Optimizing Acoustic Activation of Phase Change Contrast Agents With the Activation Pressure Matching Method: A Review

Sub-micron phase-change contrast agents consist of a liquid perfluo ocarbon core that can be vaporized by ultrasound (acoustic droplet vaporization) to generate contrast with excellent spatial and temporal control. When these agents, commonly referred to as nanodroplets, are formulated with cores of low boiling-point perfluo ocarbons such as decaflu orobutane and octafluo opropane, they can be activated with low-mechanical index imaging pulses for diagnostic applications. Since the utilization of minimum mechanical index is often desirable to avoid unnecessary biological effects, enabling consistent activation of these agents in an acoustic fiel is a challenge because the energy that must be delivered to achieve the vaporization threshold increases with depth due to attenuation. A novel vaporization approach called Activation Pressure Matching has been developed to deliver the same pressure throughout a fiel of view in order to produce uniform nanodroplet vaporization and to limit the amount of energy that is delivered. In this manuscript, we discuss the application of this method with a Versasonics V1 Research Ultrasound System to modulate the output pressure from an ATL L11–5 transducer. Vaporization-pulse spacing optimization can be used in addition to matching the activation pressure through depth, and we demonstrate the feasibility of this approach both in vivo and in vitro. The use of optimized vaporization parameters increases the amount of time a single bolus of nanodroplets can generate useful contrast and provides consistent image enhancement in vivo. Therefore, APM is a useful technique for those wishing to maximize the efficac of phase change contrast agent while minimizing delivered acoustic energy

Phase change events of volatile liquid perfluorocarbon contrast agents produce unique acoustic signatures

Phase-change contrast agents (PCCAs) provide a dynamic platform to approach problems in medical ultrasound (US). Upon US-mediated activation, the liquid core vaporizes and expands to produce a gas bubble ideal for US imaging and therapy. In this study, we demonstrate through high-speed video microscopy and US interrogation that PCCAs composed of highly volatile perfluorocarbons (PFCs) exhibit unique acoustic behavior that can be detected and differentiated from standard microbubble contrast agents. Experimental results show that when activated with short pulses PCCAs will over-expand and undergo unforced radial oscillation while settling to a final bubble diameter. The size-dependent oscillation phenomenon generates a unique acoustic signal that can be passively detected in both time and frequency domain using confocal piston transducers with an ‘activate high’ (8 MHz, 2 cycles), ‘listen low’ (1 MHz) scheme. Results show that the magnitude of the acoustic ‘signature’ increases as PFC boiling point decreases. By using a band-limited spectral processing technique, the droplet signals can be isolated from controls and used to build experimental relationships between concentration and vaporization pressure. The techniques shown here may be useful for physical studies as well as development of droplet-specific imaging techniques

The “Fingerprint” of Cancer Extends Beyond Solid Tumor Boundaries: Assessment With a Novel Ultrasound Imaging Approach

Abnormalities of microvascular morphology have been associated with tumor angiogenesis for more than a decade, and are believed to be intimately related to both tumor malignancy and response to treatment. However, the study of these vascular changes in-vivo has been challenged due to the lack of imaging approaches which can assess the microvasculature in 3-D volumes non-invasively. Here, we use contrast-enhanced “acoustic angiography” ultrasound imaging to observe and quantify heterogeneity in vascular morphology around solid tumors

Wideband acoustic activation and detection of droplet vaporization events using a capacitive micromachined ultrasonic transducer

An ongoing challenge exists in understanding and optimizing the acoustic droplet vaporization (ADV) process to enhance contrast agent effectiveness for biomedical applications. Acoustic signatures from vaporization events can be identified and differentiated from microbubble or tissue signals based on their frequency content. The present study exploited the wide bandwidth of a 128-element capacitive micromachined ultrasonic transducer (CMUT) array for activation (8 MHz) and real-time imaging (1 MHz) of ADV events from droplets circulating in a tube. Compared to a commercial piezoelectric probe, the CMUT array provides a substantial increase of the contrast-to-noise ratio

