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. 2021 Feb 26;6(10):7058–7067. doi: 10.1021/acsomega.0c06327

Antifouling Silicone Hydrogel Contact Lenses with a Bioinspired 2-Methacryloyloxyethyl Phosphorylcholine Polymer Surface

Kazuhiko Ishihara †,*, Kyoko Fukazawa †, Vinay Sharma ‡, Shuang Liang ‡, Amanda Shows ‡, Daniel Chuck Dunbar ‡, Yang Zheng §, Junhao Ge §, Steve Zhang §, Ye Hong §, Xinfeng Shi ‡, James Yuliang Wu ‡,*
PMCID: PMC7970573  PMID: 33748619

Abstract

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Inspired by the cell membrane surface as well as the ocular tissue, a novel and clinically applicable antifouling silicone hydrogel contact lens material was developed. The unique chemical and biological features on the surface on a silicone hydrogel base substrate were achieved by a cross-linked polymer layer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC), which was considered important for optimal on-eye performance. The effects of the polymer layer on adsorption of biomolecules, such as lipid and proteins, and adhesion of cells and bacteria were evaluated and compared with several conventional silicone hydrogel contact lens materials. The MPC polymer layer provided significant resistance to lipid deposition as visually demonstrated by the three-dimensional confocal images of whole contact lenses. Also, fibroblast cell adhesion was decreased to a 1% level compared with that on the conventional silicone hydrogel contact lenses. The movement of the cells on the surface of the MPC polymer-modified lens material was greater compared with other silicone hydrogel contact lenses indicating that lubrication of the contact lenses on ocular tissue might be improved. The superior hydrophilic nature of the MPC polymer layer provides improved surface properties compared to the underlying silicone hydrogel base substrate.

Introduction

Contact lenses are medical devices widely used for correcting vision. The most advanced polymer materials have been utilized to create contact lenses with good optical characteristics, comfort of wearing, and safety for various patients regardless of their ages.1−3 In the past 20 years, many high oxygen permeable silicone hydrogel materials have been developed for supplying increased oxygen levels to the ocular tissue so that they can be worn for an extended period of time.4,5 Generally, silicone hydrogel materials contain polydimethylsiloxane (PDMS) in addition to hydrophilic monomers. The PDMS phase and the hydrophilic polymer phase form a micro-phase-separated structure. Oxygen gas diffuses through the PDMS phase and is supplied to the ocular tissue.6,7 However, PDMS can pose some problems in the ocular environment due to its hydrophobic nature.8−10 The first problem is the adsorption of biomolecules. Lipids and proteins in tears are adsorbed to the PDMS phase, where a stable adsorption layer is formed. This can not only affect the optical properties, surface wettability of the contact lens, and oxygen permeability as an imperfection on the contact lens surface but also act as attachment points for bacterial adhesion. Furthermore, the hydrophobic PDMS phase can reduce the lubricating properties of the contact lens. In order to solve these problems, many silicone hydrogel contact lenses have been treated by adding surfactants or a water-soluble polymer, such as poly(N-vinylpyrrolidone), to the packaging solution, which is physically adsorbed to the surface of the lens, increasing the hydrophilicity and lubrication of the lens.11,12 However, if contact lenses are worn for a prolonged period, then the improved wettability and lubricity from the water-soluble polymers is reduced as the substance is washed away. Therefore, it is important that a polymer, developed for surface modification of silicone hydrogel lens materials, creates a stable surface that may resist lipid deposition, protein adsorption, and bacterial adhesion.

A series of polymers containing 2-methacryloyloxyethyl phosphorylcholine (MPC) unit have attracted great attention due to the bioinspired chemical structure of the MPC unit also found in phospholipids on the cell membrane surface.13,14 Due to the zwitterionic nature of the phosphorylcholine head group in the MPC polymer, water molecules surrounding the MPC unit take a unique hydration structure.13,15 Therefore, it has been observed that water lubrication properties on the substrates are improved on MPC polymer surfaces, which could contribute to a more comfortable contact lens.16−20 In addition, the MPC unit has an overall neutral charge, allowing the polymer to be excellent at suppressing protein adsorption, cell adhesion, and reduce blood coagulation and immune responses.13,21,22 Therefore, the MPC polymers have been applied as a surface treatment for medical devices including conventional soft contact lenses.16 These characteristics of the MPC polymer might be used to improve the lubricity and antifouling properties of silicone hydrogel lenses. We have reported the stable chemical reaction of the MPC polymer at the surface of the silicone hydrogel material and characterization of the surface in the aqueous medium.23 When the surface is covered with the MPC polymer on the base silicone hydrogel material, a water-rich and higher lubricious surface is formed. In this study, we evaluated the surface biological reactions of several silicone hydrogel contact lenses including the MPC polymer-modified contact lens material.

