K. Heath Martin

Current status and prospects for microbubbles in ultrasound theranostics

Encapsulated microbubbles have been developed over the past two decades to provide improvements both in imaging as well as new therapeutic applications. Microbubble contrast agents are used currently for clinical imaging where increased sensitivity to blood flow is required, such as echocardiography. These compressible spheres oscillate in an acoustic field, producing nonlinear responses which can be uniquely distinguished from surrounding tissue, resulting in substantial enhancements in imaging signal-to-noise ratio. Furthermore, with sufficient acoustic energy the oscillation of microbubbles can mediate localized biological effects in tissue including the enhancement of membrane permeability or increased thermal energy deposition. Structurally, microbubbles are comprised of two principal components--an encapsulating shell and an inner gas core. This configuration enables microbubbles to be loaded with drugs or genes for additional therapeutic effect. Application of sufficient ultrasound energy can release this payload, resulting in site-specific delivery. Extensive preclinical studies illustrate that combining microbubbles and ultrasound can result in enhanced drug delivery or gene expression at spatially selective sites. Thus, microbbubles can be used for imaging, for therapy, or for both simultaneously. In this sense, microbubbles combined with acoustics may be one of the most universal theranostic tools.

Dual-frequency piezoelectric transducers for contrast enhanced ultrasound imaging

For many years, ultrasound has provided clinicians with an affordable and effective imaging tool for applications ranging from cardiology to obstetrics. Development of microbubble contrast agents over the past several decades has enabled ultrasound to distinguish between blood flow and surrounding tissue. Current clinical practices using microbubble contrast agents rely heavily on user training to evaluate degree of localized perfusion. Advances in separating the signals produced from contrast agents versus surrounding tissue backscatter provide unique opportunities for specialized sensors designed to image microbubbles with higher signal to noise and resolution than previously possible. In this review article, we describe the background principles and recent developments of ultrasound transducer technology for receiving signals produced by contrast agents while rejecting signals arising from soft tissue. This approach relies on transmitting at a low-frequency and receiving microbubble harmonic signals at frequencies many times higher than the transmitted frequency. Design and fabrication of dual-frequency transducers and the extension of recent developments in transducer technology for dual-frequency harmonic imaging are discussed.

A preliminary engineering design of intravascular dual-frequency transducers for contrast-enhanced acoustic angiography and molecular imaging

Current intravascular ultrasound (IVUS) probes are not optimized for contrast detection because of their design for high-frequency fundamental-mode imaging. However, data from transcutaneous contrast imaging suggests the possibility of utilizing contrast ultrasound for molecular imaging or vasa vasorum assessment to further elucidate atherosclerotic plaque deposition. This paper presents the design, fabrication, and characterization of a small-aperture (0.6 × 3 mm) IVUS probe optimized for high-frequency contrast imaging. The design utilizes a dual-frequency (6.5 MHz/30 MHz) transducer arrangement for exciting microbubbles at low frequencies (near their resonance) and detecting their broadband harmonics at high frequencies, minimizing detected tissue backscatter. The prototype probe is able to generate nonlinear microbubble response with more than 1.2 MPa of rarefractional pressure (mechanical index: 0.48) at 6.5 MHz, and is also able to detect microbubble response with a broadband receiving element (center frequency: 30 MHz, -6-dB fractional bandwidth: 58.6%). Nonlinear super-harmonics from microbubbles flowing through a 200-μm-diameter micro-tube were clearly detected with a signal-to-noise ratio higher than 12 dB. Preliminary phantom imaging at the fundamental frequency (30 MHz) and dual-frequency super-harmonic imaging results suggest the promise of small aperture, dual-frequency IVUS transducers for contrast-enhanced IVUS imaging.

Design factors of intravascular dual frequency transducers for super-harmonic contrast imaging and acoustic angiography

Imaging of coronary vasa vasorum may lead to assessment of the vulnerable plaque development in diagnosis of atherosclerosis diseases. Dual frequency transducers capable of detection of microbubble super-harmonics have shown promise as a new contrast-enhanced intravascular ultrasound (CE-IVUS) platform with the capability of vasa vasorum imaging. Contrast-to-tissue ratio (CTR) in CE-IVUS imaging can be closely associated with low frequency transmitter performance. In this paper, transducer designs encompassing different transducer layouts, transmitting frequencies, and transducer materials are compared for optimization of imaging performance. In the layout selection, the stacked configuration showed superior super-harmonic imaging compared with the interleaved configuration. In the transmitter frequency selection, a decrease in frequency from 6.5 MHz to 5 MHz resulted in an increase of CTR from 15 dB to 22 dB when receiving frequency was kept constant at 30 MHz. In the material selection, the dual frequency transducer with the lead magnesium niobate-lead titanate (PMN-PT) 1-3 composite transmitter yielded higher axial resolution compared to single crystal transmitters (70 μm compared to 150 μm pulse length). These comparisons provide guidelines for the design of intravascular acoustic angiography transducers.

Small aperture, dual frequency ultrasound transducers for intravascular contrast imaging

Intravascular ultrasound imaging is a powerful tool in assessing cardiovascular diseases, and contrast enhanced ultrasound imaging has the ability to generate high signal to noise ratio images and can provide information such as degree of plaque vascularization and molecular function. Currently, however, contrast enhanced intravascular ultrasound (CE-IVUS) imaging has not been used clinically. Design, fabrication, and characterization of a small aperture (0.6 × 3 mm), dual frequency ultrasound transducer were performed, followed by microbubble tests for viability study of CE-IVUS imaging. Results show that more than 1.23 MPa (mechanical index: 0.48) was generated by the 6.5 MHz transmission component at the imaging area, where nonlinear response of microbubbles was detected by the 30 MHz broadband (-6dB bandwidth: 58.6%) receiving component. Nonlinear echo response from microbubbles flowing through a micro-tube with diameter of 0.2 mm was clearly detected with a signal to noise ratio higher than 12 dB. These promising results show that small aperture, dual frequency transducers are capable of detecting contrast agents using split frequency detection methods and suggest they are a reasonable platform for CE-IVUS imaging.

