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Elsevier Editorial System(tm) for Ultrasound in Medicine and Biology Manuscript Draft Manuscript Number: Title: Preclinical Testing of Frequency-Tunable Capacitive Micromachined Ultrasonic Transducer Probe Prototypes Article Type: Original Contribution Keywords: medical imaging; intracardiac echocardiography; capacitive micromachined ultrasonic transducer; collapse mode; frequency tunability Corresponding Author: Mr. Martin Pekař, Corresponding Author's Institution: Philips Research First Author: Martin Pekař Order of Authors: Martin Pekař; Alexander F Kolen; Harm Belt; Frank van Heesch; Nenad Mihajlović; Imo E Hoefer; Tamas Szili-Török; Hendrik J Vos; Johan G Bosch; Gijs van Soest; Antonius F. W van der Steen Abstract: In intracardiac echocardiography (ICE) it may be beneficial to generate ultrasound images acquired at multiple frequencies, having the possibility of high penetration or high resolution imaging in a single device. The objective of the presented work is to test two frequencytunable probe prototypes in a preclinical setting: a rigid probe having a diameter of 11 mm and a new flexible and steerable 12-Fr ICE catheter. Both probes feature a forward-looking 32-element capacitive micromachined ultrasonic transducer array (aperture of 2 mm x 2 mm) operated in collapse-mode, which allows for frequency-tuning in the range from 6 MHz to 18 MHz. The rigid probe prototype is tested ex-vivo in a passive heart platform. Images of an aortic valve acquired in high-penetration (6 MHz), generic (12 MHz), and high-resolution (18 MHz) mode combine satisfying image quality and penetration depth between 2.5 cm and 10 cm. The ICE catheter prototype is tested in-vivo using a porcine animal model. Images of an aortic valve are acquired in the three imaging modes with the ICE catheter placed in an ascending aorta at multiple depths. It was found that the combination of the forward-looking design and frequency-tuning capability allows visualizing intracardiac structures of various sizes at different distances relative to the catheter tip, providing both wide overviews and detailed close-ups. Suggested Reviewers: Kai Thomenius Institute of Medical Engineering & Science, MIT [email protected] Expert in ultrasound imaging, co-author of number of forward-looking intracardiac imaging catheters, e.g. Stephens, D. N., Truong, U. T., Nikoozadeh, A., Oralkan, Ö., Seo, C. H., Cannata, J., Dentinger, A., Thomenius, K., de la Rama, A., Nguyen, T., Lin, F., Khuri-Yakub, P., Mahajan, A., Shivkumar, K., O’Donnell, M. and Sahn, D. J. (2012) ‘First In Vivo Use of a Capacitive Micromachined Ultrasound Transducer Array – Based Imaging and Ablation Catheter’, Journal of Ultrasound in Medicine, 31, pp. 247–256. Available at:

http://www.jultrasoundmed.org/content/31/2/247.short (Accessed: 27 May 2013). Petr Neuzil Cardiology, Homolka hospital [email protected] Clinical expert in minimally-invasive cardiology. He routinely uses intracardiac imaging catheters and publishes on new devices in his field, e.g. Ho, I. C. K., Neuzil, P., Mraz, T., Beldova, Z., Gross, D., Formanek, P., Taborsky, M., Niederle, P., Ruskin, J. N. and Reddy, V. Y. (2007) ‘Use of intracardiac echocardiography to guide implantation of a left atrial appendage occlusion device (PLAATO)’, Heart Rhythm. Elsevier, 4(5), pp. 567–571. Alessandro Savoia Acoustoelectronics Laboratory, Univeristà degli Studi Roma Tre [email protected] Expert in capacitive-micromachined ultrasound transducer technology. Coauthor of number of publications on this topic,e.g. Savoia, A. S., Calianov, G. and Pappalardo, M. (2012) ‘A CMUT probe for medical ultrasonography: from microfabrication to system integration.’, IEEE transactions on ultrasonics, ferroelectrics, and frequency control, 59(6), pp. 1127–38. doi: http://dx.doi.org/10.1109/TUFFC.2012.2303. Opposed Reviewers:

