Ultrasound in Med. & Biol., Vol. 37, No. 10, pp. 1667–1676, 2011Copyright � 2011 World Federation for Ultrasound in Medicine & Biology

Printed in the USA. All rights reserved0301-5629/$ - see front matter

asmedbio.2011.06.017

doi:10.1016/j.ultr

d Original Contribution

DUAL-MODE IVUS TRANSDUCER FOR IMAGE-GUIDED BRAIN THERAPY:PRELIMINARY EXPERIMENTS

CARL D. HERICKHOFF,* CHRISTY M. WILSON,y GERALD A. GRANT,y GAVIN W. BRITZ,y

EDWARD D. LIGHT,* MARK L. PALMERI,* PATRICK D. WOLF,* and STEPHEN W. SMITH**Department of Biomedical Engineering; and yDivision of Neurosurgery, Duke University Medical Center, Durham, NC, USA

(Received 14 February 2011; revised 6 June 2011; in final form 23 June 2011)

ABiomeDurham

Abstract—In this study, we investigated the feasibility of using 3.5-Fr intravascular ultrasound (IVUS) cathetersfor minimally-invasive, image-guided hyperthermia treatment of tumors in the brain. Feasibility was demon-strated by: (1) retro-fitting a commercial 3.5-Fr IVUS catheter with a 5 3 0.5 3 0.22 mm PZT-4 transducerfor 9-MHz imaging and (2) testing an identical transducer for therapy potential with 3.3-MHz continuous-wave excitation. The imaging transducer was compared with a 9-Fr, 9-MHz ICE catheter when visualizing thepost-mortem ovine brain and was also used to attempt vascular access to an in vivo porcine brain. A net averageelectrical power input of 700mWwas applied to the therapy transducer, producing a temperature rise of113.5�Cat a depth of 1.5 mm in live brain tumor tissue in the mouse model. These results suggest that it may be feasible tocombine the imaging and therapeutic capabilities into a single device as a clinically-viable instrument. (E-mail:cdh14@duke.edu) � 2011 World Federation for Ultrasound in Medicine & Biology.

Key Words: Dual-mode catheter transducer, Ultrasound hyperthermia, Intravascular ultrasound.

INTRODUCTION

The long-term goal of this research is the development ofa minimally-invasive, endovascular approach to adminis-tering localized, image-guided, ultrasound-inducedhyperthermia in the brain. This localized delivery ofhyperthermia would provide targeted control of drugrelease from thermosensitive liposomes and opening ofthe blood-brain barrier, which would enhance chemother-apeutic drug delivery to malignant brain tumors. Inprevious studies, we investigated the feasibility of dual-mode intracranial catheter transducers by two differentapproaches: first, by using 14-Fr, phased-array prototypetransducers for focused tissue heating and real-timethree-dimensional (3-D) intracranial imaging and second,by modeling and measuring acoustic output for various3.5-Fr intravascular ultrasound (IVUS) catheter trans-ducer apertures (Herickhoff et al. 2009, 2010). In thiswork, we investigate the merit of using a dual-frequency PZT-4 transducer by fabricating and testingin vivo imaging and tissue-heating prototypes.

ddress correspondence to: Carl D. Herickhoff, Department ofdical Engineering, Duke University, Room 136 Hudson Hall,, NC 27708 USA. E-mail: cdh14@duke.edu

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The current treatment options for malignant centralnervous system (CNS) tumors are inadequate, due tolack of efficacy, toxicity and poor penetration of theblood-brain barrier (Fadul et al. 1988; Wrensch et al.1993; Cabantog and Bernstein 1994; Schottenfeld andFraumeni 1996; Wilkins and Rengachary 1996; Mareel1998; Mikkelsen 1998; Sawaya et al. 1998; Bernsteinet al. 2000; Kleihues et al. 2000; Prados 2000; Lesniak2005; CBTRUS 2008; ACS 2009). New methods arebeing developed that show promise to improve braintumor treatment by enhancing drug delivery andusing noninvasive approaches. The many examplesof this would include: using localized hyperthermiaand targeted, thermosensitive liposomes (drug releasethreshold 14�C above body temperature); opening theblood-brain barrier using ultrasound, with or without mi-crobubble contrast agent; and transcranial, image-guided focused ultrasound for thermal ablation(Guthkelch et al. 1991; Zunkeler et al. 1996; Hynynenand Jolesz 1998; Kroll and Neuwelt 1998; Hynynenet al. 2001, 2004; Cho et al. 2002; Dayton and Ferrara2002; Mesiwala et al. 2002; Aubry et al. 2003; Blochet al. 2004; Ponce et al. 2006; Choi et al. 2007;Kheirolomoom et al. 2007; McDannold et al. 2007,2008, 2010; Vykhodtseva et al. 2008).

