title: Microvessel rupture induced by high-intensity therapeutic ultrasound-a study of parameter sensitivity in a simple in vivo model.
abstract: BACKGROUND
  Safety analyses of transcranial therapeutic ultrasound procedures require knowledge of the dependence of the rupture probability and rupture time upon sonication parameters. As previous vessel-rupture studies have concentrated on a specific set of exposure conditions, there is a need for more comprehensive parametric studies.
  
  
  METHODS
  Probability of rupture and rupture times were measured by exposing the large blood vessel of a live earthworm to high-intensity focused ultrasound pulse trains of various characteristics. Pressures generated by the ultrasound transducers were estimated through numerical solutions to the KZK (Khokhlov-Zabolotskaya-Kuznetsov) equation. Three ultrasound frequencies (1.1, 2.5, and 3.3 MHz) were considered, as were three pulse repetition frequencies (1, 3, and 10 Hz), and two duty factors (0.0001, 0.001). The pressures produced ranged from 4 to 18 MPa. Exposures of up to 10 min in duration were employed. Trials were repeated an average of 11 times.
  
  
  RESULTS
  No trends as a function of pulse repetition rate were identifiable, for either probability of rupture or rupture time. Rupture time was found to be a strong function of duty factor at the lower pressures; at 1.1 MHz the rupture time was an order of magnitude lower for the 0.001 duty factor than the 0.0001. At moderate pressures, the difference between the duty factors was less, and there was essentially no difference between duty factors at the highest pressure. Probability of rupture was not found to be a strong function of duty factor. Rupture thresholds were about 4 MPa for the 1.1 MHz frequency, 7 MPa at 3.3 MHz, and 11 MPa for the 2.5 MHz, though the pressure value at 2.5 MHz frequency will likely be reduced when steep-angle corrections are accounted for in the KZK model used to estimate pressures. Mechanical index provided a better collapse of the data (less separation of the curves pertaining to the different frequencies) than peak negative pressure, for both probability of rupture and rupture time.
  
  
  CONCLUSIONS
  The results provide a database with which investigations in more complex animal models can be compared, potentially establishing trends by which bioeffects in human vessels can be estimated.
authors.affiliation: Preclinical Studies Core, Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 USA.
authors.forename: Yeonho
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Division of Radiological Health, Office of In-Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 66, Room 4311, Silver Spring, MD 20993 USA.
authors.forename: Marjan
authors.initials: M
authors.lastname: Nabili
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Maryland College Park, 4418 Stadium Drive, College Park, MD 20742 USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Acharya
authors.affiliation: Bioinnovation PhD Program, School of Science and Engineering, Tulane University, 6823 St. Charles Avenue, Lindy Boggs Center, Room 440, New Orleans, LA 70118 USA.
authors.forename: Asis
authors.initials: A
authors.lastname: Lopez
authors.affiliation: Division of Applied Mechanics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, U. S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 62, Room 2231, Silver Spring, MD 20993 USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Myers
keywords: High-intensity focused ultrasound; Therapeutic ultrasound; Transcranial ultrasound; Vessel rupture