Structure-property relationship of synthetic lung surfactant films

Abstract

Surfactants are ubiquitous in our daily lives as they are found in household, personal care, and pharmaceutical products. Surfactants also play an important in making life possible by helping essential cellular components organize and grow. Of particular interest is lung surfactant (LS), a lipid-protein mixture that makes breathing possible by reducing the interfacial tension of the air-liquid interface of the alveoli. This modulation of the interfacial tension enables effortless lung expansion and stabilizes the lung against collapse thus allowing for proper oxygenation of the bloodstream. The lack of LS or its inhibition leads to deadly respiratory illnesses. Various animal-based replacement lung surfactant (RLS) therapies currently exist that have decreased the mortality of neonatal and acute respiratory distress syndrome, however, these RLS therapies do not work as well as natural LS, are expensive, and vary widely in composition. This motivates the development of a synthetic LS formulation. One of the major challenges is that we do not know an ideal LS composition. Therefore, to better understand LS function and make progress towards a viable synthetic LS formulation we require a detailed study that considers both the fundamental science and physiologically relevant performance parameters. In this dissertation, we have elucidated the role of dihydrocholesterol (DChol) within the context of a simple model LS system composed of 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1-hexadecanol (HD) in modulating film microstructure, phase behavior, interfacial rheology, and film nano-mechanics. Using confocal microscopy, we found that DPPC and HD phase separate into crystalline domains within a fluid matrix. The addition of DChol to our model LS system causes domains that are initially semi-circular to develop fingering instabilities and undergo a spontaneous and reversible shape transition to stripes of uniform width. The fingering instabilities follow a version of the classical Mullins-sekerka growth instability theory and depend on domain growth kinetics. The stripe morphology is found to be an equilibrium state governed by the competition between dipole-dipole interactions within the domains and the line tension at the domain boundaries and depends on film composition, temperature, and surface pressure. To study how LS spreads on an air-water interface, we use surface micro-rheology to show that HD causes the film to resist flow while DChol causes the film to be more fluid-like. We transfer our monolayers from the air-water interface onto a supported substrate and show using atomic force microscopy that the addition of DChol destabilizes the crystalline and liquid-like phases with highly dissipative nano-structures. Overall, we believe the work presented in this dissertation provides the building blocks for using fundamental and applied science to develop a synthetic replacement LS therapy.