Development of Multifunctional Polymer-based Hydrogel with Controllable Physicochemical Properties for Biomedical Engineering

Abstract

Hydrogels consisting of aqueous 3D crosslinked polymer network are very similar to living tissue properties such as elasticity, biocompatibility, hydrophilicity and porosity, and are widely used in various biomedical applications. They are widely used as promising materials for therapeutic delivery, contact lenses, bone cements, wound dressings, and 3D tissue scaffolds for tissue engineering and so on. However, to control their properties independently to suit biomedical application purpose is often challenge. One of challenge is interdependency of hydrogel properties, since controlling the crosslinking density can also affects their other properties such as the degradation rate, hydrophilicity and mechanical properties. Also, their fabrication mechanisms are often an issue. Free radical polymerization, most commonly used to form hydrogels, is usually initiated by free radical-generating compounds, radiation or heating, which activation and residual initiators often damage cells and tissues. In addition, it is difficult to control the crosslinking kinetics at low toxicity levels. Therefore, an “in situ” crosslinking reaction would be highly favored for hydrogel fabrication in biomedical application. because, they react under mild conditions without using initiator and their crosslinking kinetics can be widely controlled with low toxicity. Due to many things in addition to the aforementioned challenges, it is important to control these properties at different levels to meet the specific requirements. Therefore, in this study, in order to overcome limitations while maintaining their intrinsic properties, a multifunctional polymer-based hydrogel was developed, and various properties were controlled. It is expected to exhibit superior properties to increase the potential use in the biomedical industry. In chapter 2, the protein release rates from hydrogels were controlled by varying the physical properties of the hydrogels while maintaining their crosslinking density. In general, the degree of crosslinking is adjusted to control the protein release of the hydrogel as a carrier. However, it is not preferred because the crosslinking density affects the mechanical properties of the hydrogels, in which the mechanical and diffusional properties are inversely correlated. To overcome these issues, by presenting functional groups having positive charge, negative charge, and hydrophobicity, respectively, on the poly(ethylene glycol) (PEG) chains, the release of proteins having various isoelectric points was controlled through electrostatic interactions. In the chapter 3, the mechanical properties and degradation behavior of PEG diacrylate (PEGDA)-polyethyleneimine (PEI) hydrogels prepared by in situ crosslinking between PEGDA and PEI via Michael addition were explored. Generally, cross-linked hydrogels involving the use of initiators to start the process often exhibit cytotoxicity depending on reagent concentrations. Therefore, their dosage must be applied carefully to prevent cytotoxicity while maintaining the ability to initiate a crosslinking reaction. As the alternative to these issues, PEGDA and PEI were used to fabricate hydrogels through "in situ" crosslinking reactions that occur under mild conditions and do not involve the use of initiators. We also explored the drug release kinetics of PEGDA-PEI hydrogels depending on their physical properties and degradation behavior. In the chapter 4, the mechanical properties of in situ forming chitosan hydrogels via Schiff base formation were controlled by introducing tunable polymer graft architecture. Due to the mechanical properties of in situ forming hydrogels depend on the crosslinking density which also controls the gelation rate, it is a significant challenge to independently control the mechanics and gelation kinetics. We synthesized PEG with varying lengths and densities conjugated to the chitosan backbone, which not only allowed dissolution in neutral aqueous solutions but also the control of mechanical properties of hydrogel while maintaining facile gelation kinetics. In addition, the tissue adhesive properties of resulting hydrogels were evaluated by ex vivo and in vivo models, demonstrating their clinical potential. In the last chapter, polyaspartamide presenting amine groups with controllable grafting density and length was synthesized using diamines with varying length of poly(ethylene glycol) linker. Small molecules can only have a few functional groups and often-show limited solubility in various solvents, limiting their controllable range. On the other hand, polymers that have functional groups throughout their repeating units serving as sites for chemical reactions can present more reactive functional groups than small molecules, resulting considered highly effective crosslinkers to develop materials with variable mechanical properties. We demonstrated the potential application as an injectable drug delivery systems undergo facile degradation and complete dissolution in physiological conditions, regardless of mechanical properties, by adjusting the graft architecture of poly(2-hydroxyethyl aspartamide)-g-amino-poly(ethylene glycol) (PHEA-PEGAm) as polymer crosslinker.