@article{arena_novell_sheeran_puett_moyer_dayton_2015, title={Dual-Frequency Acoustic Droplet Vaporization Detection for Medical Imaging}, volume={62}, ISSN={["1525-8955"]}, DOI={10.1109/tuffc.2014.006883}, abstractNote={Liquid-filled perfluorocarbon droplets emit a unique acoustic signature when vaporized into gas-filled microbubbles using ultrasound. Here, we conducted a pilot study in a tissue-mimicking flow phantom to explore the spatial aspects of droplet vaporization and investigate the effects of applied pressure and droplet concentration on image contrast and axial and lateral resolution. Control microbubble contrast agents were used for comparison. A confocal dual-frequency transducer was used to transmit at 8 MHz and passively receive at 1 MHz. Droplet signals were of significantly higher energy than microbubble signals. This resulted in improved signal separation and high contrast-to-tissue ratios (CTR). Specifically, with a peak negative pressure (PNP) of 450 kPa applied at the focus, the CTR of B-mode images was 18.3 dB for droplets and -0.4 for microbubbles. The lateral resolution was dictated by the size of the droplet activation area, with lower pressures resulting in smaller activation areas and improved lateral resolution (0.67 mm at 450 kPa). The axial resolution in droplet images was dictated by the size of the initial droplet and was independent of the properties of the transmit pulse (3.86 mm at 450 kPa). In post-processing, time-domain averaging (TDA) improved droplet and microbubble signal separation at high pressures (640 kPa and 700 kPa). Taken together, these results indicate that it is possible to generate high-sensitivity, high-contrast images of vaporization events. In the future, this has the potential to be applied in combination with dropletmediated therapy to track treatment outcomes or as a standalone diagnostic system to monitor the physical properties of the surrounding environment.}, number={9}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Arena, Christopher B. and Novell, Anthony and Sheeran, Paul S. and Puett, Connor and Moyer, Linsey C. and Dayton, Paul A.}, year={2015}, month={Sep}, pages={1623–1633} }
 @article{doinikov_bouakaz_sheeran_dayton_2014, title={Dynamics of volatile phase-change contrast agents: Theoretical model and experimental measurements}, ISSN={["1948-5719"]}, DOI={10.1109/ultsym.2014.0566}, abstractNote={Interest in perfluorocarbon (PFC) phase-change contrast agents (PCCAs) is motivated by the fact that they can be triggered to transition from the liquid state to the gas state by an externally applied acoustic pulse. This property opens up new approaches to ultrasound imaging and therapy. Insight into the physics of this process is vital for effective use of PCCAs and for anticipating bioeffects. Our paper reports on the development of a new theoretical model that describes the conversion of a PFC droplet into a vapor bubble and subsequent bubble evolution. The development of the model was specifically aimed at exploring the complex behavior which is demonstrated experimentally by volatile PFC droplets with low boiling points but has not been well-described theoretically so far. The model is validated by comparison with in vitro experimental data acquired by ultra-high-speed video microscopy for decafluorobutane (DFB) and octafluoropropane (OFP) microdroplets of different sizes.}, journal={2014 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS)}, author={Doinikov, Alexander A. and Bouakaz, Ayache and Sheeran, Paul S. and Dayton, Paul A.}, year={2014}, pages={2273–2276} }
 @article{sheeran_rojas_puett_hjelmquist_arena_dayton_2014, title={In Vivo Quantification of Image Enhancement and Circulation Kinetics for Phase Change Perfluorocarbon Agents Using Custom Pulse Sequences}, ISSN={["1948-5719"]}, DOI={10.1109/ultsym.2014.0103}, abstractNote={Few investigations have been published demonstrating the in vivo contrast characteristics of phase-change perfluorocarbon droplets. In this study, we examine the properties of low boiling point nanoscale droplets compared to microbubbles with respect to image enhancement and circulation time. To accomplish this, we develop a custom pulse sequence to vaporize and image droplets using the Verasonics research platform. Results show that droplets can produce similar contrast compared to microbubbles, and can circulate for significantly longer than microbubbles, depending on formulation. Finally, this study demonstrates a novel concept in contrast-enhanced ultrasound: capture of droplet-generated contrast wash-out in the target organ.}, journal={2014 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS)}, author={Sheeran, Paul S. and Rojas, Juan D. and Puett, Connor and Hjelmquist, Jordan and Arena, Christopher B. and Dayton, Paul A.}, year={2014}, pages={417–420} }
