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A compound droplet is composed of a traditional pendant drop (PD) or sessile drop (SD) sharing the interface with an immiscible phase of comparable sizes, which could be a solid particle, a gas bubble, or most often another droplet of an immiscible liquid. Over the past decade, the study of compound droplets has attracted increasing attention because of extensive applications in many research fields, such as complex fluids, microfluidics, foam and emulsion, and biomedical applications. Among all technical difficulties in characterizing compound droplets, a central problem in surface science is the prediction of its equilibrium shape, which requires knowledge of complicated boundary conditions. Existing dimensionless groups, such as the Bond number traditionally used to evaluate the shape of PDs and SDs, largely fail in predicting the shape of compound droplets. Here, we propose an alternative Bond number, termed the Neumann number, to characterize the shape of compound droplets. Using three dimensionless groups, that is, the Neumann number, the Bond number, and the Worthington number, we have quantitatively predicted and analyzed the shape of traditional PDs/SDs and various compound droplets, including a PD with a spherical particle suspending at the drop apex, a SD with its apex disturbed by a vertical cylinder, and a spherical SD (no gravity) with its apex disturbed by a fluid lens. It is found that the Neumann number can be readily adapted to quantitatively predict and analyze the shape of PDs/SDs and compound droplets.

Pulmonary drug delivery is superior to the systemic administration in treating lung diseases. An optimal respiratory nanocarrier should be able to efficiently and safely cross the pulmonary surfactant film, which serves as the first biological barrier for respiratory delivery and plays paramount roles in maintaining the proper mechanics of breathing. In this work, we focused on the interactions between poly(amidoamine) (PAMAM) dendrimers and a model pulmonary surfactant. With combined Langmuir monolayer experiments and coarse-grained molecular dynamics simulations, we studied the effect of environmental temperature, size, and surface property of PAMAM dendrimers (G3-OH, G3-NH 2 , G5-OH, and G5-NH 2 ) on the dipalmitoylphosphatidylcholine (DPPC) monolayer. Our simulations indicated that the environmental temperature could significantly affect the influence of PAMAM dendrimers on the DPPC monolayer. Therefore, results obtained at room temperature cannot be directly applied to elucidate interactions at body temperature. Simulations at body temperature found that all tested PAMAM dendrimers can easily penetrate the lipid monolayer during the monolayer expansion process (mimicking "inhalation"), and the cationic PAMAM dendrimers (-NH 2 ) show promising penetration ability during the monolayer compression process (mimicking "expiration"). Larger PAMAM dendrimers (G5) adsorbed onto the lipid monolayer tend to induce structural collapse and inhibit normal phase transitions of the lipid monolayer. These adverse effects could be mitigated in the subsequent expansion-compression cycle. These findings suggest that the PAMAM dendrimer may be used as a potential respiratory drug nanocarrier.

Hydrophilic drugs can be delivered into lungs via nebulization for both local and systemic therapies. Once inhaled, ultrafine nanodroplets preferentially deposit in the alveolar region, where they first interact with the pulmonary surfactant (PS) layer, with nature of the interaction determining both efficiency of the pulmonary drug delivery and extent of the PS perturbation. Here, we demonstrate by molecular dynamics simulations the transport of nanodroplets across the PS layer being improved by lipid coating. In the absence of lipids, bare nanodroplets deposit at the PS layer to release drugs that can be directly translocated across the PS layer. The translocation is quicker under higher surface tensions but at the cost of opening pores that disrupt the ultrastructure of the PS layer. When the PS layer is compressed to lower surface tensions, the nanodroplet prompts collapse of the PS layer to induce severe PS perturbation. By coating the nanodroplet with lipids, the disturbance of the nanodroplet on the PS layer can be reduced. Moreover, the lipid-coated nanodroplet can be readily wrapped by the PS layer to form vesicular structures, which are expected to fuse with the cell membrane to release drugs into secondary organs. Properties of drug bioavailability, controlled drug release, and enzymatic tolerance in real systems could be improved by lipid coating on nanodroplets. Our results provide useful guidelines for the molecular design of nanodroplets as carriers for the pulmonary drug delivery.

