Home
Search
Collections
Journals
About
Contact us
My IOPscience
Evaluation of bias voltage modulation sequence for nonlinear contrast agent imaging using a capacitive micromachined ultrasonic transducer array
This content has been downloaded from IOPscience. Please scroll down to see the full text. 2014 Phys. Med. Biol. 59 4879 (http://iopscience.iop.org/0031-9155/59/17/4879) View the table of contents for this issue, or go to the journal homepage for more
Download details: IP Address: 132.174.255.116 This content was downloaded on 11/11/2014 at 22:58
Please note that terms and conditions apply.
Institute of Physics and Engineering in Medicine Phys. Med. Biol. 59 (2014) 4879–4896
Physics in Medicine & Biology doi:10.1088/0031-9155/59/17/4879
Evaluation of bias voltage modulation sequence for nonlinear contrast agent imaging using a capacitive micromachined ultrasonic transducer array Anthony Novell1,2, Mathieu Legros3, Jean-Marc Grégoire1, Paul A Dayton2 and Ayache Bouakaz1 1
Université François-Rabelais de Tours, Inserm, Imagerie et Cerveau UMR U930, Tours, France 2 Joint Department of Biomedical Engineering, The University of North Carolina and North Carolina State University, Chapel Hill, NC 27599, USA 3 Vermon SA, Tours, France E-mail: [email protected] Received 15 May 2014, revised 2 July 2014 Accepted for publication 4 July 2014 Published 7 August 2014 Abstract
Many clinical diagnoses have now been improved thanks to the development of new techniques dedicated to contrast agent nonlinear imaging. Over the past few years, Capacitive Micromachined Ultrasonic Transducers (cMUTs) have emerged as a promising alternative to traditional piezoelectric transducers. One notable advantage of cMUTs is their wide frequency bandwidth. However, their use in nonlinear imaging approaches such as those used to detect contrast agents have been challenging due their intrinsic nonlinear character. We propose a new contrast imaging sequence, called bias voltage modulation (BVM), specifically developed for cMUTs to suppress their inherent nonlinear behavior. Theoretical and experimental results show that a complete cancellation of the nonlinear signal from the source can be reached when the BVM sequence is implemented. In-vitro validation of the sequence is performed using a cMUT probe connected to an open scanner and a flow phantom setup containing SonoVue microbubbles. Compared to the standard amplitude modulation imaging mode, a 6 dB increase of contrast-to-tissue ratio was achieved when the BVM sequence is applied. These results reveal that the problem of cMUT nonlinearity can be addressed, thus expanding the potential of this new transducer technology for nonlinear contrast agent detection and imaging.
0031-9155/14/174879+19$33.00 © 2014 Institute of Physics and Engineering in Medicine Printed in the UK & the USA
4879
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Keywords: amplitude modulation, bias voltage, cMUT, multi-pulse sequence, contrast agent imaging, harmonic, nonlinear behavior (Some figures may appear in colour only in the online journal) 1. Introduction Throughout the world, contrast agent imaging is routinely used in the fields of echocardiography for myocardial perfusion assessment (Davidson and Lindner 2012) and radiology for tumor detection and characterization (Wilson and Burns 2010, Novell et al 2013b). During the ultrasound examination, contrast agents, consisting of gas-filled microbubbles, are intravenously injected in order to enhance the backscattered signal from the blood stream. Many techniques based on the nonlinear and transient characteristics of microbubbles are used to improve the contrast-enhanced image quality and the confidence of the clinical diagnosis. These approaches have been developed to recover the specific signatures from microbubbles while the response from tissue is suppressed or reduced (De Jong et al 2009). For example, harmonic scattering from microbubbles such as 2nd harmonic (De Jong et al 2002), superharmonic (Bouakaz et al 2002, Guiroy et al 2013) or subharmonic (Chomas et al 2002) can be used to increase the contrast-to-tissue ratio (CTR). In this context, multi-pulse techniques such as pulse inversion (PI) (Simpson et al 1999), amplitude (or power) modulation (AM) (Brock-Fisher et al 1996), or contrast pulse sequencing (CPS) (Phillips 2001) have been introduced and are currently implemented in commercial ultrasound scanners. For PI and AM methods, two consecutive pulses with different phases or amplitudes are transmitted. Scheme of the standard AM method is given in figure 1(a). The PI sequence enhances the signal for the even harmonics and suppresses the odd frequency components whereas the AM method allows the detection of both the odd and even nonlinear components generated by microbubbles (Eckersley et al 2005). Previous studies reported that the AM method showed a better specificity at low (Eckersley et al 2005) and high frequency (Needles et al 2010) than a PI sequence. Moreover, both the PI and AM methods can be also combined to improve the sensitivity (Phillips 2001, Eckersley et al 2005). The use of sequences with more than two transmit pulses, such as CPS, allows the enhancement of the contrast detection (Phillips 2001) and the reduction of tissue motion artifacts (Averkiou 2000). Nevertheless, the implementation of these sequences is usually done at the expense of the frame rate and/or the resolution. Over the past 15 years, the capacitive micromachined ultrasonic transducer (cMUT) has emerged as a promising alternative to the conventional piezoelectric-based technology. A cMUT element is composed of multiple cells acting as interconnected plate capacitors in which a flexible membrane is placed between the top and the bottom electrodes. When an excitation voltage is applied, the electrostatic force exerted between the electrodes induces membrane vibrations, generating thus an acoustic wave. Nowadays, cMUT are developed and validated for a large range of uses (Oralkan et al 2002, Caliano et al 2005, Khuri-Yakub et al 2007, Cristman et al 2009). In the medical field, cMUT technology focuses on different applications such as Doppler (Shin et al 2013), intravascular ultrasound (Tekes et al 2012), photoacoustic imaging (Vaithilingam et al 2009, Chen et al 2012) as well as therapy (Bayram et al 2005, Wong et al 2010, Khuri-Yakub and Oralkan 2011). Very recently, a 12 MHz cMUT probe has been connected to a commercial ultrasound scanner and validated for medical imaging on humans (Savoia et al 2012). cMUTs offer interesting acoustic properties such as a large directivity (Certon et al 2006, Degertekin et al 2006) and a wide frequency bandwidth which can be higher than 110% at -6 dB (Huang et al 2006, Savoia et al 2012). This last property is particularly interesting for contrast agent imaging since it allows the recovery of several harmonic components, which has shown to be particularly 4880
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 1. Principle of standard amplitude modulation sequence using a piezoelectric transducer (a) and a cMUT (b).
valuable in high signal-to-noise contrast imaging (Kruse and Ferrara 2005, Gessner et al 2013). Nevertheless, cMUT are inherently nonlinear because the electrostatic force depends on the square of the applied voltage and the membrane displacement (Zhou et al 2004, Lohfink and Eccardt 2005a, Novell et al 2009). As a consequence, the acoustic wave generated by the cMUT probe contains an undesirable 2nd harmonic component in addition to the fundamental excitation. The harmonic to fundamental ratio at the cMUT outpout depends on the transmitted frequency and is proportional to the ratio vac/Vdc where vac is the applied voltage and Vdc is the bias voltage (Lohfink and Eccardt 2005b, Novell et al 2009). Harmonic distortion can be predicted by modeling the cMUT behavior (Lohfink and Eccardt 2005b, Sénégond et al 2013). For native or contrast harmonic imaging, the nonlinear component generated at the surface of the cMUT pollutes the nonlinear backscattered echoes from the explored media and thus deteriorates the image quality. Many studies describe various approaches to reduce or control the harmonic distortion induced by the cMUT. Zhou et al and our group have proposed different methods based on the transmission of a pre-distorted waveform to reduce this unwanted component (Zhou et al 2004, Novell et al 2009). Both methods consist in the addition of a new high frequency component to the original driving signal. The unwanted 2nd harmonic component from cMUT is then suppressed by linear or nonlinear interaction with the added component. Experimental results demonstrated the efficiency of these compensation approaches with a significant reduction (> 20 dB) of the 2nd harmonic amplitude at the surface of the cMUT. Recently, these compensation approaches have been successfully implemented into an open scanner allowing thus the exploitation of the frequency bandwidth of cMUT for wideband nonlinear imaging (Novell et al 2013a). We demonstrated that a significant increase of 180% in CTR could be reached by selective imaging of both the 2nd harmonic and the subharmonic components simultaneously using a cMUT linear array probe. Nevertheless, the optimization of these approaches requires the use of an ultrasound scanner with analog transmitters and a prior knowledge of the cMUT nonlinear behavior. More recently, Satir and Degertekin suggested that the nonlinearity of the cMUT is mainly caused by the inverse gap dependence of the electrostatic force (Satir and Degertekin 2012). To solve the problem of nonlinearity, a high voltage subharmonic excitation (without bias voltage) was transmitted and a nonlinear feedback is added to compensate the harmonic resulting from the gap dependence. Concretely, the gap feedback consists in the addition of a series impedance to the cMUT capacitance. Furthermore, the authors suggest the use of a dual-electrode cMUT structure to preserve the sensitivity in receive mode (Guldiken et al 2006). Experimental results 4881
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
show that a 10 dB improvement in the harmonic ratio can be achieved. Moreover, Degertekin has recently proposed cMUT fabrication methods dedicated to harmonic imaging applications (Degertekin 2009). A control of the harmonic vibrations of the membrane is suggested by adding a mass load positioned at predetermined locations along the membrane. Using a cMUT probe, the efficiency of most of the current nonlinear contrast agent imaging sequences is limited because of the intrinsic cMUT nonlinear behavior. For example, the efficacy of the standard amplitude modulation sequence is degraded because an unwanted nonlinear wave from cMUT still remains after processing as shown in figure 1(b). Unfortunately, it will not be possible to discriminate the nonlinear response from microbubbles to the propagation of the nonlinear wave generated by the cMUT. This will be expressed by a degradation of the CTR. Previous works have proposed different multiple-firing sequences based on the principle of PI specially adapted for cMUT (Panda et al 2006, Ladabaum and Panda 2009). Compared to PI, the authors have proposed the addition of a third firing in which the transmit waveform is inverted for adjacent elements (Ladabaum and Panda 2009) or by alternating the bias voltage polarity (Panda et al 2006). The inversion of bias voltage polarity can be done on the cMUT probe with a control of the elevation phase (Daft et al 2006). The nonlinearity from the cMUT can be cancelled after processing. In the present study, we investigate the potential of a new multi-pulse approach based on the modulation of the bias voltage amplitude applied to the cMUT. The bias voltage modulation is specifically chosen to suppress both the linear and the unwanted harmonic components generated by the cMUT in the final image. This approach, modifying the amplitude of the transmitted pulses, is based on the same principle as AM imaging to allow the contrast enhancement. 2. Material and methods 2.1. Principle of bias voltage modulation sequence
When an excitation voltage V(t) is applied to the cMUT electrode, the membrane is submitted to an electrostatic force inducing vibrations. The electrostatic force (F) applied to the cMUT membrane could be expressed through the following equation (Certon et al 2005): V(t)2 1 A F(t) = ε 0 el (1) 2 (hgap − d(t))2
where ε0 is the vacuum permittivity, Ael is the electrode surface area, V is the voltage applied between the two electrodes, hgap is the effective gap height, d the membrane displacement and t the time. According to (1), there are two main sources of nonlinear distortion, inherent to the cMUT principle, which are the membrane displacement and the applied voltage (Ladabaum et al 1998, Lohfink and Eccardt 2005b). For a cMUT transducer, a bias voltage Vdc is usually added to an excitation voltage Vac (t) to improve the sensitivity of the probe. The applied voltage can be expressed as: V(t) = vac cos (2πf0 t) + Vdc (2)
where Vac(t) = vac cos(2πf0t) and f0 is the frequency. As a result, the applied force is proportional to (Novell et al 2009): F α V2dc + 2 VdcVac(t) + Vac(t)2 F α
2 v2 v ac + V2dc (3) + 2 Vdcvaccos (2πf0 t) + ac cos (4πf0 t) 2 2
4882
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 2. Design of the cMUT output waveforms for the three transmitted pulses using
different bias voltage. For each pulse, an illustration of the spectral representation is given on the right column.