Results and Discussion

AFM Imaging of Contact Lens Substrates

In Table 1, the base monomer chemicals and hydration degree of silicone hydrogel contact lenses used in this study are summarized.2400,2500 We developed a new contact lens material using the bioinspired MPC polymer.23 The surface modification of the base material with the MPC polymer was carried out by chemical reaction at the surface. By conducting the XPS analysis under high vacuum conditions, XPS signals of specific atoms, that is, carbon at 285 eV, oxygen at 532 eV, nitrogen at 399 eV, and silicone at 102 eV, were observed on the base substrate (data was not shown). After surface modification with the MPC polymer, new XPS signals were observed at 133 and 403 eV.23 They were attributed to the phosphorus atom in the phosphate group and the nitrogen atom in the trimethylammonium group, respectively, in the phosphorylcholine group.24,25 These results indicated that the MPC polymer layer was formed on the surface.12,13

Table 1. Chemical Components of Contact Lens Materials Used in this Studya.

contact lens materials, United States adopted name base monomers hydration degree (%)
MPC polymer-modified lens material and its base substrate mPDMS, G-PDMS, NVP, TEGDMA, MMA, EGMEMA 55
senofilcon C mPDMS, SiGMA, DMA, HEMA, TEGDMA, bPVP 41
samfilcon A TRIS, Ma2D37, M1-(EDS)n-TMS, NVP, DMA, HEMA 46
comfilcon A M3U, FMM, VMA, HBMA, IBM, NVP, TAIC 48
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a

MPC, 2-methacryloyloxyethyl phosphorylcholine; mPDMS, polydimethylsiloxane monomethacrylate; G-PDMS, glycerol-functionalized polydimethylsiloxane dimethacrylate; SiGMA, [methyl bis(trimethylsiloxy)silyl] propyl glycerol methacrylate; NVP, N-vinyl pyrrolidone; TEGDMA, tetraethylene glycol dimethacrylate; MMA, methyl methacrylate; EGMEMA, 2-methoxyethyl methacrylate; DMA, N,N-dimethylacrylamide; HEMA, 2-hydroxyethyl methacrylate; PVP, poly(N-vinylpyrrolidone); TRIS, trimethylsiloxy silane; Ma2D37, silicone bis(meth)acrylamide monomer; M1-(EDS)n-TMS, mono ethylenically unsaturated polymerizable group containing polycarbosiloxane monomer; M3U, α-ω-bis(methacryloyloxyethyl iminocarboxy ethyloxypropyl)-poly(dimethylsiloxane)-poly(trifluoropropylmethylsiloxane)-poly(ω-methoxy-poly(ethyleneglycol)propylmethylsiloxane); FMM, 2-ethyl E2-E(2-methylprop-2-enoyl)oxyethylcarbamate; VMA, N-vinyl-N-methylacetamide; HBMA, 4-hydroxybutyl methacrylate; IBM, isobornyl methacrylate; TAIC, 1,3,5-tripop-2-enyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione.

b

Wetting reagent.

AFM is one of the most promising surface characterization tools that is capable of revealing the nanoscopic morphological features with high resolution. This imaging technique has already been employed extensively in the field of contact lens research to study different surfaces and contact lens materials.26−33 In this study, AFM surface imaging was conducted on different contact lenses including the new lens material and its non-surface modified base substrate, senofilcon C, samfilcon A, and comfilcon A. The surface of the contact lens was kept in a fully hydrated state during experiments. The AFM topographical side view images of a 5.0 μm × 5.0 μm scan area from each of these contact lenses are displayed in Figure 1 where all the images were on the same Z scale, i.e., ± 150 nm. As shown in the figure, the surface of this new lens was considerably different than the other contact lenses. The surfaces of the non-surface modified base substrate and the other three contact lenses, i.e., senofilcon C, samfilcon A, and comfilcon A, looked relatively flat with an interspersed domain feature, which is typical for silicone hydrogel contact lens materials. Conversely, the new lens exhibited distinctive surface features and topographies resulting from densely packed MPC polymer units attached to the contact lens surface. Additional AFM images of all the contact lenses with the top view angle are provided in Figure S1 as supporting information. This MPC polymer layer has been well characterized in our previous report.23

Figure 1.

