Spiros Kotopoulis

Student Member, IEEE Han Wang

Sandy Cochran

Member, IEEE Michiel Postema

Lithium niobate transducers for MRI-guided ultrasonic microsurgery

Lithium niobate transducers for MRI-guided ultrasonic microsurgery

Lithium niobate transducers for MRI-guided ultrasonic microsurgery I. INTRODUCTION Focused ultrasound surgery (FUS) is based on the application of high intensity focused ultrasound (HIFU) to heat tissue to a temperature that causes protein denaturation and coagulative necrosis [START_REF]Emerging Therapeutic Ultrasound[END_REF]. The required temperature to generate lesions is between 56 -60 • C [START_REF] Hill | Review article: High intensity focused ultrasound: Potential for cancer treatment[END_REF], [START_REF] Haar | Ultrasound focal beam surgery[END_REF]. The frequency of ultrasound used is generally around 1 MHz, generating characteristic ellipsoidal lesions on the order of 1 cm in length. Higher frequencies in the region of 4 MHz are also used where more precise treatment is needed, for example in the prostate where tumour sizes may be < 1 mm long [START_REF] Rouvière | Evaluation of color doppler in guiding prostate biopsy after HIFU ablation[END_REF]. At such frequencies, conventional piezoelectric transducers can be used, based on hard piezoceramic with high drive capability. The use of FUS is increasing as a non-invasive form of surgery and the need for even higher precision is increasing for example for use in aesthetic facial rejuvenation [START_REF] White | Selective creation of thermal injury zone in the superficial musculoaponeurotic system using intense ultrasound therapy[END_REF], ultrasonic thrombolysis [START_REF] Tachibana | Albumin microbubble echo-contrast material as an enhancer for ultrasound accelerated thrombolysis[END_REF] and treatment of malignant disease in breast [START_REF] Huston | Ablative therapies for the treatment of malignant diseases of the breast[END_REF] whilst helping maintain a patient's quality of life when compared to invasive surgery [START_REF] De La Rosette | Focal targeted therapy will be a future treatment modality for early stage prostate cancer[END_REF].

In this paper, we consider the type of device that could be used to apply HIFU at much higher frequencies, with our research ultimately targeting 50 -100 MHz. A difficulty with FUS is to necrose a clinically significant volume quickly enough for financial viability within modern medical treatment systems. However, the exquisite precision of necrosis possible with HIFU must also be recognised. The interface region may be as thin as just a few cells, with deep sub-millimetre dimensions, offering interesting possibilities for precise intervention. These may include treatment of dermatological and ophthalmological conditions, of the walls of the digestive system, for example relating to pre-cancerous tissue dysplasia, and of the walls of the vascular system. The superficial nature of these applications, if necessary handled with intralumenal and intravascular devices, significantly eases the problem of penetration depth at high frequency. The formats of the devices we report here are not suitable for these applications directly but reports on transurethral and endocavitary devices [START_REF] Seip | Transurethral high intensity focused ultrasound: catheter based prototypes and experimental results[END_REF], [START_REF] Wharton | Design and development of a prototype endocavitary probe for high-intensity focused ultrasound delivery with integrated magnetic resonance imaging[END_REF] point the way forward. In all cases, we would predict adoption of high frequency FUS for superficial treatments of small overall volumes.

As the attenuation coefficient of human tissue has a near linear dependence on frequency [START_REF] Lyons | Absorbtion and attenuation in soft tissues ii-experimental results[END_REF] greater intensity fields are necessary at higher frequencies in order to be able to penetrate deep enough into human tissue even for superficial applications. Piezoceramic is expected to be incapable of sustaining sufficiently high-power operation at such frequencies because of mechanical fragility, losses, and electrical breakdown. Instead, we have based our investigation on lithium niobate, LiNbO 3 [START_REF] Weis | Lithium niobate: Summary of physical properties and crystal structure[END_REF]. As a single crystal, this can be thinned easily without disintegrating April 1, 2011 DRAFT unlike ceramics. In addition LiNbO 3 can sustain high electric fields, and its low losses allow the use of harmonics.

The use of single crystals and LiNbO 3 for high frequency ultrasound has been explored before, but only for high-resolution imaging [START_REF] Snook | Design, fabrication, and evaluation of high frequency, single-element transducers incorporating different materials[END_REF], [START_REF] Cannata | Design of efficient, broadband single-element (20-80 MHz) ultrasonic transducers for medical imaging applications[END_REF].

