0885–3010/$25.00 © 2009 IEEE 1199 IEEE TRANSACTIONS ON ULTRASONICS, FERROELECTRICS, AND FREQUENCY CONTROL, . 56, . 6, JUNE 2009 Abstract—Active response of a microbubble is character- ized by its resonance behavior where the microbubble might oscillate after the excitation waveform has been turned off. We investigate in this paper an excitation approach based on this resonance phenomenon using chirps. The technique, called chirp reversal, consists in transmitting a first excitation signal, the up-sweep chirp (UPF) of increasing frequency with time, and a second excitation signal, the down-sweep (DNF) that is a replica of the first signal, but time reversed with a sweep of decreasing frequency with time. Simulations using a modified Rayleigh-Plesset equation were carried out to determine bub- ble response to chirp reversal. In addition, optical observations and acoustical measurements were carried out to corroborate the theoretical findings. Results of simulations show differ- ences between bubbles’ oscillations in response to up-sweep and down-sweep chirps mainly for transmitted center frequen- cies above the bubble’s resonance frequency. Bubbles that are at resonance or far away from resonance engender identical responses. From the optical data, the larger bubbles showed different dynamics when up-sweep or down-sweep chirps were transmitted. Smaller bubbles (< 2μm diameter) appear to be less sensitive to frequency sweep at 1.7 MHz center frequency. However, driven at a higher center frequency, smaller bub- bles tend to be more sensitive. These results were confirmed through the acoustical measurements. We concluded that simulations and experimental data show that significant differences might be observed between bubbles’ responses to UPF and DNF chirps. We demonstrate in this study that, for an optimal use of chirp reversal, the transmit frequency should be higher than the resonance frequency of the contrast microbubbles. I. I G  microbubbles are currently used as an ultrasound contrast agent, because they are ideal reflectors of ultrasound waves. Typical contrast microbubbles have an average size of 3 μm and are encapsulated in a biocompat- ible shell (such as a lipid) with a thickness of a few tens of nanometers. Ultrasound contrast agents (UCA) are now used routinely in cardiology and in radiology [1] to im- prove the detection and visualization of the blood pool and to evaluate vessels in a variety of organs. The con- trast-enhanced clinical diagnosis has now been improved due to new imaging methods such as pulse inversion imag- ing [1], [2] and power modulation imaging [3]. Many ef- forts are still being undertaken today to develop improved detection methods based on specific acoustic properties of the microbubbles. These methods should be sensitive to the contrast microbubbles, and they also should eliminate echoes originating from tissue. Gas microbubbles possess nonlinear acoustic properties, which make the spectral response of the bubble different from those of tissue or linear scatterers. In addition to its nonlinear response, the microbubble also provides an active response characterized by its resonance behavior. When the bubble is excited near its resonance frequency, its response characterized by the diameter-time (D-T) curve is not only stronger, but typically also longer than the excitation pulse in contrast to a bubble excited far from resonance where its response has a relatively equal length as compared with its excitation. This effect is at- tributed to the natural oscillations of the bubble, which are excited very efficiently near resonance or at the eigen- frequency of the bubble. A new multiple pulsing scheme, termed chirp reversal imaging [4], has been proposed and exploits the response of contrast microbubbles to a wideband chirped excitation where in the first pulse the frequency is swept with in- creasing frequency, termed an up-sweep chirp (UPF), and in a successive pulse with a decreasing frequency, termed a down-sweep chirp (DNF). The response of linear scat- terers is expected to be identical for both up- and down- sweep chirp excitations due to the absence of a resonance behavior. This method however would be highly sensitive to nonlinear scatterers such as gas microbubbles. In a pre- vious publication, Sun and colleagues [5] combined opti- cal and acoustical detection to compare radial oscillations and echoes of contrast bubbles. The experimental system was used to identify effects of diffusion and destruction. Another application of the hybrid system was to investi- gate the response of microbubbles to long excitations in which diffusion was shown to occur over the pulse dura- tion. In the last part of the study, the authors evaluated the response of the bubbles to chirps with increasing or decreasing frequency sweep. High-speed imaging of a bub- ble with a size of 3.5 μm displayed a difference for up- and Contrast Agent Response to Chirp Reversal: Simulations, Optical Observations, and Acoustical Verification Anthony Novell, Sander van der Meer, Michel Versluis, Nico de Jong, Associate Member, IEEE, and Ayache Bouakaz, Senior Member, IEEE Manuscript received December 27, 2008; accepted March 5, 2009. The authors would like to acknowledge l’Agence Nationale de la Rechercher (ANR) for the financial support (project ANR-07- TecSan-015-01). A. Novell and A. Bouakaz are with Inserm UMR 930, CNRS ERL 3106, Tours, France (e-mail: bouakaz@med.univ-tours.fr). A. Novell is also with the Université François Rabelais, Tours, France. S. van der Meer, M. Versluis, and N. de Jong are with the Physics of Fluids Group, University of Twente, Enschede, The Netherlands. N. de Jong is also with the Department of Biomedical Engineering, Erasmus MC, Rotterdam, The Netherlands. Digital Object Identifier 10.1109/TUFFC.2009.1161