Cover Letter

20th February, 2017 in Eindhoven, the Netherlands

Dear Editor, It is our pleasure to announce you that we have decided to submit our paper on Preclinical Testing of FrequencyTunable Capacitive Micromachined Ultrasonic Transducer Probe Prototypes to Ultrasound in Medicine & Biology (UMB). The presented study shows in-vivo the unique concept of a frequency-tunable, forward-looking and steerable intracardiac echocardiography catheter prototype, which we hope will be of a great interest to the scientific UMB community. Hereby we state that the manuscript, or specified parts of it, have not been and will not be submitted elsewhere for publication. For a review process of the submitted work we recommend the following three referees:

Kai Thomenius Petr Neužil Alessandro Savoia

Institute

Address

MIT, Institute of Medical Engineering & Science Homolka hospital, Department of Cardiology Univeristà degli Studi Roma Tre, Acoustoelectronics Laboratory

74 Vanvranken Road, Clifton Park, NY 12065, USA Roentgenova 2/37, 150 30 Praha 5, the Czech Republic via della Vasca Navale 84, 00146 Roma, Italy

With kind regards and on behalf of the authors, Martin Pekař

E-mail

Phone

[email protected]

001 518 371 2943

[email protected]

00420 257 272 211

[email protected]

0039 0657337080

*Manuscript Click here to view linked References

Preclinical Testing of Frequency-Tunable Capacitive Micromachined Ultrasonic Transducer Probe Prototypes Martin Pekaˇra,b,∗, Alexander F. Kolena , Harm Belta , Frank van Heescha , Nenad Mihajlovi´ca , Imo E. Hoeferd , Tamas Szili-T¨or¨okc , Hendrik J. Vosb , Johan G. Boschb , Gijs van Soestb , Antonius F. W. van der Steenb a

Philips Research, Royal Philips NV, High Tech Campus 34, 5656 AE Eindhoven, the Netherlands b Erasmus MC, Thorax Center Dept. of Biomedical Engineering, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands c Erasmus MC, Thorax Center Dept. of Cardiology, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands d Utrecht University, Faculty of Veterinary Medicine, Bolognalaan 50, 3508 TD Utrecht, the Netherlands

Abstract In intracardiac echocardiography (ICE) it may be beneficial to generate ultrasound images acquired at multiple frequencies, having the possibility of high penetration or high resolution imaging in a single device. The objective of the presented work is to test two frequency-tunable probe prototypes in a preclinical setting: a rigid probe having a diameter of 11 mm and a new flexible and steerable 12-Fr ICE catheter. Both probes feature a forward-looking 32-element capacitive micromachined ultrasonic transducer array (aperture of 2 × 2 mm2 ) operated in collapse-mode, which allows for frequency-tuning in the range from 6 MHz to 18 MHz. The rigid probe prototype is tested ∗

Corresponding Author: Martin Pekaˇr, Philips Research, Royal Philips NV, High Tech Campus 34, 5656 AE Eindhoven, the Netherlands; Email, [email protected]; Phone, +31 6 16 89 15 66.

Preprint submitted to Ultrasound in Medicine and Biology

February 20, 2017

ex-vivo in a passive heart platform. Images of an aortic valve acquired in high-penetration (6 MHz), generic (12 MHz), and high-resolution (18 MHz) mode combine satisfying image quality and penetration depth between 2.5 cm and 10 cm. The ICE catheter prototype is tested in-vivo using a porcine animal model. Images of an aortic valve are acquired in the three imaging modes with the ICE catheter placed in an ascending aorta at multiple depths. It was found that the combination of the forward-looking design and frequencytuning capability allows visualizing intracardiac structures of various sizes at different distances relative to the catheter tip, providing both wide overviews and detailed close-ups. Keywords: medical imaging, intracardiac echocardiography, capacitive micromachined ultrasonic transducer, collapse mode, frequency tunability,

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1

Introduction

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Cardiovascular deaths represent 31 % of all global deaths in the past few

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years, claiming more lives than all forms of cancer combined (Mozaffarian

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et al., 2016). Minimally-invasive procedures have proven to be effective in

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improving the patient outcome while minimizing trauma and complexity of

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cardiac interventions. Intracardiac echocardiography (ICE) is an established

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guidance tool for device closure of interatrial communications and electro-

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physiological ablation procedures (Earing et al., 2004; Reddy et al., 2010).