II. METHODOLOGY

A. Lithium niobate

As it was expected that piezoceramics would be unable to produce HIFU at high frequencies and harmonics due to de-poling or cracking, we have explored Y-36

B. Transducer manufacture

Three transducer designs were prepared as shown in Fig. 1: unfocused single elements with 17 mm square LiNbO 3 plates (xDucer 1); a 2D faceted bowl with three pentagonal and four hexagonal plates to mimic a spherically-focused device (xDucer 2); and a 1D faceted cylindrical section with five, 9×30 (mm) 2 rectangular plates to mimic a cylindrically focused device (xDucer 3). The equivalent radii of curvature for xDucer 2 and xDucer 3 were 50 mm and 30 mm respectively. The devices were manufactured as prototypes using a proof-of-concept approach; this limited their reliability and hence sometimes the completeness of the data that was recorded. Nevertheless, the manufacturing techniques and the principles of the devices could be taken forward to more robust examples.

To prepare the plates for each transducer, Y-36 • cut, 3-inch diameter, 0.5-mm thick LiNbO 3 wafers (Boston Piezo-Optics, Inc, Boston, MA) were obtained, polished on one side and lapped on the other. Figure 1 shows the position of each element from each wafer for each of the three transducer designs. Separation of the plates was performed with a programmable APD1 saw (Logitech Ltd, Glasgow, UK) with a spindle speed of 2900 rpm and a feed rate of 0.160 mm s -1 .

For the xDucer 1 devices, the 11 square elements cut from a single wafer were lapped individually in steps of 30 µm starting from 500 µm down to 200 µm using a PM5 precision lapping and polishing machine (Logitech Ltd, Glasgow, UK). The force applied during lapping was adjusted depending on the sample size, typically in the range 400 -900 g. A slurry of 20-µm calcined Al 2 O 3 powder in water was used as abrasive. Once the elements reached within 25 µm of the target thickness, 9-µm calcined Al 2 O 3 powder was used to avoid scratching. The lapping machine was programmed to ensure maximum flatness.

The true thickness of the samples was measured and verified at regular intervals using a CG-10 Precision Electronic Measurement System (Logitech Ltd, Glasgow, UK). Once each element was flat at the desired thickness, April 1, 2011 DRAFT it was removed from the glass lapping plate and re-measured to verify the thickness. The elements were continuously checked using a stereo microscope for flaws which could act to concentrate stress and lead to cracking.

An electrode was hand painted on to the lapped side using ELECTRODAG 1415 silver paint (Acheson Colloids BV, Scheemda, Netherlands). Excess paint around the edges was removed using a scalpel and acetone. The polished side of each element was then attached to the adhesive side of Adwill D-210 UV tape (Lintec of America, Inc., Phoenix, AZ). RG174A/U 50 Ω coaxial cable was used connected to the plates with Ag-loaded conductive epoxy, curing taking place at 80 • C for 10 min.

For xDucer 1 devices, Cu tubing with an internal diameter of 28 mm was cut into lengths of 50 mm and placed over the LiNbO 3 plates onto the adhesive side of the UV tape. Epoxy was then introduced around the sides of the LiNbO 3 plate to join it to the Cu tube. The case for the 2D faceted array, xDucer 2, had a height of 75 mm, outer diameter of 70 mm and a wall thickness of 2 mm. The case for the curvilinear array, xDucer 3, had a height of 75 mm, outer diameter of 50 mm and wall thickness of 1.5 mm. For operation within a magnetic resonance imaging (MRI) system, the cases of xDucer 2, and 3 were polyvinyl chloride (PVC) coated with a thin layer of Ag paint so they could be used as the electrical ground connections to the front face of each transducer.

To support the fragile LiNbO 3 , Epofix resin (Struers, Ballerup, Denmark) was mixed with S38 glass microballoons (Lawrence Industries, Tamworth, UK) with a weight ratio of 65 : 35. The microballoon-epoxy mix was poured into the transducer shell. The xDucer 1 devices were filled to a depth of 16 mm whereas xDucers 2 and 3 were filled to a depth of 22 mm. It was found that the acoustic output with the backing material was reduced by 5 % compared to devices made without backing. The backing was left to cure at room temperature. The earth cable was attached to the shell using conductive Ag epoxy. The UV tape was then exposed to UV light and peeled off. Any remaining adhesive residue was removed manually.

The exposed LiNbO 3 was cleaned using solvent then the front surfaces and part of each case were painted with Ag paint. The cases were then filled with 5368 silicon (Henkel AG & Co. KGaA, Düsseldorf, Germany) to waterproof the cables and 50-Ω BNC RG-174 plugs were connected to the coaxial cables.