Figure 1

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AFM topographical images (side view, 5 μm × 5 μm) of the contact lenses used in this study.

A similar polymer surface gel layer with a near 100% water content on the surface was also described by Dunn et al.34 Such highly hydrated gel surfaces are as smooth as the surface of silicone hydrogel substrates or contact lenses, which typically have 20–80% water contents.1

It is well accepted and reported in the literature that the grafting polymer layer including the polymer brush structure, extending normal to the underlying substrate can provide novel and/or enhanced surface properties such as wettability, lubricity, reduced biological responses, i.e., antifouling properties, and so on.35−42 The MPC polymers on the lens surface can provide super-hydrophilic and antifouling properties. Thus, we investigated if the MPC polymer layer would provide unique antifouling surface properties to this new contact lens in the following sections.

Lipid Adsorption on Contact Lenses

Each contact lens was incubated in fluorescently labeled ATS for 3 days followed by a cleaning in OPTI-FREE PUREMOIST MPDS. Whole lenses were submerged in PBS within a cylinder-shaped lens holder so that the spherical shape of the lens was maintained. Figure 2 displays the top views of the three-dimensional (3D) confocal imaging of this new lens and its base substrate, senofilcon C, samfilcon A, and comfilcon A. The blue color came from the fluorescence of the lens material and background at 405 nm laser excitation. The red color corresponded to the fluorescently labeled non-polar lipid, Rh-TAG, excited by a 561 nm laser. To fully demonstrate the lipid deposition on contact lens, a side view and a 45° tilted angle view are included in the Supporting Information (Figures S2 and S3). As shown in the figures, this new lens had no observable Rh-TAG deposition. As a comparison, senofilcon C had some Rh-TAG depositions near the contact lens center while the new lens non-surface modified base substrate and comfilcon A had a few Rh-TAG deposition near the contact lens center as well as on the lens edge. Samfilcon A had some large, bright Rh-TAG signals, mostly on the lens edge (Figure 2). These results demonstrate that the new lens had no detectable Rh-TAG lipid deposition compared to the other four contact lens materials. Several studies of lipid sorption on contact lenses have been reported. Zhao et al. used thin layer chromatography to measure cholesterol sorption on conventional silicone hydrogel contact lenses including senofilcon A after 30 days of wear and reported both lens type, which averaged from 0.1 to 8.2 μg/lens.43 Also, Pitt et al. reported that in the case of senofilcon A, 5.3 μg/lens of cholesterol and 4.4 μg/lens of phosphatidylcholines are absorbed, which was determined by a radio-labeled method.44 Regarding the lipid adsorption characteristics of the contact lenses used in this study, a preliminary study was conducted in which lipids adsorbed were extracted from the contact lenses after being worn for 30 days on human eye and evaluated using liquid chromatography equipped with mass spectroscopy. As a result, the amount of absorbed non-polar lipid was approximately 40 nmol/lens in senofilcon C and decreased in the order of samfilcon A (20 nmol/lens) and comfilcon A (6 nmol/lens). Furthermore, the contact lens material modified with the MPC polymer showed the lowest non-polar lipid adsorption amount, approximately 3 nmol/lens.

Figure 2.

Figure 2

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3D confocal images (top view, 14.5 mm × 14.5 mm) of the whole lenses after being soaked in ATS and cleaned by OPTI-FREE PUREMOIST MPDS.

Protein Adsorption Behavior

It is considered that the adsorption of protein to the surface of the contact lens affects the characteristics of the contact lens and is one of the factors that can deteriorate comfort during long-time wear.45−47 Furthermore, it is also known that the adsorption of a specific protein induces an infection or an immune response due to bacterial adhesion.48,49 The state of protein adsorption to the contact lens was observed using mixed protein solutions.

