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Department of Biomedical Engineering, University of Cincinnati, Medical Science Building, Rm. 6167, 231 Albert Sabin Way, Cincinnati, OH 45267-0586, USA.
Thrombosis Research (Impact Factor: 2.45). 02/2008; 121(5):663-73. DOI: 10.1016/j.thromres.2007.07.006
Source: PubMed


Thrombolytics such as recombinant tissue plasminogen activator (rt-PA) have advanced the treatment of ischemic stroke, myocardial infarction, deep vein thrombosis and pulmonary embolism.
To improve the efficacy of this thrombolytic therapy, the synergistic effect of rt-PA and 120 kHz or 1.0 MHz ultrasound was assessed in vitro using a porcine clot model.
Fully retracted whole blood clots prepared from fresh porcine blood were employed to compare rt-PA thrombolytic treatment with and without exposure to 120-kHz or 1-MHz ultrasound. For sham studies (without ultrasound), clot mass loss was measured as a function of rt-PA concentration from 0.003 to 0.107 mg/ml. For combined ultrasound and rt-PA treatments, peak-to-peak pressure amplitudes of 0.35, 0.70 or 1.0 MPa were employed. The range of duty cycles varied from 10% to 100% (continuous wave) and the pulse repetition frequency was fixed at 1.7 KHz.
For rt-PA alone, the mass loss increased monotonically as a function of rt-PA concentration up to approximately 0.050 mg/ml. With ultrasound and rt-PA exposure, clot mass loss increased by as much as 104% over rt-PA alone. Ultrasound without the presence of rt-PA did not significantly enhance thrombolysis compared to control treatment. The ultrasound-mediated clot mass loss enhancement increased with the square root of the overall treatment duration.
Both 120-kHz and 1-MHz pulsed and CW ultrasound enhanced rt-PA thrombolysis in a porcine whole blood clot model in vitro. No clear dependence of the observed thrombolytic enhancement on ultrasound duty cycle was evident. The lack of duty cycle dependence suggests a more complex mechanism that could not be sustained by merely increasing the pulse duration.

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Available from: Christy K Holland, Sep 30, 2015
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    • "This is because clinical therapies and thrombolytic agents' responses to thrombolysis depend on the thrombus age [3] [4]. Aged thrombi are more resistant to thrombolysis than fresh thrombi [5] [6] [7] [8]. Thrombi appearance may predict the efficacy of thrombolysis [9]. "
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    ABSTRACT: Ultrasound imaging is a first-line diagnostic method for screening the thrombus. During thrombus aging, the proportion of red blood cells (RBCs) in the thrombus decreases and therefore the signal intensity of B-scan can be used to detect the thrombus age. To avoid the effect of system gain on the measurements, this study proposed using the empirical mode decomposition (EMD) of ultrasound image as a strategy to classify newly formed and aged thrombi. Porcine blood samples were used for the in vitro induction of fresh and aged thrombi (at hematocrits of 40%). Each thrombus was imaged using an ultrasound scanner at different gains (15, 20, and 30 dB). Then, EMD of ultrasound signals was performed to obtain the first and second intrinsic mode functions (IMFs), which were further used to calculate the IMF-based echogenicity ratio (IER). The results showed that the performance of using signal amplitude of B-scan to reflect the thrombus age depends on gain. However, the IER is less affected by the gain in discriminating between fresh and aged thrombi. In the future, ultrasound B-scan combined with the EMD may be used to identify the thrombus age for the establishment of thrombolytic treatment planning.
    BioMed Research International 01/2015; 2015:403293. DOI:10.1155/2015/403293 · 3.17 Impact Factor
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    • "The mix was poured into a 100 mL Petri dish (⌀100 mm × 12 mm), which was incubated at 37°C for 5 min⁡ during coagulation process. Once coagulated, the blood was preserved at 4°C in the closed Petri dish during three days in order to ensure clot retraction [28–31]. It was then used for the experiments within three days. "
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    ABSTRACT: Focused ultrasound involving inertial cavitation has been shown to be an efficient method to induce thrombolysis without any pharmacological agent. However, further investigation of the mechanisms involved and further optimization of the process are still required. The present work aims at studying the relevance of a bifrequency excitation compared to a classical monofrequency excitation to achieve thrombolysis without any pharmacological agent. In vitro human blood clots were placed at the focus of a piezoelectric transducer. Efficiency of the thrombolysis was assessed by weighing each clot before and after sonication. The efficiencies of mono- (550 kHz) and bifrequency (535 and 565 kHz) excitations were compared for peak power ranging from 70 W to 220 W. The thrombolysis efficiency appears to be correlated to the inertial cavitation activity quantified by passive acoustic listening. In the conditions of the experiment, the power needed to achieve 80% of thrombolysis with a monofrequency excitation is reduced by the half with a bifrequency excitation. The thermal effects of bifrequency and monofrequency excitations, studied using MR thermometry measurements in turkey muscle samples where no cavitation occurred, did not show any difference between both types of excitations when using the same power level.
    BioMed Research International 08/2014; 2014:518787. DOI:10.1155/2014/518787 · 2.71 Impact Factor
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    • "Thrombolysis ability of the uPA-loaded nanogels The thrombolysis capacity of uPA formulations is one of the most important characteristics that are closely related to the clinical applications (Holland et al., 2007; Hölscher et al., 2009). As shown in Fig. 5, it is found in the in vitro tests that the thrombolysis of uPA-loaded nanogels in silent condition is much lower than that of the nude uPA. "
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    ABSTRACT: To find a way to modulate the effect of thrombolytic proteins by increasing their specificity, minimizing their adverse effect as well as lengthening their circulation time for the treatment of ischemic vascular disease holds great promise. In this work, urokinase-type plasminogen activator (uPA) was encapsulated into hollow nanogels which are generated by the reaction of glycol chitosan and aldehyde capped poly(ethylene glycol) (OHC-PEG-CHO) through a one-step approach of ultrasonic spray. The uPA-loaded nanogels, with size of 200-300 nm, have longer circulation time than that of the nude urokinase in vivo, besides the protein can be triggered to release in faster rate under diagnostic ultrasonic condition of 2 MHz, which significantly enhanced the thrombolysis of clots. The results are promising for increasing the specificity and positive effects of thrombolytic agents like recombinant tissue plasminogen activator (rt-PA) for the current treatment of ischemic vascular disease.
    International Journal of Pharmaceutics 06/2012; 434(1-2):384-90. DOI:10.1016/j.ijpharm.2012.06.001 · 3.65 Impact Factor
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