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The exploitation of ICE for navigation during other cardiac interventions

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and, more importantly, its use as a diagnostic tool is currently limited by

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its imaging performance at a distance and the restricted view it typically

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provides (Bartel et al., 2014). Our goal is to design a steerable forward-

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looking catheter which can change its imaging frequency between 6 MHz

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and 18 MHz, allowing for high penetration or high resolution imaging within

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a single device. The forward-looking design will offer complementary views

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to the conventional side-looking ICE concept. The frequency tunability com-

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bined with the catheter maneuverability will allow for both navigation and

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detailed close-up imaging.

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While the clinical review reports demonstrate the unmet need for a frequency-

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tunable forward-looking ICE catheter, there has been published only a single

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design of a forward-looking ultrasound transducer array which can change

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its operating frequency (Yeh et al., 2006). This design utilized a capacitive

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micromachined ultrasonic transducer (CMUT) ring array operated at 8 MHz

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and 19 MHz in conventional and collapse mode, respectively. The array could

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generate 3-D images of a wire phantom in oil, however, its integration in a 3

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steerable catheter shaft and its preclinical imaging capability remains to be

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demonstrated.

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Our design utilizes a single-type CMUT operated solely in collapse-mode,

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which has an extra feature that allows changing its operating frequency over

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a continuous range as opposed to a discrete change between conventional and

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collapse mode. This behaviour is referred to as ”frequency tunability” (Pekaˇr

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et al., 2016a). The frequency tunability is investigated in this preclinical

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study for forward-looking ICE imaging, addressing the requirement of having

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the possibility of high penetration (zoom-out) or high resolution (zoom-in).

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The principal objective of the presented work is to test two frequency-

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tunable forward-looking probe prototypes in a preclinical setting: a rigid

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probe having a diameter of 11 mm and a new flexible and steerable 12-Fr

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catheter. The acoustic characterization of the rigid probe has been published

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earlier (Pekaˇr et al., 2016b). The following section introduces the develop-

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ment of the new 12-Fr catheter. The concept of frequency tunability is first

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demonstrated on 2-D images of an aortic valve in a controlled ex-vivo setting

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using the rigid probe. Zoom-in and zoom-out capability of the developed

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catheter is presented in in-vivo imaging of the aortic valve in a live animal

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model.

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Materials and Methods

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Transducer technology

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Our design utilizes a 32-element CMUT phased array operated in collapse-

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mode Klootwijk et al. (2011), having a 9-Fr active aperture of an octagonal

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shape as shown in Fig. 1(a). The CMUT consists of thousands of tiny ca4

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pacitors (about 60 µm in diameter and 1.5 µm thick) with movable top

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membranes arranged in columns connected electrically in parallel. Static

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DC bias voltage (80 V – 160 V) is used to collapse the center area of the

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membrane onto the bottom of the cavity. Then AC voltage is applied to

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excite the free part of the membrane without releasing the center area from

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the bottom of the cavity. The CMUT transducts ultrasound and voltage

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as a result of these membrane vibrations, of which the resonance frequency

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increases for a high bias voltage magnitude, because the membrane stiffness

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and the contact radius of the collapsed portion of the membrane increases

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with larger deflection. The transmit pulse style and the bias voltage set-

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tings are tailored to the three imaging modes, based on initial resolution

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and penetration measurements on a tissue-mimicking phantom (unpublished

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observation).

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Probe prototypes

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The fabricated CMUT array is integrated with front-end electronics into

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two probe prototypes: a robust rigid probe having a diameter of 11 mm, and

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a steerable 12-Fr catheter. Both devices are equipped with identical CMUT

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array and an application specific integrated circuit (ASIC) to integrate the

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front-end electronics closely with the CMUT at the tip of the probe. The

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ASIC has 16 channels, each of which comprising of a 60-V unipolar pulser,

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a transmit and receive switch, a 27 dB amplifier, and a line driver. The

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assembled catheter tip is shown in Fig. 1(a).

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The 110-cm long catheter shaft offers omnidirectional steering achieved

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by manipulating 4 wires connected to an anchor ring near the tip and being

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controlled remotely via a mechanical joystick. The reach of the catheter is 5

(a)

(b)

Figure 1: (a) assembled forward-looking catheter tip with integrated CMUT array and front-end electronics. (b) steerability of the catheter tip by a mechanical joystick.

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38 mm when the tip is deflected at 90◦ and the maximum bending radius is

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180◦ as shown in Fig. 1(b).

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The probe prototypes are coated with a thin layer (about 15 µm) of a

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silicone-like material for electrical insulation of the array connections and

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passivation of the CMUT cells (Zhuang et al., 2007).

