Aisha Qi

Interfacial destabilization and atomization driven by surface acoustic waves

Surface acoustic wave atomization is a rapid means for generating micron and submicron aerosol droplets. Little, however, is understood about the mechanisms by which these droplets form due to the complex hydrodynamic processes that occur across widely varying length and time scales. Through experiments, scaling theory, and simple numerical modeling, we elucidate the interfacial destabilization mechanisms that lead to droplet formation. Using a millimeter-order fluid drop exposed to surface acoustic waves as it sits atop a single-crystal lithium niobate piezoelectric substrate, large aerosol droplets on the length scale of the parent drop dimension are ejected through a whipping and pinch-off phenomenon, which occurs at the asymmetrically formed crest of the drop due to leakage of acoustic radiation at the Rayleigh angle. Smaller micron order droplets, on the other hand, are formed due to the axisymmetric breakup of cylindrical liquid jets that are ejected as a consequence of interfacial destabilization. ...

Template-free synthesis and encapsulation technique for layer-by-layer polymer nanocarrier fabrication

The encapsulation of therapeutic molecules within multiple layers of biocompatible and biodegradable polymeric excipients allows exquisite design of their release profile, to the extent the drug can be selectively delivered to a specific target location in vivo. Here, we develop a novel technique for the assembly of multilayer polyelectrolyte nanocarriers based on surface acoustic wave atomization as a rapid and efficient alternative to conventional layer-by-layer assembly, which requires the use of a sacrificial colloidal template over which consecutive polyelectrolyte layers are deposited. Polymer nanocarriers are synthesized by atomizing a polymer solution and suspending them within a complementary polymer solution of opposite charge subsequent to their solidification in-flight as the solvent evaporates; reatomizing this suspension produces nanocarriers with a layer of the second polymer deposited over the initial polymer core. Successive atomization-suspension layering steps can then be repeated to produce as many additional layers as desired. Specifically, we synthesize nanocarriers comprising two and three, and up to eight, alternating layers of chitosan (or polyethyleneimine) and carboxymethyl cellulose within which plasmid DNA is encapsulated and show in vitro DNA release profiles over several days. Evidence that the plasmids viability is preserved and hence the potential of the technique for gene delivery is illustrated through efficient in vitro transfection of the encapsulated plasmid in human mesenchymal progenitor and COS-7 cells.

Effective pulmonary delivery of an aerosolized plasmid DNA vaccine via surface acoustic wave nebulization

BackgroundPulmonary-delivered gene therapy promises to mitigate vaccine safety issues and reduce the need for needles and skilled personnel to use them. While plasmid DNA (pDNA) offers a rapid route to vaccine production without side effects or reliance on cold chain storage, its delivery to the lung has proved challenging. Conventional methods, including jet and ultrasonic nebulizers, fail to deliver large biomolecules like pDNA intact due to the shear and cavitational stresses present during nebulization.MethodsIn vitro structural analysis followed by in vivo protein expression studies served in assessing the integrity of the pDNA subjected to surface acoustic wave (SAW) nebulisation. In vivo immunization trials were then carried out in rats using SAW nebulized pDNA (influenza A, human hemagglutinin H1N1) condensate delivered via intratracheal instillation. Finally, in vivo pulmonary vaccinations using pDNA for influenza was nebulized and delivered via a respirator to sheep.ResultsThe SAW nebulizer was effective at generating pDNA aerosols with sizes optimal for deep lung delivery. Successful gene expression was observed in mouse lung epithelial cells, when SAW-nebulized pDNA was delivered to male Swiss mice via intratracheal instillation. Effective systemic and mucosal antibody responses were found in rats via post-nebulized, condensed fluid instillation. Significantly, we demonstrated the suitability of the SAW nebulizer to administer unprotected pDNA encoding an influenza A virus surface glycoprotein to respirated sheep via aerosolized inhalation.ConclusionGiven the difficulty of inducing functional antibody responses for DNA vaccination in large animals, we report here the first instance of successful aerosolized inhalation delivery of a pDNA vaccine in a large animal model relevant to human lung development, structure, physiology, and disease, using a novel, low-power (<1 W) surface acoustic wave (SAW) hand-held nebulizer to produce droplets of pDNA with a size range suitable for delivery to the lower respiratory airways.