 @article{sheeran_matsunaga_dayton_2014, title={Phase change events of volatile liquid perfluorocarbon contrast agents produce unique acoustic signatures}, volume={59}, ISSN={["1361-6560"]}, DOI={10.1088/0031-9155/59/2/379}, abstractNote={Phase-change contrast agents (PCCAs) provide a dynamic platform to approach problems in medical ultrasound (US). Upon US-mediated activation, the liquid core vaporizes and expands to produce a gas bubble ideal for US imaging and therapy. In this study, we demonstrate through high-speed video microscopy and US interrogation that PCCAs composed of highly volatile perfluorocarbons (PFCs) exhibit unique acoustic behavior that can be detected and differentiated from standard microbubble contrast agents. Experimental results show that when activated with short pulses PCCAs will over-expand and undergo unforced radial oscillation while settling to a final bubble diameter. The size-dependent oscillation phenomenon generates a unique acoustic signal that can be passively detected in both time and frequency domain using confocal piston transducers with an ‘activate high’ (8 MHz, 2 cycles), ‘listen low’ (1 MHz) scheme. Results show that the magnitude of the acoustic ‘signature’ increases as PFC boiling point decreases. By using a band-limited spectral processing technique, the droplet signals can be isolated from controls and used to build experimental relationships between concentration and vaporization pressure. The techniques shown here may be useful for physical studies as well as development of droplet-specific imaging techniques.}, number={2}, journal={PHYSICS IN MEDICINE AND BIOLOGY}, author={Sheeran, Paul S. and Matsunaga, Terry O. and Dayton, Paul A.}, year={2014}, month={Jan}, pages={379–401} }
 @article{arena_novell_sheeran_puett_phillips_dayton_2014, title={Ultrasound Imaging from Vaporization Signals Emitted by Phase Change Contrast Agents}, ISSN={["1948-5719"]}, DOI={10.1109/ultsym.2014.0441}, abstractNote={Phase change contrast agents (PCCAs) exhibit a unique acoustic signature during the transition from a liquid droplet to a gas microbubble. Here, we demonstrate that this event can be used to generate an ultrasound image, and that the signal can be separated from that of a conventional microbubble. This presents a new opportunity to monitor PCCA activation in both diagnostic and therapeutic applications. A confocal, dual-frequency transducer was used to transmit 2 cycle, Gaussian enveloped sinusoids at 8 MHz and passively receive at 1 MHz. PCCAs were continuously infused through a microcellulose tube (250 μm diameter). At low pressures, vaporization signals from PCCAs were of significantly higher energy than signals emitted from the equivalent microbubble formulation. Specifically, when a peak negative pressure (PNP) of 0.51 MPa was transmitted, the contrast-to-noise ratio (CNR) was 18.94 dB for PCCAs and 2.28 dB for control microbubbles. As the PNP was increased to 0.76 MPa, these values changed to 22.1 dB and 9.73 dB, respectively. Time-domain averaging (TDA) helped to increase the separation of PCCA and microbubble signals. After TDA, the CNR at 0.76 MPa was 23.79 dB for PCCAs and 1.72 dB for microbubbles. The lateral resolution of the system was pressure dependent. With increasing pressure, the apparent diameter of the tube increased from 0.74 mm at 0.51 MPa to 1.14 mm at 0.76 MPa. This is due to the fact that the focal zone capable of activating PCCAs expands with increasing pressure.}, journal={2014 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS)}, author={Arena, Christopher B. and Novell, Anthony and Sheeran, Paul S. and Puett, Connor and Phillips, Linsey C. and Dayton, Paul A.}, year={2014}, pages={1778–1781} }
