Precision manufacture of phase-change perfluorocarbon droplets using microfluidics.

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.

[1]  Paul A Dayton,et al.  Acoustic responses of monodisperse lipid-encapsulated microbubble contrast agents produced by flow focusing. , 2010, Bubble science engineering and technology.

[2]  A. Lee,et al.  Microfluidic separation of satellite droplets as the basis of a monodispersed micron and submicron emulsification system. , 2005, Lab on a chip.

[3]  Kanaka Hettiarachchi,et al.  Controllable microfluidic synthesis of multiphase drug‐carrying lipospheres for site‐targeted therapy , 2009, Biotechnology progress.

[4]  Zhong-gao Gao,et al.  Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. , 2007, Journal of the National Cancer Institute.

[5]  M. Woydt,et al.  In vivo droplet vaporization for occlusion therapy and phase aberration correction , 2002, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[6]  O. Kripfgans,et al.  Acoustic droplet vaporization threshold: effects of pulse duration and contrast agent , 2007, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[7]  Oliver D Kripfgans,et al.  Towards aberration correction of transcranial ultrasound using acoustic droplet vaporization. , 2008, Ultrasound in medicine & biology.

[8]  Paul S. Sheeran,et al.  Decafluorobutane as a phase-change contrast agent for low-energy extravascular ultrasonic imaging. , 2011, Ultrasound in medicine & biology.

[9]  Wei Wang,et al.  Controllable microfluidic production of multicomponent multiple emulsions. , 2011, Lab on a chip.

[10]  P. Carson,et al.  Acoustic droplet vaporization for temporal and spatial control of tissue occlusion: a kidney study , 2005, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[11]  T. Porter,et al.  An in vitro study of a phase-shift nanoemulsion: a potential nucleation agent for bubble-enhanced HIFU tumor ablation. , 2010, Ultrasound in medicine & biology.

[12]  Paul A Dayton,et al.  On-chip generation of microbubbles as a practical technology for manufacturing contrast agents for ultrasonic imaging. , 2007, Lab on a chip.

[13]  P. Carson,et al.  Initial investigation of acoustic droplet vaporization for occlusion in canine kidney. , 2010, Ultrasound in medicine & biology.

[14]  S. Takayama,et al.  Gravity-driven microfluidic particle sorting device with hydrodynamic separation amplification. , 2007, Analytical chemistry.

[15]  Kullervo Hynynen,et al.  Ultrasound-mediated cavitation thresholds of liquid perfluorocarbon droplets in vitro. , 2003, Ultrasound in medicine & biology.

[16]  Oliver D Kripfgans,et al.  Acoustic droplet vaporization for enhancement of thermal ablation by high intensity focused ultrasound. , 2011, Academic radiology.

[17]  D. Christensen,et al.  Microbubble Generation in Phase-Shift Nanoemulsions used as Anticancer Drug Carriers. , 2009, Bubble science engineering and technology.

[18]  Vittorio Cristini,et al.  Design of microfluidic channel geometries for the control of droplet volume, chemical concentration, and sorting. , 2004, Lab on a chip.

[19]  D. Christensen,et al.  Cavitation properties of block copolymer stabilized phase-shift nanoemulsions used as drug carriers. , 2010, Ultrasound in medicine & biology.

[20]  Paul L. Carson,et al.  Delivery of Water-Soluble Drugs Using Acoustically Triggered Perfluorocarbon Double Emulsions , 2010, Pharmaceutical Research.

[21]  J. Shea,et al.  Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[22]  G. Luo,et al.  Controllable preparation of monodisperse O/W and W/O emulsions in the same microfluidic device. , 2006, Langmuir : the ACS journal of surfaces and colloids.

[23]  G. Whitesides,et al.  Generation of monodisperse particles by using microfluidics: control over size, shape, and composition. , 2005, Angewandte Chemie.

[24]  P. Carson,et al.  The role of inertial cavitation in acoustic droplet vaporization , 2008, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[25]  Junru Wu,et al.  Bioeffects Considerations for Diagnostic Ultrasound Contrast Agents , 2008, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[26]  A. Lee,et al.  Droplet microfluidics. , 2008, Lab on a chip.

[27]  Samuel A Wickline,et al.  Molecular imaging with targeted perfluorocarbon nanoparticles: quantification of the concentration dependence of contrast enhancement for binding to sparse cellular epitopes. , 2007, Ultrasound in medicine & biology.