In Vitro Sonothrombolysis Enhancement by Transiently Stable Microbubbles Produced by a Flow-Focusing Microfluidic Device
- 541 Downloads
Therapeutic approaches that enhance thrombolysis by combining recombinant tissue plasminogen activator (rtPA), ultrasound, and/or microbubbles (MBs) are known as sonothrombolysis techniques. To date, sonothrombolysis approaches have primarily utilized commercially available MB formulations (or derivatives thereof) with diameters in the range 1–4 µm and circulation lifetimes between 5 and 15 min. The present study evaluated the in vitro sonothrombolysis efficacy of large diameter MBs (d MB ≥ 10 µm) with much shorter lifetimes that were produced on demand and in close proximity to the blood clot using a flow-focusing microfluidic device. MBs with a N2 gas core and a non-crosslinked bovine serum albumin shell were produced with diameters between 10 and 20 µm at rates between 50 and 950 × 103 per second. Use of these large MBs resulted in approximately 4.0–8.8 fold increases in thrombolysis rates compared to a clinical rtPA dose and approximately 2.1–4.2 fold increases in thrombolysis rates compared to sonothrombolysis techniques using conventional MBs. The results of this study indicate that the large diameter microbubbles with transient stability are capable of significantly enhanced in vitro sonothrombolysis rates when delivered directly to the clot immediately following production by a flow focusing microfluidic device placed essentially in situ adjacent to the clot.
KeywordsThromboembolism Sonothrombolysis Microfluidics Microbubbles Ultrasound
Partial support for this research is provided by the National Institutes of Health under Grant NIH S10 RR025594 to JAH and by NSF GRFP and Virginia Space Grant Consortium pre-doctoral fellowships to AJD. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, NSF, or VGSC.
Supplementary Video 2: Compilation of still images taken at 1 min intervals during a 30 min sonothrombolysis experiment (Group F). For reference, the ID of the tube is 3.05 mm. Supplementary material 2 (WMV 3174 kb)
- 23.Kearon, C. Natural history of venous thromboembolism. Circulation 107:I-22–I-30, 2003.Google Scholar