Figure 3A shows the amount of proteins adsorbed on various contact lenses from the artificial tear protein solution. The adsorption amount ranged from 0.2 to 1.2 μg/cm2, depending on the type of contact lens material. Compared to senofilcon C, this new lens showed significantly more protein adsorption. It is generally known that the amount of protein adsorbed depends on the hydrophobicity of the surface and the charge density. On the other hand, in the case of hydrogels, attention must be paid to the diffusion into the materials. The water content of contact lens materials is low, senofilcon C having a water content of 41%, while this new lens is 55%. Lysozyme has a relatively small molecular weight, which makes it easy to diffuse into the contact lens, and as a result, the amount of adsorbed protein increases. Thus, the amount of lysozyme adsorbed on the contact lens from a single protein solution was measured. Even with a relatively hydrophobic base material, there is no significant difference between the amount of protein adsorbed from artificial tear protein solution and the amount of adsorbed lysozyme alone, as shown in Figure 3B. On the other hand, senofilcon C and comfilcon A reduced the amount of protein adsorbed from artificial tear protein solution. These results suggest that protein adsorption from artificial tear protein solution relies on different modes of protein adsorption to the surface and diffusion into the interior. That is, in senofilcon C and comfilcon A, albumin and immunoglobulin, with relatively high molecular weights, were adsorbed on the surface from artificial tear protein solution, and a stable adsorption layer was formed so that the diffusion of lysozyme into the substrate was suppressed. For this new lens, the protein adsorption might occur only on the hydrophobic surface of the contact lens, the amount of protein adsorption was almost the same from the artificial tear protein solution or the lysozyme alone solution. Although the adsorption itself was suppressed by the MPC polymer layer, it was hypothesized that the lysozyme was trapped inside the hydrophobic substrate material because the diffusion of lysozyme into the inside could not be prevented. Considering the results of the protein permeability of the MPC polymer hydrogel membrane reported previously, the permeability depends on the molecular weight, and the permeability of a protein of about 104 Da is relatively high.50 On the other hand, albumin and immunoglobulin (< 6 × 104 Da) hardly permeate. In addition, the protein adsorption amount is reduced without depending on the molecular weight, which supports the above hypothesis.

Figure 3.

Figure 3

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Protein adsorption on various silicone hydrogel contact lenses. (A) Amount of protein adsorbed on the surface from artificial tear protein solution and (B) amount of lysozyme adsorbed from single lysozyme solution (n = 5, mean ± SD). * represents p < 0.01 versus base substrate without the MPC polymer.

We evaluated protein adsorption of a specific protein on the substrate from the protein mixture by a gold-labeled immunoassay, which is a good methodology for visualization of proteins on the surface.20 Also, the immunoassay provides us the information from the most outer surface of contact lens because the molecular size of an antibody is large compared with the network structure of the hydrogel contact lens.50

Figure 4 shows the SEM image of adsorption of lysozyme on the contact lens surface from the artificial tear protein solution detected by immunoassay.21,51,52 The number of the white particles corresponds to the adsorbed lysozyme molecules. This MPC polymer-modified contact lens appears to reduce the amount of adsorbed lysozyme at the surface. In Figure 4, only lysozyme among the proteins adsorbed on the surface of contact lenses is selectively visualized by colloidal gold labeling immunization.51,52 If protein adsorption occurs in multiple layers, or if the protein is absorbed inside the contact lens, then it is not observed in Figure 4. In fact, the density of colloidal gold particles is not high until it completely covers the surface. This does not completely correspond to the result in Figure 3. That is, the results shown in Figure 3 quantified whole amounts of the proteins in the adsorption layer.

Figure 4.

Figure 4

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SEM image of adsorbed lysozyme on various contact lens substrates. White particles correspond to adsorbed lysozyme detected by gold-labeled immunoassay. The bar indicates 100 μm.

Cell Adhesion Inhibition on the Contact Lens Surface

Cell adhesion on various contact lens materials was evaluated. Due to the effect of autofluorescence on the contact lens material, the cells could not be fluorescently labeled and observed with a fluorescence microscope. Therefore, observation was performed with an optical phase-contrast microscope.