 @article{doinikov_sheeran_bouakaz_dayton_2014, title={Vaporization dynamics of volatile perfluorocarbon droplets: A theoretical model and in vitro validation}, volume={41}, ISSN={["0094-2405"]}, DOI={10.1118/1.4894804}, abstractNote={PURPOSE
Perfluorocarbon (PFC) microdroplets, called phase-change contrast agents (PCCAs), are a promising tool in ultrasound imaging and therapy. Interest in PCCAs is motivated by the fact that they can be triggered to transition from the liquid state to the gas state by an externally applied acoustic pulse. This property opens up new approaches to applications in ultrasound medicine. Insight into the physics of vaporization of PFC droplets is vital for effective use of PCCAs and for anticipating bioeffects. PCCAs composed of volatile PFCs (with low boiling point) exhibit complex dynamic behavior: after vaporization by a short acoustic pulse, a PFC droplet turns into a vapor bubble which undergoes overexpansion and damped radial oscillation until settling to a final diameter. This behavior has not been well described theoretically so far. The purpose of our study is to develop an improved theoretical model that describes the vaporization dynamics of volatile PFC droplets and to validate this model by comparison with in vitro experimental data.


METHODS
The derivation of the model is based on applying the mathematical methods of fluid dynamics and thermodynamics to the process of the acoustic vaporization of PFC droplets. The used approach corrects shortcomings of the existing models. The validation of the model is carried out by comparing simulated results with in vitro experimental data acquired by ultrahigh speed video microscopy for octafluoropropane (OFP) and decafluorobutane (DFB) microdroplets of different sizes.


RESULTS
The developed theory allows one to simulate the growth of a vapor bubble inside a PFC droplet until the liquid PFC is completely converted into vapor, and the subsequent overexpansion and damped oscillations of the vapor bubble, including the influence of an externally applied acoustic pulse. To evaluate quantitatively the difference between simulated and experimental results, the L2-norm errors were calculated for all cases where the simulated and experimental results are compared. These errors were found to be in the ranges of 0.043-0.067 and 0.037-0.088 for OFP and DFB droplets, respectively. These values allow one to consider agreement between the simulated and experimental results as good. This agreement is attained by varying only 2 of 16 model parameters which describe the material properties of gaseous and liquid PFCs and the liquid surrounding the PFC droplet. The fitting parameters are the viscosity and the surface tension of the surrounding liquid. All other model parameters are kept invariable.


CONCLUSIONS
The good agreement between the theoretical and experimental results suggests that the developed model is able to correctly describe the key physical processes underlying the vaporization dynamics of volatile PFC droplets. The necessity of varying the parameters of the surrounding liquid for fitting the experimental curves can be explained by the fact that the parts of the initial phospholipid shell of PFC droplets remain on the surface of vapor bubbles at the oscillatory stage and their presence affects the bubble dynamics.}, number={10}, journal={MEDICAL PHYSICS}, author={Doinikov, Alexander A. and Sheeran, Paul S. and Bouakaz, Ayache and Dayton, Paul A.}, year={2014}, month={Oct} }
 @article{shih_bardin_martz_sheeran_dayton_lee_2013, title={Flow-focusing regimes for accelerated production of monodisperse drug-loadable microbubbles toward clinical-scale applications}, volume={13}, ISSN={["1473-0189"]}, DOI={10.1039/c3lc51016f}, abstractNote={Ultrasound imaging often calls for the injection of contrast agents, micron-sized bubbles which echo strongly in blood and help distinguish vascularized tissue. Such microbubbles are also being augmented for targeted drug delivery and gene therapy, by the addition of surface receptors and therapeutic payloads. Unfortunately, conventional production methods yield a polydisperse population, whose nonuniform resonance and drug-loading are less than ideal. An alternative technique, microfluidic