Biologically relevant monolayer and bilayer films often consist of micron-scale high viscosity domains in a continuous low viscosity matrix. Here we show that this morphology can cause the overall monolayer fluidity to vary by orders of magnitude over a limited range of monolayer compositions. Modeling the system as a two-dimensional suspension in analogy with classic three-dimensional suspensions of hard spheres in a liquid solvent explains the rheological data with no adjustable parameters. In monolayers with ordered, highly viscous domains dispersed in a continuous low viscosity matrix, the surface viscosity increases as a power law with the area fraction of viscous domains. Changing the phase of the continuous matrix from a disordered fluid phase to a more ordered, condensed phase dramatically changes the overall monolayer viscosity. Small changes in the domain density and/or continuous matrix composition can alter the monolayer viscosity by orders of magnitude.

Building additional functionality into both the membrane and the internal compartments of biocompatible liposomes by self-assembly can provide ways of enhancing colloidal stability and spatial and temporal control of contents release. An interdigitation-fusion process is used to encapsulate near infrared light absorbing copper sulfide nanoparticles in the interior compartments of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol liposomes. Once formed, the liposome membrane is modified to include lysolipids and polyethylene glycol lipids by partitioning from lysolipid and PEG-lipid micelles in solution. This results in sterically stable, thermosensitive liposomes with a permeability transition near physiological temperature that can be triggered by NIR light irradiation. Rapid changes in local concentration can be induced with spatial and temporal control using NIR laser light.

Contrast in confocal microscopy of phase-separated monolayers at the air–water interface can be generated by the selective adsorption of water-soluble fluorescent dyes to disordered monolayer phases. Optical sectioning minimizes the fluorescence signal from the subphase, whereas convolution of the measured point spread function with a simple box model of the interface provides quantitative assessment of the excess dye concentration associated with the monolayer. Coexisting liquid-expanded, liquid-condensed, and gas phases could be visualized due to differential dye adsorption in the liquid-expanded and gas phases. Dye preferentially adsorbed to the liquid-disordered phase during immiscible liquid–liquid phase coexistence, and the contrast persisted through the critical point as shown by characteristic circle-to-stripe shape transitions. The measured dye concentration in the disordered phase depended on the phase composition and surface pressure, and the dye was expelled from the film at the end of coexistence. The excess concentration of a cationic dye within the double layer adjacent to an anionic phospholipid monolayer was quantified as a function of subphase ionic strength, and the changes in measured excess agreed with those predicted by the mean-field Gouy–Chapman equations. This provided a rapid and noninvasive optical method of measuring the fractional dissociation of lipid headgroups and the monolayer surface potential.

Adding small fractions of cholesterol decreases the interfacial viscosity of dipalmitoylphosphatidylcholine (DPPC) monolayers by an order of magnitude per wt %. Grazing incidence X-ray diffraction shows that cholesterol at these small fractions does not mix ideally with DPPC but rather induces nanophase separated structures of an ordered, primarily DPPC phase bordered by a line-active, disordered, mixed DPPC-cholesterol phase. We propose that the free area in the classic Cohen and Turnbull model of viscosity is inversely proportional to the number of molecules in the coherence area, or product of the two coherence lengths. Cholesterol significantly reduces the coherence area of the crystals as well as the interfacial viscosity. Using this free area collapses the surface viscosity data for all surface pressures and cholesterol fractions to a universal logarithmic relation. The extent of molecular coherence appears to be a fundamental factor in determining surface viscosity in ordered monolayers.

At low mole fractions, cholesterol segregates into 10- to 100-nm-diameter nanodomains dispersed throughout primarily dipalmitoylphosphatidylcholine (DPPC) domains in mixed DPPC:cholesterol monolayers. The nanodomains consist of 6:1 DPPC:cholesterol “complexes” that decorate and lengthen DPPC domain boundaries, consistent with a reduced line tension, λ. The surface viscosity of the monolayer, ηs, decreases exponentially with the area fraction of the nanodomains at fixed surface pressure over the 0.1- to 10-Hz range of frequencies common to respiration. At fixed cholesterol fraction, the surface viscosity increases exponentially with surface pressure in similar ways for all cholesterol fractions. This increase can be explained with a free-area model that relates ηs to the pure DPPC monolayer compressibility and collapse pressure. The elastic modulus, G′, initially decreases with cholesterol fraction, consistent with the decrease in λ expected from the line-active nanodomains, in analogy to 3D emulsions. However, increasing cholesterol further causes a sharp increase in G′ between 4 and 5 mol% cholesterol owing to an evolution in the domain morphology, so that the monolayer is elastic rather than viscous over 0.1–10 Hz. Understanding the effects of small mole fractions of cholesterol should help resolve the controversial role cholesterol plays in human lung surfactants and may give clues as to how cholesterol influences raft formation in cell membranes.

