dual-mode intracranial catheter

Dual-Mode Intracranial Cath e ter In te grat ing 3D Ul tra soundIm ag ing and Hyperthermia for Neuro-on col ogy:

Fea si bil ity Study

CARL D. HERICKHOFF,1 ED WARD D. LIGHT,1 KRISTIN F. BING,1 SRINIVASAN MUKUNDAN,2

GER ALD A. GRANT,3 PAT RICK D. WOLF1 AND STE PHEN W. SMITH1

1De part ment of Bio med i cal En gi neer ingDuke Uni ver sity

Dur ham, NC [email protected]

2De part ment of Ra di ol ogyBrigham and Women’s Hos pi tal

Boston, MA 02115

3Di vi sion of Neu ro sur geryDuke Uni ver sity Med i cal Cen ter

Dur ham, NC 27708

In this study, we in ves ti gated the fea si bil ity of an intracranial cath e ter trans ducer with dual-mode ca -pa bil ity of real-time 3D (RT3D) im ag ing and ul tra sound hyperthermia, for ap pli ca tion in the vi su al iza -tion and treat ment of tu mors in the brain. Fea si bil ity is dem on strated in two ways: first by us ing a50-el e ment lin ear ar ray trans ducer (17 mm × 3.1 mm ap er ture) op er at ing at 4.4 MHz with our Volu met -rics di ag nos tic scan ner and cus tom, elec tri cal im ped ance-match ing cir cuits to achieve a tem per a ture rise over 4°C in ex cised pork mus cle, and sec ond, by de sign ing and con struct ing a 12 Fr, in te grated ma trixand lin ear-ar ray cath e ter trans ducer pro to type for com bined RT3D im ag ing and heat ing ca pa bil ity. Thisdual-mode cath e ter in cor po rated 153 ma trix ar ray el e ments and 11 lin ear ar ray el e ments diced on a 0.2mm pitch, with a to tal ap er ture size of 8.4 mm × 2.3 mm. This 3.64 MHz ar ray achieved a 3.5°C in vi trotem per a ture rise at a 2 cm fo cal dis tance in tis sue-mim ick ing ma te rial. The dual-mode cath e ter pro to -type was com pared with a Siemens 10 Fr AcuNavTM cath e ter as a gold stan dard in ex per i ments as sess ingim age qual ity and ther a peu tic po ten tial and both probes were used in an in vivo ca nine brain model to im -age an a tom i cal struc tures and color Dopp ler blood flow and to at tempt in vivo heating.

Key words: Cath e ter trans ducer; dual-mode ar ray; real-time 3D im ag ing; ul tra sound hyperthermia.

IN TRO DUC TION

The Amer i can Can cer So ci ety es ti mates that in the United States, 21,810 new cases of pri -mary ma lig nant brain and cen tral ner vous sys tem (CNS) tu mors were di ag nosed in 2008 and 13,070 peo ple died from this con di tion, com pris ing just over 2% of all can cer deaths.1 TheCen tral Brain Tu mor Reg is try of the United States es ti mates that in the year 2000, more than81,000 per sons in the U.S. were liv ing with a pri mary ma lig nant brain/CNS tu mor di ag no -sis.2 Ma lig nant gliomas ac count for 81% of all ma lig nant pri mary brain/CNS tu mors and51% of gliomas are of the WHO grade IV sub type glioblastoma multiforme (GBM), themost com mon intracranial neo plasm.2, 3

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ULTRASONIC IMAGING 31, 81-100 (2009)

Cur rently, pri mary brain tu mors are most com monly treated by sur gery, ra dio ther apy andche mo ther apy.4 Che mo ther apy may be ad min is tered sys tem i cally, by mouth or in tra ve nousin fu sion, or lo cally, by di rect intra-ar te rial or in ter sti tial in jec tion into a tu mor tar get.5 Thema jor chal lenge to ef fec tively de liv er ing drugs to CNS tu mors is to achieve a high drug con -cen tra tion within the tu mor bed by over com ing the phys i o log i cal blood-brain bar rier, thedy namic in ter face that pro tects the brain and also ac tively ex trudes drugs from the brainthrough ac tive drug efflux trans port ers.6

