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The introduction of safe and efficacious ultrasound constationary tissue. Likewise, it is not always possible to achieve trast agents, which significantly enhance the backscattered signals, sufficient contrast resolution in gray-scale (B-mode) imaging to has allowed previously inaccessible areas of slow flow to be imaged. differentiate between normal and diseased tissues. The introducHowever, imaging organ perfusion or small deep-lying vessels retion of safe and efficacious ultrasound contrast agents, which mains difficult. The ability of harmonic imaging to resolve these probsignificantly enhance the backscattered echo-signals, should prolems has been investigated. Harmonic imaging uses the nonlinear vide increased diagnostic capabilities. properties of microbubble-based agents by transmitting at the fundamental frequency but receiving at the second harmonic. In vitro measurements revealed a harmonic response 15 dB below the fundamenA. Ultrasound Contrast Agents. The first report on the use tal for a driving frequency of 2.5 MHz at an acoustic pressure of 50 of an ultrasound contrast agent (in the aortic root) appeared kPa for one particular contrast medium. In vivo, two different gasover 25 years ago [1]. Since then, considerable efforts have filled microbubble agents were administrated to 10 dogs and three been made to produce agents capable of increasing echogenirabbits. Three different scanners were used to obtain images of kidcity and Doppler signal intensities for both cardiac and noncarneys, liver, heart, and vessels in harmonic and conventional graydiac applications. The ideal agent would be (1) nontoxic; (2) scale, pulsed Doppler, and color Doppler modes. Enhancement lasted injectable intravenously; (3) capable of traversing the pulmosignificantly longer in harmonic than in conventional modes (94 s; P Å 0.00003). Harmonic images were less susceptible to artifacts, nary, cardiac, and capillary circulations; and (4) stable for such as acoustic shadowing, and a wider range of dosages could recirculation. It is only within the last decade that pharmaceutitherefore be used. A clear increase in the (flow) signal-to-clutter ratio cal companies and researchers have approached this goal. For was observed. Harmonic images were, however, very dependent on further details on specific contrast agents we refer the reader focal zone settings. These preliminary results demonstrate the potento two recent review articles where extended bibliographies tial of contrast-enhanced harmonic imaging, but further studies are can be found [2,3]. required to establish clinical efficacy. q 1997 John Wiley & Sons, Inc. Int Increasing the power of the backscattered signal is the most J Imaging Syst Technol, 8, 69–81, 1997 important function of an ultrasound contrast agent. The received

Harmonic imaging with gas-filled microspheres: Initial experiences