Pulmonary monoclonal antibody delivery via a portable microfluidic nebulization platform

Nebulizers have considerable advantages over conventional inhalers for pulmonary drug administration, particularly because they do not require coordinated breath actuation to generate and deliver the aerosols. Nevertheless, besides being less amenable to miniaturization and hence portability, some nebulizers are prone to denature macromolecular drugs due to the large forces generated during aerosolization. Here, we demonstrate a novel portable acoustomicrofluidic device capable of nebulizing epidermal growth factor receptor (EGFR) monoclonal antibodies into a fine aerosol mist with a mass median aerodynamic diameter of approximately 1.1 μm, optimal for deep lung deposition via inhalation. The nebulized monoclonal antibodies were tested for their stability, immunoactivity, and pharmacological properties, which confirmed that nebulization did not cause significant degradation of the antibody. In particular, flow cytometry demonstrated that the antigen binding capability of the antibody is retained and able to reduce phosphorylation in cells overexpressing the EGFR, indicating that the aerosols generated by the device were loaded with stable and active monoclonal antibodies. The delivery of antibodies via inhalation, particularly for the treatment of lung cancer, is thus expected to enhance the efficacy of this protein therapeutic by increasing the local concentration where they are needed.

Precise drop dispensation on superhydrophobic surfaces using acoustic nebulization

The adhesion forces of liquid drops on superhydrophobic surfaces are typically in the nano-Newton range which presents problems in their dispensation from pipettes. Furthermore, since the liquid adheres more strongly to the pipette tip, some portion of the liquid will tend to remain on the tip, causing inaccuracy in the volume dispensed. We advance a novel approach here, in which the spray from an acoustic nebulizer is sent to a superhydrophobic receptacle and the volume ascertained precisely using a weighing scale. The superhydrophobic surface was identified to develop via a galvanic displacement mechanism in an electroless deposition process. A time dependent morphology change from granular to dendritic with longer immersion into the silver nitrate solution was found which indicated that granular growth beyond a certain size was not feasible, although granular structures were more preferentially formed just after nucleation. The dendritic structure formation was likely due to the natural tendency of the process to maintain or increase the surface area to volume ratio in order not to limit the rate of deposition. An immersion for at least 7 seconds into the silver nitrate solution, when the granular structures were predominant, was all that was needed to ensure superhydrophobicity of the surfaces. Also, the superhydrophobic state required not just significant numbers of the granular structures to be present but also interrupted coverage on the surface. On using the technique, a single drop was created by subsequently covering the receptacle with a lid and shaking it gently. The volume dispensed was found to vary linearly with the operation time of the nebulizer. We elucidated the observed increased ability of drops to reside on inclines using wetting mechanics and presented an elementary mathematical description of the extent of aerosol coverage on the surface, which has implications for the mechanics of aerosol growth into drops. The structural changes in enhanced green fluorescent protein (EGFP) observed after acoustic dispensation necessitated all samples in a fluorimetric assay to involve equal nebulized volumes of the fluorescent protein marker for measurement consistency.

Hydroxypropyl Cellulose Methacrylate as a Photo-Patternable and Biodegradable Hybrid Paper Substrate for Cell Culture and Other Bioapplications

In addition to the choice of appropriate material properties of the tissue construct to be used, such as its biocompatibility, biodegradability, cytocompatibility, and mechanical rigidity, the ability to incorporate microarchitectural patterns in the construct to mimic that found in the cellular microenvironment is an important consideration in tissue engineering and regenerative medicine. Both these issues are addressed by demonstrating a method for preparing biodegradable and photo-patternable constructs, where modified cellulose is cross-linked to form an insoluble structure in an aqueous environment. Specifically, hydroxypropyl cellulose (HPC) is rendered photocrosslinkable by grafting with methylacrylic anhydride, whose linkages also render the cross-linked construct hydrolytically degradable. The HPC is then cross-linked via a photolithography-based fabrication process. The feasibility of functionalizing these HPC structures with biochemical cues is verified post-fabrication, and shown to facilitate the adhesion of mesenchymal progenitor cells. The HPC constructs are shown to be biocompatible and hydrolytically degradable, thus enabling cell proliferation and cell migration, and therefore constituting an ideal candidate for long-term cell culture and implantable tissue scaffold applications. In addition, the potential of the HPC structure is demonstrated as an alternative substrate to paper microfluidic diagnostic devices for protein and cell assays.