Blood-brain bar rier (BBB) dis rup tion must be tran sient and re vers ible — rapid clo sure ofthe bar rier af ter dis rup tion ef fec tively traps drug within the tis sue.7, 8 High-in ten sity fo cusedul tra sound (HIFU) has been stud ied as a method for achiev ing this ef fect.9-11 The use oflow-pres sure ul tra sound (e.g., peak neg a tive pres sure am pli tudes of 0.4-1.5 MPa) at low di -ag nos tic fre quen cies (0.26-2.04 MHz), in con junc tion with microbubble con trast agent suchas Optison or Definity, has also been shown to achieve lo cal ized BBB dis rup tion.12-14 Mildhyperthermia (41°C) us ing ul tra sound (20 min, 0.4 W/cm2) has been shown to re vers ibly en -hance pas sive dif fu sion of hy dro pho bic drugs through microvessel en do the lial cell mono -layers, al low ing the drugs to by pass efflux trans port ers and dem on strat ing the abil ity toper me ate the BBB.15

Ef forts to de velop transcranial, im age-guided fo cused ul tra sound sys tems for brain tu morab la tion have shown en cour ag ing re sults; how ever, these stud ies, as well as the afore men -tioned BBB dis rup tion ex per i ments, have con cerns as so ci ated with the skull — ei ther ahighly in va sive ap proach is taken, where the skull bone must be re moved prior to sonication,or a noninvasive ap proach is taken, where the high ul tra sound at ten u a tion and re flec tionfrom the bone is ac cepted and the phase ab er ra tion from the skull’s vari able thick ness is ei -ther man aged or cor rected.16-19

Min i mally-in va sive endovascular tech niques for treat ment of var i ous intracranial dis -eases, in clud ing arteriovenous mal for ma tion, intracranial an eu rysm and dural ve nous si nusthrom bo sis, have been used in the field of interventional neuroradiology and these pro ce -dures can be ex tended to the treat ment of intracranial tu mors.20, 21 For treat ment of ce re bralve nous throm botic dis ease, a 7 Fr to 9 Fr in tro ducer sheath or guide cath e ter may be used forac cess, usu ally via a transfemoral ap proach or a di rect ret ro grade in ter nal jug u lar stick, and a5 Fr cath e ter may be in serted as far as the fron tal por tion of the su pe rior sagittal si nus.20-22 Case re ports de tail ing the use of cath e ter de vices in the dural ve nous si nuses to treat throm bo sis(by urokinase in fu sion or rheolytic thrombectomy) dem on strate the fea si bil ity of this ap proach.23-27

Dual-mode ul tra sound trans duc ers for im age-guided ther apy have been de signed and im -ple mented for sev eral ther mal ap pli ca tions, in clud ing treat ment of car diac arrhythmias andtu mors of the liver, breast, biliary ducts and pros tate.28-33 These have been de vel oped with acath e ter, en do scope or extracorporeal ap proach, us ing ei ther a sin gle el e ment or phased ar -ray for ther apy (phased ar rays al low for the most con trol over the en ergy de po si tion pat ternof ul tra sound).34 When com pared with mag netic res o nance (MR) im ag ing, ultrasound is anat trac tive mo dal ity for guid ance and treat ment mon i tor ing, be cause of its low cost, por ta bil -ity and high frame rate.32, 33 Dual-mode im ag ing/ther apy ar rays are de sir able be cause of thein her ent spa tial reg is tra tion be tween im ag ing, treat ment and mon i tor ing.35 For ex am ple,min ia tur ized lin ear ar rays, us ing a 2.3 mm × 49 mm ap er ture at 3.1 MHz, have been de vel -oped for min i mally-in va sive in ter sti tial ther mal treat ment and im ag ing of liver tis sue.28

In the 1990’s, real-time 3D (RT3D) ul tra sound im ag ing was de vel oped at Duke Uni ver -sity for transthoracic car diac ap pli ca tions and, more re cently, for intracardiac cath e ters,intravascular cath e ters, en do scopes, lap aro scopes, 3D ul tra sound guid ance of sur gi cal ro -bot ics, 3D transcranial ul tra sound and 3D intracranial ul tra sound en do scopes for neu ro sur -gery and nee dle guid ance in the brain.30, 36-45 Our Duke/Volu met rics Med i cal Im ag ing, Inc.(Dur ham, NC, USA) 3D ul tra sound sys tem scans a 65°-120° pyr a mid us ing a ma trix ar ray

82 HERICKHOFF ET AL

trans ducer to pro duce 3D scans at rates of 30 vol umes/s. Real-time dis play op tions in our3-D scan ner in clude up to five im age planes ori ented at any de sired an gle and depth withinthe py ram i dal scan, as well as real-time 3D vol ume ren der ing, 3D steer able pulsed Dopp lerand 3D color Dopp ler flow im ag ing.