Figure 5A shows optical microscopic images of contact lens surfaces after 24 h of culturing. Adhered cells were observed on the base substrate, samfilcon A, and comfilcon A. On the other hand, a small number of cells adhered on senofilcon C and almost no cells observed on the new lens itself. By quantitative counting, the number of adherent cells on the base substrate was 1.2 ± 0.3 × 104 cells/cm2, senofilcon C was 0.2 ± 0.3 × 104 cells/cm2, samfilcon A was 1.7 ± 0.3 × 104 cells/cm2, comfilcon A was 1.8 ± 0.4 × 104 cells/cm2, and MPC polymer-modified lens was 0.1 ± 0.1 × 102 cells/cm2. No significant growth of the adhered cells was observed on any of the contact lens materials during 24 h of culturing. After the cells were seeded on the surface, the cells weakly adhered to the surface and then migrated on the surface.53,54 Initial adhesion of cells to the contact lens surface was significantly different depending on the contact lens material. The migration of adhered cells on this new contact lens surface tended to be greater compared to other contact lenses. Figure 5B demonstrates a series of pictures of adhered cells on this new lens base substrate surface. After the cells were seeded and attached to the surface, cells could migrate along the surface slowly, and adhered cells were observed in the examination area even after 120 min. This phenomenon was also observed on the surface of samfilcon A and comfilcon A. For this new lens, as shown in Figure 5C, movement of adhered cells was quick, and no cells were observed in the observation area after 90 min. The surface of the MPC polymer has been reported to inhibit cell adhesion.16,35,53,54 Thus, on the surface of the new lens, the MPC polymer layer at the surface had improved resistance to cell adhesion due to the slipping property.16 This property might improve compatibility of this new contact lens material with ocular tissue due to improved cell adhesion resistance and reduced friction at the interface.

Figure 5.

Figure 5

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Phase contrast microscopic images of cells adhered on various silicone hydrogel contact lenses. (A) 24 h cell-culturing period for various silicone hydrogel contact lenses. (B, C) Time-lapse images of adherent cells cultured for 2 h on the base substrate and MPC polymer-modified lens material, respectively.

Bacterial Adhesion Resistance

Bacterial adhesion to contact lenses must be minimized to maintain optimal ocular health. In particular, when a contact lens is used for multiple days, the bacterial growth over time could become a problem. There are not many reports that have been made on the effect of bacterial types on bacterial adhesion to hydrogel materials. Absolom et al. analyzed the adhesion of five types of bacteria to polymers with different degrees of hydrophilicity using a thermodynamic model.55,56 As a result, it is concluded that bacterial adhesion is determined by the difference in bacterial surface properties and surface tension of the substrate and suspension medium, that is, the surface free energy. However, it can be said that the bacteria adhesion occurs in a very complex manner.

MPC polymers have been reported to reduce bacterial adhesion, including the common nosocomial pathogens such as Staphylococcus aureus, S. epidermidis, Candida albicans, and Pseudomonas aeruginosa.53,54,57−60 It has been reported that intraocular lenses coated with the MPC polymer suppress the adhesion of S. aureus and S. epidermidis. Also, Selan et al. compared typical materials for contact lenses, silicone hydrogel, poly(2-hydroxyethyl methacrylate (HEMA)), and MPC polymer-coating materials in terms of their susceptibility to biofilm formation by S. epidermidis and P. aeruginosa and concluded that the MPC polymer can inhibit biofilm formation significantly.60

Figure 6 shows the number of Escherichia coli and P. aeruginosa adhered to various contact lens surfaces. The poly(ethylene terephthalate) (PET) substrate served as a control sample. A little number of E. coli was adhered on the MPC polymer-modified lens material and senofilcon C as well as the new lens base substrate compared to the PET substrate, and no significant differences were observed among these test samples. On the other hand, it was found that the adhesion of P. aeruginosa was lower on the MPC polymer-modified lens material than the other contact lenses. Although there are still many unclear points about the influence of the physicochemical properties of the material on bacterial adhesion,55,56 the MPC polymer layer was considered to play a role in suppressing P. aeruginosa adhesion. As previously reported, the hydrophilic nature and water-compatible characteristics of the MPC polymer coating contribute to the reduction of bacterial adhesion on the new lens surface.15,25,61

Figure 6.

Figure 6

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Number of bacteria adhered on various silicone hydrogel contact lenses. (A) Adhesion of E. coli and (B) adhesion of P. aeruginosa. (n = 6, mean ± SD) * represents p < 0.01 versus base substrate without the MPC polymer.