Fig. 1. Schematic of proposed dual-mode intravascular ultra-sound (IVUS) operation. Radial imaging field (gray circle)with tumor (white circle). Hyperthermia beam (straight linesindicate full beamwidth at half-maximum) from catheter (black

circle) directed at tumor volume.

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Dual-mode ultrasound devices for image-guidedtherapy have been designed and implemented formany different applications using various approaches(Hynynen 1997; Wu et al. 2001; Barthe et al. 2004;Gentry and Smith 2004; Makin et al. 2005; Ebbini et al.2006; Pua et al. 2007; Bouchoux et al. 2008, 2010).Intravascular ultrasound (IVUS) catheters, which aretypically less than 4 Fr, were developed to navigateinto coronary vessels to visualize and characterizeatherosclerotic plaque (Fishbein and Siegel 1998;Mehran et al. 1998; Nishioka et al. 1998; Uren et al.1998a, 1998b). Mechanical IVUS catheters commonlyuse a single rotating piezoelectric crystal with a surfacearea less than a few square millimeters, and the use ofIVUS catheters for therapeutic applications involvingmicrobubbles is being investigated (Foster et al. 1993;Erbel 1998; Phillips et al. 2008; Kilroy et al. 2009).Furthermore, interventional neuroradiologists have usedminimally-invasive endovascular techniques to treatintracranial diseases, including inserting a 5-Fr catheteras far as the frontal portion of the superior sagittal sinusto treat thrombosis, and these procedures can be extendedto the treatment of intracranial tumors (Horowitz et al.1995; Kuether et al. 1998; Connors and Wojak 1999;Dowd et al. 1999; Opatowsky et al. 1999; Chow et al.2000; Novak et al. 2000; Morris 2002).

Our design goal is a dual-mode ultrasound catheterthat is both thin and flexible enough to navigate a vascularpathway to the brain and be placed immediately adjacentto a brain tumor target, to visualize the tumor and thendirect an ultrasound hyperthermia beam to trigger therelease of drugs contained within thermosensitive lipo-somes molecularly targeted to regions of tumor angiogen-esis (see Fig. 1). Commercially-available IVUS cathetershave an appropriate form factor (are both thin and flexibleenough) to achieve the desired placement within thebrain volume via our intended vascular approach, sothey are considered here as one possible platform fora dual-mode intracranial catheter integrating ultrasoundimaging and hyperthermia.

In this article, we describe the construction andtesting of two prototypes (one for imaging, the otherfor therapy), each using an identical, dual-frequencyPZT-4 transducer element, to independently assessimaging performance and therapeutic potential of theproposed dual-mode, intracranial IVUS catheter design.

MATERIALS AND METHODS

For our prototypes, PZT-4was used because its prop-erties (high kT and Qm, low tan d) make it an excellentchoice of material for dual-mode imaging and therapytransducers. A 9-MHz resonance for imaging correspondsto a PZT-4 thickness of 0.22 mm, and the maximum-

allowable aperture geometry for a flexible 3.5-Fr IVUScatheter was determined to be 53 0.5 mm in consultationwith neurosurgery and interventional neuroradiologycolleagues. In addition to the thickness-mode, a width-mode resonance at 3.3 MHz was designed and utilizedfor increased thermal penetration depth. Consequently,two prototypes were built using 5 3 0.5 3 0.22 mmPZT-4: one to assess imaging performance at 9 MHz ina mechanical IVUS catheter and one to assess therapeuticpotential by hyperthermia generation at 3.3 MHz.