The de vel op ment of microbubble ul tra sound con trast agents (UCAs) and tem per a -ture-sen si tive liposomes for tar geted im ag ing and tar geted drug de liv ery is also pro ceed ingrap idly. Microbubble UCAs are blood pool agents, mean size of 0.1-2 mm, ad min is tered in -tra ve nously such that a to tal in jec tion of only 0.1 mL in creases the sig nal of blood ves sels byover a fac tor of 10, en abling de tec tion of cap il lary-sized ves sels. The con trast microbubblesare used clin i cally in car diac ex ams, in ex per i men tal per fu sion stud ies of kid ney, trans cra -nial brain and liver and in blood flow mea sure ments of breast, pros tate and liver tu mors.46, 47

UCAs of fer the ad van tage of por ta ble, in ex pen sive, real-time use with out ion iz ing ra di a tionand are thus ideal for se rial stud ies as in treat ment mon i tor ing. Lipo somes are mem -brane-en closed ves i cles com posed of a lipid bilayer shell (which can trap hy dro pho bic andamphipathic drugs) sur round ing an aque ous core (which can con tain hy dro philic drugs),with a di am e ter typ i cally near 100 nm.48 Liposomes can be readily con ju gated to an ti bod iesor other ad he sion lig ands and UCAs can also be chem i cally mod i fied to en able ac tive tar get -ing of tu mor angiogenesis; for ex am ple, ul tra sound mo lec u lar im ag ing of tu mor angio -genesis in a rat af ter in tra ve nous in jec tion of microbubbles tar geted to avb3

integrins hasdem on strated en hance ment of a pri mary glioblastoma and a small me tas ta sis.49 Hy brid drugde liv ery ve hi cles, con ju gat ing liposomes and microbubbles, are also un der in ves ti ga tion.48

Tem per a ture-sen si tive liposomes con tain ing the can cer drug doxo rubicin have been shown toquickly re lease their con tents when the sur round ing tem per a ture is raised to 41°C, or 4°Cabove nor mal body tem per a ture.50 There fore, tem per a ture-sen si tive liposomes, in com bi na tionwith lo cal hyperthermia (which may be cre ated and di rected by ul tra sound), pro vide tar geted con trol of drug re lease that may aug ment chemotherapeutic ef fi cacy in many clin i cal set tings.50, 51

The goal of this pro ject is to ex tend real-time 3D ul tra sound to min i mally-in va sive cath e -ters for intracranial im ag ing of the brain and ul tra sound hyperthermia for neuro-on col ogy. This tech nol ogy could be used to vi su al ize a tu mor tar get in 3D and then trig ger the re lease of chemotherapeutic drugs con tained within microbubble or liposomal agents mo lec u larly tar -geted to re gions of tu mor angiogenesis. The cath e ter will be de signed to be both thin andflex i ble enough (ca pa ble of bend ing with a 1 cm ra dius of cur va ture) to be ma nip u latedthrough the in ter nal jug u lar vein into the dural ve nous si nuses (Fig. 1), which pro vide min i -mally-in va sive ac cess to vir tu ally the en tire brain vol ume.

In this pa per, we de scribe a se ries of ex per i ments con ducted in an ef fort to dem on strateproof of con cept. An ini tial pro to type dual-mode (RT3D im ag ing & hyperthermia) cath e tertrans ducer was de signed and con structed to de ter mine the fea si bil ity of our long term goal. The im ag ing and ther mal per for mance of the dual-mode pro to type was com pared with aSiemens (Siemens Med i cal So lu tions, Ul tra sound Di vi sion, Issaquah, WA, USA) AcuNavTM

cath e ter in in vi tro ex per i ments and in an in vivo ca nine brain model, with ac cess to the su pe -rior sagittal si nus af forded through a 1 cm burr hole in the skull. These ex per i ments dem on -strate that a com pletely in tra ve nous ap proach for such a treat ment may be suc cess ful, thuselim i nat ing the need for a burr hole.

