title: Sonothrombolysis: the contribution of stable and inertial cavitation to clot lysis.
abstract: Microbubble-mediated sonothrombolysis (STL) is a remarkable approach to vascular occlusion therapy. However, STL remains a complex process with multiple interactions between clot, ultrasound (US), microbubbles (MB) and thrombolytic drug. The aim of this study was to evaluate the ability of combining US and MB to degrade fibrin and, more specifically, to assess the roles of both stable (SC) and inertial (IC) cavitation. Human blood clots containing radiolabeled fibrin were exposed to different combinations of recombinant tissue plasminogen activator (rtPA), US (1 MHz) and phospholipid MB. Three acoustic pressures were tested: 200, 350 and 1,300 kPa (peak-negative pressure). Clot lysis was assessed by diameter loss and release of radioactive fibrin degradation products. The combination rtPA + US + MB clearly revealed that IC (1,300 kPa) was able to enhance fibrin degradation significantly (66.3 ± 1.8%) compared with rtPA alone (51.7 ± 2.0%, p < 0.001). However, SC failed to enhance fibrin degradation at an acoustic pressure of 200 kPa. At 350 kPa, a synergistic effect between rtPA and US + MB was observed with an absolute increase of 6% compared to rtPA alone (p < 0.001). Conversely, without rtPA, the combination of US + MB was unable to degrade the fibrin network (0.3 ± 0.1%, p > 0.05 vs. control), but induced a distinct loss of red blood cells throughout the entire thickness of the clot, implying that MB were able to penetrate and cavitate inside the clot.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Petit
authors.affiliation: Bracco Suisse S.A., Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Y
authors.initials: Y
authors.lastname: Bohren
authors.affiliation: Bracco Suisse S.A., Plan-les-Ouates, Geneva, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Gaud
authors.affiliation: Bracco Suisse S.A., Plan-les-Ouates, Geneva, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Bussat
authors.affiliation: Bracco Suisse S.A., Plan-les-Ouates, Geneva, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Arditi
authors.affiliation: Bracco Suisse S.A., Plan-les-Ouates, Geneva, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Yan
authors.affiliation: Bracco Suisse S.A., Plan-les-Ouates, Geneva, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Tranquart
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland. Electronic address: Eric.allemann@unige.ch.
authors.forename: E
authors.initials: E
authors.lastname: Allémann
mesh_terms: D001777:Blood Coagulation / Q000502:physiology* / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D019220:High-Energy Shock Waves; D057086:High-Intensity Focused Ultrasound Ablation / Q000379:methods*; D006801:Humans; D061185:Mechanical Thrombolysis / Q000379:methods*; D045423:Microbubbles; D011829:Radiation Dosage
keywords: Fibrinolysis; Human blood clot; Inertial cavitation; Ischemic stroke; Microbubbles; Radiolabeled fibrinogen; Recombinant tissue plasminogen activator; Sonothrombolysis; Stable cavitation; Ultrasound