In vivo imaging of microfluidic-produced microbubbles

Abstract

Microfluidics-based production of stable microbubbles for ultrasound contrast enhancement or drug/gene delivery allows for precise control over microbubble diameter but at the cost of a low production rate. In situ microfluidic production of microbubbles directly in the vasculature may eliminate the necessity for high microbubble production rates, long stability, or small diameters. Towards this goal, we investigated whether microfluidic-produced microbubbles directly administered into a mouse tail vein could provide sufficient ultrasound contrast. Microbubbles composed of nitrogen gas and stabilized with 3 % bovine serum albumin and 10 % dextrose were injected for 10 seconds into wild type C57BL/6 mice, via a tail-vein catheter. Short-axis images of the right and left ventricle were acquired at 12.5 MHz and image intensity over time was analyzed. Microbubbles were produced on the order of 10(5) microbubbles/s and were observed in both the right and left ventricles. The median rise time, duration, and decay time within the right ventricle were 2.9, 21.3, and 14.3 s, respectively. All mice survived the procedure with no observable respiratory or heart rate distress despite microbubble diameters as large as 19 μm.

Therapeutic silence of pleiotrophin by targeted delivery of siRNA and its effect on the inhibition of tumor growth and metastasis

“…In our study, all the mice are well tolerated with the size of the microbubbles showing no observable heart distress. The diameter of the microbubbles as large as 19μm was revealed to be safe from a recent in vivo imaging of microbubble study[37]. The combination of therapeutic jetPEI-siRNA complex with large size microbubbles revealed an efficient and lung targeted gene delivery system.…”

A novel technology: microfluidic devices for microbubble ultrasound contrast agent generation

“…However, in vivo imaging studies, using microfluidicproduced microbubbles, are rarely reported. Based on the albumin-stabilized microbubbles produced in situ by the flow-focusing device [19], Dhanaliwala et al [20] transported microbubbles directly from the generator outlet into the mouse vasculature via a tail vein catheter and observed in vivo US imaging. They were the first group to report intravascular administration of microfluidic-produced microbubbles.…”

Microbubble-mediated intravascular ultrasound imaging and drug delivery

“…However, microfluidics technology permits real-time, on-chip MB fabrication that, when combined with an IVUS catheter, can provide a fully integrated approach for contrastenhanced IVUS imaging and therapeutic delivery [125]- [127]. Microfluidically-produced MBs have been applied to contrast-enhanced imaging [126]- [129], molecular imaging [130], [131], and therapeutic delivery applications [132]- [134], and a 1.5-mm-diameter catheter-based microfluidic device was recently developed for use in sonothrombolysis applications [135]. On-chip MB fabrication directly within the catheter permits the use of unconventional gases and shell materials, thereby offering the option to modify MB size, concentration, and composition in real-time during an intervention [127], [133], [134].…”

“…On-chip MB fabrication directly within the catheter permits the use of unconventional gases and shell materials, thereby offering the option to modify MB size, concentration, and composition in real-time during an intervention [127], [133], [134]. This MB production paradigm also permits the use of new MB formulations, such as transiently-stable MBs that are comprised of highsolubility gases [134], or MBs larger than 10 µm in diameter that provide enhanced acoustic backscatter, improved IVUS contrast enhancement [129], and enhanced therapeutic efficacy [133]. As with IVUS-mediated stem cell delivery, integrated IVUS and MB catheter technologies are at an early stage of development and require extensive in vivo validation to evaluate their clinical utility.…”