METH ODS

The trans ducer ar ray we pro pose in te grates a 2D ma trix ar ray, which can ac quire 3D scans, withad ja cent lin ear ar rays, which con trib ute power to a beam for in duc ing hyperthermia (Fig. 2).

DUAL-MODE INTRACRANIAL CATHETER FOR NEURO-ONCOLOGY 83

Pre lim i nary ex per i ment: hyperthermia with RT3D scan ner

To es tab lish the fea si bil ity of a dual-mode im ag ing/ther apy cath e ter trans ducer, we firstsought to dem on strate that our di ag nos tic RT3D Volu met rics scan ner could be used toachieve and main tain a suf fi cient tem per a ture rise ( = 4°C). In this pre lim i nary ex per i ment, a 50 chan nel, 4.4 MHz PZT-5H, 17 mm × 3.1 mm lin ear ar ray trans ducer pre vi ously de scribed was used with elec tri cal im ped ance-match ing cir cuits cus tom ized for each chan nel in or derto max i mize power trans fer from the scan ner to the trans ducer el e ments.52 The match ing cir -cuits were sim ple ‘L-sec tion’ net works con sist ing of two re ac tive com po nents: an in duc torin se ries with the load and a ca pac i tor in par al lel. To de sign these net works, the sys tem(source) im ped ance and the cor re spond ing wa ter-cou pled trans ducer el e ment (load) im ped -ance were mea sured at the cho sen op er at ing fre quency, for each chan nel. Then, be causemax i mum real power trans fer oc curs when the in put im ped ance (L-sec tion plus load) equalsthe com plex con ju gate of the source im ped ance, we found the op ti mal val ues of in duc tanceand ca pac i tance for the L-sec tion com po nents al ge bra ically. The nec es sary se ries in duc -tance ranged from 9 to 30 mH and the par al lel ca pac i tance ranged from 47 to 268 pF.

With the match ing cir cuits in use, the scan ner gen er ated a 12-cy cle pulse at 6.6 kHz PRF— set tings found to yield max i mum sta ble power out put from the scan ner — and the spa -tial-peak, tem po ral-av er age in ten sity (ISPTA) was mea sured at a 3 cm fo cal depth with a cal i -brated mem brane hydrophone (S4-251, Sonora Med i cal Sys tems, Longmont, CO, USA) in

84 HERICKHOFF ET AL

FIG. 1 In tended cath e ter path way af ford ing min i mally-in va sive ac cess to the brain vol ume via dural ve nous si nuses.

a wa ter tank, in ac cor dance with the pro ce dures out lined in the AIUM/NEMA UD 2-2004stan dard.53 A ther mo cou ple (5TC se ries, Omega En gi neer ing, Inc., Stam ford, CT, USA)was used to mon i tor the tem per a ture of the scan ner’s in ter nal elec tron ics dur ing trans mit. With the same scan ner set tings, the hydrophone was re placed by a piece of de gassed, ex cised pork mus cle; a type T, 33 gauge, stain less steel hy po der mic nee dle ther mo cou ple (HYP-0,Omega En gi neer ing, Inc.) was in serted ap prox i mately 2 mm be neath the sur face of the tis -sue and placed at the fo cus to mea sure the achiev able tem per a ture rise. The data ac qui si tionsys tem (Integra model 2700, Keithley In stru ments, Inc., Cleve land, OH, USA), which con -tains built-in sig nal con di tion ing hard ware for fil ter ing and noise re duc tion, re corded tem -per a ture data at a sam pling fre quency of 3.8 Hz. The tis sue tem per a ture rise mea sure mentwas rep li cated four times. The nonat ten u at ing wa ter path be tween the trans ducer and the tis -sue served to iso late the tis sue from con duc tive heat ing so as to better cor re late tem per a turemea sure ments with in ten sity mea sure ments. Pos si ble ar ti facts as so ci ated with this type ofther mal mea sure ment are vis cous heat ing, re flec tions and con duc tion along the wire; oursmall-di am e ter, fine-wire ther mo cou ple sheathed in stain less steel was cho sen to min i mizethese ef fects and we dis re gard them for the proof-of-con cept ex per i ments de scribed here.54, 55

