Investigating the Synergistic Interactions of Surface Immobilized and Free Natural Ocular Lubricants for Contact Lens Applications: A Comparative Study between Hyaluronic Acid and Proteoglycan 4 (Lubricin).

The main reasons for the discontinuation of contact lens wear are ocular dryness and discomfort. Proteoglycan 4 (PRG4), a mucinous glycoprotein, and hyaluronic acid (HA), a nonsulfated linear glycosaminoglycan, are naturally present in the eye and contribute to ocular hydration and lubrication. This study aimed to investigate the impact of the structure of the recombinant human PRG4 (rhPRG4)/HA complex on contact lens properties, when one agent is grafted and the counterpart is physisorbed on the surface of model conventional or silicone contact lens materials. Investigation of the wettability, water retention, antifouling, and boundary lubricant properties of the prepared hydrogels showed that the rhPRG4/HA interactions varied with the rhPRG/HA configuration on the hydrogel surface as well as the composition of the underlying substrate used. The rhPRG4-physisorbed/HA-grafted sample was characterized by better antifouling and boundary lubricant properties on the model conventional hydrogels, while the HA-physisorbed/rhPRG4-grafted sample exhibited improved surface wettability, antifouling, and water-retentive properties on the model silicone hydrogels. The results of this study contribute to the design of biomimetic contact lens surfaces that work synergistically with ocular fluid-phase biological agents to enhance compatibility between the contact lens and the ocular environment, alleviating dry eye symptoms and improving comfort.

Antifouling silicone hydrogel contact lenses via densely grafted phosphorylcholine polymers.

Silicone hydrogel contact lenses (CLs) permit increased oxygen permeability through their incorporation of siloxane functional groups. However, contact lens biofouling can be problematic with these materials; surface modification to increase lens compatibility is necessary for acceptable properties. This work focuses on the creation of an antifouling CL surface through a novel grafting method. A polymer incorporating 2-methacryloyloxyethyl phosphorylcholine (MPC), well known for its antifouling and biomimetic properties, was grafted to the model lens surfaces using surface-initiated atom transfer radical polymerization (SI-ATRP). The SI-ATRP modification generated a unique double-grafted polymeric architecture designed to resist protein adsorption through the presence of a surrounding hydration layer due to the PC groups and steric repulsion due to the density of the grafted chains. The polymer was grafted from model silicone hydrogel CL using a four-step SI-ATRP process. Attenuated total reflectance-Fourier transform infrared spectroscopy and XPS were used to confirm the surface chemical composition at each step of the synthesis. Both the surface wettability and equilibrium water content of the materials increased significantly upon polyMPC modification. The surface water contact angle was as low as 16.04 ± 2.37° for polyMPC-50 surfaces; complete wetting (∼0°) was observed for polyMPC-100 surfaces. A decrease in the protein adsorption by as much as 83% (p < 0.000 36) for lysozyme and 73% (p < 0.0076) for bovine serum albumin was observed, with no significant difference between different polyMPC chain lengths. The data demonstrate the potential of this novel modification process for the creation of extremely wettable and superior antifouling surfaces, useful for silicone hydrogel CL surfaces.

Impact of a Hyaluronic Acid-Grafted Layer on the Surface Properties of Model Silicone Hydrogel Contact Lenses.

The introduction of high oxygen transmissibility silicone hydrogel lenses ameliorated hypoxia-related complications, making them the most prescribed type of contact lens (CL). Despite the progress made over the last 2 decades to improve their clinical performance, symptoms of ocular dryness and discomfort and a variety of adverse clinical events are still reported. Consequently, the rate of CL wear discontinuation has not been appreciably diminished by their introduction. Aiming to improve the interfacial interactions of silicone hydrogel CLs with the ocular surface, a biomimetic layer of hydrophilic glycosaminoglycan hyaluronic acid (HA) (100 kDa) was covalently attached to the surface of model poly(2-hydroxyethyl methacrylate- co-3-methacryloxypropyl-tris-(trimethylsiloxy)silane) (pHEMA- co-TRIS) silicone hydrogel materials via UV-induced thiol-ene "click" chemistry. The surface structural changes after each modification step were studied by Fourier transform infrared spectroscopy-attenuated total reflectance and X-ray photoelectron spectroscopy (XPS). Successful grafting of a homogeneous HA layer to the surface of the model silicone hydrogels was confirmed by the consistent appearance of N (1s) and the significant decrease of the Si (2p) peaks, as determined by low-resolution angle-resolved XPS. The HA-grafted surfaces demonstrated reduced contact angles, dehydration rate, and nonspecific deposition of lysozyme and albumin, while maintaining their optical transparency (>90%). In vitro studies demonstrated that the HA-grafted pHEMA- co-TRIS materials did not show any toxicity to human corneal epithelial cells. These results suggest that surface immobilization of HA via thiol-ene "click" chemistry can be used as a promising surface treatment for silicone hydrogel CLs.

