Effect of modulated ultrasound parameters on ultrasound-induced thrombolysis

The potential of ultrasound to enhance enzyme-mediated thrombolysis by application of constant operating parameters (COP) has been widely demonstrated. In this study, the effect of ultrasound with modulated operating parameters (MOP) on enzyme-mediated thrombolysis was investigated. The MOP protocol was applied to an in vitro model of thrombolysis. The results were compared to a COP with the equivalent soft tissue thermal index (TIS) over the duration of ultrasound exposure of 30 min (p < 0.14). To explore potential differences in the mechanism responsible for ultrasound-induced thrombolysis, a perfusion model was used to measure changes in average fibrin pore size of clot before, after and during exposure to MOP and COP protocols and cavitational activity was monitored in real time for both protocols using a passive cavitation detection system. The relative lysis enhancement by each COP and MOP protocol compared to alteplase alone yielded values of 33.69 +/- 12.09% and 63.89 +/- 15.02% in a thrombolysis model, respectively (p < 0.007). Both COP and MOP protocols caused an equivalent significant increase in average clot pore size of 2.09 x 10(-2) +/- 0.01 microm and 1.99 x 10(-2) +/- 0.004 microm, respectively (p < 0.74). No signatures of inertial or stable cavitation were observed for either acoustic protocol. In conclusion, due to mechanisms other than cavitation, application of ultrasound with modulated operating parameters has the potential to significantly enhance the relative lysis enhancement compared to application of ultrasound with constant operating parameters.