As a result, the ultrasound wave emitted by a cMUT is composed of a linear fundamental component depending on the term “Vdc vac” and a 2nd harmonic component depending on 2 the term “ v ac ”. For contrast harmonic imaging and using multi-pulse excitations, it is necessary to cancel both linear and nonlinear echoes from tissue scatterers. To this purpose, a specific multi-pulse scheme, called bias voltage modulation (BVM) sequence, is designed in which three successive pulses (respectively called P1, P2 and P3) are transmitted with different amplitudes. Compared to the traditional AM sequence, the amplitude of excitation voltage (vac) remains the same for the three transmitted pulses. Here, the amplitude variation is only applied on the bias voltage (Vdc), which is varied with an amplification factor of 1, 2 and 3 according to the transmitted pulse. For each pulse, the driving amplitude is defined as: v(4) ac1 = vac2 = vac3 = A V (5) dc1 = B;Vdc2 = 2B; Vdc3 = 3B
Where vaci and vdci are the excitation voltage and the bias voltage of the pulse Pi, respectively. A and B are constants. Using these parameters, the three acoustic waves (successively transmitted to the media) theoretically contain a linear component with different factor amplitude of 1, 2 and 3 for P1, P2 and P3, respectively, but exactly the same second harmonic amplitude (figure 2). In fact, according to (3), a variation of the bias voltage only modifies the amplitude of the linear component and does not affect the level of the second harmonic component. This property is true when a cMUT operates in a conventional regime or, in other words, when the bias voltage is below the collapse voltage (Oralkan et al 2006, 4883
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 3. Principle of the bias voltage modulation approach on a linear reflector. For each step, the spectral representation is given on the bottom.
Legros et al 2011). For high bias voltage, the membrane of the cMUT cells collapses on to the substrate, so the center of the membrane cannot move freely and the output acoustic wave becomes strongly nonlinear. In the particular case of nonlinear imaging, the linear response from tissue must be eliminated. However, echoes from linear reflectors like normal tissue will be composed of two frequency components at f0 and 2 f0 because of cMUT nonlinear behavior. One solution to cancel the unwanted echoes consists in the following post-processing operation: E (6) 1 + E 3 – 2E 2
where Ei is the backscattered signal from Pi. This operation is available when the cMUT is used in transmit mode. In fact, the fundamental component from Pi generated by the source is proportional to the term. As a result, after post-processing, the linear part of the three output waves emitted by the cMUT (3) can be expressed as: Vdc1vac1 + Vdc3vac3 − 2 Vdc2vac2 = AB + 3AB − 2*2AB = 0
(7)
Similarly, the harmonic component generated from Pi is proportional to vaci 2. The resulting harmonic part can be expressed as: 2 vac1 + vac3 2 − 2vac2 2 = A2 + A2 − 2A2 = 0 (8) Consequently, both the linear and the nonlinear components resulting from the source are suppressed thanks to this combination. The BVM sequence is described for a linear (i.e. tissue) and a nonlinear reflector (i.e. microbubbles) in figures 3 and 4, respectively using the transmitted pulses P1, P2 and P3 (figure 2). After processing, the resulting signal from a linear reflector such as tissue would be cancelled (figure 3) while a significant nonlinear response from microbubbles could be preserved (figure 4). Nevertheless, the operation in (6) cannot be applied when the cMUT is used in receive mode because the cMUT electromechanical conversion efficiency depends on the bias voltage. In 4884
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 4. Principle of the bias voltage modulation approach on a contrast agent micro-
bubble. For each step, the spectral representation is given on the bottom.
other words, the cMUT sensitivity in receive mode will be different for each pulse. For example, the amplitude of the E3 response will increase by a factor 3 compared to the amplitude of E1 during the electromechanical conversion step. As a result, in pulse-echo mode (i.e. for imaging), the difference of sensitivity for each pulse must be scaled up and new appropriate coefficients must be defined and applied. Theoretically, when a cMUT is used in pulse-echo mode, responses from a linear reflector (nonlinear propagation is neglected) can be written as: E1 = α cos (2πf0 t) + β cos (4πf0 t);
⎡ ⎤ E 2 = 2 ⎣2α cos (2πf0 t) + β cos (4πf0 t)⎦; E 3 = 3 ⎡⎣3α cos (2πf0 t) + β cos (4πf0 t)⎤⎦
(9)
where α and β are constants. A complete suppression of the echoes from a linear reflector can be obtained using the following operation: E (10) 3 + 3*E1 − 3*E 2 2.2. cMUT probe specifications
A 64-element cMUT linear array probe (Vermon SA, Tours, France) centered at 5 MHz with a pitch of 305 µm and an elevation of 8 mm is used in this study. The measured fractional bandwidth at -3 dB of the cMUT probe is 99% which is approximately 40% much wider than an equivalent commercial linear array piezoelectric probe) (Novell et al 2013a). For this probe, the static collapse voltage of the membranes is estimated at 100 V. 2.3. Hydrophone measurements
Hydrophone measurements are performed using a 0.2 mm needle hydrophone (Precision Acoustics, Dorchester Dorset, UK) mounted on a XYZ positioning system (TriOptics, Wedel, 4885
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 5. Picture of the cMUT probe (a) and experimental setup used for the hydrophone measurements (b).
Germany) and positioned in front of the probe as shown in figure 5(b). The output waveform generated from the cMUT probe is measured in the immediate vicinity of the source surface (2 mm). The excitation signal is generated using Matlab (Mathworks, Natick, MA) and then transmitted to a 64-channel fully programmable ultrasound system (M2M, Les Ulis, France) equipped with analog transmitters. The transmitted signal consisted of a Gaussian pulse, centered at 3 MHz, with a bandwidth of 30% to avoid frequency overlapping. The bias voltage issued from a controllable power supply (PPS1007, Motech, Tainan, Taiwan) is coupled to the excitation voltage and applied to the cMUT probe. First, the bias voltage is varied from 0 V to 120 V in order to evaluate the behavior of the cMUT in different operation regimes. In this experiment, the excitation voltage is relatively low (20 Vpeak) to avoid the dynamic collapse of cMUT membranes. For the other experiments using the BVM sequence, the bias voltage is fixed at 20 V, 40 V and 60 V according to the transmitted pulse (Pi). In order to preserve a good sensitivity, the excitation voltage is set to the maximal value delivered by the open scanner (40 Vpeak). Acoustic signals received by the hydrophone are then visualized with a digital oscilloscope (Tektronix, Beaverton, OR) and transferred to a personal computer through a GPIB port (National Instruments, Austin, TX) for further analysis using Matlab. The BVM sequence is first evaluated on three adjacent elements of the cMUT probe (figure 5(a)). Excitation voltage and bias voltage are independently transmitted to the elements. To avoid the temporal overlapping and extract the response of each element, the excitation 4886
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 6. Acoustical measurements setup (a) and flow phantom setup used for contrast
agent imaging (b).
voltage is transmitted with a delay of 10 µs between each element. A homemade electronic board is used to simultaneously dispatch the three bias voltages to the three adjacent cMUT elements. 2.4. Simulations
Simulations are carried out in order to evaluate the efficiency of the sequence for detecting the response of a single microbubble. The acoustic response of 3 µm diameter microbubble is calculated using a modified Rayleigh-Plesset equation (De Jong et al 1994). The shell parameters given by Gorce et al (2000) are used to simulate a SonoVue® microbubble. The microbubble resonance frequency corresponds to the excitation frequency (i.e. 3 MHz). For each of three pulses, the acoustic waveform measured in the vicinity of the cMUT output is introduced into the equation as the driving signal. The microbubble is excited at a corresponding peak negative pressure of 92 kPa, 184 kPa and 275 kPa at the fundamental frequency (3 MHz) for P1, P2 and P3, respectively. 2.5. Validation of the BVM sequence on in-vitro setup
The ability of the BVM sequence in cancelling linear echo is evaluated on an in-vitro setup in which the cMUT probe is mounted in a water bath with a piezoelectric single-element transducer (Sofranel, Sartrouville, France) placed perpendicularly. This transducer had a center frequency of 5 MHz (81% bandwidth at -6 dB) and is used in receive mode to collect the scattered echoes from a linear reflector as shown in figure 6(a). The linear reflector is a 50 µm diameter copper wire placed simultaneously at 5 mm from the source and at the focus of the receive transducer (5 cm). The three pulses are transmitted on three different elements with amplitudes of 10 kPa, 20 kPa and 30 kPa according to the applied bias voltage. For flow phantom imaging, the BVM sequence is applied on the total cMUT probe elements. For this purpose, the excitation voltage is simultaneously transmitted to all the elements of the probe. BVM imaging is performed by the acquisition of three consecutive frames for which the bias voltage is varied. The delay between each frame is limited by the programming speed of the power supply and is reduced to the minimum in the experiment (30 ms). The bias voltage used for frames 1, 2 and 3 are 20 V, 40 V and 60 V, respectively. After acquisition of the three frames, the post processing is completed to display the resulting image. The 4887
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 7. Normalized amplitude of the cMUT output wave as a function of the bias
voltage. The fundamental and the harmonic components are extracted from the hydrophone measurements.
experiments are performed on a tissue-mimicking phantom (ATS Laboratories, Bridgeport, CT) containing a 4 mm diameter tube in which a solution of SonoVue microbubbles (Bracco Research, Geneva, Switzerland) is circulating as shown in figure 6(b). The tube is positioned at a distance of 28 mm from the probe surface and thus the electronic focus is set accordingly. The contrast agent solution, SonoVue, is injected into a reservoir with a dilution of 1/2000 and circulated at a fixed flow rate controlled using a pump (Cole-Parmer, Chicago, IL) and set to minimal (20 mL/min). The flow is stopped during the acquisition to minimize the microbubble motion artifacts. The amplitude of the fundamental component at the focus is varied from 185 kPa to 562 kPa (the corresponding non derated Mechanical Index ranged from 0.11 to 0.32 at 3 MHz). For each pulse, sets of 150 radiofrequency (RF) lines are recorded, transferred to Matlab and B-mode images are reconstructed offline using the combination described in (10). 3. Results 3.1. Behavior of the cMUT as a function of the bias voltage amplitude
First, the acoustic wave generated by the cMUT probe was recovered by hydrophone measurements for different bias voltages. The purpose of these measurements was to define the cMUT operation regime for which the BVM sequence can be applied. The normalized amplitude of the cMUT output wave as a function of the bias voltage is shown in figure 7. The solid line corresponds to the amplitude of the whole wave (i.e. fundamental + harmonic component) while the fundamental and the harmonic components are given by the dashed and the dotted lines, respectively. The curve for fundamental component was obtained by filtering the measured acoustic waves in the range from 2 MHz to 4 MHz (Matlab, Butterworth filter, order 3). Similarly, the 2nd harmonic was extracted using a bandpass filter in the range from 5 MHz to 7 MHz. 4888
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 8. Hydrophone measurements of the output pressures (O1, O2, and O3) emitted
by the cMUT for the three transmitted pulses (P1, P2, and P3). The resulting signal after BVM post-processing is shown on the bottom. The corresponding spectra are displayed on the right panel.