Conclusions

The properties of silicone hydrogel contact lenses were studied with a focus on the biological response at the surface. A cell membrane-like structure was formed by adding an MPC polymer layer on the new lens contact lens surface. The effects of reduced lipid and protein adsorption were observed on this surface. In addition, clear effects were also exhibited for the inhibition of cell and bacterial adhesion. These results suggest that effective methodologies of preparing a new surface for a silicone hydrogel contact lens that can lead to significant improvements on antifouling properties, which were considered important for cleanness and safety benefits.

Experimental Section

Preparation of the MPC Polymer-Modified Lens Material

The base substrate was prepared by radical polymerization of a monomer mixture under general manufacture conditions using 2,2′-azobisisobutyronitrile as an initiator.23 Mixture of monomers, polydimethylsiloxane monomethacrylate, glycerol-functionalized polydimethylsiloxane dimethacrylate, N-vinylpyrrolidone, tetra(ethylene glycol) dimethacrylate, methyl methacrylate, and ethylene glycol methyl ether methacrylate was prepared, and the initiator was added. Then, the mixture was heated and cured by polymerization in the mold. The surface modification of the base substrate with the MPC polymer was carried out by the following two-step procedure.23,62 At first, the cured base substrate was put into a solution of commercial-grade poly(methacrylic acid) (weight-averaged molecular weight is up to 100 kDa) to produce an interpenetrating anchoring layer on the base substrate surface. Second, the treated substrate was immersed into an aqueous solution containing 0.2 wt % polyaminoamide-epichlorohydrin (PAE) (Ashland, Wilmington, DE, USA) and 0.2 wt % poly(MPC-co-2-aminoethyl methacrylate) (PMA) (NOF, Co., Tokyo, Japan) having the MPC units and the amino groups. The PAE and PMA can react with carboxylic groups in the poly(methacrylic acid), and stable amide-bond cross-linking was formed. The specific atoms at the surface of the MPC polymer-modified lens material were confirmed by X-ray photoelectron spectroscopy (XPS).23

Monomer species and hydration degree of conventional silicone hydrogel contact lenses examined in this study and the MPC polymer-modified lens material are summarized in Table 1.

XPS Measurement

The surface elemental composition of the samples was analyzed using XPS, AXIS-His 165 Kratos/Shimadzu Co., Kyoto, Japan. The takeoff angle of the photoelectrons was set to be 90°. The binding energies of the elements were corrected with reference to the carbon atom (C1s) in alkyl groups at 285.0 eV, and the peak areas of the corresponding elements were calculated to evaluate the elemental composition of the samples.

Atomic Force Microscopy (AFM) Imaging

Surface morphology of contact lens substrates, in their respective lens packaging solution, was examined using a Dimension FastScan Bio Icon atomic force microscope and PFQNM-HIRS-F-A probe (AFM, Bruker Nano, Santa Barbara, California, USA). The AFM images for the samples were captured at a 0.5 Hz scan rate in the “PeakForce QNM in Fluid” operating mode in an anti-vibration enclosure and at room temperature.

In Vitro Lipid Adsorption Experiment

Lipid Adsorption on Contact Lenses in Artificial Tear Solution

An artificial tear solution (ATS) based on the literature63−67 was used for the in vitro lipid adsorption experiment. A fluorescently labeled triglyceride, 1,2-dioleoyl-3-[16-N-(lissamine rhodamine B sulfonyl) amino]palmitoyl-sn-glycerol (Rh-TAG, Avanti Polar Lipids, Inc., AL, USA), was added to the ATS as a model non-polar lipid for confocal imaging of the in vitro lipid uptake and distribution on contact lenses. Each contact lens was incubated in an amber glass vial with 5.0 mL of ATS on an incubating plate shaker set to 35 °C and 150 rpm for 3 days. The contact lens was then cleaned by submerging lenses in 5.0 mL of OPTI-FREE PUREMOIST multi-purpose disinfecting solution (MPDS) at ambient temperature overnight. After overnight cleaning, each contact lens was rinsed in a fresh aliquot of 4.0 mL of OPTI-FREE PUREMOIST MPDS and followed by 4.0 mL of PBS to remove any loosely bound lipids.

