Monthly replacement contact lenses offer a replacement schedule that is preferred by many wearers. A summary of results from multiple surveys indicates that 32% to 36% of wearers use monthly replacement lenses.1 Given this evident popularity, it is surprising that advancements in the technology for these lenses have lagged behind those for daily disposable lenses.
One current ‘state-of-the-art’ design for daily disposable lenses includes the patented Water Gradient Technology employed with delefilcon A (see Optician 04.03.22 and 01.04.22). This has resulted in a lens that provides both superior wettability and very high oxygen transfer.2 This lens transitions from a highly breathable silicone hydrogel material at the core to a non-silicone hydrophilic polymer structure at the surface and has a Dk/t of 156 (at the centre of a -3.00DS lens) and a surface water content of nearly 100% (see table 1).2
While there appear to be no insurmountable barriers to transferring Water Gradient Technology to a monthly replacement lens, there are issues that must be addressed in order to make this platform available to contact lens wearers who prefer this schedule.3-6 These include the following:
- Enhanced protection against infection
- Compatibility with lens care disinfection solutions
- Resistance to potentially irritating deposits
- Good durability
Table 1: Delefilcon A material specifications in Alcon Dailies Total 1 lenses
Bio-mimetic: What does it mean?
While terms such as bionic, biomimetic, and biomimicry have been widely used, they are poorly defined in general and inappropriate use is frequent.1 Biomimetics is the study of nature and natural phenomena to understand the principles of underlying mechanisms, to obtain ideas from nature, and to apply concepts that may benefit science, engineering and medicine.2,3 A number of different views/definitions have been put forward for the terms biomimicry, biomimetic and bioinspired. In one view, biomimicry is simply superficial imitation of biological systems; biomimetics can be defined as copying and recreating the structure-function relations observed in living organisms; and bioinspiration is a process in which structure and function are extended beyond a natural example to provide the impetus for the product being developed.4 How biological, biomimetic and bio-inspired are separate systems that can work together can be seen in the figure below.
How biological, biomimetic, and bio-inspired systems can work together7
In the context of contact lenses, the term ‘biomimetic’ has been used to describe a very wide range of design and manufacturing approaches, with widely varying degrees of adherence to the definition set forth above. In many instances, a product is referred to as biomimetic even when the approach in no way resembles its biology. For example, hyaluronic acid (HA) is a naturally occurring glycosaminoglycan that is distributed widely in many tissues. It is used in a variety of tear supplements to increase viscosity and enhance lubrication.5 A contact lens described as biomimetic, has been developed, coated with an HA binding protein, the aim being to improve binding of water to the lens.6 While this is an interesting approach to improving lens wettability, it appears to have been inspired by the properties of artificial tears rather than any properties of the cornea.
Optimisation with a biomimetic surface
The human cornea is a remarkable structure, and not just for its refractive capabilities. Though constantly exposed to opportunistic and potentially pathogenic microbes in the environment, it rarely becomes inflamed or infected, indicating the presence of a formidable, highly effective protection system.7 In developing an optimal monthly replacement contact lens, it makes sense to draw on our understanding of the properties of the cornea and use them to inform the design and fabrication of the contact lens surface.
The corneal epithelial surface is intrinsically hydrophobic and multiple factors contribute to the development of a hydrophilic surface. There are outward projecting microvilli on the corneal epithelium and goblet cells from the conjunctiva produce mucous, which migrates across the epithelial surface. The mucous coats the epithelial microvilli, comprising the glycocalyx. Once the mucous layer has dispersed across its surface, the cornea becomes hydrophilic.8 Ocular mucins contribute to the formation of the mucus layer of the tear film; and they also modulate tear film spread. These molecules also inhibit adhesion of pathogens to the ocular surface.
Proteoglycans (lumican, keratocan and mimecan) and interfibrillar proteins (such as collagens type VI and XII) are essential for the maintenance of corneal transparency.9
The apical and basal surfaces of the corneal epithelium are highly specialised. The cells of the apical surface have small micro-ridges, termed microplicae, which increase the epithelial surface area. Along the tips of these ridges, glycoproteins of the membrane-associated mucin class form a glycocalyx (figure 1).10 This mucin-rich layer provides a hydrophilic surface over which the tear film can spread, thus lubricating the ocular surface and establishing a barrier to pathogens.11 How can we approximate this complex surface structure on a contact lens?