Advances in Molecular Imaging with Ultrasound

Ultrasound imaging has long demonstrated utility in the study and measurement of anatomic features and noninvasive observation of blood flow. Within the last decade, advances in molecular biology and contrast agents have allowed researchers to use ultrasound to detect changes in the expression of molecular markers on the vascular endothelium and other intravascular targets. This new technology, referred to as ultrasonic molecular imaging, is still in its infancy. However, in preclinical studies, ultrasonic molecular imaging has shown promise in assessing angiogenesis, inflammation, and thrombus. In this review, we discuss recent advances in microbubble-type contrast agent development, ultrasound technology, and signal processing strategies that have the potential to substantially improve the capabilities and utility of ultrasonic molecular imaging

Adaptive windowing in contrast-enhanced intravascular ultrasound imaging

Intravascular ultrasound (IVUS) is one of the most commonly-used interventional imaging techniques and has seen recent innovations which attempt to characterize the risk posed by atherosclerotic plaques. One such development is the use of microbubble contrast agents to image vasa vasorum, fine vessels which supply oxygen and nutrients to the walls of coronary arteries and typically have diameters less than 200 µm. The degree of vasa vasorum neovascularization within plaques is positively correlated with plaque vulnerability. Having recently presented a prototype dual-frequency transducer for contrast agent-specific intravascular imaging, here we describe signal processing approaches based on minimum variance (MV) beamforming and the phase coherence factor (PCF) for improving the spatial resolution and contrast-to-tissue ratio (CTR) in IVUS imaging. These approaches are examined through simulations, phantom studies, ex vivo studies in porcine arteries, and in vivo studies in chicken embryos. In phantom studies, PCF processing improved CTR by a mean of 4.2 dB, while combined MV and PCF processing improved spatial resolution by 41.7%. Improvements of 2.2 dB in CTR and 37.2% in resolution were observed in vivo. Applying these processing strategies can enhance image quality in conventional B-mode IVUS or in contrast-enhanced IVUS, where signal-to-noise ratio is relatively low and resolution is at a premium

Enhancing Nanoparticle Accumulation and Retention in Desmoplastic Tumors via Vascular Disruption for Internal Radiation Therapy

Aggressive, desmoplastic tumors are notoriously difficult to treat because of their extensive stroma, high interstitial pressure, and resistant tumor microenvironment. We have developed a combination therapy that can significantly slow the growth of large, stroma-rich tumors by causing massive apoptosis in the tumor center while simultaneously increasing nanoparticle uptake through a treatment-induced increase in the accumulation and retention of nanoparticles in the tumor. The vascular disrupting agent Combretastatin A-4 Phosphate (CA4P) is able to increase the accumulation of radiation-containing nanoparticles for internal radiation therapy, and the retention of these delivered radioisotopes is maintained over several days. We use ultrasound to measure the effect of CA4P in live tumor-bearing mice, and we encapsulate the radio-theranostic isotope 177Lutetium as a therapeutic agent as well as a means to measure nanoparticle accumulation and retention in the tumor. This combination therapy induces prolonged apoptosis in the tumor, decreasing both the fibroblast and total cell density and allowing further tumor growth inhibition using a cisplatin-containing nanoparticle

Contrast Enhanced Superharmonic Imaging for Acoustic Angiography Using Reduced Form-Factor Lateral Mode Transmitters for Intravascular and Intracavity Applications

Techniques to image the microvasculature may play an important role in imaging tumor-related angiogenesis and vasa vasorum associated with vulnerable atherosclerotic plaques. However, the microvasculature associated with these pathologies is difficult to detect using traditional B-mode ultrasound or even harmonic imaging due to small vessel size and poor differentiation from surrounding tissue. Acoustic angiography, a microvascular imaging technique which utilizes superharmonic imaging (detection of higher order harmonics of microbubble response), can yield a much higher contrast to tissue ratio (CTR) than second harmonic imaging methods. In this work, two dual-frequency transducers using lateral mode transmitters were developed for superharmonic detection and acoustic angiography imaging in intracavity applications. A single element dual-frequency IVUS transducer was developed for concept validation, which achieved larger signal amplitude, better contrast to noise ratio (CNR) and pulse length compared to the previous work. A dual-frequency PMN-PT array transducer was then developed for superharmonic imaging with dynamic focusing. The axial and lateral size of the microbubbles in a 200 μm tube were measured to be 269 μm and 200 μm, respectively. The maximum CNR was calculated to be 22 dB. These results show that superharmonic imaging with a low frequency lateral mode transmitter is a feasible alternative to thickness mode transmitters when final transducer size requirements dictate design choices