C. Acoustic pressure

Each transducer was driven by a continuous wave at its fundamental frequency, generated by an AFG3102 waveform generator (Tektronix, Everett, WA). The signal was passed through a -20-dB attenuator before being used as the input to a power amplifier. The single element transducers were tested using a 3100LA, +55-dB RF amplifier (Electronics & Innovation, Rochester, NY). To test xDucer 2, the pentagonal elements were linked and driven by a 2100L, +50-dB RF amplifier (Electronics & Innovation, Rochester, NY) and the hexagonal elements were linked and driven by the 3100LA amplifier. This was done to give the ability to improve on the April 1, 2011 DRAFT alignment of the multiple sound fields by shifting the phase of each group of elements. The pressures outputs were measured using a calibrated fibre-optic hydrophone (Precision Acoustics, Dorchester, UK) and verified using an HGL-0200 piezoelectric hydrophone (Onda, Sunnyvale, CA). The curvilinear transducer, (xDucer 3), was tested using a 150A250, 150W RF amplifier (Amplifier Research, Souderton, PA). The acoustic pressure was measured at the acoustic focus, 13 mm from the transducer face using the HGL-0200 hydrophone. The maximum peak-to-peak acoustic pressure was defined at the acoustic focus of each transducer in a 25×17×12 (cm) 3 , water filled, low-density polyethylene container. For all measurements the free field was manually scanned to locate the acoustic focus of each transducer using an M-652 x-y-z micro-translation stage (Newport, Didcot, Oxfordshire, UK).

D. LiNbO 3 Properties

Data available for the properties of Y-36 • LiNbO 3 were found to be limited and incomplete in the literature so values for one-dimensional simulation were obtained using PRAP version 2.2 software (TASI Technical Software Inc, Ontario, Canada) using electrical impedance data from a plate measured with a 4395A impedance analyser (Agilent, Santa Clara, CA). Table I shows the measured properties for Y-36 • cut LiNbO 3 , with figures for Z-cut material shown for comparison. The resonance frequencies of the transducers were also measured using the same impedance analyser.

E. Acoustic radiation

The acoustic radiation force output of the transducers was measured using an EMS Model 67 ultrasound radiation force balance (EMS Physio Ltd, Wantage, UK). The transducers were placed within 20 mm of the surface of the ultrasound absorber in the balance to ensure that the total radiated flux was incident on it. The output voltage of the waveform generator was increased and the amplifier forward and reflected power and the transducer acoustic power were recorded.

F. MRI temperature measurements

MRI guidance is used for FUS [START_REF] Hynynen | Mri-guided focused ultrasound treatements[END_REF] as it allows precise targeting of the HIFU field and direct temperature measurement at the focus.

G. Tissue sonication

To test the effect of the HIFU field on tissue, two boneless, skinless chicken breasts (Tesco, Cheshunt, UK) were cut into 12, 2 × 2 × 8 (cm) 3 strips. The strips were placed in a 10 × 15 × 5 (cm) 3 container filled with tap water at room temperature and xDucer 3 was clamped vertically with the acoustic focus on the surface of the tissue. Each sample was sonicated once. For tests beneath the surface of the tissue the transducer was lowered closer to the chicken. In all experiments it was ensured that the transducer surface was not in contact with the tissue. The chicken breast was sonicated using the same settings as in the MRgFUS measurements. Sonication time was increased in steps of 10 s. Lesion sizes were measured manually using ImageJ (National Institutes of Health, Bethesda, MD).

III. RESULTS AND DISCUSSION

A. LiNbO 3 Properties

The resonant frequency and third harmonic of the xDucer 1 devices made with different LiNbO 3 thicknesses are compared to one-dimensional modelling (ODM) for both Z-cut and Y-36 • cut LiNbO 3 in Fig. 2. Although the Z-cut material gives a higher frequency for a given material thickness, other key properties such as d 33 and k T are much lower, hence the preference for Y-36 • cut material.

B. Acoustic pressure

The acoustic pressures generated by the three transducers is given in Table II. The xDucer 2 device generated a modulated sound field. It was possible to improve the output and reduce the envelope frequency of the modulation by shifting the phase of each set of elements. The lowest modulation frequency of 550 kHz was achieved with a phase difference of 12 • . The modulated sound field was generated as a result of multiple interacting sound fields.

This was due to misaligned elements in our proof of concept devices. To cancel out the modulation, the phase of each element would have to be controlled independently, or the faceted bowl must be manufactured to tolerances at < 1 4 λ of the operating frequency. Higher harmonics of xDucer 2 were not tested due to low reproducibility. The acoustic pressures generated were limited by the maximum outputs of the RF amplifiers used. From the fundamental pressure measurements, the design of xDucer 2 would be the most logical to pursue.

