New Insights into Mechanisms of Sonothrombolysis Using Ultra-High-Speed Imaging

Chen, Xucai; Leeman, Jonathan E.; Wang, Jianjun; Pacella, John J.; Villanueva, Flordeliza S.

doi:10.1016/j.ultrasmedbio.2013.08.021

Cited by 62 publications

(50 citation statements)

References 11 publications

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“…5a). Previous studies have documented microbubble interactions with clots (Acconcia et al, 2013; Chen et al, 2013), but have not correlated the instantaneous lytic rate with microbubble activity. Furthermore, these studies primarily focused on inertial cavitation, whereas the present study focused on promoting sustained stable cavitation.…”

Section: Discussionmentioning

confidence: 99%

Shaken and Stirred: Mechanisms of Ultrasound-Enhanced Thrombolysis

Bader

Gruber

Holland

2015

Ultrasound in Medicine & Biology

110

191

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The use of ultrasound and microbubbles as an effective adjuvant to thrombolytics has been demonstrated in vitro, ex vivo, and in vivo. However, the specific mechanisms of ultrasound-enhanced thrombolysis (UET) have yet to be elucidated. We present visual observations illustrating two mechanisms of UET: acoustic cavitation and radiation force. An in vitro flow model was developed to observe human whole blood clots exposed to human fresh-frozen plasma, rt-PA (0, 0.32, 1.58, or 3.15 μg/mL), and the ultrasound contrast agent Definity® (2 μL/mL). Intermittent, continuous-wave, ultrasound (120 kHz, 0.44 MPa peak-to-peak pressure) was used to insonify the perfusate. Ultraharmonic (UH) emissions indicative of stable cavitation were monitored with a passive cavitation detector. The clot was observed with an inverted microscope, and images were recorded with a charge-coupled device (CCD) camera. The images were post processed to determine the time-dependent clot diameter and root-mean-square velocity of the clot position. Clot lysis occurred preferentially surrounding large, resonant-sized bubbles undergoing stable oscillations. UH emissions from stable cavitation were found to correlate with the lytic rate. Clots were observed to translate synchronously with the initiation and cessation of the ultrasound exposure. The root-mean-square velocity of the clot correlated with the lytic rate. These data provide visual documentation of stable cavitation activity and radiation force during sub-megahertz sonothrombolysis. The observations of this study suggest that the process of clot lysis is complex, and both stable cavitation and radiation force are mechanistically responsible for this beneficial bioeffect in this in vitro model.

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Section: Discussionmentioning

confidence: 99%

Shaken and Stirred: Mechanisms of Ultrasound-Enhanced Thrombolysis

Bader

Gruber

Holland

2015

Ultrasound in Medicine & Biology

110

191

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“…This critical feature allows us to visualize MB events at various time points of relatively long acoustic tone bursts, which is a crucial capability as the therapeutic efficacy of long pulses for therapeutic applications has become evident. 12,31 In conclusion, our imaging system is capable of both bright field and fluorescent in vitro imaging of MBs at high speed. Its high speed fluorescence imaging capabilities confers the potential for in vivo (fluorescent) high speed observations during intravital microscopy.…”

Section: Conclusion and Discussionmentioning

confidence: 88%

Ultra-fast bright field and fluorescence imaging of the dynamics of micrometer-sized objects

Chen

Wang

Versluis

et al. 2013

Review of Scientific Instruments

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High speed imaging has application in a wide area of industry and scientific research. In medical research, high speed imaging has the potential to reveal insight into mechanisms of action of various therapeutic interventions. Examples include ultrasound assisted thrombolysis, drug delivery, and gene therapy. Visual observation of the ultrasound, microbubble, and biological cell interaction may help the understanding of the dynamic behavior of microbubbles and may eventually lead to better design of such delivery systems. We present the development of a high speed bright field and fluorescence imaging system that incorporates external mechanical waves such as ultrasound. Through collaborative design and contract manufacturing, a high speed imaging system has been successfully developed at the University of Pittsburgh Medical Center. We named the system "UPMC Cam," to refer to the integrated imaging system that includes the multi-frame camera and its unique software control, the customized modular microscope, the customized laser delivery system, its auxiliary ultrasound generator, and the combined ultrasound and optical imaging chamber for in vitro and in vivo observations. This system is capable of imaging microscopic bright field and fluorescence movies at 25 × 10 6 frames per second for 128 frames, with a frame size of 920 × 616 pixels. Example images of microbubble under ultrasound are shown to demonstrate the potential application of the system.

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“…When used with fibrinolytic agents, ultrasound-induced cavitation has been associated with greater plasminogen exposure to the clot surface 15. Ultrasound-induced inertial cavitation produces surrounding axial fluid acceleration, acoustic streaming and high-velocity flow gradients that may penetrate and destabilise the infrastructure of a thrombus 16 17. More recently, ultra-high frame rate cameras have visually demonstrated the potential for microbubble cavitation to dissolve thrombi 17.…”

Section: Discussionmentioning

confidence: 99%

“…Ultrasound-induced inertial cavitation produces surrounding axial fluid acceleration, acoustic streaming and high-velocity flow gradients that may penetrate and destabilise the infrastructure of a thrombus 16 17. More recently, ultra-high frame rate cameras have visually demonstrated the potential for microbubble cavitation to dissolve thrombi 17. Although some form of cavitation (stable or inertial) was observed in these in vitro studies, a cause and effect relationship cannot be assumed, as other ultrasound-induced interactions with microbubbles (eg, radiation forces) may contribute to both mechanical thrombus dissolution and enhanced plasminogen exposure to thrombus.…”

Section: Discussionmentioning

confidence: 99%