The behavior of the cMUT as a function of the bias voltage can be separated into three regimes: growth, maximum and decay. For the total signal curve, the maximum amplitude is reached at a bias voltage of 105 V. From 0 V to 80 V, the amplitude slightly increases while the growth is more pronounced for bias voltages ranging from 80 V to 105 V. For voltages above 105 V, the amplitude of the acoustic wave decreases because of the collapse of the membrane. In fact, in this operating regime, the membrane has fully collapsed and is stuck against the substrate, resulting thus in the generation of a low amplitude acoustic wave. The fundamental component of the acoustic wave shows a similar trend but the maximal value is obtained for 100 V, corresponding to the cMUT collapse voltage. As one can see, the harmonic level remains quasi-constant for bias voltages below a threshold value of 80% collapse voltage. Above this value, the nonlinear level considerably increases because the center of the membrane is probably in contact with the substrate. Furthermore, one can notice that the harmonic level still increases until 105 V, enhancing at the same time, the amplitude of the total acoustic wave. 3.2. Hydrophone measurements of the output waveforms
Figure 8 displays cMUT output waveforms (Oi) at a depth of 2 mm for the three different voltages (Pi) applied on three adjacent elements. The waveform measured for the lower bias voltage (i.e. P1) is given on the top panel. The output waveforms for P2 and P3 are shown in the 2nd and 3rd panels on the left column respectively. As expected, the output amplitude is 4889
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 9. Simulated responses (E1, E2, and E3) from a 3 µm diameter microbubble ex-
cited by the three measured output pressures (P1, P2, and P3) emitted by the cMUT. The resulting signal after BVM post-processing is shown on the bottom. The corresponding spectra are displayed on the right panel.
stronger when the highest bias voltage is transmitted (P3). The bottom panel on the left column displays the resulting signal when BVM processing is applied in transmit mode (i.e. O1 + O3 -2*O2). As expected, no signal persists after the application of this processing method. This result demonstrates that the sequence can be used to efficiently cancel the harmonic signal generated by the source. The corresponding spectra are displayed on the right panel. Compared to the waveform transmitted by P3 (gray dashed line), the fundamental amplitude is reduced by 30 dB while the harmonic level decreases by 15 dB after BVM processing (solid line). Actually, only noise is measured using the processing sequence for fundamental, 2nd harmonic or 3rd harmonic components so the approach allows the suppression of both the fundamental and the harmonic components transmitted by the source. 3.3. Validation of the sequence on a simulated response of microbubble
The three waveforms shown in figure 8 are introduced in the modified Rayleigh-Plesset equation as excitation signals. Corresponding responses of a single microbubble are simulated and echoes are given in figure 9. For all pulses, the microbubble response is strongly asymmetric revealing a high nonlinear response. As one can see on the bottom panel of the left column, the resulting signal after BVM processing is now nonzero. As the unwanted signal generated by the source is entirely cancelled (figure 8), we assume that this resulting signal only 4890
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 10. Echoes (E1, E2, and E3) from a solid reflector for each transmitted pulse.
A PZT single-element is used in receive mode. The resulting signal after BVM postprocessing is shown on the bottom. The corresponding spectra are displayed on the right panel.
corresponds to the microbubble acoustic signature. The spectral analysis (right panel) shows that strong frequency components at 3 MHz, 6 MHz and 9 MHz are preserved after application of the method (solid line). Actually, our approach based on amplitude modulation not only allows the preservation of the 2nd harmonic and 3rd harmonic components but also the detection of a nonlinear component at the fundamental frequency (Eckersley et al 2005). 3.4. In-vitro evaluation of the BVM sequence
Echoes from a solid reflector are shown in figure 10 (left panels). As expected, the signal is drastically reduced after processing. The corresponding spectrum (right panel) reveals that the level of signal cancellation is similar to that obtained with the hydrophone measurements as shown in figure 8 (i.e. 30 dB and 15 dB decrease for the fundamental and harmonic levels respectively). The efficiency of the BVM approach for nonlinear contrast imaging was compared to other standard contrast imaging methods using the cMUT probe. Acquired RF lines were processed and B-mode images of the flow phantom were reconstructed. figure 11 displays the images for 2nd harmonic imaging (A), AM (B) and BVM (C) sequences with the same dynamic range of 35 dB. Each image is normalized by its maximal intensity (i.e. maximal contrast agent response). For each excitation method, the CTR has been calculated from the highlighted region-of-interests (ROIs) shown in the different panels. Each method allows a good 4891
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 11. In-vitro images of a flow phantom containing a diluted solution of SonoVue
using a 64-element cMUT probe. Second harmonic imaging, amplitude modulation imaging and bias voltage modulation imaging are displayed in panel (a), (b) and (c), respectively. Each image is displayed with 35 dB dynamic range. The experiments are realized at 3 MHz, MI = 0.32. For each image, the CTR is calculated for the displayed ROIs.
visualization of the flow of microbubbles circulating in the tube surrounded by the tissue mimicking phantom. Nevertheless, the tissue appearance is considerably degraded in 2nd harmonic imaging mode (figure 11(a)) due to the presence of a strong nonlinear signal generated by the source. As shown in figure 11(b), the nonlinear echo in tissue response is considerably reduced while the signal from microbubbles is enhanced when AM sequence is used. In fact, the application of the AM sequence reduces the nonlinearity from cMUT by half, as shown in figure 1. As a consequence, the nonlinear echo from tissue is partially suppressed. Moreover, compared to 2nd harmonic imaging, the nonlinear response from microbubbles is considerably improved since several nonlinear components (i.e. f0, 2 f0 and 3 f0) are preserved using this approach. An enhancement of the contrast agent discrimination occurs when the BVM sequence is applied (figure 11(c)). This improved discrimination is mainly expressed by a lower nonlinear response in tissue due to the complete cancellation of the nonlinear signal from the source. These qualitative results are confirmed by the CTR measurements which are 11.8 dB, 23.1 dB and 29.2 dB for 2nd harmonic, AM and BVM imaging, respectively. Compared to AM imaging, a gain in CTR of approximately 6 dB is achieved when the BVM sequence is transmitted. One can notice that a nonlinear echo appears beyond the flow of microbubbles in all the images (i.e. 2.8 to 3.6 cm). This artifact, which is known to reduce the CTR, is attributed to the nonlinear propagation of the ultrasound through the cloud of microbubbles (Tang et al 2011). 4892
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
4. Discussion The theoretical and experimental results presented here demonstrated that a new highly sensitive contrast imaging sequence can be applied using a cMUT probe. The BVM approach was specifically designed to cancel out the second harmonic generation of the cMUT. When applied on a cMUT probe, data suggests that our sequence is more sensitive than conventional contrast imaging approaches (figure 11). The efficiency of the BVM approach described in this study implies a consistency of the second harmonic level when the three pulses with different bias voltages are transmitted. As a result, the BVM sequence can be only applied when cMUT is used in its conventional operation regime (i.e. Vdc 15 dB). In this study, the sequence was only evaluated using narrow band excitations (30% at -6 dB) in order to quantify the harmonic cancellation from the source. Even if this frequency band was chosen to avoid frequency band overlap, the multi-pulse approach is also suitable for wide band pulses traditionally used for imaging. In the same way, the method does not depend on the transmit frequency and can be easily applied on the whole cMUT bandwidth. Currently, only the nonlinear fundamental and the 2nd harmonic components are recovered when AM sequence is applied due to the narrow bandwidth of piezoelectric transducers. However, the wide frequency bandwidth of the cMUT can be fully exploited to add other frequency components such as subharmonic or superharmonic to enhance the sensitivity of contrast agent detection (Bouakaz et al 2002, Novell et al 2013a). Similarly to other traditional multi-pulse sequences used for contrast agent imaging (i.e. PI, AM, CPS), the nonlinear propagation of the acoustic wave in the media (Humphrey 2000) is not compensated using the BVM approach. As the transmitted acoustic wave is composed of a linear component at f0 and a 2nd harmonic component at 2 f0, its nonlinear propagation at high acoustic pressure in the media (i.e. tissue) could generate new harmonic components mainly at 2 f0 and 4 f0. The presence of these frequency components can pollute the image quality by reducing the CTR in the case of harmonic or superharmonic imaging. To solve this problem, 4893
