Self-assembly of nanostructured amphiphiles onto surfaces: Design principles for substrate mediated biomedical applications

Amphiphilic in nature, lipids spontaneously self-assemble into various nanostructures in aqueous solution. Among lipid self-assembled structures, liposomes and supported lipid bilayers have long held scientific interest for their main applications in drug delivery and plasma membrane models, respectively. In contrast, lipid multi-layered films on solid supports only recently begun drawing scientists’ attention for their potentials to catalyze many substrate-mediated biomedical applications. These applications include artificial transplants, stents, scaffolds for tissue engineering, and underlying matrices for surface-based drug/gene delivery (also known as macro-scale drug delivery). They all require biocompatible surface coatings that function as a reservoir for therapeutic molecules and a regulator for the controlled release of cargo. My research focused on revealing unique structural characteristics and properties of lipid-based thin films to demonstrate their promises as matrices for substrate-mediated small molecule delivery. Lipid self-assembly behavior on solid support was studied in comparison with the one in bulk solution. A judicious choice of lipid molecules and environmental conditions led to the stabilization of lipid films with highly oriented nanostructures of diverse symmetry. The lipid films displayed 3D bicontinuous cubic, 2D inverted hexagonal, and 1D lamellar structures yielding X-ray diffraction patterns resembling that of single crystals. The genetic materials (small interfering RNA or siRNA) were successfully incorporated into the films. Interestingly, highly ordered lipid film structures at the nanoscale offered distinct biomolecule diffusion pathways as well as cell penetration capacities. Also, the films were highly responsive to environmental conditions, transforming one phase to another which allowed the actuation of siRNA release to cells. These findings indicate the importance of controlling the structure of surface materials at the nanoscale in order to achieve more efficient siRNA delivery from solid substrates. I also investigated new structures of composite lipid-polymer hybrid films that augment the functionality of drug-eluting substrates for substrate-mediated delivery applications. Concurrent self-assembly of lipids and polymers into the same membrane resulted in hybrid membranes showing peculiar phase behavior. A hybrid material composed of phospholipids and block-copolymers was engineered to adopt a multi-layered membrane structure supported on a solid surface. It was observed that in each lamella, lipids and polymers partition unevenly within the membrane plane segregating into lipid or polymer rich domains. Interestingly, like-domains aligned in registry across multilayers, thereby making phase separation three-dimensional. Phase boundaries were shown to exist over extended length scales to compensate the height mismatch between lipid and polymer molecules. I demonstrated that those 3D micro-phase separations in hybrid films serve as functional hotspots for transporting drugs across the bilayer membranes. The hybrid films revealed much faster release rates of hydrophobic drugs (Paclitaxel) compared to single-component films. Plausible mechanisms driving this synergistic release were studied in connection with the structure characteristics of the hybrid films. The registered domains and domain boundaries contributed to impeding paclitaxel crystallization, increasing the total concentration of paclitaxel molecules available for release. My thesis research presents lipid- and lipid-polymer thin film phases that are beyond simple multilamellar structures with a focus on surface-mediated phase transitions. Engineered lipid-based thin films yield unique structural characteristics and properties which cannot be attained from simple multi-layered structure. Extensive structural characterization supports the findings, performed using atomic force microscopy, solid-state NMR, confocal laser scanning microscopy, and grazing incidence small-angle X-ray scattering. The work offers new perspectives in designing lipid-based nanostructured films that exert the control over the release of payloads for substrate-mediated biomedical applications.LimitedAuthor requested closed access (OA after 2yrs) in Vireo ETD syste