BIOMECHANICS OF THE ATHEROSCLEROTIC LIPIDOME: (UN)EXPECTED STATIN INTERACTIONS AND MEMBRANE REMODELLING

Statins interact with lipid membranes in ways that shape their pharmacokinetics, off-target effects, and pleiotropic actions, yet these interactions' mechanical and biophysical consequences remain poorly understood. This thesis employs a combination of surface plasmon resonance (SPR), quartz crystal microbalance with dissipation monitoring (QCM-D), and rheological modelling to characterize how representative statins intercalate within biomimetic supported lipid bilayers (SLBs) of healthy and diseased composition. SPR reveals that lipophilic statins exhibit higher apparent affinities and slower dissociation kinetics, especially in cholesterol- and anionic lipid-rich membranes. QCM-D analyses demonstrate that statins alter membrane mass, dissipation, and interfacial stiffness in a statin- and membrane-dependent manner. Frequency sweeps of the storage modulus (G′) reveal nonlinear elastic remodelling after statin loading, with Zener model fits yielding nanosecond-scale relaxation times that shorten in both membrane types, indicative of membrane fluidization. Notably, healthy SLBs exhibit mechanical hysteresis and dissipative remodelling that fails to reverse after Pravastatin washout, while diseased SLBs undergo reversible elastic softening. Mapping frequency–dissipation trajectories further reveals asymmetric mechanical pathways between membrane types. Together, these results demonstrate that statin–membrane interactions are both composition-dependent and mechanically consequential, explaining tissue-specific statin effects mechanistically. This work supports a biomechanical theory of statin selectivity, wherein membrane composition governs drug partitioning and the mechanical remodelling that determines statin retention, efficacy, and cytotoxic potential in healthy versus diseased cellular environments.