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Imaging

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The two probe prototypes are connected to a Verasonics Vantage imaging

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system (Kirkland, WA, USA), which is used to generate transmit pulses of

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arbitrary frequency (5 MHz – 20 MHz), amplify, digitize (14-bit, 62.5 MHz),

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and transfer the received sensor data to a host controller PC for real-time

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ultrasound image visualization or data recording. The transmit pulse fre-

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quency, number of transmit pulses and the CMUT bias voltage can be set

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via a graphical user interface which controls the Verasonics system and a

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programmable electronic toolbox.

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Conventional line-based sector scanning (von Ramm and Smith, 1983) is

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implemented on the Verasonics system for the real-time visualization, which

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is used to navigate the probes, whereas the recording option facilitates high 6

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frame rate data acquisition for off-line processing (Montaldo et al., 2009).

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The beamformed, high frame rate images are filtered in the fast-time do-

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main with 50 % band-pass finite impulse response filter (FIR) centered at

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6 MHz, 12 MHz, or 18 MHz yielding high-penetration, generic, or high-

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resolution imaging performance, respectively. A median-filter is applied on

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the consecutive frames to improve an image signal-to-noise ratio and to yield

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about 25 FPS, which is at the order of magnitude typically used for cardiac

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imaging. Electrocardiogram (ECG) is recorded synchronously with the pulse

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transmission via an audio card fitted on the host controller PC.

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Passive heart platform

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The concept of frequency tunability is first demonstrated by imaging an

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aortic valve in a passive beating heart platform (LifeTec Group BV, Eind-

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hoven, the Netherlands) which features mechanical pumping of a porcine ex-

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vivo heart freshly collected from a local abattoir. Air bubble-free, heparinized

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blood is pumped through the left ventricle of the heart. The system allows

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precise control and monitoring of hemodynamical parameters and robust per-

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formance for up to 12 hours. Earlier validation of this platform shows repro-

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ducible physiological hemodynamics, e.g. aortic pressures of 120/80 mmHg

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with 5 L/min of cardiac output (Leopaldi et al., 2015).

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The rigid probe prototype was inserted and sealed in the aorta facing the

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aortic valve (Fig. 2), of which the long-axis images were acquired in the three

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imaging modes.

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Figure 2: Photograph of the ex-vivo testing of the rigid probe prototype using a passive heart platform.

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Porcine animal model

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Live animal studies were carried out after securing approval from the

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Dutch Central Commission for Animal Studies (protocol nr. AVD/115002015205)

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and according to the European directives (2010/63/EU) and the Guidelines

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for the Care and Use of Laboratory Animals (NIH). The forward-looking

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ICE catheter was tested in a porcine model (about 70 kg) under general

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anaesthesia with a mixture of midazolam, sufentail and pancuronium, and

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low-frequency mechanical ventilation. The animal was heparinized to avoid

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thrombus formation. The ECG and oxygen saturation were monitored con-

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tinuously throughout the study. Access for the aortic valve imaging was

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obtained via a femoral artery or a left common carotid artery. Fluoroscopic

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images of the catheter position inside the heart were taken from the left

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anterior oblique view (LAO) with cranial angulation.

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Results

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Ex-vivo passive heart study

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The frequency-tunable collapse-mode CMUT array is utilized to gener-

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ate high-penetration depth (6 MHz), generic (12 MHz), and high-resolution

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(18 MHz) images of an aortic valve in an ex-vivo passive heart platform.

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Fig. 3 compares imaging performance of these three modes. The penetration

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mode shown in Fig. 3(a, d) allows imaging the heart up to 10 cm, clearly vi-

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sualizing the aorta, left atrium, left ventricle and providing a coarse imaging

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of the opening and closing of the aortic and the mitral valve. The generic

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mode (Fig. 3(b, e)) provides increased resolution clearly depicting the leaflets

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of the aortic valve and a portion of the mitral valve up to the depth of about

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5 cm. The high-resolution mode (Fig. 3(c, f)) generates the finest detail of

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the aortic valve with penetration depth of about 2.5 cm.