Surface-Functionalized Model Contact Lenses with a Bioinspired Proteoglycan 4 (PRG4)-Grafted Layer.

Ocular dryness and discomfort are the primary reasons for the discontinuation of contact lens wear. This is mainly due to poorly hydrated contact lens surfaces and increased friction, particularly at the end of the day and can potentially cause reduced vision or even inflammation. Proteoglycan 4 (PRG4) is a mucinous glycoprotein with boundary lubricating properties, naturally found in the eye, able to prevent tear film evaporation and protect the ocular surface during blinking. Aiming to improve the interfacial interactions between the ocular surface and the contact lens, the synthesis and characterization of surface-modified model contact lenses with PRG4 is described. Full-length recombinant human PRG4 (rhPRG4) was successfully grafted onto the surface of model conventional and silicone hydrogel (SiHy) contact lenses via its somatomedin B-like end-domain using N, N'-carbonyldiimidazole linking chemistry. Grafting was assessed by Fourier transform infrared spectroscopy-attenuated total reflectance, X-ray photoelectron spectroscopy, and radioactive (I131) labeling. Surface immobilization of rhPRG4 led to model conventional and SiHy materials with improved antifouling properties, without impacting optical transparency or causing any toxic effects to human corneal epithelial cells in vitro. The surface wettability and the boundary friction against human corneal tissue were found to be substrate-dependent, with only the rhPRG4-grafted model SiHy exhibiting a reduced contact angle and kinetic friction coefficient compared to the unmodified surfaces. Hence, clinical grade rhPRG4 can be an attractive candidate for the development of novel bioinspired SiHy contact lenses, providing improved comfort and overall lens performance.

Hyaluronan incorporation into model contact lens hydrogels as a built-in lubricant: Effect of hydrogel composition and proteoglycan 4 as a lubricant in solution.

Contact lens friction significantly correlates with subjective comfort. Hyaluronan (HA) and proteoglycan 4 (PRG4) are natural boundary lubricants present in the body. The objective of this study was to assess the effect of crosslinked HA into the bulk of model contact lens materials pHEMA, pHEMA/TRIS, and DMAA/TRIS on surface wettability, protein sorption, and boundary lubricating properties at a material-cornea biointerface, both alone and synergistically with PRG4 in solution. Surface wettability was assessed by water contact angle measurement, protein sorption by lysozyme sorption assay, and boundary lubricating properties using an in vitro friction test method. HA incorporation (HAinc ) increased the surface wettability of all materials, and reduced protein sorption for pHEMA and DMAA/TRIS. HAinc increased friction for pHEMA, and DMAA/TRIS, whereas a decrease was observed for pHEMA/TRIS. A combination of HAinc and PRG4sol had a synergistic effect of reducing friction only for pHEMA/TRIS. This combination had similar friction reduction compared with PRG4sol alone for DMAA/TRIS. These results indicate HA incorporation could be an effective internal wetting agent, antiadhesive, and boundary lubricant for pHEMA/TRIS silicone hydrogels. In conclusion, HA incorporation can reduce friction of hydrogels alone and in combination with PRG4 in solution, though in a hydrogel composition-dependent (e.g., TRIS) manner. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1818-1826, 2018.

Surface modification of model hydrogel contact lenses with hyaluronic acid via thiol-ene "click" chemistry for enhancing surface characteristics.

Discontinuation of contact lens wear as a result of ocular dryness and discomfort is extremely common; as many as 26% of contact lens wearers discontinue use within the first year. While patients are generally satisfied with conventional hydrogel lenses, improving on-eye comfort continues to remain a goal. Surface modification with a biomimetic, ocular friendly hydrophilic layer of a wetting agent is hypothesized to improve the interfacial interactions of the contact lens with the ocular surface. In this work, the synthesis and characterization of poly(2-hydroxyethyl methacrylate) surfaces grafted with a hydrophilic layer of hyaluronic acid are described. The immobilization reaction involved the covalent attachment of thiolated hyaluronic acid (20 kDa) on acrylated poly(2-hydroxyethyl methacrylate) via nucleophile-initiated Michael addition thiol-ene "click" chemistry. The surface chemistry of the modified surfaces was analyzed by Fourier transform infrared spectroscopy-attenuated total reflectance and X-ray photoelectron spectroscopy. The appearance of N (1s) and S (2p) peaks on the low resolution X-ray photoelectron spectroscopy spectra confirmed successful immobilization of hyaluronic acid. Grafting hyaluronic acid to the poly(2-hydroxyethyl methacrylate) surfaces decreased the contact angle, the dehydration rate, and the amount of nonspecific sorption of lysozyme and albumin in comparison to pristine hydrogel materials, suggesting the development of more wettable surfaces with improved water-retentive and antifouling properties, while maintaining optical transparency (>92%). In vitro testing also showed excellent viability of human corneal epithelial cells with the hyaluronic acid-grafted poly(2-hydroxyethyl methacrylate) surfaces. Hence, surface modification with hyaluronic acid via thiol-ene "click" chemistry could be useful in improving contact lens surface properties, potentially alleviating symptoms of contact lens related dryness and discomfort during wear.