Investigation of SAW atomization

Surface acoustic wave atomization is promising in various kinds of industrial and pharmaceutical processes. In order to properly apply this technology for a wide range of applications, controlling the aerosol size distribution is crucial. It is widely believed that the aerosol size can be controlled by the driving frequency, our experimental results, show a rather weak frequency dependence, especially when the driving frequency is above 10 MHz. Fundamental studies were therefore carried out to determine the underlying mechanism associated with the destabilization of the liquid interface leading towards atomization with the objective of elucidating this apparent contradiction. Our investigation supports the notion that the droplet sizes appear to be governed by the capillary vibration frequency given by a balance between the capillary stress and viscous forcing, not the driving frequency as previously claimed. Furthermore, the aerosol size can be altered by controlling the surface tension and viscosity. For this case, we employ the laser diffraction to obtain the size distributions of octanol aerosol and water aerosol generated by SAWatomization. The experimental results matches our theocratical prediction that water, with higher surface tension and lower viscosity, generates relatively larger aerosols than octanol.

SAW atomization application on inhaled pulmonary drug delivery

Pulmonary drug delivery transports the drug formulations directly to the respiratory tract in the form of inhaled particles or droplets. Because of the direct target treatment, it has significant advantages in the treatment of respiratory diseases, for example asthma. However, it is difficult to produce monodispersed particles/droplets in the 1-10 micron range, which is necessary for deposition in the targeted lung area or lower respiratory airways, in a controllable fashion. We demonstrate the use of surface acoustic waves (SAWs) as an efficient method for the generation of monodispersed micron dimension aerosols for the treatment of asthma. SAWs are ten nanometer order amplitude electroacoustic waves generated by applying an oscillating electric field to an interdigital transducer patterned on a piezoelectric substrate. The acoustic energy in the waves induces atomization of the working fluid, which contains a model drug, albuterol. Laser diffraction techniques employed to characterize the aerosols revealed mean diameter of the aerosol was around 3-4 μm. Parallel experiments employing a one-stage (glass) twin impinger as a lung model demonstrated a nearly 80% of atomized drug aerosol was deposited in the lung. The aerosol size distribution is relatively independent of the SAW frequency, which is consistent with our predictive scaling theory which accounts for the dominant balance between viscous and capillary stresses. Moreover, only 1-3 W powers consumption of SAW atomization suggests that the SAW atomizer can be miniaturized into dimensions commensurate with portable consumer devices.

A miniaturized surface acoustic wave atomizer with a disposable pump-free liquid supply system for continuous atomization

Surface acoustic wave (SAW) atomization has been found to be a rapid and efficient way for generating micron or submicron aerosols within a controllable fashion. The SAW atomizer is small and light-weighted, attractive for many applications, especially for pulmonary drug delivery and biomicrofluidics. Control the sizes of the aerosols generated by SAW is crucial for successful applications. Unlike the theory applied and published in many SAW atomization works—the size of the aerosol can be tuned by manipulating the driving frequency; —we however found the aerosol size is irrelevant to the driving frequency, but governed by the capillary vibration frequency given by the balance between the acoustic forcing and capillary stress. The self-pumping effect of SAW, on the other hand, leads to the design of a disposable pump-free liquid supply system, which is able to deliver liquids to atomizer automatically for continuous atomization.

Evaporative Self-Assembly of Gold Nanorings via a Surface Acoustic Wave Atomization

Ring of close packed gold nanoparticle arrays offers many fascinating properties that are not found in others assembly patterns. One of the most fantastic features of this unique organization is its ability to reroute shorter wavelengths of light in the visible region of electromagnetic spectrum, making it a very promising nanophotonic components for guiding light at the true nanoscale. Also, the creation of ring with gold nanoparticles can be used to make the worlds smallest biosensors possible for multiple disease detection. Herein, we demonstrate a new paradigm for generating rings of CTAB-capped gold nanorods with the implementation of surface acoustic wave (SAW) atomization. With the ultrafast microfluidics actuation, the SAW atomizer can rapidly generate submicron fluids and efficiently form ring arrays onto desired substrates in less than 1s via the evaporative self-assembly process. The technique is able to provide a rational control over the of microfluids size distributions to engineer the smaller monodisperse rings arrays at micrometer scale. This microfluidics-assisted evaporative self assembly approach is also applicable to DNA-capped gold nanoparticles. The non-uniform mass distribution of ring is formed upon the pinning of contact line to substrates during a far-fromequilibrium dewetting process. Our method opens an avenue towards the ring assembly of gold nanoparticles in their ultimate microscopic minimal threshold to facilitate the generation of metamaterials.