The polymorphism of phospholipid monolayers has been extensively studied because of its importance in surface thermodynamics, soft matter physics, and biomembranes. To date, the phase behavior of phospholipid monolayers has been nearly exclusively studied with the classical Langmuir-type film balance. However, because of experimental artifacts caused by film leakage, the Langmuir balance fails to study the reversibility of two-dimensional surface phase transitions. We have developed a novel experimental methodology called the constrained drop surfactometry capable of providing a leakage-proof environment, thus allowing reversibility studies of two-dimensional surface phase transitions. Using dipalmitoylphosphatidylcholine (DPPC) as a model system, we have studied the reversibility of isothermal and isobaric phase transitions in the monolayer. It is found that not only the compression and expansion isotherms but also the heating and cooling isobars, completely superimpose with each other without hysteresis. Microscopic lateral structures of the DPPC monolayer also show reversibility not only during the isothermal compression and expansion processes but also during the isobaric heating and cooling processes. It is concluded that the two-dimensional surface phase transitions in phospholipid monolayers are reversible, which is consistent with the reversibility of phase transitions in bulk pure substances. Our results provide a better understanding of surface thermodynamics, phase change materials, and biophysical studies of membranes and pulmonary surfactants.

Oscillating droplets and bubbles have been developed into a novel experimental platform for a wide range of analytical and biological applications, such as digital microfluidics, thin film, biophysical simulation, and interfacial rheology. A central effort of developing any droplet-based experimental platform is to increase the effectiveness and accuracy of droplet oscillations. Here, we developed a novel system of droplet-based arbitrary waveform generator (AWG) for feedback-controlling single-droplet oscillations. This AWG was developed through closed-loop axisymmetric drop shape analysis and based on the hardware of constrained drop surfactometry. We have demonstrated the capacity of this AWG in oscillating the volume and surface area of a millimeter-sized droplet to follow four representative waveforms, sine, triangle, square, and sawtooth. The capacity of oscillating the surface area of a droplet across the frequency spectrum makes the AWG an ideal tool for studying interfacial rheology. The AWG was used to determine the surface dilational modulus of a commonly studied nonionic surfactant, dodecyldimethylphosphine oxide. The droplet-based AWG developed in this study is expected to achieve accuracy, versatility, and applicability in a wide range of research areas, such as thin film and interfacial rheology.

Langmuir monolayer self-assembled at the air-water interface represents an excellent model for studying phase transition and lipid polymorphism in two dimensions. Compared with numerous studies of phospholipid phase transitions induced by isothermal compression, there are very scarce reports on two-dimensional phase transitions induced by isobaric heating. This is mainly due to technical difficulties of continuously regulating temperature variations while maintaining a constant surface pressure in a classical Langmuir-type film balance. Here, with technological advances in constrained drop surfactometry and closed-loop axisymmetric drop shape analysis, we studied the isobaric heating process of the dipalmitoylphosphatidylcholine (DPPC) monolayer. It is found that temperature and surface pressure are two equally important intensive properties that jointly determine the phase behavior of the phospholipid monolayer. We have determined a critical point of the DPPC monolayer at a temperature of 44 °C and a surface pressure of 57 mN/m. Beyond this critical point, no phase transition can exist in the DPPC monolayer, either by isothermal compression or by isobaric heating. The melting process of the DPPC monolayer studied here provides novel insights into the understanding of a wide range of physicochemical and biophysical phenomena, such as surface thermodynamics, critical phenomena, and biophysical study of pulmonary surfactants.

