One fundamental limitation with contrast-enhanced ultrasound is that nonlinear imaging techniques utilized for contrast-enhanced ultrasound do not work well at high frequencies. This is because for these techniques to be effective, microbubble contrast agents must be excited near their resonant frequencies, which are typically in the 1-7 MHz range. Thus, as imaging frequency is increased for improved resolution, sensitivity to contrast agents decreases. Although this is not as much of an issue for clinical studies, it has posed a challenge for small animal imaging, which is often performed in the 30-40 MHz range. However, there is a unique solution to this challenge.
Figure: Acoustic Angiography, illustrating high resolution, high-contrast-to-noise images of contrast-delineated microvasculature – a stark contrast to traditional grayscale imaging. A) R3230 mammary carcinoma tumor in rat, with vasculature (red) overlaid on grayscale tissue data to show microvascular relation to anatomical structure (FOV ~ 2x1 cm). B) rat kidney vascular tree (FOV ~ 1.5 cm), C) microvasculature in subcutaneous fibrosarcoma tumor in rat (FOV ~ 1.5 cm) D-G) 2-D slices of R3230 tumor (D-E) and healthy tissue (F-G) in rodents. Data illustrate readily observable microvascular tortuosity and increased vascular density near tumor (D-E) compared tissue from the same anatomical location (F-G) in rodents without tumors (FOV ~ 2 cm).
As originally discussed by Kruse et al. (IEEE UFFC, 2005 Aug;52(8):1320-9), a microbubble contrast agent excited near resonance produces very broadband harmonic energy. This energy can be detected as high as 45 MHz. Hence, it is possible to excite contrast agents near resonance, and detect microbubble harmonics at high-frequencies, such as 15-45 MHz. The result of such an approach has major significance. First, it means that microbubbles can be excited near resonance (5 MHz, for example), and a receiver can detect harmonics at 15-45 MHz. By filtering energy out below 15 MHz, such as system can detect microbubbles with nearly complete suppression of tissue background – which results in an extremely high sensitivity and signal to noise ratio. Second, because the microbubbles act as high-frequency point “transmitters” when exited near resonance, this means that such an approach only involves one way attenuation for the high frequency components. Thus, such as system can achieve on the order of twice the resolution at a similar penetration depth as standard ultrasound methods. While this dual-frequency, ultra broadband contrast imaging approach has enormous potential, it has not been possible until recently. This is because no commercial ultrasound transducers exist that can simultaneously transmit near 2-5 MHz, and receive with reasonable sensitivity at a much higher frequency (15-45 MHz).
Our group, in collaboration with F. Stuart Foster from the University of Toronto, has recently designed and fabricated the first dual-frequency ultra-broadband transducer for contrast enhanced imaging at 30 MHz, and integrated this transducer with the commercial Visualsonics platform. Imaging with this transducer has produced some of the highest resolution, highest signal-to-noise, contrast images to date (Figure above); some of which were recently published on the cover of IEEE UFFC. Our current research includes applying this transducer for several new imaging approaches, and future research will involve designing new versions of this transducer technology for various clinical imaging applications.