Lipid Imaging by Confocal Microscopy

The confocal imaging was performed on a Zeiss LSM880 laser scanning microscope (Carl Zeiss Microscopy, LLC., NY, USA). Whole lens images were acquired by a Fluar 2.5x/0.12 M27 objective (Carl Zeiss Microscopy, LLC., NY, USA) with z-stack and tile scan modes. The contact lens was imaged while submerged in a phosphate buffered saline solution (PBS, pH 7.4) in a lens holder using a 561 nm diode pumped solid state laser and a 405 nm diode laser. The imaging conditions were kept consistent for all contact lenses.

Protein Adsorption Experiments

Measurement of the Amount of Lysozyme Adsorbed on the Contact Lens Substrate

A previously reported micro bicinchoninic acid (BCA) protein assay method (Thermo Scientific Inc., Waltham, MA, USA) was used to determine the concentration of the adsorbed proteins.68 Lysozyme (human, Sigma-Aldrich, St. Louis, MO, USA) was dissolved in PBS at a concentration of 1.20 mg/mL. The solution was used for the lysozyme adsorption test. The contact lens substrates were inserted into a 24-well tissue culture plate and were pre-wetted with double-distilled water overnight at 37 °C. After the removal of water, 1.0 mL of lysozyme solution was added into each well, and the plate was incubated at 37 °C for different time points. The contact lenses were then rinsed with PBS several times to remove the lysozyme solution and weakly adsorbed proteins. The adsorbed lysozyme was detached using 1.0 wt % sodium dodecyl sulfate (SDS) solution and a 5 min sonication. The lysozyme was measured using a 150 μL aliquot of SDS solution gently mixed with BCA reagents in a 96-well tissue culture plate. The reaction was incubated at 37 °C for 2 h, and the absorbance was determined at a wavelength of 562 nm with a microplate reader (Wallac 1420; Perkin Elmer Co., Ltd., MA, USA). The amount of proteins adsorbed on the lens materials was calculated using a calibration curve with a standard solution of bovine serum albumin (BSA, Sigma-Aldrich). Each measurement was performed six times for each lens material.

The same procedure was carried out to determine the total amount of proteins adsorbed on the contact lens from artificial tear protein solution, which contained three kinds of major proteins in tear, including lysozyme (1.20 mg/mL), BSA (3.88 mg/mL), and immunoglobulin (IgG) from bovine serum (Sigma-Aldrich) (1.66 mg/mL).

Visualization of the Proteins Adsorbed at the Tear-Contacting Surface

Densities of lysozyme, albumin, and IgG adsorbed on the tear-contacting surface of the lens materials were examined using the gold colloid-labeled immunoassay method.21,51,52 Contact lenses were placed in a 24-well tissue culture plate. To equilibrate the substrate surfaces, each lens was soaked overnight in PBS. The PBS was removed, and the artificial tear protein solution was added into each well incubated at 37 °C for 24 h.69 The contact lenses were sufficiently rinsed with PBS and treated overnight with 1.0 wt % BSA solution at 4 °C. The lenses were rinsed again with PBS and incubated in PBS solution containing a primary antibody (1.0 wt % BSA solution containing IgG from rabbit and anti-human lysozyme) for 1 h at 37 °C. The lenses were rinsed with PBS and incubated overnight with 2.5 wt % of glutaraldehyde in PBS at 4 °C. After that, the contact lenses were immersed in 50 mM glycine solution. The lenses were rinsed with PBS and subjected to the secondary antibody (anti-rabbit IgG and goat IgG labeled with 10 nm gold colloid) treatment for 1 h at 37 °C. The size of the gold colloid retained after rinsing increased to 200–300 nm as detected using a silver enhancer kit (SE-100, Sigma-Aldrich). The surface of the contact lens was observed using scanning electron microscopy (SEM, SM-200, TOPCON, Tokyo, Japan) after being freeze dried and sputtered with gold. The amount of gold particle-labeled proteins on the surface was calculated based on SEM images.

Cell Adhesion Experiment

Preparation of Cell Suspensions

Mouse fibroblast L929 cells were used as model cells in this study.24 The L929 cells were purchased from RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan. The cells were cultured routinely in Dulbecco’s modified Eagle medium (DMEM) containing 10% fetal bovine serum (FBS) and 1.0% penicillin at 37 °C in a 5.0% CO2 atmosphere. The cell density was counted after trypsinization.

