Medical ultrasonography is a powerful and costeffective diagnostic technique. To date, high-end medical imaging systems are able to efficiently implement real-time image formation techniques that can dramatically improve the diagnostic capabilities of ultrasound. Highly performing and thermally efficient ultrasound probes are then required to successfully enable the most advanced techniques. In this context, ultrasound transducer technology is the current limiting factor. Capacitive micromachined ultrasonic transducers (CMUTs) are micro-electro-mechanical systems (MEMS)-based devices that have been widely recognized as a valuable alternative to piezoelectric transducer technology in a variety of medical imaging applications. Wideband operation, good thermal efficiency, and low fabrication cost, especially for those applications requiring high-volume production of small-area dice, are strength factors that may justify the adoption of this MEMS technology in the medical ultrasound imaging field. This paper presents the design, development, fabrication, and characterization of a 12-MHz ultrasound probe for medical imaging, based on a CMUT array. The CMUT array is microfabricated and packed using a novel fabrication concept specifically conceived for imaging transducer arrays. The performance of the developed probe is optimized by including analog front-end reception electronics. Characterization and imaging results are used to assess the performance of CMUTs with respect to conventional piezoelectric transducers.

A CMUT probe for medical ultrasonography: from microfabrication to system integration

Tools for noninvasively modulating neural signaling in peripheral organs will advance the study of nerves and their effect on homeostasis and disease. Herein, we demonstrate a noninvasive method to modulate specific signaling pathways within organs using ultrasound (U/S). U/S is first applied to spleen to modulate the cholinergic anti-inflammatory pathway (CAP), and US stimulation is shown to reduce cytokine response to endotoxin to the same levels as implant-based vagus nerve stimulation (VNS). Next, hepatic U/S stimulation is shown to modulate pathways that regulate blood glucose and is as effective as VNS in suppressing the hyperglycemic effect of endotoxin exposure. This response to hepatic U/S is only found when targeting specific sub-organ locations known to contain glucose sensory neurons, and both molecular (i.e. neurotransmitter concentration and cFOS expression) and neuroimaging results indicate US induced signaling to metabolism-related hypothalamic sub-nuclei. These data demonstrate that U/S stimulation within organs provides a new method for site-selective neuromodulation to regulate specific physiological functions.

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Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation

Focused ultrasound offers a non-invasive way of depositing acoustic energy deep into the body, which can be harnessed for a broad spectrum of therapeutic purposes, including tissue ablation, the targeting of therapeutic agents, and stem cell delivery. Phased array transducers enable electronic control over the beam geometry and direction, and can be tailored to provide optimal energy deposition patterns for a given therapeutic application. Their use in combination with modern medical imaging for therapy guidance allows precise targeting, online monitoring, and post-treatment evaluation of the ultrasound-mediated bioeffects. In the past there have been some technical obstacles hindering the construction of large aperture, high-power, densely-populated phased arrays and, as a result, they have not been fully exploited for therapy delivery to date. However, recent research has made the construction of such arrays feasible, and it is expected that their continued development will both greatly improve the safety and efficacy of existing ultrasound therapies as well as enable treatments that are not currently possible with existing technology. This review will summarize the basic principles, current statures, and future potential of image-guided ultrasound phased arrays for therapy.

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Image-guided ultrasound phased arrays are a disruptive technology for non-invasive therapy

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.

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Dual-Frequency Piezoelectric Transducers for Contrast Enhanced Ultrasound Imaging

For several years, the standard in ultrasound imaging has been second-harmonic imaging. A new imaging technique dubbed "super-harmonic imaging" (SHI) was recently proposed. It takes advantage of the higher-third to fifth-harmonics arising from nonlinear propagation or ultrasound-contrast-agent (UCA) response. Next to its better suppression of near-field artifacts, tissue SHI is expected to improve axial and lateral resolutions resulting in clearer images than second-harmonic imaging. When SHI is used in combination with UCAs, a better contrast-to-tissue ratio can be obtained. The use of SHI implies a large dynamic range and requires a sufficiently sensitive array over a frequency range from the transmission frequency up to its fifth harmonic (bandwidth > 130%). In this paper, we present the characteristics and performance of a new interleaved dual frequency array built chiefly for SHI. We report the rationale behind the design choice, frequencies, aperture, and piezomaterials used. The array is efficient both in transmission and reception with well-behaved transfer functions and a combined -6-dB bandwidth of 144%. In addition, there is virtually no contamination of the harmonic components by spurious transducer transmission, due to low element-to-element crosstalk (< 30 dB) and a low transmission efficiency of the odd harmonics (< 46 dB). The interleaved array presented in this article possesses ideal characteristics for SHI and is suitable for other methods like second-harmonic, subharmonic, and second-order ultrasound field (SURF) imaging.