flow-focusing, is able to produce highly monodisperse microbubbles with stabilizing lipid membranes and drug-carrying oil layers. However, the published 1 kHz production rate for these uniform drug bubbles is very low compared to conventional methods, and must be improved before clinical use can be practical. In this study, flow-focusing production of oil-layered lipid microbubbles was tested up to 300 kHz, with coalescence suppressed by high lipid concentrations or inclusion of Pluronic F68 surfactant in the lipid solution. The transition between geometry-controlled and dripping production regimes was analysed, and production scaling was found to be continuous, with a power trend of exponent ~5/12 similar to literature. Unlike prior studies with this trend, however, scaling curves here were found to be pressure-dependent, particularly at lower pressure-flow equilibria (e.g. <15 psi). Adjustments in oil flow rate were observed to have a similar effect, akin to a pressure change of 1-3 psi. This analysis and characterization of high-speed dual-layer bubble generation will enable more-predictive production control, at rates practical for in vivo or clinical use.}, number={24}, journal={LAB ON A CHIP}, author={Shih, Roger and Bardin, David and Martz, Thomas D. and Sheeran, Paul S. and Dayton, Paul A. and Lee, Abraham P.}, year={2013}, pages={4816–4826} }
 @article{sheeran_matsunaga_dayton_2013, title={Phase-transition thresholds and vaporization phenomena for ultrasound phase-change nanoemulsions assessed via high-speed optical microscopy}, volume={58}, ISSN={["1361-6560"]}, DOI={10.1088/0031-9155/58/13/4513}, abstractNote={Ultrasonically activated phase-change contrast agents (PCCAs) based on perfluorocarbon droplets have been proposed for a variety of therapeutic and diagnostic clinical applications. When generated at the nanoscale, droplets may be small enough to exit the vascular space and then be induced to vaporize with high spatial and temporal specificity by externally-applied ultrasound. The use of acoustical techniques for optimizing ultrasound parameters for given applications can be a significant challenge for nanoscale PCCAs due to the contributions of larger outlier droplets. Similarly, optical techniques can be a challenge due to the sub-micron size of nanodroplet agents and resolution limits of optical microscopy. In this study, an optical method for determining activation thresholds of nanoscale emulsions based on the in vitro distribution of bubbles resulting from vaporization of PCCAs after single, short (<10 cycles) ultrasound pulses is evaluated. Through ultra-high-speed microscopy it is shown that the bubbles produced early in the pulse from vaporized droplets are strongly affected by subsequent cycles of the vaporization pulse, and these effects increase with pulse length. Results show that decafluorobutane nanoemulsions with peak diameters on the order of 200 nm can be optimally vaporized with short pulses using pressures amenable to clinical diagnostic ultrasound machines.}, number={13}, journal={PHYSICS IN MEDICINE AND BIOLOGY}, author={Sheeran, Paul S. and Matsunaga, Terry O. and Dayton, Paul A.}, year={2013}, month={Jul}, pages={4513–4534} }
 @article{sheeran_streeter_mullin_matsunaga_dayton_2013, title={TOWARD ULTRASOUND MOLECULAR IMAGING WITH PHASE-CHANGE CONTRAST AGENTS: AN IN VITRO PROOF OF PRINCIPLE}, volume={39}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2012.11.017}, abstractNote={Phase-change contrast agents (PCCAs), which normally consist of nanoscale or microscale droplets of liquid perfluorocarbons in an encapsulating shell, can be triggered to undergo a phase transition to the highly echogenic gaseous state upon the input of sufficient acoustic energy. As a result of the subsequent volumetric expansion, a number of unique applications have emerged that are not possible with traditional ultrasound microbubble contrast agents. Although many studies have explored the therapeutic aspects of the PCCA platform, few have examined the potential of PCCAs for molecular imaging purposes. In this study, we demonstrate a PCCA-based platform for molecular imaging using α(v)β(3)-targeted nanoscale PCCAs composed of low-boiling-point perfluorocarbons. In vitro, nanoscale PCCAs adhered to target cells, could be activated and imaged with a clinical ultrasound system and produced a six-fold increase in image contrast compared with non-targeted control PCCAs and a greater than fifty-fold increase over baseline. Data suggest that low-boiling-point nanoscale PCCAs could enable future ultrasound-based molecular imaging techniques in both the vascular and extravascular spaces.}, number={5}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Sheeran, Paul S. and Streeter, Jason E. and Mullin, Lee B. and Matsunaga, Terry O. and Dayton, Paul A.}, year={2013}, month={May}, pages={893–902} }