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Pasovic et al suggested a multi-pulse approach in which two pulses were transmitted with a phase shift to cancel out the second harmonic generated by nonlinearities of media (Pasovic et al 2011). This approach could be combined with the BVM sequence to suppress the artefact induced by nonlinear propagation. The post-processing exploited very basic operations (sum, multiplication and subtraction), so it is simple, fast and does not require filtering. Time and data memory for post-processing will be the same as for CPS, which is already implemented in several commercial ultrasound scanners. The BVM sequence can be implemented into an ultrasound scanner by modifying the bias voltage for adjacent elements (figures 8–10) or for successive firings (figure 11). Figures 8 and 10 demonstrate that there is no inter-element variability and consequently the method can be successfully applied on adjacent elements. The development of an electronic board is necessary to quickly switch the bias voltage between elements or firings and avoid the limitation of the programming speed of the power supply. An adaptation of the AM for cMUT technology has been chosen in this study because previous works have demonstrated that AM is more sensitive than PI sequence for contrast agent detection (Eckersley et al 2005, Needles et al 2010). Nevertheless, a combination of BVM approach with PI could be done to further increase the CTR. For example, by inverting the phase of the excitation signal or the bias voltage polarity of the 2nd transmitted pulse (i.e. P2), a complete cancellation of the linear and nonlinear signal generated by the source could be obtained following the operation: E3+E2-5*E1. 5. Conclusions The results of this study demonstrate that the problem of cMUT nonlinearity can be addressed using a specific sequence based on bias voltage modulation. This sequence is highly sensitive to contrast agent response and can be easily implemented into a scanner since no modification of the excitation signal is required. In terms of temporal resolution and frame rate, the BVM sequence is similar to other standard contrast imaging methods already implemented in commercial ultrasound scanners (i.e. Contrast Pulse Sequencing). Compared to amplitude modulation imaging traditionally used with a piezoelectric probe, the BVM increases the CTR by 6 dB thanks to a complete suppression of the nonlinear signal generated by the source. Further investigations could include the in-vivo validation of the BVM sequence. Furthermore, we believe that this multi-pulse sequence can be combined with PI and could take advantage of the wide cMUT bandwidth to recover subharmonic and superharmonic components to improve the contrast agent detection. Acknowledgements We would like to acknowledge Bracco Research, Geneva for supplying contrast agent, the Agence Nationale pour la Recherche (ANR-11 TecSan-008–01 BBMUT) and the foundation ARC (n°SAE20130606511) for financial support. References Averkiou M 2000 Tissue harmonic imaging Proc. IEEE Ultrason. Sympos. 2 1530–41 Bayram B, Oralkan O, Ergun A S, Haeggstrom E, Yaralioglu G G and Khuri-Yakub B T 2005 Capacitive micromachined ultrasonic transducer design for high power transmission IEEE Trans. Ultrason. Ferroelectr. Freq. Control 52 326–39 4894
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Bouakaz A, Frigstad S, Ten Cate F J and De Jong N 2002 Super harmonic imaging: a new imaging technique for improved contrast detection Ultrasound Med. Biol. 28 59–68 Brock-Fisher G, Poland M and Rafter P 1996 Means for increasing sensitivity in non-linear ultrasound imaging systems USA Patent Application 5577505 A Caliano G, Carotenuto R, Cianci E, Foglietti V, Caronti A, Iula A and Pappalardo M 2005 Design, fabrication and characterization of a capacitive micromachined ultrasonic probe for medical imaging IEEE Trans. Ultrason. Ferroelectr. Freq. Control 52 2259–69 Certon D, Patat F, Meynier C and Teston F 2006 Collective behavior of a cMUT cells for the prediction of electroacoustic response and directivity pattern Proc. IEEE Ultrason. Symp. 1967–70 Certon D, Teston F and Patat F 2005 A finite difference model for cMUT devices IEEE Trans. Ultrason. Ferroelectr. Freq. Control 52 2199–210 Chen J, Wang M, Cheng J C, Wang Y H, Li P C and Cheng X 2012 A photoacoustic imager with light illumination through an infrared-transparent silicon CMUT array IEEE Trans. Ultrason. Ferroelectr. Freq. Control 59 766–75 Chomas J, Dayton P, May D and Ferrara K 2002 Nondestructive subharmonic imaging IEEE Trans. Ultrason. Ferroelectr. Freq. Control 49 883–92 Cristman P, Oralkan O, Zhuang X, Ma T J, Vaithilingam S, Carver T, Wygant I O and Khuri-Yakub B T 2009 A 2D CMUT hydrophone array: characterization results Proc. IEEE Ultrason. Symp. 992–5 Daft C M, Wagner P A and Ladabaum I 2006 Microfabricated ultrasonic transducers with bias polarity beam profile control and method of operating the same USA Patent Application 7087023 B2 Davidson B P and Lindner J R 2012 Future applications of contrast echocardiography Heart 98 246–53 De Jong N, Bouakaz A and Frinking P 2002 Basic acoustic properties of microbubbles. Echocardiography 19 229–40 De Jong N, Cornet R and Lancee C 1994 Higher harmonics of vibrating gas filled microspheres. Part one: simulations Ultrason. 32 447–53 De Jong N, Emmer M, Van Wamel A and Versluis M 2009 Ultrasonic characterization of ultrasound contrast agents Med. Biol. Eng. Comput. 47 861–73 Degertekin F L 2009 Harmonic CMUT devices and fabrication methods USA Patent Application 7612483 B2 Degertekin F L, Guldiken R O and Karaman M 2006 Annular-ring CMUT arrays for forward-looking IVUS: transducer characterization and imaging IEEE Trans. Ultrason. Ferroelectr. Freq. Control 53 474–82 Eckersley R J, Chin C T and Burns P N 2005 Optimising phase and amplitude modulation schemes for imaging microbubble contrast agents at low acoustic power Ultrasound Med. Biol. 31 213–9 Gessner R C, Frederick C B, Foster F S and Dayton P A 2013 Acoustic angiography: a new imaging modality for assessing microvasculature architecture Int. J. Biomed. Imag. 2013 936593 Gorce J M, Arditi M and Schneider M 2000 Influence of bubble size distribution on the echogenicity of ultrasound contrast agents: a study of SonoVue Invest. Radiol. 35 661–71 Guiroy A, Novell A, Ringgaard E, Lou-Moeller R, Gregoire J M, Abellard A P, Zawada T, Bouakaz A and Levassort F 2013 Dual-frequency transducer for nonlinear contrast agent imaging IEEE Trans. Ultrason. Ferroelectr. Freq. Control 60 2634–44 Guldiken R O, Mclean J and Degertekin F L 2006 CMUTS with dual-electrode structure for improved transmit and receive performance IEEE Trans. Ultrason. Ferroelectr. Freq. Control 53 483–91 Huang Y, Haeggstrom E, Bayram B, Zhuang X, Ergun A S, Cheng C H and Khuri-Yakub B T 2006 Comparison of conventional and collapsed region operation of capacitive micromachined ultrasonic transducers IEEE Trans. Ultrason. Ferroelectr. Freq. Control 53 1918–33 Humphrey V F 2000 Nonlinear propagation in ultrasonic fields: measurements, modelling and harmonic imaging Ultrason. 38 267–72 Khuri-Yakub B T and Oralkan O 2011 Capacitive micromachined ultrasonic transducers for medical imaging and therapy J. Micromech. Microeng. 21 54004–14 Khuri-Yakub B T et al 2007 The capacitive micromachined ultrasonic transducer (cmut) as a chem/bio sensor Proc. IEEE Ultrason. Sympos. 472–5 Kruse D E and Ferrara K W 2005 A new imaging strategy using wideband transient response of ultrasound contrast agents IEEE Trans. Ultrason. Ferroelectr. Freq. Control 52 1320–9 Ladabaum I, Jin X, Soh H T, Atalar A and Khuri-Yakub B T 1998 Surface micromachined capacitive ultrasonic transducers IEEE Trans. Ultrason. Ferroelectr. Freq. Control 45 678–90 Ladabaum I and Panda S 2009 System and method of operating microfabricated ultrasonic transducers for harmonic imaging USA Patent Application 7635332 B2 Legros M, Novell A, Bouakaz A, Férin G, Dufait R and Certon D 2011 Tissue harmonic imaging with CMUTs Proc. IEEE Ultrason. Sympos. 2249–52 4895
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Lohfink A and Eccardt P C 2005a Investigation of nonlinear CMUT behavior Proc. IEEE Ultrason. Sympos. 1 1585–8 Lohfink A and Eccardt P C 2005b Linear and nonlinear equivalent circuit modeling of CMUTs IEEE Trans. Ultrason. Ferroelectr. Freq. Control 52 2163–72 Needles A, Arditi M, Rognin N G, Mehi J, Coulthard T, Bilan-Tracey C, Gaud E, Frinking P, Hirson D and Foster F S 2010 Nonlinear contrast imaging with an array-based micro-ultrasound system Ultrasound Med. Biol. 36 2097–106 Novell A, Escoffre J M and Bouakaz A 2013a Second harmonic and subharmonic for non-linear wideband contrast imaging using a capacitive micromachined ultrasonic transducer array Ultrasound Med. Biol. 39 1500–12 Novell A, Escoffre J M and Bouakaz A 2013b Ultrasound contrast imaging in cancer – technical aspects and prospects Curr. Mol. Imaging 2 77–88 Novell A, Legros M, Felix N and Bouakaz A 2009 Exploitation of capacitive micromachined transducers for nonlinear ultrasound imaging IEEE Trans. Ultrason. Ferroelectr. Freq. Control 56 2733–43 Oralkan O, Bayram B, Yaralioglu G G, Ergun A S, Kupnik M, Yeh D T, Wygant I O and Khuri-Yakub B T 2006 Experimental characterization of collapse-mode CMUT operation IEEE Trans. Ultrason. Ferroelectr. Freq. Control 53 1513–23 Oralkan O, Ergun A S, Johnson J A, Karaman M, Demirci U, Kaviani K, Lee T H and Khuri-Yakub B T 2002 Capacitive micromachined ultrasonic transducers: next-generation arrays for acoustic imaging? IEEE Trans. Ultrason. Ferroelectr. Freq. Control 49 1596–610 Panda S, Wagner P A, Daft C M and Ladabaum I 2006 Method and apparatuse for improving the performance of capacitive acoustic transducers usung bias polarity control and multiple firings USA Patent Application 20060173342 A1 Pasovic M, Danilouchkine M, Faez T, Van Neer P L, Cachard C, Van Der Steen A F, Basset O and De Jong N 2011 Second harmonic inversion for ultrasound contrast harmonic imaging Phys. Med. Biol. 56 3163–80 Phillips P J 2001 Contrast Pulse Sequences (CPS): imaging nonlinear microbubbles Proc. IEEE Ultrason. Sympos. 2 1739–45 Satir S and Degertekin F L 2012 Harmonic reduction in capacitive micromachined ultrasonic transducers by gap feedback linearization IEEE Trans. Ultrason. Ferroelectr. Freq. Control 59 50–9 Savoia A, Calianov G and Pappalardo M 2012 A CMUT probe for medical ultrasonography: from microfabrication to system integration IEEE Trans. Ultrason. Ferroelectr. Freq. Control 59 1127–38 Sénégond N, Boulmé A, Plag C, Teston F and Certon D 2013 Fast time-domain modeling of fluidcoupled cMUT cells: from the single cell to the 1-D linear array element IEEE Trans. Ultrason. Ferroelectr. Freq. Control 60 1505–18 Shin M, Krause J S, Debitetto P and White R D 2013 Acoustic Doppler velocity measurement system using capacitive micromachined ultrasound transducer array technology J. Acoust. Soc. Am. 134 1011–20 Simpson D, Chin C and Burns P 1999 Pulse inversion Doppler: a new method for detecting nonlinear echoes from microbubble contrast agents IEEE Trans. Ultrason. Ferroelectr. Freq. Control 46 372–82 Tang M X, Loughran J, Stride E, Zhang D and Eckersley R J 2011 Effect of bubble shell nonlinearity on ultrasound nonlinear propagation through microbubble populations J. Acoust. Soc. Am. 129 EL76–82 Tekes C, Zahorian J, Gurun G, Satir S, Xu T, Hochman M and Degertekin F L 2012 Volumetric imaging using single chip integrated CMUT-on-CMOS IVUS array Conf. Proc. IEEE Eng. Med. Biol. Soc. 3195–8 Vaithilingam S et al 2009 Three-dimensional photoacoustic imaging using a two-dimensional CMUT array IEEE Trans. Ultrason. Ferroelectr. Freq. Control 56 2411–9 Wilson S R and Burns P N 2010 Microbubble-enhanced US in body imaging: what role? Radiology 257 24–39 Wong S H, Kupnik M, Watkins R D, Butts-Pauly K and Khuri-Yakub B T 2010 Capacitive micromachined ultrasonic transducers for therapeutic ultrasound applications IEEE Trans. Biomed. Eng. 57 114–23 Zhou S, Reynolds P and Hossack J 2004 Precompensated excitation waveforms to suppress harmonic generation in MEMS electrostatic transducers IEEE Trans. Ultrason. Ferroelectr. Freq. Control 51 1564–74
4896
Search
Collections
Journals
About
Contact us
My IOPscience
Evaluation of bias voltage modulation sequence for nonlinear contrast agent imaging using a capacitive micromachined ultrasonic transducer array
This content has been downloaded from IOPscience. Please scroll down to see the full text. 2014 Phys. Med. Biol. 59 4879 (http://iopscience.iop.org/0031-9155/59/17/4879) View the table of contents for this issue, or go to the journal homepage for more
Download details: IP Address: 132.174.255.116 This content was downloaded on 11/11/2014 at 22:58
Please note that terms and conditions apply.
