Two profound changes will soon modify medical ultrasound use: on-screen safety indexes (regulatory), and 2) the emergence of clinically-useful microbubbles for contrast enhancement. The safety indexes relate clinical ultrasound (US) fields to the potential for bioeffects. The Thermal Index concerns US-generated temperature increments in tissues. The Mechanical Index (MI) is defined in terms of peak negative acoustic pressure and concerns non-thermal bioeffects. Both indexes are based upon knowledge of the mechanisms of action of US fields on tissues/cells. The bioeffect and physical bases for the MI are limited; e.g., the MI does not acknowledge the importance of US pulse length for generating inertial cavitation (IC). Doppler US device output levels generally exceed those requisite for IC from micron-sized nuclei. The general aim of the project is to provide mechanistic insights on dynamic US-induced bubble interactions with in vitro and in vivo biological systems in relation to the MI. The overall hypothesis guiding the proposed project is that non-thermal US-induced cellular effects are due primarily to the action of bubbles. All projects involve the use of a stabilized microbubble echo contrast agent as a control on the presence of bubbles during insonation. SupportIng preliminary data or demonstrable expertise in the area of investigation exists for all projects. Ten hypotheses are proposed for testing, and deal with acoustic thresholds for: (1) pulsed US exposure conditions and hemolysis in vitro, (2) 'jet'-induced erosion of artificial and natural membranes, (3) increases in in vitro mammalian cell mutation and sister chromatid exchanges, (4) confirmation of US-induced potentiation of in vitro cell killing by an anti-cancer drug, (5) confirmation that a specific US exposure of cells in vitro inhibits adenylate cyclase activity, (6) discerning the mechanism for US-induced cell lysis in vitro, (7) ascertaining if species-specific differences in erythrocyte cell size and critical shear stress correspond to differences in sensitivity to US-induced hemolysis, and (8) verifying the detectability of US-induced bubbles in the guinea pig hind limb and ascertaining if injected, stabilized microbubbles enhance the frequency of detectable bubbles. Hypotheses (9) and (10) entail developing comprehensive analytic constructs of US-induced kinetics of bubble action under blood vessel confinement to determine if rigorous theory supports the current MI definition, and if cavitation microjets may occur in vivo. The proposed experiments are aimed at elucidating the physical mechanism(s) of action involved in US bioeffect induction, with particular emphasis on the relationships between the US exposure conditions associated with effect induction and the MI as proposed for use in clinical US applications.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA039230-25
Application #
2894627
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Torres-Anjel, Manuel J
Project Start
1985-09-01
Project End
2000-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
25
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Rochester
Department
Biochemistry
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Miller, Morton W; Church, Charles C; Labuda, Cecille et al. (2006) Biological and environmental factors affecting ultrasound-induced hemolysis in vitro: 5. Temperature. Ultrasound Med Biol 32:893-904
Gracewski, Sheryl M; Miao, Hongyu; Dalecki, Diane (2005) Ultrasonic excitation of a bubble near a rigid or deformable sphere: implications for ultrasonically induced hemolysis. J Acoust Soc Am 117:1440-7
Miller, Morton W (2004) Cell size relations for sonolysis. Ultrasound Med Biol 30:1263-7
Miller, Morton W; Battaglia, Linda F (2003) The relevance of cell size on ultrasound-induced hemolysis in mouse and human blood in vitro. Ultrasound Med Biol 29:1479-85
Miller, Morton W; Dewey, William C (2003) An extended commentary on ""Models and regulatory considerations for transient temperature rise during diagnostic ultrasound pulses"" by Herman and Harris (2002). Ultrasound Med Biol 29:1653-9; author response 1661-2
Miller, Morton W; Luque, Amneris E; Battaglia, Linda F et al. (2003) Biological and environmental factors affecting ultrasound-induced hemolysis in vitro: 1. HIV macrocytosis (cell size). Ultrasound Med Biol 29:77-91
Miller, Morton W; Everbach, E Carr; Miller, W Marcus et al. (2003) Biological and environmental factors affecting ultrasound-induced hemolysis in vitro: 2. Medium dissolved gas (pO2) content. Ultrasound Med Biol 29:93-102
Miller, Morton W; Miller, W Marcus; Battaglia, Linda F (2003) Biological and environmental factors affecting ultrasound-induced hemolysis in vitro: 3. Antioxidant (Trolox) inclusion. Ultrasound Med Biol 29:103-12
Miller, Morton W; Battaglia, Linda F; Mazza, Salvatore (2003) Biological and environmental factors affecting ultrasound-induced hemolysis in vitro: medium tonicity. Ultrasound Med Biol 29:713-24
Church, Charles C (2003) A theoretical study of acoustic cavitation produced by ""positive-only"" and ""negative-only"" pressure waves in relation to in vivo studies. Ultrasound Med Biol 29:319-30

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