ImagingFor the imaging prototype, a mechanical IVUS cath-

eter was needed as a construction template. A BostonScientific (Natick, MA, USA) Atlantis� SR Pro coronaryimaging catheter, with a nominal frequency of 40 MHz,was chosen and tested prior to modification by connect-ing to a Boston Scientific ClearView Ultra� scanner.Figure 2 shows a 40-MHz image of a portion ofa 2.5-cm-diameter cyst phantom acquired with theunmodified Atlantis.

The Atlantis’ original 40-MHz element was care-fully removed from the distal end of the catheter andthe roundedmetal housing was filed down to create a levelshelf. The 5 3 0.5 3 0.22 mm PZT-4 element was thenbonded to the shelf with silver epoxy (CHO-BOND;Chomerics,Woburn,MA, USA) to secure and electricallyconnect to the ground contact on the back of the element.The front contact was then connected to the signal wire,

Fig. 2. 40-MHz image of 2.5-cm cyst phantom, acquired withAtlantis intravascular ultrasound (IVUS) catheter. Arrows

indicate cyst wall. Tick mark spacing is 1 mm.

Fig. 4. Catheter devices and 9-MHz images of 2.5-cm cystphantom. (a) 9-Fr ICE with 2.1-mm-diameter transducer. (b)ICE catheter cyst image. (c) Modified intravascular ultrasound(IVUS) prototype outside of 3.5-Fr sheath. (d) Modified IVUS

cyst image. Tick mark spacing is 16 mm.

Dual-mode IVUS transducer for image-guided brain therapy d C. D. HERICKHOFF et al. 1669

protruding from the middle of the housing, with silverepoxy. To reinforce the delicate bonds of silver epoxy,a coating of 20-min epoxy (Finish-Cure; Bob SmithIndustries, Atascadero, CA, USA) was applied aroundthe proximal end of the element. Finally, to ensure thatsound was transmitted and received only through the frontface of the transducer, an improvised air backing wascreated using a mixture of 20-min epoxy and phenolicmicroballoons (BJO-0930; Asia Pacific Microballoons,Selangor, Malaysia). Figure 3 shows a top-view andside-view schematic of the prototype.

To initially assess imaging performance, the modi-fiedAtlantis IVUS prototypewas comparedwith a BostonScientific 9-Fr intracardiac echo catheter (Ultra ICE�;see Fig. 4a) as a gold standard for 9-MHz imaging. Usingthe ClearView Ultra scanner, each catheter was used toimage two targets: a 2.5-cm-diameter cyst phantom andthree post-mortem ovine brains. To image the ovine brain30 min post-mortem, a burr hole was made along themidline of the skull, angled posteriorly. This allowed

Fig. 3. Schematic of 9 MHz imaging prototype. (a) Top view oftransducer bonded to metal housing (light gray). (b) Side viewshowing phenolicmicroballoon backing (dark gray). Scale inmm.

catheter insertion into the superior sagittal sinus, suchthat the imaging plane (perpendicular to the catheteraxis) could be swept over the brain volume by push-through or pull-back (see Fig. 5).

The final experiment with the 9-MHz imagingprototype attempted to access the cranial cavity viaa minimally-invasive vascular approach in an in vivoporcine model. The Institutional Animal Care and UseCommittee at Duke University approved the followingprocedure. An intravenous (IV) line was established ina peripheral vein and the animal was sedated with thio-pental sodium, 20 mg/kg administered intravenously.Anesthesia was induced with inhalation of isofluranegas 1% to 5% delivered through a nose cone. The animalwas intubated, placed on a water heated thermal pad andstarted on a ventilator. A line was placed in the leftfemoral artery via a percutaneous puncture or cutdown.Electrolyte and ventilator adjustments were made basedon serial electrolyte and arterial blood gas measurements.

