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Ultrasound-responsive agents have shown great potential as targeted drug delivery agents, effectively augmenting cell permeability and facilitating drug absorption. This review focuses on two specific agents, microbubbles and nanodroplets, and provides a sequential overview of their drug delivery process. Particular emphasis is given to the mechanical response of the agents under ultrasound, and the subsequent physical and biological effects on the cells. Finally, the state-of-the-art in their pre-clinical and clinical implementation are discussed. Throughout the review, major challenges that need to be overcome in order to accelerate their clinical translation are highlighted.

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Vaporizable endoskeletal droplets are solid hydrocarbons in liquid fluorocarbon droplets in which melting of the hydrocarbon phase leads to the vaporization of the fluorocarbon phase. In prior work, vaporization of the endoskeletal droplets was achieved thermally by heating the surrounding aqueous medium. In this work, we introduce a near-infrared (NIR) optically absorbing naphthalocyanine dye (zinc 2,11,20,29-tetra-tert-butyl-2,3-naphthalocynanine) into the solid hydrocarbon (eicosane, n-C20H42) core of liquid fluorocarbon (C5F12) drops suspended in an aqueous medium. Droplets with a uniform diameter of 11.7 ± 0.7 µm were formed using a flow-focusing microfluidic device. The solid hydrocarbon formed a crumpled spherical structure within the liquid fluorocarbon droplet. The photoactivation behavior of these dye-containing endoskeletal droplets was investigated using NIR laser irradiation. When exposed to a pulsed laser of 720 nm wavelength, the dye-containing droplets vaporized at an average laser fluence of 65 mJ/cm2, whereas blank droplets without the dye did not vaporize at any fluence up to 100 mJ/cm2. Furthermore, dye-loaded droplets with a smaller, polydisperse size distribution were prepared using a simple shaking method and studied in a flow phantom for their photoacoustic signal and ultrasound contrast imaging. These results demonstrate that dye-containing endoskeletal droplets can be made to vaporize by externally applied optical energy. Such droplets may be useful for a variety of photoacoustic applications for sensing, imaging, and therapy.

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Vaporizable hydrocarbon-in-fluorocarbon endoskeletal droplets are a unique category of phase-change emulsions with interesting physical and thermodynamic features. Here, we show microfluidic fabrication of various morphologies, such as solid-in-liquid, liquid-in-solid, and Janus-type, of complex solid n-C20H42 or n-C21H44 and liquid n-C5F12 droplets. Furthermore, we investigated the vaporization behavior of these endoskeletal droplets, focusing on the effects of heat treatment and core size. Comparison of vaporization and differential scanning calorimetry results indicated that vaporization occurs prior to melting of the bulk hydrocarbon phase for C20H42/C5F10 droplets and near the rotator phase for C21H44/C5F10 droplets. We found that heat treatment of the droplets increased the fraction of droplets that vaporized and also increased the vaporization temperature of the droplets, although the effect was temporary. Furthermore, we found that changing the relative size of the solid hydrocarbon core compared to the surrounding liquid shell increased the vaporization temperature and the vaporizing fraction. Taken together, these data support the hypothesis that surface melting behavior exhibited by the linear alkane may trigger the fluorocarbon vaporization event. These results may aid in the understanding of the interfacial thermodynamics and transport and the engineering of novel vaporizable endoskeletal droplets for biomedical imaging and other applications.

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Manipulation of micro/nano particles has been well studied and demonstrated by optical, electromagnetic, and acoustic approaches, or their combinations. Manipulation of internal structure of droplet/particle is rarely explored and remains challenging due to its complicated nature. Here we demonstrated the manipulation of internal structure of disk-in-sphere endoskeletal droplets using acoustic wave. We developed a model to investigate the physical mechanisms behind this interesting phenomenon. Theoretical analysis of the acoustic interactions indicated that these assembly dynamics arise from a balance of the primary and secondary radiation forces. Additionally, the disk orientation was found to change with acoustic driving frequency, which allowed on-demand, reversible adjustment of the disk orientations with respect to the substrate. This dynamic behavior leads to unique reversible arrangements of the endoskeletal droplets and their internal architecture, which may provide an avenue for directed assembly of novel hierarchical colloidal architectures and intracellular organelles or intra-organoid structures.

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Manipulation of fluid flow is paramount for microfluidic device operation. Conventional microfluidic pumps are often expensive, bulky, complicated, and not amenable in limited resource settings. Here, we introduce a Fully self-sufficient, RobUst, Gravity-Assisted, Low-cost (FRUGAL) microfluidic pump. The pump consists of a syringe, a syringe holder and loading masses. The system is easy to assemble, inexpensive, portable, and electrical power-free. Inside the syringe, the fluid is driven by the pressure from the weight of the loading masses. During operation, the exerted pressure is dynamically controllable and stable for hours. These features are useful for optimization of microfluidics assays and dynamic temporal studies. We demonstrate the application of this system to control the formation of water-in-oil droplet emulsion. Benefitting from its simplicity and versatility, the frugal microfluidic pump will enable global adoption of microfluidic technology in chemistry and biomedical applications, especially in limited resource environments.

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Acoustic nanodrops are designed to vaporize into ultrasound-responsive microbubbles, which presents certain challenges nonexistent for conventional nano-emulsions. The requirements of biocompatibility, vaporizability and colloidal stability has focused research on perfluorocarbons (PFCs). Shorter PFCs yield better vaporizability via their lower critical temperature, but they also dissolve more easily owing to their higher vapor pressure and solubility. Thus, acoustic nanodrops have required a tradeoff between vaporizability and colloidal stability in vivo. The recent advent of vaporizable endoskeletal droplets, which are both stable and vaporizable, may have solved this problem. The purpose of this review is to justify this premise by pointing out the beneficial properties of acoustic nanodrops, providing an analysis of vaporization and dissolution mechanisms, and reviewing current biomedical applications.

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Liquid emulsion droplet evaporation is of importance for various sensing and imaging applications. The liquid-to-gas phase transformation is typically triggered thermally or acoustically by low-boiling point liquids, or by inclusion of solid structures that pin the vapor/liquid contact line to facilitate heterogeneous nucleation. However, these approaches lack precise tunability in vaporization behavior. Here, we describe a previously unused approach to control vaporization behavior through an endoskeleton that can melt and blend into the liquid core to either enhance or disrupt cohesive intermolecular forces. This effect is demonstrated using perfluoropentane (C5F12) droplets encapsulating a fluorocarbon (FC) or hydrocarbon (HC) endoskeleton. FC skeletons inhibit vaporization, whereas HC skeletons trigger vaporization near the rotator melting transition. Our findings highlight the importance of skeletal interfacial mixing for initiating droplet vaporization. Tuning molecular interactions between the endoskeleton and droplet phase is generalizable for achieving emulsion or other secondary phase transitions, in emulsions.