Institute of Physics and Engineering in Medicine Phys. Med. Biol. 59 (2014) 4879–4896
Physics in Medicine & Biology doi:10.1088/0031-9155/59/17/4879
Evaluation of bias voltage modulation sequence for nonlinear contrast agent imaging using a capacitive micromachined ultrasonic transducer array Anthony Novell1,2, Mathieu Legros3, Jean-Marc Grégoire1, Paul A Dayton2 and Ayache Bouakaz1 1
Université François-Rabelais de Tours, Inserm, Imagerie et Cerveau UMR U930, Tours, France 2 Joint Department of Biomedical Engineering, The University of North Carolina and North Carolina State University, Chapel Hill, NC 27599, USA 3 Vermon SA, Tours, France E-mail: [email protected] Received 15 May 2014, revised 2 July 2014 Accepted for publication 4 July 2014 Published 7 August 2014 Abstract
Many clinical diagnoses have now been improved thanks to the development of new techniques dedicated to contrast agent nonlinear imaging. Over the past few years, Capacitive Micromachined Ultrasonic Transducers (cMUTs) have emerged as a promising alternative to traditional piezoelectric transducers. One notable advantage of cMUTs is their wide frequency bandwidth. However, their use in nonlinear imaging approaches such as those used to detect contrast agents have been challenging due their intrinsic nonlinear character. We propose a new contrast imaging sequence, called bias voltage modulation (BVM), specifically developed for cMUTs to suppress their inherent nonlinear behavior. Theoretical and experimental results show that a complete cancellation of the nonlinear signal from the source can be reached when the BVM sequence is implemented. In-vitro validation of the sequence is performed using a cMUT probe connected to an open scanner and a flow phantom setup containing SonoVue microbubbles. Compared to the standard amplitude modulation imaging mode, a 6 dB increase of contrast-to-tissue ratio was achieved when the BVM sequence is applied. These results reveal that the problem of cMUT nonlinearity can be addressed, thus expanding the potential of this new transducer technology for nonlinear contrast agent detection and imaging.
0031-9155/14/174879+19$33.00 © 2014 Institute of Physics and Engineering in Medicine Printed in the UK & the USA
4879
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Keywords: amplitude modulation, bias voltage, cMUT, multi-pulse sequence, contrast agent imaging, harmonic, nonlinear behavior (Some figures may appear in colour only in the online journal) 1. Introduction Throughout the world, contrast agent imaging is routinely used in the fields of echocardiography for myocardial perfusion assessment (Davidson and Lindner 2012) and radiology for tumor detection and characterization (Wilson and Burns 2010, Novell et al 2013b). During the ultrasound examination, contrast agents, consisting of gas-filled microbubbles, are intravenously injected in order to enhance the backscattered signal from the blood stream. Many techniques based on the nonlinear and transient characteristics of microbubbles are used to improve the contrast-enhanced image quality and the confidence of the clinical diagnosis. These approaches have been developed to recover the specific signatures from microbubbles while the response from tissue is suppressed or reduced (De Jong et al 2009). For example, harmonic scattering from microbubbles such as 2nd harmonic (De Jong et al 2002), superharmonic (Bouakaz et al 2002, Guiroy et al 2013) or subharmonic (Chomas et al 2002) can be used to increase the contrast-to-tissue ratio (CTR). In this context, multi-pulse techniques such as pulse inversion (PI) (Simpson et al 1999), amplitude (or power) modulation (AM) (Brock-Fisher et al 1996), or contrast pulse sequencing (CPS) (Phillips 2001) have been introduced and are currently implemented in commercial ultrasound scanners. For PI and AM methods, two consecutive pulses with different phases or amplitudes are transmitted. Scheme of the standard AM method is given in figure 1(a). The PI sequence enhances the signal for the even harmonics and suppresses the odd frequency components whereas the AM method allows the detection of both the odd and even nonlinear components generated by microbubbles (Eckersley et al 2005). Previous studies reported that the AM method showed a better specificity at low (Eckersley et al 2005) and high frequency (Needles et al 2010) than a PI sequence. Moreover, both the PI and AM methods can be also combined to improve the sensitivity (Phillips 2001, Eckersley et al 2005). The use of sequences with more than two transmit pulses, such as CPS, allows the enhancement of the contrast detection (Phillips 2001) and the reduction of tissue motion artifacts (Averkiou 2000). Nevertheless, the implementation of these sequences is usually done at the expense of the frame rate and/or the resolution. Over the past 15 years, the capacitive micromachined ultrasonic transducer (cMUT) has emerged as a promising alternative to the conventional piezoelectric-based technology. A cMUT element is composed of multiple cells acting as interconnected plate capacitors in which a flexible membrane is placed between the top and the bottom electrodes. When an excitation voltage is applied, the electrostatic force exerted between the electrodes induces membrane vibrations, generating thus an acoustic wave. Nowadays, cMUT are developed and validated for a large range of uses (Oralkan et al 2002, Caliano et al 2005, Khuri-Yakub et al 2007, Cristman et al 2009). In the medical field, cMUT technology focuses on different applications such as Doppler (Shin et al 2013), intravascular ultrasound (Tekes et al 2012), photoacoustic imaging (Vaithilingam et al 2009, Chen et al 2012) as well as therapy (Bayram et al 2005, Wong et al 2010, Khuri-Yakub and Oralkan 2011). Very recently, a 12 MHz cMUT probe has been connected to a commercial ultrasound scanner and validated for medical imaging on humans (Savoia et al 2012). cMUTs offer interesting acoustic properties such as a large directivity (Certon et al 2006, Degertekin et al 2006) and a wide frequency bandwidth which can be higher than 110% at -6 dB (Huang et al 2006, Savoia et al 2012). This last property is particularly interesting for contrast agent imaging since it allows the recovery of several harmonic components, which has shown to be particularly 4880
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 1. Principle of standard amplitude modulation sequence using a piezoelectric transducer (a) and a cMUT (b).
valuable in high signal-to-noise contrast imaging (Kruse and Ferrara 2005, Gessner et al 2013). Nevertheless, cMUT are inherently nonlinear because the electrostatic force depends on the square of the applied voltage and the membrane displacement (Zhou et al 2004, Lohfink and Eccardt 2005a, Novell et al 2009). As a consequence, the acoustic wave generated by the cMUT probe contains an undesirable 2nd harmonic component in addition to the fundamental excitation. The harmonic to fundamental ratio at the cMUT outpout depends on the transmitted frequency and is proportional to the ratio vac/Vdc where vac is the applied voltage and Vdc is the bias voltage (Lohfink and Eccardt 2005b, Novell et al 2009). Harmonic distortion can be predicted by modeling the cMUT behavior (Lohfink and Eccardt 2005b, Sénégond et al 2013). For native or contrast harmonic imaging, the nonlinear component generated at the surface of the cMUT pollutes the nonlinear backscattered echoes from the explored media and thus deteriorates the image quality. Many studies describe various approaches to reduce or control the harmonic distortion induced by the cMUT. Zhou et al and our group have proposed different methods based on the transmission of a pre-distorted waveform to reduce this unwanted component (Zhou et al 2004, Novell et al 2009). Both methods consist in the addition of a new high frequency component to the original driving signal. The unwanted 2nd harmonic component from cMUT is then suppressed by linear or nonlinear interaction with the added component. Experimental results demonstrated the efficiency of these compensation approaches with a significant reduction (> 20 dB) of the 2nd harmonic amplitude at the surface of the cMUT. Recently, these compensation approaches have been successfully implemented into an open scanner allowing thus the exploitation of the frequency bandwidth of cMUT for wideband nonlinear imaging (Novell et al 2013a). We demonstrated that a significant increase of 180% in CTR could be reached by selective imaging of both the 2nd harmonic and the subharmonic components simultaneously using a cMUT linear array probe. Nevertheless, the optimization of these approaches requires the use of an ultrasound scanner with analog transmitters and a prior knowledge of the cMUT nonlinear behavior. More recently, Satir and Degertekin suggested that the nonlinearity of the cMUT is mainly caused by the inverse gap dependence of the electrostatic force (Satir and Degertekin 2012). To solve the problem of nonlinearity, a high voltage subharmonic excitation (without bias voltage) was transmitted and a nonlinear feedback is added to compensate the harmonic resulting from the gap dependence. Concretely, the gap feedback consists in the addition of a series impedance to the cMUT capacitance. Furthermore, the authors suggest the use of a dual-electrode cMUT structure to preserve the sensitivity in receive mode (Guldiken et al 2006). Experimental results 4881
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
show that a 10 dB improvement in the harmonic ratio can be achieved. Moreover, Degertekin has recently proposed cMUT fabrication methods dedicated to harmonic imaging applications (Degertekin 2009). A control of the harmonic vibrations of the membrane is suggested by adding a mass load positioned at predetermined locations along the membrane. Using a cMUT probe, the efficiency of most of the current nonlinear contrast agent imaging sequences is limited because of the intrinsic cMUT nonlinear behavior. For example, the efficacy of the standard amplitude modulation sequence is degraded because an unwanted nonlinear wave from cMUT still remains after processing as shown in figure 1(b). Unfortunately, it will not be possible to discriminate the nonlinear response from microbubbles to the propagation of the nonlinear wave generated by the cMUT. This will be expressed by a degradation of the CTR. Previous works have proposed different multiple-firing sequences based on the principle of PI specially adapted for cMUT (Panda et al 2006, Ladabaum and Panda 2009). Compared to PI, the authors have proposed the addition of a third firing in which the transmit waveform is inverted for adjacent elements (Ladabaum and Panda 2009) or by alternating the bias voltage polarity (Panda et al 2006). The inversion of bias voltage polarity can be done on the cMUT probe with a control of the elevation phase (Daft et al 2006). The nonlinearity from the cMUT can be cancelled after processing. In the present study, we investigate the potential of a new multi-pulse approach based on the modulation of the bias voltage amplitude applied to the cMUT. The bias voltage modulation is specifically chosen to suppress both the linear and the unwanted harmonic components generated by the cMUT in the final image. This approach, modifying the amplitude of the transmitted pulses, is based on the same principle as AM imaging to allow the contrast enhancement. 2. Material and methods 2.1. Principle of bias voltage modulation sequence
When an excitation voltage V(t) is applied to the cMUT electrode, the membrane is submitted to an electrostatic force inducing vibrations. The electrostatic force (F) applied to the cMUT membrane could be expressed through the following equation (Certon et al 2005): V(t)2 1 A F(t) = ε 0 el (1) 2 (hgap − d(t))2
where ε0 is the vacuum permittivity, Ael is the electrode surface area, V is the voltage applied between the two electrodes, hgap is the effective gap height, d the membrane displacement and t the time. According to (1), there are two main sources of nonlinear distortion, inherent to the cMUT principle, which are the membrane displacement and the applied voltage (Ladabaum et al 1998, Lohfink and Eccardt 2005b). For a cMUT transducer, a bias voltage Vdc is usually added to an excitation voltage Vac (t) to improve the sensitivity of the probe. The applied voltage can be expressed as: V(t) = vac cos (2πf0 t) + Vdc (2)
where Vac(t) = vac cos(2πf0t) and f0 is the frequency. As a result, the applied force is proportional to (Novell et al 2009): F α V2dc + 2 VdcVac(t) + Vac(t)2 F α
2 v2 v ac + V2dc (3) + 2 Vdcvaccos (2πf0 t) + ac cos (4πf0 t) 2 2
4882
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 2. Design of the cMUT output waveforms for the three transmitted pulses using
different bias voltage. For each pulse, an illustration of the spectral representation is given on the right column.
