title: Interactions between individual ultrasound-stimulated microbubbles and fibrin clots.
abstract: The use of ultrasound-stimulated microbubbles (USMBs) to promote thrombolysis is well established, but there remains considerable uncertainty about the mechanisms of this process. Here we examine the microscale interactions between individual USMBs and fibrin clots as a function of bubble size, exposure conditions and clot type. Microbubbles (n = 185) were placed adjacent to clot boundaries ("coarse" or "fine") using optical tweezers and exposed to 1-MHz ultrasound as a function of pressure (0.1-0.39 MPa). High-speed (10 kfps) imaging was employed, and clots were subsequently assessed with 2-photon microscopy. For fine clots, 46% of bubbles "embedded" within 10 μm of the clot boundary at pressures of 0.1 and 0.2 MPa, whereas at 0.39 MPa, 53% of bubbles penetrated and transited into the clots with an incidence inversely related to their diameter. A substantial fraction of penetrating bubbles induced fibrin network damage and promoted the uptake of nanobeads. In coarse clots, penetration occurred more readily and at lower pressures than in fine clots. The results therefore provide direct evidence of therapeutically relevant effects of USMBs and indicate their dependence on size, exposure conditions and clot properties.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Sunnybrook Research Institute, Toronto, Ontario, Canada. Electronic address: chrisacc@sri.utoronto.ca.
authors.forename: Christopher
authors.initials: C
authors.lastname: Acconcia
authors.affiliation: Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Ben Y C
authors.initials: BY
authors.lastname: Leung
authors.affiliation: Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Anoop
authors.initials: A
authors.lastname: Manjunath
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: David E
authors.initials: DE
authors.lastname: Goertz
mesh_terms: D001777:Blood Coagulation / Q000502:physiology*; D003287:Contrast Media; D005337:Fibrin; D005466:Fluorocarbons; D006801:Humans; D061185:Mechanical Thrombolysis / Q000379:methods*; D045423:Microbubbles; D014464:Ultrasonic Therapy / Q000379:methods*
chemical_list: D003287:Contrast Media; D005466:Fluorocarbons; D005337:Fibrin; C042852:perflutren
keywords: Contrast agent; Fibrin clot; Microbubbles; Sonothrombolysis; Thrombolysis; Ultrasound