2-Methacryloyloxyethyl Phosphorylcholine
2-Methacryloyloxyethyl phosphorylcholine (MPC) is a water-soluble molecule that contains a hydrophobic methacrylate group and a hydrophilic, phosphorylcholine (PC) group (figure 2).12 In a similar fashion to the mucin molecules of the glycocalyx, this structure lends itself to the modification of surfaces that are intrinsically hydrophobic. A zwitterionic PC group in the side chain of MPC is responsible for its bioinert properties. When a layer of MPC polymer is formed on the surface of the lens, it is hydrated by the effect of PC groups and this increases lubricity. Importantly, the net neutral charge on PC does not attract charged proteins or other deposits.12,13 Since their development, MPC polymers have been incorporated into many materials with the aim of preventing adverse biological responses and reactions and have been shown to suppress protein adsorption and cell adhesion to many different materials.14
These properties emerge from three critical characteristics of MPC polymer:
- Extreme hydrophilicity
- Electrical neutrality
- Ability of PC to induce bulk-like behaviour in surrounding water.14
A molecule within the bulk of a liquid is attracted to neighbouring molecules in all directions, so that there is no net force on the molecule. In contrast, a molecule at the surface experiences only net inward forces (surface tension).14 The PC groups permit the natural movement of water in a manner superior to that which can be achieved with other contact lenses. The lack of surface tension improves contact lens wetting.15
Figure 2: The chemical structure of MPC12
Figure 3: Hydration state of the MPC polymer at the aqueous interface14
MPC can be used to construct a range of molecular architectures, with customisable properties, using a sequence of polymerisation methods, including living radical polymerisation.13 The MPC polymer can be used to construct a surface similar to a cell membrane.16 The material is non-toxic and it has already been employed in a wide range of biomedical devices, including biosensors, cardiovascular stents, implantable blood pumps, microcatheters, artificial hip joints, and suture materials.14,17
MPC Influence on the properties of a contact lens
Bio-inspired MPC polymer has the potential to play an important role in enhancing the antibiofouling properties, biocompatibility and wettability of contact lens biomaterials.16 An MPC polymer coating mimics the surface of the cornea and may act in a similar way.
Infection resistance
The cornea has multiple mechanisms that contribute to a defence against infection. Innate defences include anti-microbial peptides associated with the epithelium, the multi-layered structure of the epithelium, anti-microbial activity of the tear film, barrier function of the basal lamina and the resident population of antibacterial cells in the epithelium.7 These defences may be compromised by contact lens wear. Adherence of bacteria to contact lenses is an undesirable complication that is associated with the development of infection.18 Bacteria associated with contact lens contamination (for example, Pseudomonas aeruginosa19,20) often survive as biofilms on lenses.18 Thus, it is important to reduce or prevent formation of these biofilms.18
Figure 4: Application of MPC to a surface.13 A transmission electron microscopy image of the surface is shown on the right. Orange and blue lines indicate the poly(MPC) layer and the liner surface, respectively
Figure 5: Qualitative scanning electron microscopic images of bacteria attached to the surfaces without MPC (control) and with coating of 1.5% and 3.0% MPC24
The complex structure of the surface of the cornea (figure 1) is closely mimicked by the surface structure of MPC units (figures 3 and 4).14,21,22 The biomimetic structure of the MPC unit decreases adherence of bacteria to contact lenses and may provide protection against infection. It has been shown that coating a surface with MPC polymer significantly reduces retention of human pathogenic microorganisms.23
For instance, binding of Staphylococcus aureus, Streptococcus mutans, P. aeruginosa, and Candida albicans to each of three different surfaces were all decreased by coating with MPC polymer.23 This effect was attributed to the ‘superhydrophilicity’ of MPC polymer surfaces,23 a conclusion consistent with results indicating that adhesion and formation of biofilms by P. aeruginosa is facilitated by a hydrophobic surface.19 The results from this study are consistent with those from others demonstrating the ability of MPC polymer to prevent formation of bacterial biofilms (figure 5).24 The ability of MPC to inhibit bacterial adhesion across a wide range of surfaces does not come at the expense of safety or biocompatibility. For example, an MPC polymer-based mouthwash has been shown to be safe and effective for preventing bacterial adhesion to oral surfaces in human volunteers.25
Protein deposition
During contact lens wear, different substances may deposit on, and adhere to, lenses due to interactions between the contact lens and the tear film. Protein deposition on hydrogel contact lenses is affected by the water content, surface charge, hydrophobicity and pore size of the lens material.26 Contact lens deposits have the potential to adversely affect the wearer’s experience and ocular health by decreasing lens surface wettability and creating discomfort.27 These deposits may also lead to contact lens-related ocular pathology, including papillary conjunctivitis, punctate keratitis and corneal inflammatory events.28,29