Liposomes are single bilayer capsules with distinct interior compartments in which hydrophilic drugs, imaging agents, diagnostics, etc. can be sequestered from the exterior environment. The polar parts of the individual lipids face the water compartments, while the hydrophobic parts of the lipid provide a barrier in which hydrophilic or charged molecules are poorly soluble. Hydrophobic molecules can be dissolved within the bilayer. The bilayers are typically from 3 to 6 nm thick and the liposome can range from about 50 nm to 50 μm in diameter. The question asked in this review is if any one bilayer, regardless of its composition, can provide the extended drug retention, long lifetime in the circulation, active targeting to specific tissues and rapid and controllable drug release at the site of interest. As an alternative, we review methods of self-assembling multicompartment lipid structures that provide enhanced drug retention in physiological environments. We also review the methods of externally targeting and triggering drug release via the near infrared heating of gold nanoshells attached to or encapsulated within bilayer vesicles.Research Highlights► Premature leakage and difficulty targeting have stymied liposomal drug delivery. ► A single bilayer may not be enough to protect drugs and target liposomes. ► Multiple lipid bilayers extend drug retention in physiological environments. ► Liposome targeting and drug release can be initiated by pulsed laser light. ► Near infrared light and gold nanoshells can rupture endosomes without killing cells. ► Multicompartment liposomes with nanoshells may be the drug carrier of the future.

We investigated a model of acute respiratory distress syndrome in which the serum protein albumin adsorbs to an air-liquid interface and prevents the thermodynamically preferable adsorption of the clinical lung surfactant Survanta by inducing steric and electrostatic energy barriers analogous to those that prevent colloidal aggregation. Chitosan and polyethylene glycol (PEG), two polymers that traditionally have been used to aggregate colloids, both allow Survanta to quantitatively displace albumin from the interface, but through two distinct mechanisms. Direct visualization with confocal microscopy shows that the polycation chitosan coadsorbs to interfacial layers of both Survanta and albumin, and also colocalizes with the anionic domains of Survanta at the air-liquid interface, consistent with it eliminating the electrostatic repulsion by neutralizing the surface charges on albumin and Survanta. In contrast, the PEG distribution does not change during the displacement of albumin by Survanta, consistent with PEG inducing a depletion attraction sufficient to overcome the repulsive energy barrier toward adsorption.

Monolayers based on the composition of the cytoplasmic (CYT) or extracellular (EXT) sides of the myelin bilayer form coexisting immiscible liquid phases similar to the liquid-ordered/liquid-disordered phases in phospholipid/cholesterol monolayers. Increasing the temperature or surface pressure causes the two liquid phases to mix, although in significantly different fashion for the CYT and EXT monolayers. The cerebroside-rich EXT monolayer is near a critical composition and the domains undergo coalescence and a circle-to-stripe transition along with significant roughening of the domain boundaries before mixing. The phase transition in the cerebroside-free cytoplasmic side occurs abruptly without domain coalescence; hence, the cytoplasmic monolayer is not near a critical composition, although the domains exhibit shape instabilities within 1–2 mN/m of the transition. The change in mixing pressure decreases significantly with temperature for the EXT monolayer, with dΠcrit/dT ∼ 1.5 mN/m/°C, but the mixing pressure of the CYT monolayer varies little with temperature. This is due to the differences in the nonideality of cholesterol interactions with cerebrosides (EXT) relative to phospholipids (CYT). EXT monolayers based on the composition of white matter from marmosets with experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis, remain phase-separated at higher surface pressures than control, while EAE CYT monolayers are similar to control. Myelin basic protein, when added to the CYT monolayer, increases lipid miscibility in CYT monolayers; likely done by altering the dipole density difference between the two phases.

Building additional functionality into both the membrane and the internal compartments of biocompatible liposomes by self-assembly can provide ways of enhancing colloidal stability and spatial and temporal control of contents release. An interdigitation-fusion process is used to encapsulate near infrared light absorbing copper sulfide nanoparticles in the interior compartments of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol liposomes. Once formed, the liposome membrane is modified to include lysolipids and polyethylene glycol lipids by partitioning from lysolipid and PEG-lipid micelles in solution. This results in sterically stable, thermosensitive liposomes with a permeability transition near physiological temperature that can be triggered by NIR light irradiation. Rapid changes in local concentration can be induced with spatial and temporal control using NIR laser light.