"Click" Chemistry-Tethered Hyaluronic Acid-Based Contact Lens Coatings Improve Lens Wettability and Lower Protein Adsorption.

Improving the wettability of and reducing the protein adsorption to contact lenses may be beneficial for improving wearer comfort. Herein, we describe a simple "click" chemistry approach to surface functionalize poly(2-hydroxyethyl methacrylate) (pHEMA)-based contact lenses with hyaluronic acid (HA), a carbohydrate naturally contributing to the wettability of the native tear film. A two-step preparation technique consisting of laccase/TEMPO-mediated oxidation followed by covalent grafting of hydrazide-functionalized HA via simple immersion resulted in a model lens surface that is significantly more wettable, more water retentive, and less protein binding than unmodified pHEMA while maintaining the favorable transparency, refractive, and mechanical properties of a native lens. The dipping/coating method we developed to covalently tether the HA wetting agent is simple, readily scalable, and a highly efficient route for contact lens modification.

Timolol maleate release from hyaluronic acid-containing model silicone hydrogel contact lens materials.

This study was designed to assess the impact of a releasable wetting agent, such as hyaluronic acid (HA), on the release profile of timolol maleate (TM) from model silicone hydrogel contact lens materials. Polyvinylpyrrolidone (PVP) was used as an alternative wetting agent for comparison. The model lenses consisted of a hydrophilic monomer, either 2-hydroxyethyl methacrylate or N,N-dimethylacrylamide and a hydrophobic silicone monomer of methacryloxypropyltris (trimethylsiloxy) silane. The loading of the wetting and the therapeutic agent occurred during the synthesis of the silicone hydrogels through the method of direct entrapment. The developed materials were characterized by minimal changes in the water uptake, while lower molecular weight of HA improved their surface wettability. The transparency of the examined silicone hydrogels was found to be affected by the miscibility of the wetting agent in the prepolymer mixture as well as the composition of the developed silicone hydrogels. Sustained release of TM from 4 to 14 days was observed, with the drug transport occurring presumably through the hydrophilic domains of the silicone hydrogels. The release profile was strongly dependent on the hydrophilic monomer composition, the distribution of hydrophobic (silane) domains, and the affinity of the therapeutic agent for the silicone hydrogel matrix. Noncovalent entrapment of the wetting agent did not change the in vitro release duration and kinetics of TM, however the drug release profile was found to be controlled by the simultaneous release of TM and HA or PVP. In the case of HA, depending on the HA:drug ratio, the release rate was decreased and controlled by the release of HA, likely due to electrostatic interactions between protonated TM and anionic HA. Overall, partitioning of the drug within the hydrophilic domains of the silicone hydrogels as well as interactions with the wetting agent determined the drug release profile.

Modification of timolol release from silicone hydrogel model contact lens materials using hyaluronic acid.

OBJECTIVES: The ability of hyaluronic acid (HA) to act as a functional additive in model silicone hydrogel contact lenses to alter the uptake and release characteristics of timolol was investigated. METHODS: Model contact lenses were prepared using 2 primary formulations: 2-hydroxyethyl methacrylate (HEMA) with 3-methacryloxypropyltris (trimethylsiloxy) silane (TRIS) in a 9:1 (wt:wt) ratio or N,N-dimethylacrylamide (DMA) with TRIS in a 1:1 (wt:wt) ratio. Ethylene glycol dimethacrylate (EGDMA) was used as the cross-linker. Four different model lens compositions were explored: unmodified controls, lenses containing HA, lenses that were molecularly imprinted with timolol maleate, and those that were both imprinted and contained HA. Model lenses were then used in subsequent materials characterization, drug loading, and drug release studies. RESULTS: Hyaluronic acid was shown to have the ability to act as a functional additive in these model contact lenses, significantly increasing the drug loading and release mass. This ability seemed to be independent of molecular imprinting, but its efficacy was related to the concentration of HA contained within model lenses and the concentration of drug loading solution used to facilitate uptake. Timolol release was sustained for a duration of approximately 2 days, and the dose of drug was shown to be controlled by both HA-drug interactions and molecular imprinting within the silicone hydrogels. CONCLUSIONS: Hyaluronic acid, although different than typical functional monomers used in molecular imprinting, can be a useful additive to modify the mass of drug release from model silicone hydrogel lenses.