Fig. 5. Diagram of ovine brain imaging scheme. Catheter inser-tion into posterior portion of superior sagittal sinus, withrotating transducer scanning a perpendicular plane (dark

blue). Reproduced with permission (Miselis 2006).

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An IV maintenance drip of D-5 lactated Ringer’s solutionwas started and maintained at 5 mL/kg/min. Blood pres-sure, lead II electrocardiogram and temperature werecontinuously monitored throughout the procedure. Theanimal was placed in a supine position and the rightfemoral artery was punctured using the Seldinger tech-nique and dilated over a guide wire. A preliminary angio-gram of the right common carotid and vertebral arterieswas performed and recorded to identify the locationsand anatomy of proximate branch vessels. With a 6-FrEnvoy� XB (670-258-90B; Cordis Corp., Bridgewater,NJ, USA) guiding catheter in place over a wire guide,the modified Atlantis IVUS prototype was advancedtoward the cranial vessels via either the carotid or verte-bral arteries. Real-time images of the vessels andsurrounding tissue were acquired at 9 MHz using theClearView Ultra scanner.

TherapyA therapy prototype designed for high-power opera-

tion was constructed using a piece of PZT-4 identical to

Fig. 6. Therapy experiment procedures. (a) 40-MHz VisualSothe surface in tissue-mimicking material. (b) in vitro therapy e

anesthetized mouse on foil-lined heating pad

that used in the 9-MHz imaging prototype (5 3 0.5 30.22 mm). Double-sided metallized liquid crystal poly-mer (LCP, 20 mm thick) was bonded to the face of theceramic with silver epoxy, to provide both a signal groundcontact and a separate outer ground layer to shield RFnoise. Four feet of IVUS-catheter coaxial cable wasremoved from the inside of a spare Atlantis catheter,and the cable’s ground and signal wires were carefullyexposed and separated at the distal end before beingbonded to the front and back contacts of the PZT-4,respectively. An epoxy-and-microballoons air backingwas applied (similar to the imaging prototype) and thetransducer was secured and sealed in a 9-Fr catheterscrap, in side-viewing configuration.

An impedance analyzer (Model 4194A; Hewlett-Packard, Palo Alto, CA, USA) was used to measurethe electrical impedances of both the therapy prototypeand a 25-W RF power amplifier (Model 525LA; ENI,Rochester, NY, USA) at 3.3 MHz. These impedancevalues were used to calculate the optimal inductanceand capacitance values (7.7 mH and 55 pF, respectively)for the design of a simple L-section impedance matchingnetwork, which would be used to maximize powertransfer from the power source (amplifier) to the load(therapy prototype transducer) at a single frequency(3.3 MHz).

To initially assess therapeutic potential, the trans-ducer was used in vitro with tissue-mimicking material(National Physical Laboratory, Teddington, UK), whichis 4 cm in diameter, 4 mm thick, and has thermalproperties similar to brain tissue (Goss et al. 1978; Baconand Shaw 1993; Shaw et al. 1999). To measure theachievable temperature, a type T, 33-gauge, hypodermicneedle thermocouple (HYP-0; Omega Engineering,Stamford, CT, USA) was used. This small-diameter, fine-wire thermocouple sheathed in stainless steel was chosento minimize the possibility of artifacts (e.g., viscousheating, reflections, conduction along the wire) in the

nics image verifying thermocouple needle 1 mm beneathxperiment setup. (c) in vivo glioblastoma therapy setup:. Arrow indicates transducer position.

Fig. 7. Post-mortem ovine brain: 9-MHz imaging comparisonshowing lateral ventricles. (a) 9-Fr ICE catheter image. (b)Anatomical diagram, reproduced with permission (Fletcheret al. 2006). (c) 3.5-Fr modified intravascular ultrasound

(IVUS) prototype image. Tick mark spacing is 16 mm.

Dual-mode IVUS transducer for image-guided brain therapy d C. D. HERICKHOFF et al. 1671

thermal measurement (Fry and Fry 1954; Hynynen andEdwards 1989). We do not otherwise consider theseeffects in the proof-of-concept experiments describedhere.