C. Acoustic Radiation Power

The acoustic power generated by the xDucer 1 devices is shown in Fig. 3. Efficiency for these devices was found to be 33±5% throughout the frequency spectrum. Sustained operation of up to 5 minutes was possible without damaging the transducers at the resonance frequency, 3 rd and 5 th harmonic. The output power is seen to drop as the element thickness decreases. This is due to the increasing electrical impedance mismatch shown in Fig. 4. For April 1, 2011 DRAFT maximum output power the impedance magnitude and phase should be 50Ω and 0 • respectively. As the element thickness decreases the impedance magnitude also decreases. This is seen for both the fundamental resonance and 3 rd harmonic. The phase of the 3 rd harmonic increases with element thickness due to the inductance generated by the cable. Factors such as amount of Ag-loaded epoxy and cable length were seen to affect the impedance of the transducers [START_REF] Schmerr | Complete ultrasonic transducer characterization and its use for models and measurements[END_REF]. The xDucer 3 device had an efficiency of 25±2% whereas a commercial 3.28-MHz, 58-mm diameter HIFU transducer made with piezoceramic (Precision Acoustics, Dorchester, UK) was found to have an efficiency of 20±1%. After sonication, cavitation related bubbles formed on the front surface of the transducer shown in Fig. 5. These measurements demonstrate the viability of MRI ultrasonically-elevated temperature measurement with the devices reported here; it should be noted that at the 3 rd and 5 th harmonics (21.1 MHz and 35.2 MHz respectively), the ultrasound wavelength is substantially smaller than the spatial resolution of the 1.5T MRI system.

D. MRI temperature measurements

E. Tissue sonication

Figure 8 shows the effect of xDucer 3 on chicken breast. An increased sonication time was necessary in order to induce a lesion beneath the tissue surface, of similar size to the MRI measured results. This is partially due to scattering and gas content in the tissue. The lesions dimensions after 90 s of sonication at 6.6 MHz matched those measured with the MRI. In Fig. 8, the chicken has been sliced open to locate the region of sonication. The lesion was formed 60 mm beneath the surface of the tissue without affecting the upper tissue boundary or the surrounding tissue. In further tests, after two minutes continuous sonication, when the transducer surface was in contact with the chicken tissue, sufficient heat was generated to cause protein denaturation on the chicken surface. Thus, in a practical (clinical) setting, contact with tissue would have to be avoided. Impedance matching and better-attached electrodes might reduce element heating; water-cooling of commercial FUS transducers is also common.

IV. CONCLUSIONS

In conclusion, we have shown that it is feasible to manufacture high-frequency, high-intensity, focused ultrasound transducers based on Y-36 designed to be operated under MRI guidance. We have shown that this design was successful and have used one of the devices to increase the temperature within a gel phantom, measured with MRI, to more than 50 • C following sonication of 55 s with an equivalent acoustic intensity of 163 Wcm -2 . We also created lesions within chicken tissue after 90 s sonication.

Several aspects can be addressed in order to improve the performance of the transducers. At high acoustic intensities the Ag-paint electrode was damaged. This is attributed to air pockets trapped between the electrode and the LiNbO 3 . The use of thin film Cr-Au, Ti-Pt or Al electrodes would be better acoustically and electrically as electrodes compared to conductive Ag paint [START_REF] Nakazawa | A high frequency variable focus ultrasonic transducer using polyurea thin film[END_REF]. The cases of the devices for MRI guidance were made with PVC tubing coated with Ag paint; using an alternative such as Cu-epoxy composite [START_REF] Gerold | Early exploration of MRI-compatible diagnositc ultrasound transducers[END_REF] would aid manufacture and reliability and assist with shielding. The thin LiNbO 3 piezoelectric elements were supported by microballoon-filled epoxy backing; this reduced the transducer output thus necessitating exploration of support materials with a lower acoustic impedance or other methods to support the plates. Finally, electrical impedance matching was neglected.

However, as frequency increases electrical impedance decreases and sustained operation would be enhanced by electrical impedance matching.

