TY - JOUR
T1 - Ultrasound-Enhanced Thrombolysis Using Definity® as a Cavitation Nucleation Agent
AU - Datta, Saurabh
AU - Coussios, Constantin C.
AU - Ammi, Azzdine Y.
AU - Mast, T. Douglas
AU - de Courten-Myers, Gabrielle M.
AU - Holland, Christy K.
N1 - Funding Information:
This research was supported by the National Institutes of Health, grant number NIH/NINDS R01-NS047603. We gratefully acknowledge the assistance of Drs. George Shaw and Jason Meunier for the human whole blood clot model and valuable discussions. We also acknowledge the assistance of Stella Nicolaou and Sampada Vaidya for developing the fluorescent imaging technique.
PY - 2008/9
Y1 - 2008/9
N2 - Ultrasound has been shown previously to act synergistically with a thrombolytic agent, such as recombinant tissue plasminogen activator (rt-PA) to accelerate thrombolysis. In this in vitro study, a commercial contrast agent, Definity®, was used to promote and sustain the nucleation of cavitation during pulsed ultrasound exposure at 120 kHz. Ultraharmonic signals, broadband emissions and harmonics of the fundamental were measured acoustically by using a focused hydrophone as a passive cavitation detector and used to quantify the level of cavitation activity. Human whole blood clots suspended in human plasma were exposed to a combination of rt-PA, Definity® and ultrasound at a range of ultrasound peak-to-peak pressure amplitudes, which were selected to expose clots to various degrees of cavitation activity. Thrombolytic efficacy was determined by measuring clot mass loss before and after the treatment and correlated with the degree of cavitation activity. The penetration depth of rt-PA and plasminogen was also evaluated in the presence of cavitating microbubbles using a dual-antibody fluorescence imaging technique. The largest mass loss (26.2%) was observed for clots treated with 120-kHz ultrasound (0.32-MPa peak-to-peak pressure amplitude), rt-PA and stable cavitation nucleated by Definity®. A significant correlation was observed between mass loss and ultraharmonic signals (r = 0.85, p < 0.0001, n = 24). The largest mean penetration depth of rt-PA (222 μm) and plasminogen (241 μm) was observed in the presence of stable cavitation activity. Stable cavitation activity plays an important role in enhancement of thrombolysis and can be monitored to evaluate the efficacy of thrombolytic treatment. (E-mail: Christy.Holland@uc.edu).
AB - Ultrasound has been shown previously to act synergistically with a thrombolytic agent, such as recombinant tissue plasminogen activator (rt-PA) to accelerate thrombolysis. In this in vitro study, a commercial contrast agent, Definity®, was used to promote and sustain the nucleation of cavitation during pulsed ultrasound exposure at 120 kHz. Ultraharmonic signals, broadband emissions and harmonics of the fundamental were measured acoustically by using a focused hydrophone as a passive cavitation detector and used to quantify the level of cavitation activity. Human whole blood clots suspended in human plasma were exposed to a combination of rt-PA, Definity® and ultrasound at a range of ultrasound peak-to-peak pressure amplitudes, which were selected to expose clots to various degrees of cavitation activity. Thrombolytic efficacy was determined by measuring clot mass loss before and after the treatment and correlated with the degree of cavitation activity. The penetration depth of rt-PA and plasminogen was also evaluated in the presence of cavitating microbubbles using a dual-antibody fluorescence imaging technique. The largest mass loss (26.2%) was observed for clots treated with 120-kHz ultrasound (0.32-MPa peak-to-peak pressure amplitude), rt-PA and stable cavitation nucleated by Definity®. A significant correlation was observed between mass loss and ultraharmonic signals (r = 0.85, p < 0.0001, n = 24). The largest mean penetration depth of rt-PA (222 μm) and plasminogen (241 μm) was observed in the presence of stable cavitation activity. Stable cavitation activity plays an important role in enhancement of thrombolysis and can be monitored to evaluate the efficacy of thrombolytic treatment. (E-mail: Christy.Holland@uc.edu).
KW - Stable cavitation
KW - Stroke therapy
KW - Therapeutic ultrasound
KW - Ultraharmonics
KW - Ultrasound-assisted thrombolysis
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U2 - 10.1016/j.ultrasmedbio.2008.01.016
DO - 10.1016/j.ultrasmedbio.2008.01.016
M3 - Article
C2 - 18378380
AN - SCOPUS:49849085719
SN - 0301-5629
VL - 34
SP - 1421
EP - 1433
JO - Ultrasound in Medicine and Biology
JF - Ultrasound in Medicine and Biology
IS - 9
ER -