The thermocouplewas inserted approximately 1mmbeneath the surface of the material and the depth ofthe thermocouple was verified by imaging the samplewith a Vevo 770� scanner and RMV706� scanhead(VisualSonics, Toronto, Ontario, Canada) at 40 MHz(see Fig. 6a). The prototype transducer was alignedwith the thermocouple and placed within 1 mm of thesurface of the submerged material sample (see Fig. 6b).A waveform generator (Model 33250; Agilent, SantaClara, CA, USA) was connected to the power amplifierto produce continuous-wave (CW) excitation at a netaverage electric power of 700 mWat 3.3 MHz for nearly2 min while the thermocouple recorded temperature.Electrical input to the matching network and therapyprototype transducer, including average forward and re-flected power, was measured using a power reflectionmeter (NRT; Rohde & Schwarz, Munich, Germany).

The therapy prototype transducer was tested on anexcised glioblastoma tumor, which had been grown arti-ficially on the flank of a nudemouse. The tumor measured13 mm along the long axis and 10 mm along the shortaxis. A minimal amount of standard ultrasound transmis-sion gel (Conductor; Chattanooga Group, Hixson, TN,USA) was applied to the face of the transducer beforeplacing it in contact with the tumor. The thermocouplewas inserted approximately 1.5 mm beneath the surfaceof the tissue and aligned with the center of the transducer.The waveform generator and power amplifier created3.3MHzCWexcitation. The power was alternately turnedon and off for 90 s at a time, at levels of 700, 350 and175 mW, while the thermocouple recorded temperature.

Finally, the therapy prototype was tested on a humanglioblastoma xenograft tumor, grown to approximately1 cm 3 2 cm in the flank of a nude mouse. The animalwas anesthetized with 100 mg/kg ketamine/xylazineand monitored by toe pinch reflex. The anesthetic wasre-administered as needed on a per animal basis whenthe animal responded to the toe-pinch. Animal bodytemperature was maintained at 37�C using a homeo-thermic heating blanket. The skin around the tumorwas carefully dissected away so that the transducercould be placed directly on the surface of the tumor,using minimal ultrasound transmission gel. The tumormeasured 18 mm along the long axis and 16 mm alongthe short axis. The thermocouple was inserted approxi-mately 1.5 mm beneath the tissue surface and alignedwith the transducer (see Fig. 6c). The waveform gener-ator and power amplifier produced 3.3-MHz CW excita-tion for 60 s, followed by 120 s of off-time, to allow thetissue temperature to recover to nearer its baseline

temperature. This was done sequentially at power levelsof 700, 350 and 175 mW, while the thermocouplerecorded temperature.

RESULTS

ImagingFigure 4a shows the 9-Fr ICE catheter used as an

imaging gold standard and the modified Atlantis IVUS

Fig. 8. In vivo porcine imaging results. (a) Angiogram showing modified intravascular ultrasound (IVUS) prototype(arrow) in right vertebral artery. (b) 9-MHz image of vertebral artery lumen (arrow) and surrounding tissue near

subclavian junction. Tick mark spacing is 16 mm.

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prototype transducer is shown in Figure 4c. The ICEtransducer is 2.1 mm in diameter, while the IVUS proto-type has an aperture 0.5 mm in azimuth. Figures 4b and4d are 9-MHz images of a 2.5-cm cyst phantom acquiredby the commercial 9-Fr ICE catheter and the 3.5-Frmodified IVUS prototype, respectively. Though thegold-standard ICE catheter outperforms the prototype interms of lateral resolution and sensitivity, the imagesare roughly comparable. The IVUS prototype hasa greater degree of beam divergence due to its muchsmaller aperture, resulting in poorer lateral resolutionrelative to the ICE gold standard.

Figure 7 compares the imaging performance of the9-Fr ICE and 3.5-Fr modified IVUS catheter probes ina post-mortem ovine brain, with an anatomical diagramfor reference. In both images, the skull is seen outlining

Fig. 9. Thermocouple data from in vitro therapy experimentwith tissue-mimicking material. Resulting temperature rise

was 6.7�C in under 2 min.

the cranial cavity and the symmetric wings of the lateralventricles are clearly visible in the center of the brainvolume as well.

