Nucleophilic thiol-yne addition chemistry for the synthesis of tuneable and cytocompatible poly(ethylene glycol) hydrogel materials

This thesis explores the nucleophilic thiol-yne reaction as a crosslinking method for the synthesis of hydrogel materials under biologically relevant conditions. The reaction, using simple functional groups, can be carried out without the use of an external catalyst. This thesis aims to portray the immense potential this reaction has in creating hydrated polymer networks for a wide range of biomedical applications. In the review of the literature (Chapter 1), the popularity and future of hydrogels in tissue engineering has been discussed and the advantages of using alkyne functional groups to crosslink polymers has been highlighted. The main aim of this thesis is to further develop the nucleophilic thiol-yne reaction and to prepare poly(ethylene glycol) (PEG) hydrogel materials with superior performance for application as tissue engineered scaffolds (e.g. extracellular matrix (ECM) mimics or injectable scaffolds). This aim has been approached through a variety of experimental pathways in this thesis demonstrating the suitability of this reaction in the biomaterials field. In Chapter 2, the nucleophilic thiol-yne reaction has been presented as a highly efficient chemistry for producing robust, high water content hydrogels which could be repeatably compressed without hysteresis. Through a straightforward blending process of PEG thiol precursors, the material properties were easily tuned to a range of relevant biological environments. In a similar manner, using the PEG precursors to tune the resultant properties, Chapter 3 addresses the swelling profiles of the thiol-yne hydrogels. By increasing the number of hydrophobic crosslinking points within the networks, nonswelling, cytocompatible hydrogel material were created when immersed in aqueous environments. The monoaddition product of the nucleophilic thiol-yne reaction results in a vinyl thioether bond which can favour different isomers, depending on the reaction conditions. To exploit this in hydrogel synthesis, Chapter 4 describes the formation of sterecontrolled hydrogels. Significantly, an impressive range of mechanical properties was achieved, without affecting the structure or swelling behaviour of the materials. To achieve a structure with more advantageous properties (e.g. self-healing and stretchability) thiol-yne interpenetrating networks (IPNs) were synthesised through the inclusion of natural polymer hydrogels (Chapter 5). These IPNs achieved the advantageous properties required in a simple and effective manner, while retaining the characteristics already exhibited by these materials. To improve on this aim, the thiol-yne PEG hydrogels successfully encapsulated breast cancer cells with enhanced viability compared to the widely used radical thiol-ene reaction (Chapter 6). Controlled matrix degradation allowed for cell proliferation and the formation of cell clusters. Chapter 7 investigates the kinetics of the nucleophilic thiol-yne reaction with different activating groups (e.g. adjacent group to the alkyne), to reduce the toxicity of the PEG alkyne precursors and degradation of the resultant thiol-yne hydrogels. This chapter highlights key requirements of the functionalisation reaction to form alkyne and thiol precursors for successful hydrogel synthesis. Chapter 8 provides a summary of the key findings from Chapters 2-7 and Chapter 9 states the experimental procedures of this thesis