As a result, the ultrasound wave emitted by a cMUT is composed of a linear fundamental component depending on the term “Vdc vac” and a 2nd harmonic component depending on 2 the term “ v ac ”. For contrast harmonic imaging and using multi-pulse excitations, it is necessary to cancel both linear and nonlinear echoes from tissue scatterers. To this purpose, a specific multi-pulse scheme, called bias voltage modulation (BVM) sequence, is designed in which three successive pulses (respectively called P1, P2 and P3) are transmitted with different amplitudes. Compared to the traditional AM sequence, the amplitude of excitation voltage (vac) remains the same for the three transmitted pulses. Here, the amplitude variation is only applied on the bias voltage (Vdc), which is varied with an amplification factor of 1, 2 and 3 according to the transmitted pulse. For each pulse, the driving amplitude is defined as: v(4) ac1 = vac2 = vac3 = A V (5) dc1 = B;Vdc2 = 2B; Vdc3 = 3B
Where vaci and vdci are the excitation voltage and the bias voltage of the pulse Pi, respectively. A and B are constants. Using these parameters, the three acoustic waves (successively transmitted to the media) theoretically contain a linear component with different factor amplitude of 1, 2 and 3 for P1, P2 and P3, respectively, but exactly the same second harmonic amplitude (figure 2). In fact, according to (3), a variation of the bias voltage only modifies the amplitude of the linear component and does not affect the level of the second harmonic component. This property is true when a cMUT operates in a conventional regime or, in other words, when the bias voltage is below the collapse voltage (Oralkan et al 2006, 4883
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 3. Principle of the bias voltage modulation approach on a linear reflector. For each step, the spectral representation is given on the bottom.
Legros et al 2011). For high bias voltage, the membrane of the cMUT cells collapses on to the substrate, so the center of the membrane cannot move freely and the output acoustic wave becomes strongly nonlinear. In the particular case of nonlinear imaging, the linear response from tissue must be eliminated. However, echoes from linear reflectors like normal tissue will be composed of two frequency components at f0 and 2 f0 because of cMUT nonlinear behavior. One solution to cancel the unwanted echoes consists in the following post-processing operation: E (6) 1 + E 3 – 2E 2
where Ei is the backscattered signal from Pi. This operation is available when the cMUT is used in transmit mode. In fact, the fundamental component from Pi generated by the source is proportional to the term. As a result, after post-processing, the linear part of the three output waves emitted by the cMUT (3) can be expressed as: Vdc1vac1 + Vdc3vac3 − 2 Vdc2vac2 = AB + 3AB − 2*2AB = 0
(7)
Similarly, the harmonic component generated from Pi is proportional to vaci 2. The resulting harmonic part can be expressed as: 2 vac1 + vac3 2 − 2vac2 2 = A2 + A2 − 2A2 = 0 (8) Consequently, both the linear and the nonlinear components resulting from the source are suppressed thanks to this combination. The BVM sequence is described for a linear (i.e. tissue) and a nonlinear reflector (i.e. microbubbles) in figures 3 and 4, respectively using the transmitted pulses P1, P2 and P3 (figure 2). After processing, the resulting signal from a linear reflector such as tissue would be cancelled (figure 3) while a significant nonlinear response from microbubbles could be preserved (figure 4). Nevertheless, the operation in (6) cannot be applied when the cMUT is used in receive mode because the cMUT electromechanical conversion efficiency depends on the bias voltage. In 4884
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 4. Principle of the bias voltage modulation approach on a contrast agent micro-
bubble. For each step, the spectral representation is given on the bottom.
other words, the cMUT sensitivity in receive mode will be different for each pulse. For example, the amplitude of the E3 response will increase by a factor 3 compared to the amplitude of E1 during the electromechanical conversion step. As a result, in pulse-echo mode (i.e. for imaging), the difference of sensitivity for each pulse must be scaled up and new appropriate coefficients must be defined and applied. Theoretically, when a cMUT is used in pulse-echo mode, responses from a linear reflector (nonlinear propagation is neglected) can be written as: E1 = α cos (2πf0 t) + β cos (4πf0 t);
⎡ ⎤ E 2 = 2 ⎣2α cos (2πf0 t) + β cos (4πf0 t)⎦; E 3 = 3 ⎡⎣3α cos (2πf0 t) + β cos (4πf0 t)⎤⎦
(9)
where α and β are constants. A complete suppression of the echoes from a linear reflector can be obtained using the following operation: E (10) 3 + 3*E1 − 3*E 2 2.2. cMUT probe specifications
A 64-element cMUT linear array probe (Vermon SA, Tours, France) centered at 5 MHz with a pitch of 305 µm and an elevation of 8 mm is used in this study. The measured fractional bandwidth at -3 dB of the cMUT probe is 99% which is approximately 40% much wider than an equivalent commercial linear array piezoelectric probe) (Novell et al 2013a). For this probe, the static collapse voltage of the membranes is estimated at 100 V. 2.3. Hydrophone measurements
Hydrophone measurements are performed using a 0.2 mm needle hydrophone (Precision Acoustics, Dorchester Dorset, UK) mounted on a XYZ positioning system (TriOptics, Wedel, 4885
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 5. Picture of the cMUT probe (a) and experimental setup used for the hydrophone measurements (b).
Germany) and positioned in front of the probe as shown in figure 5(b). The output waveform generated from the cMUT probe is measured in the immediate vicinity of the source surface (2 mm). The excitation signal is generated using Matlab (Mathworks, Natick, MA) and then transmitted to a 64-channel fully programmable ultrasound system (M2M, Les Ulis, France) equipped with analog transmitters. The transmitted signal consisted of a Gaussian pulse, centered at 3 MHz, with a bandwidth of 30% to avoid frequency overlapping. The bias voltage issued from a controllable power supply (PPS1007, Motech, Tainan, Taiwan) is coupled to the excitation voltage and applied to the cMUT probe. First, the bias voltage is varied from 0 V to 120 V in order to evaluate the behavior of the cMUT in different operation regimes. In this experiment, the excitation voltage is relatively low (20 Vpeak) to avoid the dynamic collapse of cMUT membranes. For the other experiments using the BVM sequence, the bias voltage is fixed at 20 V, 40 V and 60 V according to the transmitted pulse (Pi). In order to preserve a good sensitivity, the excitation voltage is set to the maximal value delivered by the open scanner (40 Vpeak). Acoustic signals received by the hydrophone are then visualized with a digital oscilloscope (Tektronix, Beaverton, OR) and transferred to a personal computer through a GPIB port (National Instruments, Austin, TX) for further analysis using Matlab. The BVM sequence is first evaluated on three adjacent elements of the cMUT probe (figure 5(a)). Excitation voltage and bias voltage are independently transmitted to the elements. To avoid the temporal overlapping and extract the response of each element, the excitation 4886
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 6. Acoustical measurements setup (a) and flow phantom setup used for contrast
agent imaging (b).
voltage is transmitted with a delay of 10 µs between each element. A homemade electronic board is used to simultaneously dispatch the three bias voltages to the three adjacent cMUT elements. 2.4. Simulations
Simulations are carried out in order to evaluate the efficiency of the sequence for detecting the response of a single microbubble. The acoustic response of 3 µm diameter microbubble is calculated using a modified Rayleigh-Plesset equation (De Jong et al 1994). The shell parameters given by Gorce et al (2000) are used to simulate a SonoVue® microbubble. The microbubble resonance frequency corresponds to the excitation frequency (i.e. 3 MHz). For each of three pulses, the acoustic waveform measured in the vicinity of the cMUT output is introduced into the equation as the driving signal. The microbubble is excited at a corresponding peak negative pressure of 92 kPa, 184 kPa and 275 kPa at the fundamental frequency (3 MHz) for P1, P2 and P3, respectively. 2.5. Validation of the BVM sequence on in-vitro setup
The ability of the BVM sequence in cancelling linear echo is evaluated on an in-vitro setup in which the cMUT probe is mounted in a water bath with a piezoelectric single-element transducer (Sofranel, Sartrouville, France) placed perpendicularly. This transducer had a center frequency of 5 MHz (81% bandwidth at -6 dB) and is used in receive mode to collect the scattered echoes from a linear reflector as shown in figure 6(a). The linear reflector is a 50 µm diameter copper wire placed simultaneously at 5 mm from the source and at the focus of the receive transducer (5 cm). The three pulses are transmitted on three different elements with amplitudes of 10 kPa, 20 kPa and 30 kPa according to the applied bias voltage. For flow phantom imaging, the BVM sequence is applied on the total cMUT probe elements. For this purpose, the excitation voltage is simultaneously transmitted to all the elements of the probe. BVM imaging is performed by the acquisition of three consecutive frames for which the bias voltage is varied. The delay between each frame is limited by the programming speed of the power supply and is reduced to the minimum in the experiment (30 ms). The bias voltage used for frames 1, 2 and 3 are 20 V, 40 V and 60 V, respectively. After acquisition of the three frames, the post processing is completed to display the resulting image. The 4887
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 7. Normalized amplitude of the cMUT output wave as a function of the bias
voltage. The fundamental and the harmonic components are extracted from the hydrophone measurements.
experiments are performed on a tissue-mimicking phantom (ATS Laboratories, Bridgeport, CT) containing a 4 mm diameter tube in which a solution of SonoVue microbubbles (Bracco Research, Geneva, Switzerland) is circulating as shown in figure 6(b). The tube is positioned at a distance of 28 mm from the probe surface and thus the electronic focus is set accordingly. The contrast agent solution, SonoVue, is injected into a reservoir with a dilution of 1/2000 and circulated at a fixed flow rate controlled using a pump (Cole-Parmer, Chicago, IL) and set to minimal (20 mL/min). The flow is stopped during the acquisition to minimize the microbubble motion artifacts. The amplitude of the fundamental component at the focus is varied from 185 kPa to 562 kPa (the corresponding non derated Mechanical Index ranged from 0.11 to 0.32 at 3 MHz). For each pulse, sets of 150 radiofrequency (RF) lines are recorded, transferred to Matlab and B-mode images are reconstructed offline using the combination described in (10). 3. Results 3.1. Behavior of the cMUT as a function of the bias voltage amplitude
First, the acoustic wave generated by the cMUT probe was recovered by hydrophone measurements for different bias voltages. The purpose of these measurements was to define the cMUT operation regime for which the BVM sequence can be applied. The normalized amplitude of the cMUT output wave as a function of the bias voltage is shown in figure 7. The solid line corresponds to the amplitude of the whole wave (i.e. fundamental + harmonic component) while the fundamental and the harmonic components are given by the dashed and the dotted lines, respectively. The curve for fundamental component was obtained by filtering the measured acoustic waves in the range from 2 MHz to 4 MHz (Matlab, Butterworth filter, order 3). Similarly, the 2nd harmonic was extracted using a bandpass filter in the range from 5 MHz to 7 MHz. 4888
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 8. Hydrophone measurements of the output pressures (O1, O2, and O3) emitted
by the cMUT for the three transmitted pulses (P1, P2, and P3). The resulting signal after BVM post-processing is shown on the bottom. The corresponding spectra are displayed on the right panel.