 @article{chen_sheeran_wu_olumolade_dayton_konofagou_2013, title={Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets}, volume={172}, ISSN={["1873-4995"]}, DOI={10.1016/j.jconrel.2013.09.025}, abstractNote={Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood-brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature.}, number={3}, journal={JOURNAL OF CONTROLLED RELEASE}, author={Chen, Cherry C. and Sheeran, Paul S. and Wu, Shih-Ying and Olumolade, Oluyemi O. and Dayton, Paul A. and Konofagou, Elisa E.}, year={2013}, month={Dec}, pages={795–804} }
 @article{sheeran_luois_mullin_matsunaga_dayton_2012, title={Design of ultrasonically-activatable nanoparticles using low boiling point perfluorocarbons}, volume={33}, ISSN={["1878-5905"]}, DOI={10.1016/j.biomaterials.2012.01.021}, abstractNote={Recently, an interest has developed in designing biomaterials for medical ultrasonics that can provide the acoustic activity of microbubbles, but with improved stability in vivo and a smaller size distribution for extravascular interrogation. One proposed alternative is the phase-change contrast agent. Phase-change contrast agents (PCCAs) consist of perfluorocarbons (PFCs) that are initially in liquid form, but can then be vaporized with acoustic energy. Crucial parameters for PCCAs include their sensitivity to acoustic energy, their size distribution, and their stability, and this manuscript provides insight into the custom design of PCCAs for balancing these parameters. Specifically, the relationship between size, thermal stability and sensitivity to ultrasound as a function of PFC boiling point and ambient temperature is illustrated. Emulsion stability and sensitivity can be 'tuned' by mixing PFCs in the gaseous state prior to condensation. Novel observations illustrate that stable droplets can be generated from PFCs with extremely low boiling points, such as octafluoropropane (b.p. -36.7 °C), which can be vaporized with acoustic parameters lower than previously observed. Results demonstrate the potential for low boiling point PFCs as a useful new class of compounds for activatable agents, which can be tailored to the desired application.}, number={11}, journal={BIOMATERIALS}, author={Sheeran, Paul S. and Luois, Samantha H. and Mullin, Lee B. and Matsunaga, Terry O. and Dayton, Paul A.}, year={2012}, month={Apr}, pages={3262–3269} }
 @article{martz_bardin_sheeran_lee_dayton_2012, title={Microfluidic Generation of Acoustically Active Nanodroplets}, volume={8}, ISSN={["1613-6810"]}, DOI={10.1002/smll.201102418}, abstractNote={A microfluidic approach for the generation of perfluorocarbon nanodroplets as the primary emulsion with diameters as small as 300-400 nm is described. The system uses a pressure-controlled delivery of all reagents and increased viscosity in the continuous phase to drive the device into an advanced tip-streaming regime, which results in generation of droplets in the sub-micrometer range. Such nanodroplets may be appropriate for emerging biomedical applications.}, number={12}, journal={SMALL}, author={Martz, Thomas D. and Bardin, David and Sheeran, Paul S. and Lee, Abraham P. and Dayton, Paul A.}, year={2012}, month={Jun}, pages={1876–1879} }