  For MRI-guided focused ultrasound surgery (MRgFUS) tests in the present work, xDucer 3 and a DQA Gel Phantom (ATS Laboratories, Bridgeport, CT) placed in a cylindrical perspex chamber filled with tap water were placed in a GE Signa HDx 1.5T MRI system (GE Healthcare, Waukesha, WI). A gradient echo planar image (EPI) was recorded with TE = 17.0 ms, ER = 230.0 ms and BW at 62.0 kHz to capture the temperature increase of the phantom. The curvilinear transducer was turned on at t = 0 s with a pk-pk input voltage of 101 V, equivalent to 8 W acoustic power and 32 W forward electrical power. The transducer was turned off after 55 s. The size of the acoustic focus was determined by the area heated above the surrounding ambient temperature.April 1, 2011 DRAFT

Figure 5

 5 Figure 5 is an MRI image of xDucer 3 positioned on the DQA gel phantom. Figure 6 shows the area heated by xDucer 3 in the plane of the MRI scan, aligned with its focus. The surface area of heating after 55 s of sonication was 2.5 mm × 3.4 mm. Within 31 s the temperature in the acoustic focus of the transducer had increased 18 • C above ambient to a temperature of 38 • C. A peak temperature of 52 • C was reached after 55 s of sonication, 32 • C above ambient, as shown in Fig. 7. The acoustic intensity at the focus of the transducer was equivalent to 163 Wcm -2 .

11 2 12 3 13 4 16 7 17 8 18 AprilFig. 1 .

 1112131617181 Fig. 1. Transducer manufacturing: (a) position of plates in single wafer used for each transducer, (b) dimensions of plates for each transducer, (c) computer-aided design representation of transducers, and (d) completed transducers.

Fig. 2 .Fig. 3 .Fig. 4 .Fig. 5 .Fig. 6 .Fig. 7 .

 234567 Fig. 2. Resonance frequency and third harmonic as a function of element thickness for single-element LiNbO 3 microballoon-backed transducers. The diamonds indicate the z-cut LiNbO 3 simulations, the circles indicate the experimental measurements, and the five-point stars indicate the Y-36 • LiNbO 3 cut simulations. The grey data points show the 3 rd harmonic. The error bars indicate the confidence interval for the LiNbO 3 thickness.

Fig. 8 .

 8 Fig. 8. Photograph showing lesion formed on chicken tissue after 90 s sonication using xDucer 3. The acoustic focus was beneath tissue surface. The direction of acoustic propagation is into the image as indicated by the arrows.

  • LiNbO 3 . As well as its basic advantages, it has a high resonant frequency of 3.3 MHz mm -1 , thus allowing for thicker elements at higher frequencies for cost effective manufacturing compared to piezoceramics, and it has the highest electromechanical coupling coefficient compared to other LiNbO 3 cuts[START_REF] Warner | Determination of elastic and piezoelectric constants for crystals in class (3m)[END_REF].

  MHz using the 3 rd harmonic of 200-µm thick LiNbO 3 , focal pressures of 4 MPa at 35 MHz, and MI = 4.7 at 6.6 MHz. Two of the devices made, with faceted bowl and faceted cylindrical sections respectively, were

	more than 50
	April 1, 2011	DRAFT

• cut LiNbO 3 . In a range of tests, we have demonstrated operating frequencies up to

TABLE II PEAK

 II -TO-PEAK ACOUSTIC PRESSURES GENERATED BY XDUCER 1, XDUCER 2 AND XDUCER 3 AT THEIR FUNDAMENTAL FREQUENCY, 3 rd AND 5 th HARMONIC. member of the editorial board of Bubble Science, Engineering and Technology (Maney). He is also Fellow of the UK Institute of Acoustics (IOA), member of the IOA Research Coordination Committee and member of the Scientific Committee of Revue des Sciences et Technologie (Université de Batna). He has written more than 70 scientific publications on medical acoustics and cavitation, including 40 first-author papers and five co-authored textbooks. His particular expertise lies in analysing medical microbubble behaviour under sonication and in high-speed photography. He also explores non-medical applications of bubbles and droplets in sound fields. Since 2007, he has pulled in more than US$ 4.4 Million in research grants.

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VI. BIOSKETCHES Spiros Kotopoulis (S'08) was born in Athens, Greece, in 1987. He received a first class B.Eng. (Hons) in Mechanical Engineering from The University of Hull, England, in 2008. Mr. Kotopoulis is a member of the U.K. Institute of Acoustics. He is currently pursuing a Ph.D. under the supervision of Professor Dr. Michiel Postema at The University of Hull. His research interests include high-speed photography, microscopy, ultrasound transducer manufacture and sonoporation. Han Wang was born in Tianjin, China, in 1986. He received his B.Eng. in Electronic Science and Technology from Tianjin University, China, in 2009. He then gained an MSc with Distinction in Biomedical Engineering from University of Dundee, Scotland, UK, in 2010. Mr. Han Wang is currently pursuing a Ph.D. under the supervision of Dr. Christine E. M. Démoré at Institute for Medical Science and Technology, University of Dundee. His current research interests are in ultrasonic device development for life sciences and electronics instrumentation for ultrasound devices and system.