The behavior of the cMUT as a function of the bias voltage can be separated into three regimes: growth, maximum and decay. For the total signal curve, the maximum amplitude is reached at a bias voltage of 105 V. From 0 V to 80 V, the amplitude slightly increases while the growth is more pronounced for bias voltages ranging from 80 V to 105 V. For voltages above 105 V, the amplitude of the acoustic wave decreases because of the collapse of the membrane. In fact, in this operating regime, the membrane has fully collapsed and is stuck against the substrate, resulting thus in the generation of a low amplitude acoustic wave. The fundamental component of the acoustic wave shows a similar trend but the maximal value is obtained for 100 V, corresponding to the cMUT collapse voltage. As one can see, the harmonic level remains quasi-constant for bias voltages below a threshold value of 80% collapse voltage. Above this value, the nonlinear level considerably increases because the center of the membrane is probably in contact with the substrate. Furthermore, one can notice that the harmonic level still increases until 105 V, enhancing at the same time, the amplitude of the total acoustic wave. 3.2. Hydrophone measurements of the output waveforms
Figure 8 displays cMUT output waveforms (Oi) at a depth of 2 mm for the three different voltages (Pi) applied on three adjacent elements. The waveform measured for the lower bias voltage (i.e. P1) is given on the top panel. The output waveforms for P2 and P3 are shown in the 2nd and 3rd panels on the left column respectively. As expected, the output amplitude is 4889
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 9. Simulated responses (E1, E2, and E3) from a 3 µm diameter microbubble ex-
cited by the three measured output pressures (P1, P2, and P3) emitted by the cMUT. The resulting signal after BVM post-processing is shown on the bottom. The corresponding spectra are displayed on the right panel.
stronger when the highest bias voltage is transmitted (P3). The bottom panel on the left column displays the resulting signal when BVM processing is applied in transmit mode (i.e. O1 + O3 -2*O2). As expected, no signal persists after the application of this processing method. This result demonstrates that the sequence can be used to efficiently cancel the harmonic signal generated by the source. The corresponding spectra are displayed on the right panel. Compared to the waveform transmitted by P3 (gray dashed line), the fundamental amplitude is reduced by 30 dB while the harmonic level decreases by 15 dB after BVM processing (solid line). Actually, only noise is measured using the processing sequence for fundamental, 2nd harmonic or 3rd harmonic components so the approach allows the suppression of both the fundamental and the harmonic components transmitted by the source. 3.3. Validation of the sequence on a simulated response of microbubble
The three waveforms shown in figure 8 are introduced in the modified Rayleigh-Plesset equation as excitation signals. Corresponding responses of a single microbubble are simulated and echoes are given in figure 9. For all pulses, the microbubble response is strongly asymmetric revealing a high nonlinear response. As one can see on the bottom panel of the left column, the resulting signal after BVM processing is now nonzero. As the unwanted signal generated by the source is entirely cancelled (figure 8), we assume that this resulting signal only 4890
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 10. Echoes (E1, E2, and E3) from a solid reflector for each transmitted pulse.
A PZT single-element is used in receive mode. The resulting signal after BVM postprocessing is shown on the bottom. The corresponding spectra are displayed on the right panel.
corresponds to the microbubble acoustic signature. The spectral analysis (right panel) shows that strong frequency components at 3 MHz, 6 MHz and 9 MHz are preserved after application of the method (solid line). Actually, our approach based on amplitude modulation not only allows the preservation of the 2nd harmonic and 3rd harmonic components but also the detection of a nonlinear component at the fundamental frequency (Eckersley et al 2005). 3.4. In-vitro evaluation of the BVM sequence
Echoes from a solid reflector are shown in figure 10 (left panels). As expected, the signal is drastically reduced after processing. The corresponding spectrum (right panel) reveals that the level of signal cancellation is similar to that obtained with the hydrophone measurements as shown in figure 8 (i.e. 30 dB and 15 dB decrease for the fundamental and harmonic levels respectively). The efficiency of the BVM approach for nonlinear contrast imaging was compared to other standard contrast imaging methods using the cMUT probe. Acquired RF lines were processed and B-mode images of the flow phantom were reconstructed. figure 11 displays the images for 2nd harmonic imaging (A), AM (B) and BVM (C) sequences with the same dynamic range of 35 dB. Each image is normalized by its maximal intensity (i.e. maximal contrast agent response). For each excitation method, the CTR has been calculated from the highlighted region-of-interests (ROIs) shown in the different panels. Each method allows a good 4891
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Figure 11. In-vitro images of a flow phantom containing a diluted solution of SonoVue
using a 64-element cMUT probe. Second harmonic imaging, amplitude modulation imaging and bias voltage modulation imaging are displayed in panel (a), (b) and (c), respectively. Each image is displayed with 35 dB dynamic range. The experiments are realized at 3 MHz, MI = 0.32. For each image, the CTR is calculated for the displayed ROIs.
visualization of the flow of microbubbles circulating in the tube surrounded by the tissue mimicking phantom. Nevertheless, the tissue appearance is considerably degraded in 2nd harmonic imaging mode (figure 11(a)) due to the presence of a strong nonlinear signal generated by the source. As shown in figure 11(b), the nonlinear echo in tissue response is considerably reduced while the signal from microbubbles is enhanced when AM sequence is used. In fact, the application of the AM sequence reduces the nonlinearity from cMUT by half, as shown in figure 1. As a consequence, the nonlinear echo from tissue is partially suppressed. Moreover, compared to 2nd harmonic imaging, the nonlinear response from microbubbles is considerably improved since several nonlinear components (i.e. f0, 2 f0 and 3 f0) are preserved using this approach. An enhancement of the contrast agent discrimination occurs when the BVM sequence is applied (figure 11(c)). This improved discrimination is mainly expressed by a lower nonlinear response in tissue due to the complete cancellation of the nonlinear signal from the source. These qualitative results are confirmed by the CTR measurements which are 11.8 dB, 23.1 dB and 29.2 dB for 2nd harmonic, AM and BVM imaging, respectively. Compared to AM imaging, a gain in CTR of approximately 6 dB is achieved when the BVM sequence is transmitted. One can notice that a nonlinear echo appears beyond the flow of microbubbles in all the images (i.e. 2.8 to 3.6 cm). This artifact, which is known to reduce the CTR, is attributed to the nonlinear propagation of the ultrasound through the cloud of microbubbles (Tang et al 2011). 4892
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
4. Discussion The theoretical and experimental results presented here demonstrated that a new highly sensitive contrast imaging sequence can be applied using a cMUT probe. The BVM approach was specifically designed to cancel out the second harmonic generation of the cMUT. When applied on a cMUT probe, data suggests that our sequence is more sensitive than conventional contrast imaging approaches (figure 11). The efficiency of the BVM approach described in this study implies a consistency of the second harmonic level when the three pulses with different bias voltages are transmitted. As a result, the BVM sequence can be only applied when cMUT is used in its conventional operation regime (i.e. Vdc 15 dB). In this study, the sequence was only evaluated using narrow band excitations (30% at -6 dB) in order to quantify the harmonic cancellation from the source. Even if this frequency band was chosen to avoid frequency band overlap, the multi-pulse approach is also suitable for wide band pulses traditionally used for imaging. In the same way, the method does not depend on the transmit frequency and can be easily applied on the whole cMUT bandwidth. Currently, only the nonlinear fundamental and the 2nd harmonic components are recovered when AM sequence is applied due to the narrow bandwidth of piezoelectric transducers. However, the wide frequency bandwidth of the cMUT can be fully exploited to add other frequency components such as subharmonic or superharmonic to enhance the sensitivity of contrast agent detection (Bouakaz et al 2002, Novell et al 2013a). Similarly to other traditional multi-pulse sequences used for contrast agent imaging (i.e. PI, AM, CPS), the nonlinear propagation of the acoustic wave in the media (Humphrey 2000) is not compensated using the BVM approach. As the transmitted acoustic wave is composed of a linear component at f0 and a 2nd harmonic component at 2 f0, its nonlinear propagation at high acoustic pressure in the media (i.e. tissue) could generate new harmonic components mainly at 2 f0 and 4 f0. The presence of these frequency components can pollute the image quality by reducing the CTR in the case of harmonic or superharmonic imaging. To solve this problem, 4893