In the in vivo porcine experiment, the prototypecatheter was unfortunately unable to advance beyondthe pig’s vertebral artery into the basilar artery at thebase of the brain. Figure 8 shows the prototype transducerat its farthest advancement in the vertebral artery, as wellas a real-time, 9-MHz ultrasound image of the vertebralartery near the subclavian junction.

TherapyIn the tissue-mimicking material, the 3.3-MHz

therapy prototype transducer was able to create a temper-ature rise of 6.7�C in less than 2 min with CW

Fig. 10. Thermocouple data showing sequential temperaturerises in excised glioblastoma tumor of 19.1�C, 9.2�C and4.9�C after 90 s of on-time for power levels of 700, 350 and

175 mW, respectively.

Fig. 11. Thermocouple data for in vivo xenograft glioblastomatumor grown in the flank of a nude mouse, showing sequentialtemperature rises of 13.5�C, 6.8�C and 3.0�C after 60 s of on-time for power levels of 700, 350 and 175 mW, respectively.

Dual-mode IVUS transducer for image-guided brain therapy d C. D. HERICKHOFF et al. 1673

transmission at 700 mW (see Fig. 9). In the excised glio-blastoma brain tumor, the therapy prototype createda temperature rise of 19.1�C in 90 s of CW excitationat 700 mW. Subsequently, temperature rises of 9.2�Cand 4.9�C were created using 350 mW and 175 mW ofCW power, respectively (see Fig. 10). Finally, in thein vivo tumor experiment, the therapy prototype achievedtemperature rises of 13.5�C, 6.8�C and 3.0�C in 60 s ofCW excitation at 700, 350 and 175 mW, respectively(see Fig. 11).

Fig. 12. In vivo porcine vascular imaging results. (a) Angiogramright vertebral artery. (b) Volcano ChromoFlo image showing

puncture site, acquired with 20-MHz Eagle E

DISCUSSION

A 53 0.53 0.22 mm PZT-4 transducer was used tobuild a 9-MHz imaging prototype in a 3.5-Fr mechanicalIVUS catheter and a 3.3-MHz high-power prototypefor therapy. The 3.5-Fr imaging prototype performedcomparably to a 9-Fr commercial ICE catheter in imaginga 2.5-cm cyst phantom and visualizing brain anatomy ina post-mortem ovine brain. The ovine brain images showthat a 3.5-Fr IVUS catheter is capable of resolvingfeatures (including the lateral ventricles and skull) ata depth of up to 3 cm.

To our knowledge, we have shown the first attemptto access and image the brain via a minimally-invasive,vascular approach using an ultrasound catheter. The3.5-Fr, 9-MHz modified-Atlantis imaging prototype wasable to navigate as far as the vertebral artery and imagesurrounding tissue before vessel narrowing and tortuosityprevented further catheter advancement. Although accessto the brain volume was not achieved in the porcinemodel, the authors’ experience in the field of interven-tional neuroradiology gives confidence that such restrict-ing vessel size and tortuosity issues would not be presentin a human procedure.

The results from the 3.5-Fr, 9-MHz IVUS imagingprototype can be compared with the findings of two finalexperiments using a 20-MHz Volcano (San Diego, CA,USA) 3.5-Fr phased-array IVUS imaging catheter withan In-Vision� scanner. First, a Volcano Eagle Eye�Gold was used in the same porcine model experimentas the modified Atlantis, to visualize the vessel and

showing a regional hematoma (arrows) surrounding thenon-uniform flow (arrow) in the lumen near the vesselye Gold. Tick mark spacing is 1 mm.

Fig. 13. In vivo porcine brain imaging results. (a) VolcanoPV018 image showing bordering skull (red arrow) and threegyri in close proximity (green arrows). Tick mark spacing is2 mm. (b) Anatomical diagram, reproduced with permission

(Welker 2011).