 @misc{sheeran_dayton_2012, title={Phase-change contrast agents for imaging and therapy}, volume={18}, DOI={10.2174/138161212800099883}, abstractNote={Phase-change contrast agents (PCCAs) for ultrasound-based applications have resulted in novel ways of approaching diagnostic and therapeutic techniques beyond what is possible with microbubble contrast agents and liquid emulsions. When subjected to sufficient pressures delivered by an ultrasound transducer, stabilized droplets undergo a phase-transition to the gaseous state and a volumetric expansion occurs. This phenomenon, termed acoustic droplet vaporization, has been proposed as a means to address a number of in vivo applications at the microscale and nanoscale. In this review, the history of PCCAs, physical mechanisms involved, and proposed applications are discussed with a summary of studies demonstrated in vivo. Factors that influence the design of PCCAs are discussed, as well as the need for future studies to characterize potential bioeffects for administration in humans and optimization of ultrasound parameters.}, number={15}, journal={Current Pharmaceutical Design}, author={Sheeran, P. S. and Dayton, P. A.}, year={2012}, pages={2152–2165} }
 @misc{matsunaga_sheeran_luois_streeter_mullin_banerjee_dayton_2012, title={Phase-change nanoparticles using highly volatile perfluorocarbons: Toward a platform for extravascular ultrasound imaging}, volume={2}, number={12}, journal={Theranostics}, author={Matsunaga, T. O. and Sheeran, P. S. and Luois, S. and Streeter, J. E. and Mullin, L. B. and Banerjee, B. and Dayton, P. A.}, year={2012}, pages={1185–1198} }
 @article{li_sheeran_kleinstreuer_2011, title={Analysis of Multi-Layer Immiscible Fluid Flow in a Microchannel}, volume={133}, ISSN={["1528-901X"]}, DOI={10.1115/1.4005134}, abstractNote={The development of microfluidics platforms in recent years has led to an increase in the number of applications involving the flow of multiple immiscible layers of viscous electrolyte fluids. In this study, numerical results as well as analytic equations for velocity and shear stress profiles were derived for N layers with known viscosities, assuming steady laminar flow in a microchannel driven by pressure and/or electro-static (Coulomb) forces. Numerical simulation results, using a commercial software package, match analytical results for fully-developed flow. Entrance flow effects with centered fluid-layer shrinking were studied as well. Specifically, cases with larger viscosities in the inner layers show a very good agreement with experimental correlations for the dimensionless entrance length as a function of inlet Reynolds number. However, significant deviations may occur for multilayer flows with smaller viscosities in the inner layers. A correlation was deduced for the two-layer electroosmotic flow and the pressure driven flow, both being more complex when compared with single-layer flows. The impact of using power-law fluids on resulting velocity profiles has also been explored and compared to Newtonian fluid flows. The present model readily allows for an exploration of the impact of design choices on velocity profiles, shear stress, and channel distribution in multilayer microchannel flows as a function of layered viscosity distribution and type of driving force.}, number={11}, journal={JOURNAL OF FLUIDS ENGINEERING-TRANSACTIONS OF THE ASME}, author={Li, Jie and Sheeran, Paul S. and Kleinstreuer, Clement}, year={2011}, month={Nov} }
 @article{sheeran_luois_dayton_matsunaga_2011, title={Formulation and Acoustic Studies of a New Phase-Shift Agent for Diagnostic and Therapeutic Ultrasound}, volume={27}, ISSN={["0743-7463"]}, DOI={10.1021/la2013705}, abstractNote={Recent efforts in the area of acoustic droplet vaporization with the objective of designing extravascular ultrasound contrast agents has led to the development of stabilized, lipid-encapsulated nanodroplets of the highly volatile compound decafluorobutane (DFB). We developed two methods of generating DFB droplets, the first of which involves condensing DFB gas (boiling point from -1.1 to -2 °C) followed by extrusion with a lipid formulation in HEPES buffer. Acoustic droplet vaporization of micrometer-sized lipid-coated droplets at diagnostic ultrasound frequencies and mechanical indices were confirmed optically. In our second formulation methodology, we demonstrate the formulation of submicrometer-sized lipid-coated nanodroplets based upon condensation of preformed microbubbles containing DFB. The droplets are routinely in the 200-300 nm range and yield microbubbles on the order of 1-5 μm once vaporized, consistent with ideal gas law expansion predictions. The simple and effective nature of this methodology