Cell Morphology Observation on the Boundary of the Contact Lens and Dish Surface

A sterilized contact lens was cut into strip to keep them horizontal and placed on the bottom of a glass bottom cell culture dish (35 mm in diameter, IWAKI, ASAHI GLASS Co., Ltd., Japan) and then fixed using a metal ring (external diameter 13 mm, inner diameter 6 mm). L929 cells, with 4 × 105 cells/dish, were added into each sample and cultured in a stage top incubator for microscopy (Tokai Hit., Co, Ltd.) with 3.0 mL of DMEM containing 10% FBS and 1.0% penicillin at 37 °C in a 5.0% CO2 atmosphere. After 24 h, the adhesion states of the cells on the surfaces of the various contact lenses were examined using a phase contrast microscope (IX71, Olympus Co., Ltd., Tokyo, Japan). The number of cells adhered on the surface was counted from the corresponded microscopic image. Four microscopic images of each contact lens were used to determine the number of adherent cells.

The initial attachment of the cells was observed for over 3 h. After the cell suspension was put on the contact lens surface using the same procedure described above, the cell movement was observed with a time-lapse video for 3 h. Time-lapse videos were recorded using a phase contrast mode of the confocal laser scanning microscope (FV1000-D IX81, Olympus Co., Ltd., Tokyo, Japan). Picture frames were taken every 30 min.

Bacterial Adhesion Experiment

The antibacterial activity of various contact lens substrate samples was evaluated using a previously reported procedure.25,61 Two Gram-negative bacteria were used as bacteria models, Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa). To control the number of bacteria, they were first incubated in a Luria–Bertani (LB) medium at 37 °C for 12–16 h. The optical density of the LB medium at 600 nm (OD600) was measured, and the number of bacteria was calculated as follows: 1.0 OD600 = 8.0 × 108 bacteria/mL. After the suspension was centrifuged several times, bacteria were collected and washed with PBS. A bacteria suspension in PBS was prepared, and the number of bacteria was adjusted to the range of 3.0–10.0 × 106 bacteria/mL. The contact lens samples were soaked in PBS at 37 °C overnight to reach equilibrium, the surface liquid was blown off, and the lenses were then added to a 24-well cell culture plate. Then, 50 μL of bacteria suspension was spread onto each contact lens sample, and PBS was added to all the wells of the cell culture plate to prevent the suspension from drying. The culture plate was covered with a lid and was maintained at 37 °C for 1 h in an incubator under normal atmospheric conditions. Subsequently, 950 μL of PBS was added to each well, and the culture plate was gently shaken for 3 min manually. The suspension was removed from the microplate and added to a fresh 24-well cell culture plate.

Statistical Analysis

The results were evaluated by Student’s t test. The significance of differences was evaluated by p < 0.01 against the control. All the statistical analyses were performed using Microsoft Excel 2016 (Microsoft Corp., Redmond, WA, USA).

Acknowledgments

The authors would like to thank Ms. Keiko Oai, Mr. Katsuya Mitera, Dr. Ren Zhang, and Mr. Bohan Cheng, The University of Tokyo, for their significant technical support on the evaluations of bacteria adhesion, protein adsorption, and cell adhesion, respectively. We also would like to thank Dr. George Yao, Dr. Rebecca Rice, Dr. Stephen “Paul” Shannon, and Dr. John Pruitt, Alcon Vision LLC, for the in-depth and productive discussions.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c06327.

  • Representative AFM topographical images (top view) of the contact lenses used in this study, 3D confocal images (side view) of the whole lenses after being soaked in ATS and cleaned by OPTI-FREE PUREMOIST MPDS, and 3D confocal images (45° tilted angle view) of the whole lenses after being soaked in ATS and cleaned by OPTI-FREE PUREMOIST MPDS (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare the following competing financial interest(s): V.S., S.L., A.S, D.C.D., Y.Z., J.G., S.Z., Y.H., X.S., and J.Y.W. are employees of Alcon Vision, LLC, Fort Worth, TX, and Duluth, GA, USA. The authors declare no competing financial interest.

Supplementary Material

ao0c06327_si_001.pdf (2.3MB, pdf)

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