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The dynamic range in the obtained images is scaled to the peak signal

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intensity and optimized subjectively for display. If the Fig. 3(f) would be

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displayed at the same dynamic range as Fig. 3(e), it would exhibit lower

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contrast. Figs. 3(b, c, e, f) utilize imaging frequency higher than 10 MHz,

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at which the spontaneous echo contrast of blood appears. This results in the

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white swirl seen above the closed aortic valve in Figs. 3(b, c). The white

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pattern throughout the vertical center of the displayed images is common

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mode noise which is dominant at steering angles close to 0◦ . To better ap-

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preciate the frequency-tunability, a video corresponding to Fig. 3 is included

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as an online supplement (Movie 1). This recording shows frequency-tunable

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imaging of the ex-vivo aortic valve placed at a fixed distance.

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Figure 3: Imaging of an aortic valve using the frequency-tunable probe prototype in an ex-vivo passive heart platform. Closed and open state of the aortic valve is shown in the top and bottom row, respectively. The imaging modes (HPEN indicates high-penetration; GEN, generic; HRES, high-resolution) and the displayed dynamic range are shown in the top-right corner. The white curve at the bottom of each image depicts the recorded ECG signal, of which the cursor indicates the displayed moment in the heart cycle.

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Live animal study

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To investigate the usability of having the high penetration (zoom-out)

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or high resolution (zoom-in) in a single device, the frequency tunability for

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forward-looking ICE imaging was studied in an in-vivo animal model. The

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catheter prototype was first inserted via a femoral artery to the ascending

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part of the aorta facing the aortic valve (Fig. 4(b)). Images of long-axis view

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of the aortic valve located at a depth of about 2.5 cm were acquired in the

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general mode (Figs. 5(b, e)). The catheter could not be advanced closer to

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the aortic valve, due to its bending profile not allowing the advancement

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through the tight aortic arc of the porcine heart. It was therefore removed

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Figure 4: Fluoroscopic images indicating the position of the catheter’s tip during the zoomin and zoom-out imaging of an aortic valve using the developed prototype of frequencytunable forward-looking ICE catheter in an in-vivo animal model. The catheter is positioned at about (a) 5 cm, (b) 2.5 cm and (c) 1 cm from the aortic valve. These fluoroscopic images correspond to the ultrasound images shown in Fig. 5.

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and inserted via the carotid artery (Fig. 4(c)). Thus close-up images of the

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aortic valve at a depth of about 1 cm in the high-resolution mode (zoom-in)

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have been obtained as shown in Figs. 5(c, f). Subsequently, the catheter was

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pulled back to about 5 cm from the aortic valve (Fig. 4(a)) and images in

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the penetration mode were recorded (Figs. 5(a, d)).

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The zoom-in and zoom-out capability of the developed forward-looking

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frequency-tunable ICE catheter is shown in comparison of opened and closed

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aortic valve images (Fig. 5) displayed at 28 FPS. The opened and closed state

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of the valve can be identified in all three imaging modes. The penetration

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mode enables anatomical overview for navigation whereas the high-resolution

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mode allows a close-range, more detailed anatomic image of the aortic valve.

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The generic imaging mode provides a compromise of the two.

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Figure 5: Imaging of an aortic valve using the developed prototype of frequency-tunable forward-looking ICE catheter in an in-vivo animal model. Closed and open state of the aortic valve are shown in the top and bottom row, respectively. The imaging modes (HPEN indicates high-penetration; GEN, generic; HRES, high-resolution) and the displayed dynamic range are shown in the top-right corner. The white curve at the bottom of each image depicts the recorded ECG signal, of which the cursor indicates the displayed moment in the heart cycle.

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Discussion

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This study reports on preclinical testing of a novel forward-looking ICE

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catheter prototype. The catheter is based on collapse-mode CMUT tech-

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nology which features bias voltage-based frequency tuning to generate ultra-

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sound images at the center frequencies of 6 MHz, 12 MHz, and 18 MHz, but

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any frequency in between is possible and can be changed in realtime.

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It was found that intracardiac structures were delineated with satisfying

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image resolution or penetration depth. The frequency-tunable catheter can

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visualize anatomical structures of various sizes at different distances relative 12

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to the catheter tip, enabling both wide overviews and detailed close-ups.

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The catheter prototype presented in this study has an active aperture of

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9 Fr but outer diameter of 12 Fr, due to the wirebonds which connect the

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CMUT array with the front-end electronics. Clinical practise requires the

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diameter to be reduced to at least 10 Fr. This could be achieved either by

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monolithic integration with the front-end electronics or by utilizing a flex-

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to-rigid technology (Khuri-Yakub and Oralkan, 2011; Mimoun et al., 2010).