A configurable dual-frequency transmit/receive system for acoustic angiography imaging

Acoustic angiography is a high-resolution imaging modality for small vascular structure. It utilizes the nonlinear backscatter of microbubble contrast agents (MCAs) to delineate blood vessels. In acoustic angiography, where MCAs are insonified with high rarefractional pressures at resonance frequency (6.5MHz), high-order harmonics (30 MHz) become more evident and can be utilized to produce high-resolution images for detecting small vascular structures. We developed a configurable dual-frequency system platform dedicated to acoustic angiography. The system consists of pulse generation, data acquisition and signal processing blocks. It is controlled by a field programmable gate array (FPGA), which enables flexible programming, and many on-board processing and stimulation modes. The system was shown to be capable of acoustic angiography as well as traditional B-mode 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 200μm. 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 4.2dB, while combined MV and PCF processing improved spatial resolution by 41.7%. Improvements of 2.2dB 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.

Dual-frequency IVUS array for contrast enhanced intravascular ultrasound imaging

Recent studies suggest that contrast enhanced intravascular ultrasound (CE-IVUS) may be used for identifying vulnerable plaques through molecular imaging or detecting neovascularizations within a growing atherosclerotic lesion. However, typical intravascular ultrasound (IVUS) transducers operate at a high frequency band (20-60 MHz) which makes them not ideal for imaging microbubble contrast agents due to the less effective microbubble excitation at high frequencies. In this paper, a prototyped dual-frequency array for CE-IVUS was developed and tested. The prototype flat transducer array consists of a receiving array (32 elements, 30 MHz) built on the top of a transmitting array (8 sub-elements, 2.25 MHz) to achieve real-time superharmonic contrast enhanced imaging. The size of the receiving aperture was varied, tested and resultant images were compared. Images of a contrast-filled microtube can be observed clearly with only 4 receiving elements at an excitation voltage of 55 V, which indicates feasibility of CE-IVUS imaging after circularly wrapping the array for catheter integration.

A Dual Frequency IVUS Transducer With a Lateral Mode Transmitter for Contrast Enhanced Intravascular Ultrasound Imaging

Recent studies suggest that dual frequency intravascular ultrasound (IVUS) transducers are promising in contrast ultrasound for molecular imaging or vasa vasorum (VV) assessment to identify vulnerable plaques. Low frequency (1–3 MHz) acoustic waves are widely used for contrast imaging because it can excite microbubbles more effectively. However, conventional thickness mode 1–3 MHz transducers are not suitable for IVUS since bulky transducer size is not permitted in fine IVUS catheters used for coronary interventions (approx. 3-French). In this paper, a dual frequency (2.25 MHz/30 MHz) IVUS transducer with a lateral mode transmitter (2.25 MHz) and a thickness mode high frequency receiver (30 MHz) was designed, fabricated and characterized. In contrast detection tests, superharmonic microbubble responses flown through a 200 μm diameter tube was successfully detected with a contrast to noise ratio (CNR) of 13 dB and an axial resolution (−6 dB) of 0.1 μs (150 μm). The results showed that this dual frequency IVUS transducer with a lateral mode transmitter can be used to detect super-harmonic signal (12th to 15th harmonic) ideal for superharmonic imaging of microvascular structures.Copyright

Real-time ultrasound angiography using superharmonic dual-frequency (2.25 MHz/30 MHz) cylindrical array: In vitro study

HIGHLIGHTSA dual‐frequency IVUS array transducer is developed for acoustic angiography.The small size is obtained with a reduced form‐factor lateral mode transmitter.The superharmonic imaging is rendered using the Verasonics system.High CNR and good spatial resolution are achieved with 1‐cycle burst excitation. ABSTRACT Recent studies suggest that dual‐frequency intravascular ultrasound (IVUS) transducers allow detection of superharmonic bubble signatures, enabling acoustic angiography for microvascular and molecular imaging. In this paper, a dual‐frequency IVUS cylindrical array transducer was developed for real‐time superharmonic imaging. A reduced form‐factor lateral mode transmitter (2.25 MHz) was used to excite microbubbles effectively at 782 kPa with single‐cycle excitation while still maintaining the small size and low profile (5 Fr) (3 Fr = 1 mm) for intravascular imaging applications. Superharmonic microbubble responses generated in simulated microvessels were captured by the high frequency receiver (30 MHz). The axial and lateral full‐width half‐maximum of microbubbles in a 200‐&mgr;m‐diameter cellulose tube were measured to be 162 &mgr;m and 1039 &mgr;m, respectively, with a contrast‐to‐noise ratio (CNR) of 16.6 dB. Compared to our previously reported single‐element IVUS transducers, this IVUS array design achieves a higher CNR (16.6 dB vs 11 dB) and improved axial resolution (162 &mgr;m vs 616 &mgr;m). The results show that this dual‐frequency IVUS array transducer with a lateral‐mode transmitter can fulfill the native design requirement (˜3–5 Fr) for acoustic angiography by generating nonlinear microbubble responses as well as detecting their superharmonic responses in a 5 Fr form factor.