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Pasovic et al suggested a multi-pulse approach in which two pulses were transmitted with a phase shift to cancel out the second harmonic generated by nonlinearities of media (Pasovic et al 2011). This approach could be combined with the BVM sequence to suppress the artefact induced by nonlinear propagation. The post-processing exploited very basic operations (sum, multiplication and subtraction), so it is simple, fast and does not require filtering. Time and data memory for post-processing will be the same as for CPS, which is already implemented in several commercial ultrasound scanners. The BVM sequence can be implemented into an ultrasound scanner by modifying the bias voltage for adjacent elements (figures 8–10) or for successive firings (figure 11). Figures 8 and 10 demonstrate that there is no inter-element variability and consequently the method can be successfully applied on adjacent elements. The development of an electronic board is necessary to quickly switch the bias voltage between elements or firings and avoid the limitation of the programming speed of the power supply. An adaptation of the AM for cMUT technology has been chosen in this study because previous works have demonstrated that AM is more sensitive than PI sequence for contrast agent detection (Eckersley et al 2005, Needles et al 2010). Nevertheless, a combination of BVM approach with PI could be done to further increase the CTR. For example, by inverting the phase of the excitation signal or the bias voltage polarity of the 2nd transmitted pulse (i.e. P2), a complete cancellation of the linear and nonlinear signal generated by the source could be obtained following the operation: E3+E2-5*E1. 5. Conclusions The results of this study demonstrate that the problem of cMUT nonlinearity can be addressed using a specific sequence based on bias voltage modulation. This sequence is highly sensitive to contrast agent response and can be easily implemented into a scanner since no modification of the excitation signal is required. In terms of temporal resolution and frame rate, the BVM sequence is similar to other standard contrast imaging methods already implemented in commercial ultrasound scanners (i.e. Contrast Pulse Sequencing). Compared to amplitude modulation imaging traditionally used with a piezoelectric probe, the BVM increases the CTR by 6 dB thanks to a complete suppression of the nonlinear signal generated by the source. Further investigations could include the in-vivo validation of the BVM sequence. Furthermore, we believe that this multi-pulse sequence can be combined with PI and could take advantage of the wide cMUT bandwidth to recover subharmonic and superharmonic components to improve the contrast agent detection. Acknowledgements We would like to acknowledge Bracco Research, Geneva for supplying contrast agent, the Agence Nationale pour la Recherche (ANR-11 TecSan-008–01 BBMUT) and the foundation ARC (n°SAE20130606511) for financial support. References Averkiou M 2000 Tissue harmonic imaging Proc. IEEE Ultrason. Sympos. 2 1530–41 Bayram B, Oralkan O, Ergun A S, Haeggstrom E, Yaralioglu G G and Khuri-Yakub B T 2005 Capacitive micromachined ultrasonic transducer design for high power transmission IEEE Trans. Ultrason. Ferroelectr. Freq. Control 52 326–39 4894
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Bouakaz A, Frigstad S, Ten Cate F J and De Jong N 2002 Super harmonic imaging: a new imaging technique for improved contrast detection Ultrasound Med. Biol. 28 59–68 Brock-Fisher G, Poland M and Rafter P 1996 Means for increasing sensitivity in non-linear ultrasound imaging systems USA Patent Application 5577505 A Caliano G, Carotenuto R, Cianci E, Foglietti V, Caronti A, Iula A and Pappalardo M 2005 Design, fabrication and characterization of a capacitive micromachined ultrasonic probe for medical imaging IEEE Trans. Ultrason. Ferroelectr. Freq. Control 52 2259–69 Certon D, Patat F, Meynier C and Teston F 2006 Collective behavior of a cMUT cells for the prediction of electroacoustic response and directivity pattern Proc. IEEE Ultrason. Symp. 1967–70 Certon D, Teston F and Patat F 2005 A finite difference model for cMUT devices IEEE Trans. Ultrason. Ferroelectr. Freq. Control 52 2199–210 Chen J, Wang M, Cheng J C, Wang Y H, Li P C and Cheng X 2012 A photoacoustic imager with light illumination through an infrared-transparent silicon CMUT array IEEE Trans. Ultrason. Ferroelectr. Freq. Control 59 766–75 Chomas J, Dayton P, May D and Ferrara K 2002 Nondestructive subharmonic imaging IEEE Trans. Ultrason. Ferroelectr. Freq. Control 49 883–92 Cristman P, Oralkan O, Zhuang X, Ma T J, Vaithilingam S, Carver T, Wygant I O and Khuri-Yakub B T 2009 A 2D CMUT hydrophone array: characterization results Proc. IEEE Ultrason. Symp. 992–5 Daft C M, Wagner P A and Ladabaum I 2006 Microfabricated ultrasonic transducers with bias polarity beam profile control and method of operating the same USA Patent Application 7087023 B2 Davidson B P and Lindner J R 2012 Future applications of contrast echocardiography Heart 98 246–53 De Jong N, Bouakaz A and Frinking P 2002 Basic acoustic properties of microbubbles. Echocardiography 19 229–40 De Jong N, Cornet R and Lancee C 1994 Higher harmonics of vibrating gas filled microspheres. Part one: simulations Ultrason. 32 447–53 De Jong N, Emmer M, Van Wamel A and Versluis M 2009 Ultrasonic characterization of ultrasound contrast agents Med. Biol. Eng. Comput. 47 861–73 Degertekin F L 2009 Harmonic CMUT devices and fabrication methods USA Patent Application 7612483 B2 Degertekin F L, Guldiken R O and Karaman M 2006 Annular-ring CMUT arrays for forward-looking IVUS: transducer characterization and imaging IEEE Trans. Ultrason. Ferroelectr. Freq. Control 53 474–82 Eckersley R J, Chin C T and Burns P N 2005 Optimising phase and amplitude modulation schemes for imaging microbubble contrast agents at low acoustic power Ultrasound Med. Biol. 31 213–9 Gessner R C, Frederick C B, Foster F S and Dayton P A 2013 Acoustic angiography: a new imaging modality for assessing microvasculature architecture Int. J. Biomed. Imag. 2013 936593 Gorce J M, Arditi M and Schneider M 2000 Influence of bubble size distribution on the echogenicity of ultrasound contrast agents: a study of SonoVue Invest. Radiol. 35 661–71 Guiroy A, Novell A, Ringgaard E, Lou-Moeller R, Gregoire J M, Abellard A P, Zawada T, Bouakaz A and Levassort F 2013 Dual-frequency transducer for nonlinear contrast agent imaging IEEE Trans. Ultrason. Ferroelectr. Freq. Control 60 2634–44 Guldiken R O, Mclean J and Degertekin F L 2006 CMUTS with dual-electrode structure for improved transmit and receive performance IEEE Trans. Ultrason. Ferroelectr. Freq. Control 53 483–91 Huang Y, Haeggstrom E, Bayram B, Zhuang X, Ergun A S, Cheng C H and Khuri-Yakub B T 2006 Comparison of conventional and collapsed region operation of capacitive micromachined ultrasonic transducers IEEE Trans. Ultrason. Ferroelectr. Freq. Control 53 1918–33 Humphrey V F 2000 Nonlinear propagation in ultrasonic fields: measurements, modelling and harmonic imaging Ultrason. 38 267–72 Khuri-Yakub B T and Oralkan O 2011 Capacitive micromachined ultrasonic transducers for medical imaging and therapy J. Micromech. Microeng. 21 54004–14 Khuri-Yakub B T et al 2007 The capacitive micromachined ultrasonic transducer (cmut) as a chem/bio sensor Proc. IEEE Ultrason. Sympos. 472–5 Kruse D E and Ferrara K W 2005 A new imaging strategy using wideband transient response of ultrasound contrast agents IEEE Trans. Ultrason. Ferroelectr. Freq. Control 52 1320–9 Ladabaum I, Jin X, Soh H T, Atalar A and Khuri-Yakub B T 1998 Surface micromachined capacitive ultrasonic transducers IEEE Trans. Ultrason. Ferroelectr. Freq. Control 45 678–90 Ladabaum I and Panda S 2009 System and method of operating microfabricated ultrasonic transducers for harmonic imaging USA Patent Application 7635332 B2 Legros M, Novell A, Bouakaz A, Férin G, Dufait R and Certon D 2011 Tissue harmonic imaging with CMUTs Proc. IEEE Ultrason. Sympos. 2249–52 4895
A Novell et al
Phys. Med. Biol. 59 (2014) 4879
Lohfink A and Eccardt P C 2005a Investigation of nonlinear CMUT behavior Proc. IEEE Ultrason. Sympos. 1 1585–8 Lohfink A and Eccardt P C 2005b Linear and nonlinear equivalent circuit modeling of CMUTs IEEE Trans. Ultrason. Ferroelectr. Freq. Control 52 2163–72 Needles A, Arditi M, Rognin N G, Mehi J, Coulthard T, Bilan-Tracey C, Gaud E, Frinking P, Hirson D and Foster F S 2010 Nonlinear contrast imaging with an array-based micro-ultrasound system Ultrasound Med. Biol. 36 2097–106 Novell A, Escoffre J M and Bouakaz A 2013a Second harmonic and subharmonic for non-linear wideband contrast imaging using a capacitive micromachined ultrasonic transducer array Ultrasound Med. Biol. 39 1500–12 Novell A, Escoffre J M and Bouakaz A 2013b Ultrasound contrast imaging in cancer – technical aspects and prospects Curr. Mol. Imaging 2 77–88 Novell A, Legros M, Felix N and Bouakaz A 2009 Exploitation of capacitive micromachined transducers for nonlinear ultrasound imaging IEEE Trans. Ultrason. Ferroelectr. Freq. Control 56 2733–43 Oralkan O, Bayram B, Yaralioglu G G, Ergun A S, Kupnik M, Yeh D T, Wygant I O and Khuri-Yakub B T 2006 Experimental characterization of collapse-mode CMUT operation IEEE Trans. Ultrason. Ferroelectr. Freq. Control 53 1513–23 Oralkan O, Ergun A S, Johnson J A, Karaman M, Demirci U, Kaviani K, Lee T H and Khuri-Yakub B T 2002 Capacitive micromachined ultrasonic transducers: next-generation arrays for acoustic imaging? IEEE Trans. Ultrason. Ferroelectr. Freq. Control 49 1596–610 Panda S, Wagner P A, Daft C M and Ladabaum I 2006 Method and apparatuse for improving the performance of capacitive acoustic transducers usung bias polarity control and multiple firings USA Patent Application 20060173342 A1 Pasovic M, Danilouchkine M, Faez T, Van Neer P L, Cachard C, Van Der Steen A F, Basset O and De Jong N 2011 Second harmonic inversion for ultrasound contrast harmonic imaging Phys. Med. Biol. 56 3163–80 Phillips P J 2001 Contrast Pulse Sequences (CPS): imaging nonlinear microbubbles Proc. IEEE Ultrason. Sympos. 2 1739–45 Satir S and Degertekin F L 2012 Harmonic reduction in capacitive micromachined ultrasonic transducers by gap feedback linearization IEEE Trans. Ultrason. Ferroelectr. Freq. Control 59 50–9 Savoia A, Calianov G and Pappalardo M 2012 A CMUT probe for medical ultrasonography: from microfabrication to system integration IEEE Trans. Ultrason. Ferroelectr. Freq. Control 59 1127–38 Sénégond N, Boulmé A, Plag C, Teston F and Certon D 2013 Fast time-domain modeling of fluidcoupled cMUT cells: from the single cell to the 1-D linear array element IEEE Trans. Ultrason. Ferroelectr. Freq. Control 60 1505–18 Shin M, Krause J S, Debitetto P and White R D 2013 Acoustic Doppler velocity measurement system using capacitive micromachined ultrasound transducer array technology J. Acoust. Soc. Am. 134 1011–20 Simpson D, Chin C and Burns P 1999 Pulse inversion Doppler: a new method for detecting nonlinear echoes from microbubble contrast agents IEEE Trans. Ultrason. Ferroelectr. Freq. Control 46 372–82 Tang M X, Loughran J, Stride E, Zhang D and Eckersley R J 2011 Effect of bubble shell nonlinearity on ultrasound nonlinear propagation through microbubble populations J. Acoust. Soc. Am. 129 EL76–82 Tekes C, Zahorian J, Gurun G, Satir S, Xu T, Hochman M and Degertekin F L 2012 Volumetric imaging using single chip integrated CMUT-on-CMOS IVUS array Conf. Proc. IEEE Eng. Med. Biol. Soc. 3195–8 Vaithilingam S et al 2009 Three-dimensional photoacoustic imaging using a two-dimensional CMUT array IEEE Trans. Ultrason. Ferroelectr. Freq. Control 56 2411–9 Wilson S R and Burns P N 2010 Microbubble-enhanced US in body imaging: what role? Radiology 257 24–39 Wong S H, Kupnik M, Watkins R D, Butts-Pauly K and Khuri-Yakub B T 2010 Capacitive micromachined ultrasonic transducers for therapeutic ultrasound applications IEEE Trans. Biomed. Eng. 57 114–23 Zhou S, Reynolds P and Hossack J 2004 Precompensated excitation waveforms to suppress harmonic generation in MEMS electrostatic transducers IEEE Trans. Ultrason. Ferroelectr. Freq. Control 51 1564–74
4896
