The research goal of this proposal is to build a comprehensive model of mechano-lipidomics and mechanocytosis by designing careful experiments and constructing solid-mechanics based models that are consistent with the classical understanding of membrane fusion mechanics. Nano-/micro-scale liposomes and freestanding membranes will be fabricated using common drug delivery lipids and lipid extracts from cell membrane of ovarian cancer cells. Empirical investigations will include: (i) membrane-elasticity characterization, where a nano-indenter or AFM tip indents and taps the sample vesicles and freestanding membranes, and an optical microscope monitors and records the deformed profiles in-situ; and (ii) mechano-cytosis test, where a mechanical probe forces endocytosis of a liposome into a freestanding membrane or to another liposome. A comprehensive model of deformation-adhesion-endocytosis mechanics will be constructed based on (i) linear elastic approximation, (ii) visco-hyperelastic behavior of lipid membranes, (iii) nonspecific intersurface forces at liposome-membrane and liposome-liposome interfaces, (iv) thermodynamic energy balance for adhesion-fusion. Analytical solutions will first be derived by assuming axisymmetric geometries, linear elastic material responses, and square-well adhesion potential (i.e. cohesive zone approximation), in order to identify the system parameters. The more realistic but sophisticated materials laws and surface potential will then be implemented using numerical routines.
Despite progress in empirical design of drug delivery liposomes, mechanical deformation is missing from the fundamental understanding of lipid membrane fusion and endocytotic energetics. This research will address this shortcoming by designing feasible experiments to investigate the mechanical aspects of lipid membranes and liposomes with a focus in mechano-cytosis and constructing biomechanics models, aiming to build mechano-lipidomics. The research will addres a small but critical part of mechano-lipidomics, rather than building a comprehensive model for lipidomics and drug delivery. Outcomes from these measurements, models and analysis will be used by pharmacist to design and fabricate the next generation of drug delivery liposomes to be tested in-vivo in the future.