Axisymmetric drop shape analysis (ADSA) has been used in a broad range of applications for determining surface tensions of air-liquid surfaces and interfacial tensions of liquid-liquid interfaces. However, it is well-known that the accuracy of ADSA deteriorates upon the reduction of drop volume. Here, we systematically compared different criteria and parameters in evaluating the accuracy of ADSA upon reducing drop volume. By scrutinizing the dependence of ADSA accuracy on various parameters, including the capillary constant (c), the Bond number (Bo), the Worthington number (Wo), and the shape parameter (P s ), we concluded that the classical Bond number failed to predict the accuracy of drop shape analysis at very small drop volumes. Thus, we proposed a replacement of the classical Bond number, called the Neumann number Ne ≡ (ΔρgR 0 H)/γ. The design rationale of this new dimensionless number lies in the use of the geometric mean of the radius of curvature at the drop apex (R 0 ) and the drop height (H) as the new characteristic length (L) to represent the drop size, that is, L = (R 0 H) 1/2 . It is found that the Neumann number is capable of evaluating the accuracy of ADSA. Moreover, we have demonstrated the usefulness of the local Neumann number, Ne z ≡ (ΔρgR 0 /γ)z, in evaluating the contribution of the local drop profile to the accuracy of ADSA.

A self-assembled phospholipid monolayer at an air-water interface is a well-defined model system for studying surface thermodynamics, membrane biophysics, thin-film materials, and colloidal soft matter. Here we report a study of two-dimensional phase transitions in the dipalmitoylphosphatidylcholine (DPPC) monolayer at the air-water interface using a newly developed methodology called constrained drop surfactometry (CDS). CDS is superior to the classical Langmuir balance in its capacity for rigorous temperature control and leak-proof environments, thus making it an ideal alternative to the Langmuir balance for studying lipid polymorphism. In addition, we have developed a novel Langmuir-Blodgett (LB) transfer technique that allows the direct transfer of lipid monolayers from the droplet surface under well-controlled conditions. This LB transfer technique permits the direct visualization of phase coexistence in the DPPC monolayer. With these technological advances, we found that the two-dimensional phase behavior of the DPPC monolayer is analogous to the three-dimensional phase transition of a pure substance. This study has implications in the fundamental understanding of surface thermodynamics as well as applications such as self-assembled monolayers and pulmonary surfactant biophysics.

Droplet manipulation plays an important role in a wide range of scientific and industrial applications, such as synthesis of thin-film materials, control of interfacial reactions, and operation of digital microfluidics. Compared to micron-sized droplets, which are commonly considered as spherical beads, millimeter-sized droplets are generally deformable by gravity, thus introducing nonlinearity into control of droplet properties. Such a nonlinear drop shape effect is especially crucial for droplet manipulation, even for small droplets, at the presence of surfactants. In this paper, we have developed a novel closed-loop axisymmetric drop shape analysis (ADSA), integrated into a constrained drop surfactometer (CDS), for manipulating millimeter-sized droplets. The closed-loop ADSA generalizes applications of the traditional drop shape analysis from a surface tension measurement methodology to a sophisticated tool for manipulating droplets in real time. We have demonstrated the feasibility and advantages of the closed-loop ADSA in three applications, including control of drop volume by automatically compensating natural evaporation, precise control of surface area variations for high-fidelity biophysical simulations of natural pulmonary surfactant, and steady control of surface pressure for in situ Langmuir-Blodgett transfer from droplets. All these applications have demonstrated the accuracy, versatility, applicability, and automation of this new ADSA-based droplet manipulation technique. Combining with CDS, the closed-loop ADSA holds great promise for advancing droplet manipulation in a variety of material and surface science applications, such as thin-film fabrication, self-assembly, and biophysical study of pulmonary surfactant.

Natural lung surfactant contains less than 40% disaturated phospholipids, mainly dipalmitoylphosphatidylcholine (DPPC). The mechanism by which lung surfactant achieves very low near-zero surface tensions, well below its equilibrium value, is not fully understood. To date, the low surface tension of lung surfactant is usually explained by a squeeze-out model which predicts that upon film compression non-DPPC components are gradually excluded from the air-water interface into a surface-associated surfactant reservoir. However, detailed experimental evidence of the squeeze-out within the physiologically relevant high surface pressure range is still lacking. In the present work, we studied four animal-derived clinical surfactant preparations, including Survanta, Curosurf, Infasurf, and BLES. By comparing compression isotherms and lateral structures of these surfactant films obtained by atomic force microscopy within the physiologically relevant high surface pressure range, we have derived an updated squeeze-out model. Our model suggests that the squeeze-out originates from fluid phases of a phase-separated monolayer. The squeeze-out process follows a nucleation-growth model and only occurs within a narrow surface pressure range around the equilibrium spreading pressure of lung surfactant. After the squeeze-out, three-dimensional nuclei stop growing, thereby resulting in a DPPC-enriched interfacial monolayer to reduce the air-water surface tension to very low values., (© 2011 American Chemical Society)

