The design of materials able to undergo changes in response to an applied stimulus (e.g. temperature, pH or magnetic fields) is relevant for biomedical applications. In the context of hydrogels, the design of triggers for hydrogelation has enabled precise control over hydrogelation kinetics and mechanical properties. One trigger that has yet to be explored for hydrogelation is ultrasound; a widely-used biomedical platform that is non-invasive, with tuneable tissue penetration depth and high spatiotemporal control. The use of ultrasound as a remote trigger for enzymatic activity and hydrogelation was explored in this thesis. In particular, the ability of liposomes and microbubble-liposome conjugates to release encapsulated payloads upon ultrasound exposure was leveraged. The designed field-responsive system required that the amount of encapsulated calcium in liposomes was maximised. Hence, cryo-TEM and small-angle neutron scattering were used to investigate the effect of the formulation method and the lipid composition on vesicle lamellarity, which determines the volume of the internal liposomal aqueous compartment. In another study, X-ray and neutron scattering corroborated with all-atom molecular dynamics simulations were used to elucidate the effect of sodium and calcium ions on ethanol-induced lipid membrane interdigitation. The results of this study, which spanned a wide range of length scales, furthered the understanding of ethanol-induced interdigitation of bulk and vesicular lipid formulations, with important implications for the production of interdigitation-fusion vesicles.
Calcium-loaded liposomes produced via the interdigitation fusion vesicle method that were able to release their payload upon ultrasound exposure were utilised to trigger the catalytic activity of a calcium-dependent tissue transglutaminase. The ultrasound-activated transglutaminase could then catalyse intermolecular covalent crosslinking between the lysine and glutamine sidechain residues of soluble fibrinogen molecules, yielding fibrinogen hydrogels. Precise control over these processes could be achieved, with the calcium release, catalysis rate and hydrogelation rate all shown to be dependent upon the ultrasound exposure time. Calcium-loaded liposomes were also conjugated to the surface of gaseous microbubbles that are commonly used for in vivo drug delivery. These microbubble-liposome conjugates exhibited enhanced response to the applied acoustic field and could also be used for ultrasound-triggered hydrogelation. Taken together, these results represent an entirely new class of stimuli for enzyme activity and hydrogelation and open up a wide range of opportunities for ultrasound-triggered molecular biology, synthetic biology and material science.