allows for the development of a variety of different formulations that can be used for imaging, drug and gene delivery, and therapy. This study is the first to our knowledge to demonstrate both a method of generating ADV agents by microbubble condensation and formulation of primarily submicrometer droplets of decafluorobutane that remain stable at physiological temperatures. Finally, activation of DFB nanodroplets is demonstrated using pressures within the FDA guidelines for diagnostic imaging, which may minimize the potential for bioeffects in humans. This methodology offers a new means of developing extravascular contrast agents for diagnostic and therapeutic applications.}, number={17}, journal={LANGMUIR}, author={Sheeran, Paul S. and Luois, Samantha and Dayton, Paul A. and Matsunaga, Terry O.}, year={2011}, month={Sep}, pages={10412–10420} }
 @article{bardin_martz_sheeran_shih_dayton_lee_2011, title={High-speed, clinical-scale microfluidic generation of stable phase-change droplets for gas embolotherapy}, volume={11}, ISSN={["1473-0197"]}, DOI={10.1039/c1lc20615j}, abstractNote={In this study we report on a microfluidic device and droplet formation regime capable of generating clinical-scale quantities of droplet emulsions suitable in size and functionality for in vivo therapeutics. By increasing the capillary number-based on the flow rate of the continuous outer phase-in our flow-focusing device, we examine three modes of droplet breakup: geometry-controlled, dripping, and jetting. Operation of our device in the dripping regime results in the generation of highly monodisperse liquid perfluoropentane droplets in the appropriate 3-6 μm range at rates exceeding 10(5) droplets per second. Based on experimental results relating droplet diameter and the ratio of the continuous and dispersed phase flow rates, we derive a power series equation, valid in the dripping regime, to predict droplet size, D(d) approximately equal 27(Q(C)/Q(D))(-5/12). The volatile droplets in this study are stable for weeks at room temperature yet undergo rapid liquid-to-gas phase transition, and volume expansion, above a uniform thermal activation threshold. The opportunity exists to potentiate locoregional cancer therapies such as thermal ablation and percutaneous ethanol injection using thermal or acoustic vaporization of these monodisperse phase-change droplets to intentionally occlude the vessels of a cancer.}, number={23}, journal={LAB ON A CHIP}, author={Bardin, David and Martz, Thomas D. and Sheeran, Paul S. and Shih, Roger and Dayton, Paul A. and Lee, Abraham P.}, year={2011}, pages={3990–3998} }
 @article{martz_sheeran_bardin_lee_dayton_2011, title={PRECISION MANUFACTURE OF PHASE-CHANGE PERFLUOROCARBON DROPLETS USING MICROFLUIDICS}, volume={37}, ISSN={["0301-5629"]}, DOI={10.1016/j.ultrasmedbio.2011.08.012}, abstractNote={Liquid perfluorocarbon droplets have been of interest in the medical acoustics community for use as acoustically activated particles for tissue occlusion, imaging and therapeutics. To date, methods to produce liquid perfluorocarbon droplets typically result in a polydisperse size distribution. Because the threshold of acoustic activation is a function of diameter, there would be benefit from a monodisperse population to preserve uniformity in acoustic activation parameters. Through use of a microfluidic device with flow-focusing technology, the production of droplets of perfluoropentane with a uniform size distribution is demonstrated. Stability studies indicate that these droplets are stable in storage for at least two weeks. Acoustic studies illustrate the thresholds of vaporization as a function of droplet diameter, and a logarithmic relationship is observed between acoustic pressure and vaporization threshold within the size ranges studied. Droplets of uniform size have very little variability in acoustic vaporization threshold. Results indicate that microfluidic technology can enable greater manufacturing control of phase-change perfluorocarbons for acoustic droplet vaporization applications.}, number={11}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Martz, Thomas D. and Sheeran, Paul S. and Bardin, David and Lee, Abraham P. and Dayton, Paul A.}, year={2011}, month={Nov}, pages={1952–1957} }