Preparation And Ophthalmic Applications Of Libraries Of Amino Acids Based Zwitterionic Hydrogels

Poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels and silicone hydrogels play an important role in biomedical field, especially in the development of soft contact lens. However, the surface of these hydrogels possesses hydrophobicity, which may induce accumulation of proteins and lipids so as to give rise to clinical complications, such as microbial colonization and infections, limiting their wider practical applications. Therefore, it is needed to modify the surface of the hydrogels so as to improve their hydrophilicity and antiprotein adsorption performance. In this paper, zwitterionic amino acids and short peptides were grafted onto hydrogel surfaces by amino groups induced epoxy ring opening click reaction to improve hydrophilicity and antifouling performance.In the first part, zwitterionic PHEMA hydrogels were developed by the copolymerization of 2-hydroxyethyl methacrylate (HEMA) and glycidyl methacrylate (GMA) followed by grafting zwitterionic amino acids through epoxy ring opening reaction between the amino groups of amino acids and epoxy groups of copolymers. The analysis of attenuated total reflectance Fourier transform infrared spectroscopy (ATR/FTIR) and X-ray photoelectron spectroscopy (XPS) confirmed the successful immobilization of amino acids on the hydrogel surfaces. The contact angle and equilibrium water content of the modified hydrogels showed that the hydrogels exhibited improved hydrophilicity compared with the parent hydrogel. Furthermore, the results of protein deposition indicated that the performance of the hydrogels was determined by the nature of incorporated amino acid:the hydrogels incorporated with neutral amino acids had nonspecific antiadsorption capability to both bovine serum albumin (BSA) and lysozyme (Lyz); the hydrogels incorporated with charged amino acids showed antiadsorption behaviors against protein with same charge and enhanced adsorption to the protein with opposite charge. Preliminary cytotoxicity test revealed that the zwitterionic silicone hydrogels were non-cytotoxic. Finally, a couple of soft contact lenses grafted with amino acids were fabricated having improved antifouling property and hydrophilicity, while no irritating and no damage to rabbit’s eyes were detected.The second part is the development of zwitterionic silicone hydrogels. They were prepared by copolymerization of silicone-containing monomer and GMA followed by grafting zwitterionic amino acids through similar epoxy ring opening reaction. The analysis of ATR/FTIR and XPS demonstrated the successful immobilization of amino acids on the hydrogel surfaces. The grafted silicone hydrogels were characterized by contact angle and equilibrium water content. It was found that the hydrophilicity of the zwitterionic silicone hydrogels was significantly improved after grafting with amino acids. After that, BSA and Lyz were also used as target proteins to monitor antifouling performance of the silicone hydrogels. It was revealed that neutral amino acid immobilized silicone hydrogels had remarkable resistance to BSA and Lyz deposition. It may be ascribed to the formation of zwitterionic surfaces with pairs of protonated secondary ammonium cations and deprotonated carboxyl anions. Meanwhile, the charged amino acid grafted silicone hydrogels were able to repulse same charged protein with reduced deposition and attract oppositely charged protein with increased adsorption. Furthermore, the zwitterionic silicone hydrogels were non-cytotoxic evaluated by preliminary cytotoxicity test. Finally, three types of zwitterionic silicone hydrogel contact lenses were fabricated using polypropylene model. We found that they exhibited good hydrophilicity and anti-protein deposition, while no irritating and no damage to rabbit’s eyes were detected.In the third part, fluorinated silicone hydrogels were modified using the same strategy as above. The fluorinated siloxane macromolecular monomers were designed and synthesized which were able to be soluble with hydrophilic monomers without cosolvents. Zwitterionic fluorinated silicone hydrogels were prepared by copolymerization of fluorinated siloxane macromolecular monomer, silicone-containing monomer and GMA followed by grafting zwitterionic amino acids. The hydrogels exhibited improved hydrophilicity compared with the parent hydrogel. The zwitterinic fluorinated silicone hydrogels incorporated with neutral amino acids had nonspecific antiadsorption capability to both BSA and lysozyme; the hydrogels incorporated with charged amino acids showed antiadsorption behaviors against protein with same charge and enhanced adsorption to the protein with opposite charge. Furthermore, preliminary cytotoxicity test revealed that the zwitterionic fluoride silicone hydrogels were non-cytotoxic.In the last part, short peptides glycine-glycine (GG) and glycine-glycine-glycine (GGG) were applied to modify the surface of silicone hydrogels through the terminal amino groups of short peptides induced epoxy ring opening reaction. We found that the short peptides grafted zwitterionic silicone hydrogels exhibited improved hydrophilicity and equilibrium water content. The protein resistance of the silicone hydrogels was further evaluated by bicinchoninic acid assay (BCA). The data showed that all of the grafted silicone hydrogels have strong resistance against both BSA and Lyz adsorption, which may be ascribed to the formation of zwitterionic structure of short peptides after grafting. Interestingly, the longer the peptide grafted, the better the protein resistance, and the GGG grafted silicone hydrogel has the best resistance. The cytotoxicity test in vitro demonstrated that the silicone hydrogels were non-cytotoxic, indicating their inherent biocompatibility. Furthermore, silicone hydrogel contact lenses grafted with short peptides were prepared. It was revealed that the grafted contact lenses had excellent hydrophilicity and antifouling property, while no damage to rabbit eyes was observed after continuous wearing.In a summary, a simple and effective strategy to combat surface biofouling is developed by grafting of amino acids or short peptides onto hydrogel surfaces to form zwitterionic structure, which may have applications in ophthalmology.