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A decreased shaft diameter would increase the catheter’s deflectability and

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steerability, which were found to be crucial for easy navigation in the confined

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space of the heart.

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The potential gain in navigation efficiency of the forward-looking design,

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which is similar to using a flashlight, towards the specific feature of interest

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needs to be proven in a future study.

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Even though it is common practice to place a commercial ICE catheter

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inside the aorta for investigational guidance (Bartel et al., 2014), its restricted

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bandwidth and side-looking design limits its diagnostic capability, e.g. for

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infective endocarditis. The catheter design presented in this study allows

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for a complementary view and its switching to higher operation frequency

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exploits the usage of ICE for close-up high frequency diagnosis of the heart

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valves.

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High frequency imaging would also allow for near-by thrombus detection

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or guidance of percutaneous biopsies of intra-aortic masses suspected to be

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tumours. It is foreseen that frequency-tunable forward-looking ICE catheter

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will exploit the use of ICE for diagnosis of heart valves, guiding LAA closure

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and real-time lesion visualization during ablation procedures.

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Conclusions

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A rigid probe and a steerable ICE catheter prototype, both equipped with

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collapse-mode frequency-tunable forward-looking CMUT array, have been

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successfully tested in a passive heart platform and an animal experiment,

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respectively. Images of the aortic valve acquired in high-penetration (6 MHz),

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generic (12 MHz), and high-resolution (18 MHz) mode show satisfying image

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quality and penetration depth between 2.5 cm and 10 cm for the imaging

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aperture of 2 × 2 mm2 . The ICE catheter prototype placed in the ascending

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aorta was utilized to image the aortic valve at multiple depths in-vivo. It

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was found that the combination of the forward-looking design and frequency-

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tuning feature allows visualizing intracardiac structures of various sizes, e.g.

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leaflets of the heart valves and the ventricle at different distances relative to

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the catheter tip, providing both wide overviews and detailed close-ups. The

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promising approach may substantially influence the future role of forward-

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looking ICE in the clinical practice.

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Acknowledgements

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The authors would like to thank the following people for their effort and

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support in this study: Michel van Bruggen, Frank Budzelaar, Geert Gijsbers,

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Jeannet van Rens, Marc Notten, Bas Jacobs, Wim Weekamp, Alfons Groen-

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land, Ferry van der Linde, Maurice van der Beek, Debbie Rem-Bronneberg,

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Wendy Dittmer and Ren´e Aarnink.

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This research is in part funded by European Union Seventh Framework Programme project ”OILTEBIA”, grant no. 317526.

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URL http://www.ncbi.nlm.nih.gov/pubmed/20637313

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¨ Wygant IO, O’Donnell M, Khuri-Yakub BT. 3-D UlYeh DT, Oralkan O,

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trasound Imaging Using a Forward-Looking CMUT Ring Array for In-

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travascular / Intracardiac Applications. IEEE Transactions on Ultrasonics,

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Ferroelectrics, and Frequency Control, 2006;53:1202–1211.

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Zhuang X, Nikoozadeh A, Beasley MA, Yaralioglu GG, Khuri-Yakub BT,

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Pruitt BL. Biocompatible coatings for CMUTs in a harsh, aqueous envi-

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ronment. Journal of Micromechanics and Microengineering, 2007;17:994–

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1001.

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Video Recordings

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Movie 1: Recording of the aortic valve acquired during one cardiac cycle

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with the frequency-tunable probe prototype in the ex-vivo passive heart

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platform. (a) high-penetration, (b) generic and (c) high-resolution

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mode. The penetration depth is fixed to 10 cm. The white curve

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at the bottom of each image depicts the recorded ECG signal, of which

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the cursor indicates the displayed moment in the heart cycle.

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Figure 1a Click here to download high resolution image

Figure 1b Click here to download high resolution image

Figure 2 Click here to download high resolution image

Figure 3 Click here to download high resolution image

Figure 4 Click here to download high resolution image

Figure 5 Click here to download high resolution image

Movie 1 Click here to download Supplemental Video: 2016-04-21_HPEN_GEN_HRES_forUMBpaper_v2.avi

Movie 1 (still) Click here to download high resolution image

LaTeX Source Files Click here to download LaTeX Source Files: 2017-02-20_PreclinicalFreqTuning_v07_sentToUMB.zip