Parallel output, liquid flooded flow-focusing microfluidic device for generating monodisperse microbubbles within a catheter

A new method for supplying the liquid phase to a flow focusing microfluidic device (FFMD), designed for the production of monodisperse microbubbles (MBs), is introduced. The FFMD is coupled to a pressurized liquid-filled chamber, avoiding the need for dedicated liquid phase tubing or interconnects from the external field to the microfluidics device. This method significantly reduces the complexity of FFMD fabrication and simplifies the parallelization of FFMDs - an important consideration for increasing MB production rate. Using this new method, flooded FFMDs were fabricated and MB diameter and production rate were measured. The minimum MB size produced was 7.1±0.5 μm. The maximum production rate from a single nozzle FFMD was 333,000, MB/s. Production was increased 1.5-fold using a two nozzle, parallelized device, for a maximum production rate of approximately 500,000 MB/s. In addition to increased production, the flooded design allows for miniaturization, with the smallest FFMD measuring 14.5 × 2.8 × 2.3 mm. Finally, B-mode and intravascular ultrasound images were obtained, highlighting the potential for flooded FFMDs to generate microbubbles in situ in a catheter and immediately thereafter image the same MBs in a target blood vessel.

[1]  J. Hossack,et al.  Ultrasound-microbubble-mediated drug delivery efficacy and cell viability depend on microbubble radius and ultrasound frequency , 2010, 2010 IEEE International Ultrasonics Symposium.

[2]  Jameel A Feshitan,et al.  Microbubble size isolation by differential centrifugation. , 2009, Journal of colloid and interface science.

[3]  O. A. Asbjornsen,et al.  Size fractionation of gas-filled microspheres by flotation , 1996 .

[4]  Paul A Dayton,et al.  Tailoring the Size Distribution of Ultrasound Contrast Agents: Possible Method for Improving Sensitivity in Molecular Imaging , 2007, Molecular imaging.

[5]  Eleanor Stride,et al.  Novel microbubble preparation technologies , 2008 .

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

[7]  Paul A Dayton,et al.  Molecular ultrasound imaging using microbubble contrast agents. , 2007, Frontiers in bioscience : a journal and virtual library.

[8]  John A Hossack,et al.  Dual frequency method for simultaneous translation and real-time imaging of ultrasound contrast agents within large blood vessels. , 2009, Ultrasound in medicine & biology.

[9]  David A. Weitz,et al.  A new device for the generation of microbubbles , 2004 .

[10]  A. Gañán-Calvo,et al.  Perfectly monodisperse microbubbling by capillary flow focusing. , 2001, Physical review letters.

[11]  A. Klibanov,et al.  Ultrasound triggered image-guided drug delivery. , 2009, European journal of radiology.

[12]  Paul A Dayton,et al.  Advances in Molecular Imaging with Ultrasound , 2010, Molecular imaging.

[13]  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.

[14]  Alfonso M Gañán-Calvo,et al.  Perfectly monodisperse microbubbling by capillary flow focusing: an alternate physical description and universal scaling. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[15]  Angeliki Tserepi,et al.  A low temperature surface modification assisted method for bonding plastic substrates , 2008 .

[16]  R. Powell,et al.  Needle size and injection rate impact microbubble contrast agent population. , 2008, Ultrasound in medicine & biology.

[17]  Victor Steinberg,et al.  Continuous particle size separation and size sorting using ultrasound in a microchannel , 2006 .

[18]  B D Butler,et al.  The lung as a filter for microbubbles. , 1979, Journal of applied physiology: respiratory, environmental and exercise physiology.

[19]  Mark Borden,et al.  Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery. , 2007, Annual review of biomedical engineering.

[20]  Vittorio Cristini,et al.  Monodispersed microfluidic droplet generation by shear focusing microfluidic device , 2006 .

[21]  P. Dayton,et al.  Influence of lipid shell physicochemical properties on ultrasound-induced microbubble destruction , 2005, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[22]  W. Wagner,et al.  Targeting and ultrasound imaging of microbubble-based contrast agents , 1999, Magnetic Resonance Materials in Physics, Biology and Medicine.