLC: high performance liquid chromatography, OFE: Optifree Express, OFR:Optifree Replenish, SDS: sodium dodecyl suphate, SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis, sol: solution, UV: ultraviolet.

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D. Luensmann, L. Jones / Contact

pecific surface treatments or internal wetting agents are not usedn these lens types [105]. Since their launch in 2007, only one studyas presented data on protein deposition with comfilcon A. In thisx vivo study a total of 8 �g protein/lens was determined, whichncluded <2 �g of lysozyme/lens after 25 days of wear [106].

.7. Filcon II 3

Little is known about filcon II 3, which is currently only availablen Europe. It incorporates a surface wetting technology namedquaGenTM, but no data on protein deposition rates have beenublished to-date.

In summary, bulk material composition and surface modifi-ation methods vary greatly between silicone hydrogel lenses.owever, the amount of protein deposition on these lens types is

airly similar and typically <10 �g/lens, with the exception of bal-filcon A, which accumulates approximately three times as muchTable 1b).

. Contact lens materials and surface modifications – theuture

Silicone hydrogel materials have solved hypoxia-related com-lications and show low rates of protein deposition, but the relativemount of denatured protein detected on these materials is typi-ally higher than that measured on pHEMA-based lenses [39,107].urthermore, corneal inflammatory events tend to be equal origher with silicone hydrogel lenses compared to hydrogel lenses108], which raises the question of whether surface engineeringechniques or other material components can improve the biocom-atibility of these latest contact lens materials.

A number of different approaches to passivate synthetic oratural biomaterials have been developed for blood contacting

mplants, and some of these have been evaluated for contact lensaterials [109].Surface coatings containing phosphorylcholine (PC) have

een used in various biomedical applications, as they showcceptable level of biocompatibility [110,111] and attract onlymall amounts of protein [39,72,79,112,113]. Novel materialompositions with 2-methacryloyloxyethyl phosphorylcholineMPC) confirmed a decrease in protein deposition rates withncreasing amounts of PC [114,115]. The combination of MPC

ith bis(trimethylsilyloxy)methylsilylpropyl glycerol methacry-ate (SiMA) has recently been suggested as a potential sili-one hydrogel contact lens material, as it reaches an oxygenransmissibility of >125 units [116]. An in vitro experi-

ent with this material confirmed the relationship betweenncreased MPC content and reduced protein deposition rates,nd these materials deposited less protein than senofilcon

lenses [116]. In another study, a hydrogel lens materialas synthesized using MPC with 2-(methacryloyloxy)ethyl-N-(2-ethacryloyloxy)ethyl]phosphorylcholine (MMPC). This material

xhibited an oxygen permeability of 64 units, which is significantlyigher than pHEMA, and the highly wettable surface depositedpproximately three times less protein than omafilcon A lenses117].

Polyethers such as poly(ethylene glycol) (PEG) or poly(ethylenexide) (PEO) are currently used in various biomaterial applications,ue to their hydrophilicity, bioinertness and resistance to proteinnd cell adsorption [118,119]. In a recent clinical study, lotrafilcon

lenses were coated with PEO using an allylamine plasma poly-er interlayer and their in vivo performance was evaluated [120].

he researchers confirmed good biocompatibility after 6 h of lensear and reported that modified lenses attracted less than half the

Anterior Eye 35 (2012) 53– 64 61

amount of protein compared to non-modified lotrafilcon A lenses[120].

Crosslinking hyaluronic acid (HA) into pHEMA, siliconehydrogel-like materials or PMMA also reduces protein deposi-tion rates compared to non-treated materials [121–123]. PHEMAcrosslinked to HA of differing molecular weights accumulated sig-nificantly lower amounts of albumin and IgG compared to nelfilconA (FDA Group II) and the silicone hydrogel lens material senofil-con A [121]. Lysozyme was found in lower amounts on nelfilconA, but no difference between the HA-crosslinked materials andsenofilcon A was seen [121]. A strong lysozyme repelling effectwas also seen when HA was crosslinked to methacryloxy propyltris(trimethylsiloxy) silane (Tris)-pHEMA hydrogels, independentof the ratio between Tris:pHEMA [122].

Finally, other approaches for ophthalmic material/surfacedesigns use combinations of frequently used materials withperfluoropolyethers [124], polyvinyl alcohol [125] and surfacecoatings with pyrolytic carbon [126], albumin, elastin [109] orcationic peptide [127] to reduce protein accumulation and micro-bial adherence.

In conclusion, improvement in contact lens biocompatibility isan ongoing process and controlling the amount and conformationalstate of deposited protein remains one of the major challenges.The ocular surface environment is very complex, and tear filmcomposition varies greatly between individuals [14]. While thisreview has only dealt with protein deposition, it is known that sili-cone hydrogel lenses attract greater amounts of lipid compared tomany polyHEMA-based lenses [87], which is the opposite trendto that seen with protein accumulation. Increased lipid deposi-tion may impact clarity of vision, wettability and comfort, buthas not been associated directly with ocular surface inflamma-tory responses. Although silicone hydrogel lenses have significantlyreduced complications related to hypoxia [107] they have notreduced the prevalence of ocular complications such as inflamma-tion and microbial keratitis, and the role of material deposition tothese complications remains unclear [108].

Optimal biocompatibility with lens materials may not requirethe material to be resistant to all tear film components. Rather,it is important that the material is accepted by the ocular envi-ronment and this may require the deposition of selected tear filmcomponents. In respect to proteins, the ideal contact lens mate-rial should bind proteins only loosely, allowing the protein to bereadily removed when exposed to contact lens care regimens andmaintaining the native state of any bound proteins. New contactlens material designs and surface modifications are currently underinvestigation, but only the future will show whether or not they canprovide enhanced on eye biocompatibility.

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