In the lungs, oxygen transfer from the inspired air to the capillary blood needs to cross the surfactant lining layer of the alveoli. Therefore, the gas transfer characteristics of lung surfactant film are of fundamental physiological interest. However, previous in vitro studies-most relied on the Langmuir-type balance-fail to cover the low surface tension range (i.e., less than the equilibrium surface tension of approximately 25 mJ/m2) due to film leakage. We have recently developed a novel in vitro experimental strategy, the combination of axisymmetric drop shape analysis and captive bubble technique (ADSA-CB), in studying the effect of surfactant films on interfacial gas transfer (Langmuir 2005, 21, 5446). In the present work, ADSA-CB is used as a micro-film-balance to study the effect of compressed bovine lipid extract surfactant (BLES) films on oxygen transfer. A low surface tension ranging from approximately 25 mJ/m2 to 2 mJ/m2 is studied. The experimental results suggest that lung surfactant films at a low surface tension near 2 mJ/m2 provide resistance to oxygen transfer, as indicated by a decrease of 30-50% in the mass transfer coefficient (kL) of oxygen in BLES suspensions with respect to water. At higher surface tension (i.e., >6 mJ/m2), the resistance to oxygen transfer is only modest, i.e., the decrease in kL is less than 20% compared to water. The experimental results suggest that lung surfactant plays a role in oxygen transfer in the pulmonary system.

The in vitro adsorption kinetics of lung surfactant at air-water interfaces is affected by both the composition of the surfactant preparations and the conditions under which the assessment is conducted. Relevant experimental conditions are surfactant concentration, temperature, subphase pH, electrolyte concentration, humidity, and gas composition of the atmosphere exposed to the interface. The effect of humidity on the adsorption kinetics of a therapeutic lung surfactant preparation, bovine lipid extract surfactant (BLES), was studied by measuring the dynamic surface tension (DST). Axisymmetric drop shape analysis (ADSA) was used in conjunction with three different experimental methodologies, i.e., captive bubble (CB), pendant drop (PD), and constrained sessile drop (CSD), to measure the DST. The experimental results obtained from these three methodologies show that for 100% relative humidity (RH) at 37 degrees C the rate of adsorption of BLES at an air-water interface is substantially slower than for low humidity. It is also found that there is a difference in the rate of surface tension decrease measured from the PD and CB/CSD methods. These experimental results agree well with an adsorption model that considers the combined effects of entropic force, electrostatic interaction, and gravity. These findings have implications for the development and evaluation of new formulations for surfactant replacement therapy.

A new method combining axisymmetric drop shape analysis (ADSA) and a captive bubble (CB) is proposed to study the effect of surfactant on interfacial gas transfer. In this method, gas transfer from a static CB to the surrounding quiescent liquid is continuously recorded for a short period (i.e., 5 min). By photographical analysis, ADSA-CB is capable of yielding detailed information pertinent to the surface tension and geometry of the CB, e.g., bubble area, volume, curvature at the apex, and the contact radius and height of the bubble. A steady-state mass transfer model is established to evaluate the mass transfer coefficient on the basis of the output of ADSA-CB. In this way, we are able to develop a working prototype capable of simultaneously measuring dynamic surface tension and interfacial gas transfer. Other advantages of this method are that it allows for the study of very low surface tensions (<5 mJ/m2) and does not require equilibrium of gas transfer. Consequently, reproducible experimental results can be obtained in a relatively short time. As a demonstration, this method was used to study the effect of lung surfactant on oxygen transfer. It was found that the adsorbed lung surfactant film shows a retardation effect on oxygen transfer, similar to the behavior of a pure DPPC film. However, this retardation effect at low surface tensions is less than that of a pure DPPC film.