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its surroundings with a higher-frequency, commercialIVUS catheter. As the Eagle Eye was advanced into thevertebral artery, the wire guide accidentally puncturedthe vessel wall, creating a regional hematoma that wasvisible under fluoroscopy (see Fig. 12a). The turbulentblood flow created by the puncture was visible whenusing the scanner’s ChromaFlo� feature to image thelumen (see Fig. 12b).

The other auxiliary experiment used a VolcanoPV018 catheter to visualize structures near the brainsurface. The 3.5-Fr catheter was inserted through a 1-cmburr hole in a porcine skull, placing the IVUS arraybetween the inner surface of the skull and the dura mater,a few millimeters adjacent to the midline. The scan depthwas maximized to 12 mm and features including cerebralgyri, sulci and pulsating vessels could be clearly seen outto a range of 5–6 mm (see Fig. 13). The findings fromthese auxiliary experiments suggest that additional usefulinformation might be obtained with a more sophisticateddevice designed to operate at a frequency above 9 MHz.

The therapy prototype achieved a temperature rise of6.7�C in tissue-mimicking material before testing tissue-heating capability in glioblastoma tumors. In an excisedtumor, the therapy prototype achieved a temperaturerise as high as 19.1�C in 90 s at 1.5 mm deep. When simi-larly tested on an in vivo tumor, the prototype achieveda temperature rise of 13.5�C in 60 s.

The sharp rise and fall of the temperature dataas power was turned on and off in the tumor therapyexperiments (Figs. 10 and 11) further suggests that theobserved heating was predominantly due to absorptionof ultrasound energy (rather than thermal conduction ofany internal transducer heating), and it alsodemonstrates the range and control of achievable tissuetemperatures using an IVUS-sized transducer (Frinkleyet al. 2005). The sequential excitations were effectivelyset at 100% power, 50% power, and 25% power, andthe resulting increases in temperature were proportional.

The lower temperature increase in the tissue-mimicking material, relative to the tumor experimentresults, is likely due to the fact that the transducer wasnot directly in contact with the tissue. This may haveallowed for some amount of divergence and reflectionof the ultrasound energy beam (Herickhoff et al. 2010).The presence of a water path also served to somewhatisolate the sample from any conductive heating contribu-tions that may have been present. The 19.1�C and 13.5�Cincreases in the excised and in vivo tumor experimentswere much higher than the minimum increase of 4�Cnecessary for drug release from thermosensitive lipo-somes, demonstrating that it is possible to facilitatethermally-targeted drug delivery using a transducer smallenough to be packaged in a 3.5-Fr IVUS catheter.The challenges that remain for realizing a dual-mode,

catheter device for image-guided therapy include furtherimproving transducer efficiency (by incorporatingacoustic matching layers), customizing packaging, andwiring to electronics capable of both higher-frequencypulsed excitation (for imaging) and lower-frequencycontinuous-wave excitation (for therapy).

CONCLUSIONS

In total, the images obtained using the 3.5-Frmodified Atlantis prototype and commercially-availableVolcano catheters in brain and vascular-access experi-ments demonstrate that: (1) it is possible to use an intravas-cular ultrasound device to effectively visualize structuresin the brain that are in close proximity to the transducer,

Dual-mode IVUS transducer for image-guided brain therapy d C. D. HERICKHOFF et al. 1675

and (2) that catheter probes may be placed intracraniallyvia a minimally-invasive vascular approach. It was alsoshown that a 5 3 0.5 3 0.22 mm PZT-4 transducer iscapable of heating a tumor in vivo113.5�C above baselinetemperature, a value well above the 14�C threshold fordrug release from thermosensitive liposomes.

Our results indicate that combining these imagingand therapeutic capabilities into a single dual-modedevice may be feasible, and that this could yield a clini-cally-viable technology for brain tumor treatment. Futureexperiments will investigate the therapeutic effect sucha device may have on an intracranial brain tumor.

Acknowledgments—The authors thank Volcano Corporation for theirsupport in this study, as well as Veronica Rotemberg, Samantha Lipman,Josh Doherty, Tat-Jin Teo, Rick Stouffer and Ellen Dixon-Tulloch fortheir assistance. This work was supported by NIH grant HL089507.

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