Super-harmonic imaging: development of an interleaved phased-array transducer

Capacitive micromachined ultrasonic transducers (CMUTs) present advantages such as wide frequency bandwidth, which could be further developed for nonlinear imaging. However, the driving electrostatic force induces a nonlinear behavior of the CMUT, thus generating undesirable harmonic components in the generated acoustic signal. Consequently, the use of CMUT for harmonic imaging (with or without contrast agents) becomes challenging. This paper suggests 2 compensation approaches, linear and nonlinear methods, to cancel unwanted nonlinear components. Furthermore, nonlinear responses from contrast agent were evaluated using CMUT in transmit before and after compensation. The results were compared with those obtained using a PZT transducer in transmit. Results showed that CMUT nonlinear behavior is highly influenced by the excitation to bias voltage ratio. Measurements of output pressure very close to the CMUT surface allow the estimation of optimal parameters for each compensation approach. Both methods showed a harmonic reduction higher than 20 dB when one element or several elements are excited. In addition, the study demonstrates that nonlinear approach seems to be more efficient because it is shown to be less sensitive to interelement variability and further avoids fundamental component deterioration. The results from contrast agent measurements showed that the responses obtained using CMUT elements in transmit with compensation were similar to those from PZT transducer excitation. This experimental study demonstrates the opportunity to use CMUT with traditional harmonic contrast imaging techniques.

Exploitation of capacitive micromachined transducers for nonlinear ultrasound imaging

Piezoelectric and capacitive micromachined ultrasound transducers (CMUT) are usually measured and compared in regards to acoustic and electro-acoustic performances. This paper is focused on the imaging performances of such transducers and propose a quantitative imaging assessment of B-mode images. In this purpose, fully integrated CMUT and piezocomposite-based probes were manufactured. Transducers were designed with close features (geometries, center frequency, interconnect and packaging) and plug on a clinical ultrasound system with a research interface. Major imaging performances (speckle to noise ratio, resolutions and contrast) of the probes are presented. Despite an environment dedicated to piezoelectric transducers, CMUT probe exhibits comparable image quality as compared to a state-of-the-art piezocomposite probe. Indeed, close resolutions are calculated, field of view is improved in phased-array imaging, and contrast is significantly improved.

Piezocomposite and CMUT arrays assessment through in vitro imaging performances

A wide range of ultrasound methods has been proposed to assess the mechanical strength of bone. The axial transmission technique, which consists of measuring guided elastic modes through the cortical shell of long bones such as the radius or tibia, has recently emerged as one of the most promising approaches of all bone exploration methods. Determination of dispersion curves of guided waves is therefore of prime interest because they provide a large set of input data required to perform inverse process, and hence to evaluate bone properties (elastic and geometric). The cortical thickness of long bones ranges from approximately 1 to 7 mm, resulting in wide inter-individual variability in the guided wave response. This variability can be overcome by using a single probe able to operate with a tunable central frequency, typically within the 100 kHz to 2 MHz frequency range. However, there are certain limitations in the design of low-frequency arrays using traditional PZT technology; these limitations have triggered active research to find alternative solutions. Capacitive micromachined ultrasonic transducers (cMUTs) have the potential to overcome these limitations and to improve axial transmission measurement significantly. The objective of this study was to design and construct a new cMUT-based axial transmission probe and to validate the approach. We report all the steps followed to construct such a prototype, from the description of the fabrication of the cMUT (based on a surface micromachining process) through probe packaging. The fabricated device was carefully characterized using both electrical and optical measurements to check the homogeneity of the device, first from cMUT to cMUT and then from element to element. Finally, axial transmission measurements carried out with the prototype cMUT probe are shown and compared with results obtained with a PZT-based array.

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A capacitive micromachined ultrasonic transducer probe for assessment of cortical bone

In this work, we report on the characterization of a CMUT probe (Capactive Micromachined Ultrasound Transducer) for Tissue Harmonic Imaging (THI). The intrinsic nonlinear behavior of the CMUT probe was first investigated. Matched electrical waveforms were transmitted to limit the impact of the transmit response distortion. With the implemented method, we demonstrated higher performances through in-vitro harmonic imaging.

Tissue harmonic imaging with CMUTs

Ultrasound-mediated targeted therapy represents a promising strategy in the arsenal of modern therapy. Capacitive micromachined ultrasonic transducer (cMUT) technology could overcome some difficulties encountered by traditional piezoelectric transducers. In this study, we report on the design, fabrication, and characterization of an ultrasound-guided focused ultrasound (USgFUS) cMUT probe dedicated to preclinical evaluation of targeted therapy (hyperthermia, thermosensitive liposomes activation, and sonoporation) at low frequency (1 MHz) with simultaneous ultrasonic imaging and guidance (15 to 20 MHz). The probe embeds two types of cMUT arrays to perform the modalities of targeted therapy and imaging respectively. The wafer-bonding process flow employed for the manufacturing of the cMUTs is reported. One of its main features is the possibility of implementing two different gap heights on the same wafer. All the design and characterization steps of the devices are described and discussed, starting from the array design up to the first in vitro measurements: optical (microscopy) and electrical (impedance) measurements, arrays’ electroacoustic responses, focused pressure field mapping (maximum peak-to-peak pressure = 2.5 MPa), and the first B-scan image of a wire-target phantom.

Mathieu Legros

Papers

Exploitation of capacitive micromachined transducers for nonlinear ultrasound imaging

Piezocomposite and CMUT arrays assessment through in vitro imaging performances

A capacitive micromachined ultrasonic transducer probe for assessment of cortical bone

Tissue harmonic imaging with CMUTs

A cMUT probe for ultrasound-guided focused ultrasound targeted therapy