The availability of a permanent artificial vitreous substitute for the human eye would significantly reduce the incidence of blindness caused by retinal detachments. The quest for a biomaterial capable of mimicking the functional capability of the natural vitreous, in particular, the viscoelastic character, has been hindered by injection-induced alterations in polymeric hydrogels resulting from fragmentation. This has been reflected in their inability to assure sufficient intraocular pressure.
The goal of this thesis was to address these medical challenges, through the development of a biomaterial to fulfil these requirements. Towards this goal, the possibility of utilising self-healing supramolecular hydrogels was explored and investigated for the first time for this application. The uniqueness of these materials is that the hydrogel network is constructed using the multiple-point hydrogen bonding motif 2-ureido-4[1H]-pyrimidinone (UPy). It was expected that these hydrogels may possess self-healing ability due to the reversible nature of the hydrogen bonds, rendering them injectable, and thus delivering a long-term tamponade to the retina.
The most challenging aspect of this work was to ensure that the hydrogel was capable of sustaining its physical gel form though the formation of a stable hydrogen bonded supramolecular network in an aqueous environment, as the natural vitreous is composed largely of water (> 99 %). Such an environment can be unfavourable for hydrogen bonds, because the water molecules also compete for the hydrogen bonding sites and thus disrupt the dimers. The employment of the UPy motif which is characterised by high dimerisation strength may minimise, but not eliminate this effect. It was envisaged that the introduction of 6-position alkyl substituents would create an effective “hydrophobic pocket” to prevent the disruption of hydrogen bonds by the water molecules, which is crucial for gel formation. The bulky adamantyl group was chosen to be evaluated for this purpose and the much smaller methyl group was employed for comparison.
Taking these design criteria into account, the work in this thesis featured three generations of supramolecular polymers created by different synthetic approaches. Generation One (main-chain) and Two (star) supramolecular polymers involved the modification of bifunctional and tetrafunctional building blocks by end-functionalisation of PPO/PEO copolymers with UPy motifs. Generation Three (side-chain) supramolecular polymers were synthesised by free radical polymerisation, resulting in polymers with the UPy motifs as pendant groups. The purpose of creating structurally different architectures was to gain further insight into the structure-property relationships, most notably with respect to gelation.
The formation of hydrogels was not observed for Generation One (main-chain) and Two (star) supramolecular polymers due to a number of factors, with the most important being an insufficient number of UPy motifs to induce gelation. This approach, however, did lead to a transparent organogelator with interesting properties. End-functionalisation of a bifunctional Jeffamine® with UPy motifs resulted in the formation of a reversible and thermoresponsive gel in tetrachloroethane (TCE) at a low concentration. The formation of the gel was assisted by fibre formation resulting from the lateral stacking of the urea functionalities.
One of the motivating factors for the design of Generation Three (side-chain) supramolecular polymers was to increase the number of UPy motifs to induce gelation. In this approach, UPy-functionalised methacrylate monomers were synthesised and copolymerised with N,N-dimethylacrylamide (DMAAm). The copolymers formed insoluble gels, which precluded standard solution characterisation. The addition of a naphthyridine (NaPy) derivative as a solubilising agent was able to disrupt the hydrogen bonds of the UPy dimers, leading to dissolution of the gels, thus permitting characterisation by NMR spectroscopy. Similarly, the addition of NaOH solution to break the hydrogen bonds allowed SEC measurements.
It was found that the strongest hydrogels were produced when the shielding group was the adamantyl moiety, which supported the proposed hypothesis. These hydrogels could retain their physical gel form and transparency in water for a period of more than one year (an evaluation still ongoing). The self-healing capability was demonstrated by rheological analysis, which showed a negligible loss of gel properties after extruding these materials through a small gauge needle. Preliminary in vitro cytotoxicity tests showed that these materials were non-toxic to a retinal cell line.
Based on these findings, it can be concluded that the self-healing hydrogels presented in this thesis have fulfilled many of the essential criteria to advance as potential artificial vitreous substitutes. It is emphasised that the novelty of this work comes from the ability of these non-covalently bonded hydrogels to maintain their hydrogen bonds in water and their self-healing capability. A continuation of the work should proceed with further in vitro and in vivo studies of these hydrogels, which could lead to eventual clinical trials.