Immediately after being placed on the eye, contact lenses are coated with a protein layer and most proteins attach strongly to the material, with typically less than 50% being removed by conventional care regimens.30 Proteins that adhere to contact lenses may be denatured, but the relationship between this change and reduced contact lens comfort has not been clearly established.31 However, it has been suggested that conformational changes in proteins and antibacterial proteins accumulated on hydrogel lenses may alter the antimicrobial properties of the ocular surface and elevate the risk for bacterial adherence and infection.19,32 The deposition of certain proteins to contact lenses has been shown to increase the risk of microbial cell attachment to the lens material, and is also associated with inflammatory complications.30
Proteomic analysis has shown that lysozyme and lipocalin 1 are the most common proteins adherent to contact lenses.33 The binding of lysozyme to some contact lens materials may result in a conformational change that denatures the protein to an ‘inactive’ form.34 It has been shown that exposure of human corneal epithelial cells to denatured lysosome results in decreased metabolic activity, an increase in the release of inflammatory cytokines and decreased viability.34 The cytokines with expression increased by denatured lysozyme include various interleukins (1b, 2, 4, 6, 8, 10, 12, and 13), interferon-g, and tumour necrosis factor-a. They are potential contributors to irritation and inflammation that may occur with contact lens wear.34,35
Figure 6: Amount of lysozyme (1.9mg/mL) and bovine serum albumin (0.2mg/mL) adsorbed to unmodified vs polyMPC-50 (pMPC-50) modified model silicone hydrogel lenses after a 24-hour incubation period37
Grafting of MPC polymer onto the surfaces of other materials, via a process termed free-radical polymerisation, results in reduced protein adsorption and enhanced biocompatibility.36 Coating with MPC polymer has been demonstrated to reduce adhesion of potentially contaminating molecules to contact lenses.37 In this study, grafting of a thin layer of MPC polymer onto the surface of silicone hydrogel contact lenses, rather than having it present throughout the lens, increased both the surface wettability and equilibrium water content of the materials. A decrease in protein adsorption by as much as 83% for lysozyme and 73% for bovine serum albumin was observed for the MPC polymer-grafted coated lens (figure 6).37 These results have been replicated in another study that assessed the ability of MPC polymer coating to decrease both protein and lipid adhesion to a wide range of contact lenses.38
The very high hydrophilicity of the MPC unit, like that for the cornea surface, is viewed as the most likely reason for the prevention of non-specific protein binding to this material.39 The presence of zwitterionic MPC units significantly decreases protein and bacterial adsorption to the modified hydrogels, due a unique hydration layer formed by the MPC polymer layer on the surfaces of the hydrogels.12,39,40 It is also worth noting that coating with MPC polymer has been demonstrated to decrease adhesion of proteins and other substances to a wide range of materials repeatedly exposed to biologic fluids in medical applications.14,41
Durability
The durability of an MPC polymer coating has yet to be evaluated on contact lenses, but its antifouling characteristics have been shown to remain unchanged after a friction test that included 500 brushing cycles after application to denture materials.42 Moreover, the grafting of the MPC polymer on polyethylene surface resulted in very stable anti-wear properties even when it was subjected to a 20-million cycle friction test in serum medium.43 These results support the durability of the MPC polymer, itself, and indicate that it is well suited for surface modification on a monthly replacement contact lens.
Compatibility with lens care solutions
An MPC polymer-coated lens should have good compatibility with lens care solutions. In fact, packing solutions for contact lenses have been enhanced by inclusion of this material.44
Reducing dropout
All of the properties described above have the potential to decrease dropouts among contact lens wearers. The combination of Water Gradient Technology with a biomimetic approach to lens surface coating has the potential to provide a very high degree of comfort; and discomfort is a major reason for discontinuing lens use.45 The MPC polymer-based lens surface mimics the cornea in resisting the adhesion of proteins and bacteria, phenomena that may also contribute to discontinuation from lens use.46,47
Conclusions
Development of a new monthly replacement contact lens requires combination of the best available existing technologies with a biomimetic approach using materials, such as MPC polymer, with properties similar to the corneal surface. Such lenses have the potential to improve comfort and safety and to reduce discontinuation due to adverse events for patients who prefer a monthly wearing schedule.
- Kazuhiko Ishihara is a professor at the Department of Materials Engineering at the University of Tokyo, Japan.
- Eric Papas is professor in the School of Optometry & Vision Science at the University of New South Wales, Sydney, Australia.
- Dr John Pruit is a chemical engineer developing new contact lens materials with Alcon Vision Care.
- Dr Carolina Kunnen is a Senior Clinical Development & Medical Affairs Project Lead for Alcon Vision Care Global.
- Dr Carla Mack is the Global Head of Professional Affairs at Alcon. Dr Erich Bauman is Senior Director, Project Leadership for Alcon’s Vision Care R&D unit in Atlanta.
- Dr Ye Hong is currently a research and development director for ocular health and dry eye at Alcon.
- This article is based on a publication in Contact Lens Spectrum and is supported by Alcon.
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