In te grated cath e ter trans ducer de sign and fab ri ca tion

The re sults from our pre lim i nary ex per i ment gave us con fi dence to de velop a new de signfor a pro to type cath e ter de vice in te grat ing a ma trix ar ray and a lin ear ar ray. We used a cus -tom 10 Fr multi-layer flex i ble cir cuit made by Microconnex (Snoqualmie, WA, USA) as acon struc tion tem plate. The flex cir cuit could ac com mo date an ar ray with 198 ma trix el e -ments and 18 lin ear el e ments, diced on a 0.2 mm pitch, for a to tal ap er ture size of 8.4 mm ×


FIG. 2 In te grated 2D ma trix & lin ear ar ray de sign for RT3D im ag ing & hyperthermia. The cen tered 2D ar rayscans a py ram i dal vol ume in real time and the ad ja cent lin ear ar rays pro duce a hyperthermia beam (shown in redwithin the vol ume), steer able in az i muth (dif fer ent pos si ble foci in di cated by red ‘x’s).

2.3 mm. Two dif fer ent schemes were con sid ered as meth ods to achieve op ti mal tis sue heat -ing: one with all the el e ments (both the ma trix and lin ear ar rays) fo cused at 2 cm driven bythe Volu met rics scan ner and one unfocused scheme us ing only the lin ear ar ray el e mentsdriven by a sin gle-chan nel, 25-Watt rf power am pli fier (Model 525LA, ENI, Roch es ter, NY, USA) con nected to a wave form gen er a tor (Model 33250, Agilent, Santa Clara, CA, USA). The unfocused lin ear ar ray with sin gle-chan nel power am pli fier was con sid ered as an al ter -na tive to us ing the Volu met rics scan ner at high power set tings that could po ten tially harm itsin ter nal elec tron ics. Both schemes used a 4.4 MHz op er at ing fre quency.

To aid our de sign pro cess, the beam pat tern for each of these pro to type schemes was sim u -lated and com pared with that of a Siemens 10 Fr AcuNav cath e ter probe us ing Field II.56 TheAcuNav is a lin ear ar ray with 64 el e ments on a 0.11 mm pitch, for an ap er ture size of ap prox -i mately 7.1 mm × 2.5 mm; this ar ray was fo cused at 2 cm, op er at ing at 5.33 MHz. Each com -pu ta tion in cluded a 0.5 dB/cm/MHz at ten u a tion fac tor to sim u late brain tis sue.57 Thesim u la tions did not cal cu late the first 5 mm in front of the trans ducer be cause the model isless ac cu rate for very short dis tances due to use of a far-field ap prox i ma tion of the re sponseof each trans ducer el e ment.

Fig ure 3 il lus trates this stage of the de sign pro cess. Fig ures 3a, 3b and 3c show the foot -print of the ac tive ap er ture in each case: the en tire in te grated ar ray (2 cm trans mit fo cus), thein te grated de sign’s lin ear ar ray el e ments only (unfocused trans mit) and the AcuNav (2 cmtrans mit fo cus), re spec tively. Fig ures 3d, 3e and 3f dis play the beam’s rel a tive pres sure am -pli tude in the zero-el e va tion plane for each case, re spec tively, and fig ures 3g, 3h and 3i showeach beam’s rel a tive am pli tude at a depth of 2 cm. For the case of the en tire in te grated ar ray,the -6 dB az i muthal beam width was 7.5 mm at 0.5 cm deep. For the case of the in te gratedde sign’s unfocused lin ear ar ray el e ments, the -6 dB beam beam width was 7.8 mm at 0.5 cmdeep. For the fo cused AcuNav, the -6 dB beam width was 4.6 mm at 0.5 cm deep.

86 HERICKHOFF ET AL

FIG. 3 Field II sim u la tion ap er tures and beam plots. (a, b, c) Ac tive ap er tures for each case: the en tire in te grated

ar ray with 2 cm fo cus, the in te grated cath e ter’s lin ear ar rays with unfocused trans mit and the AcuNav with 2 cm fo -cus, re spec tively. (d, e, f) Rel a tive pres sure am pli tude in the zero-el e va tion plane for each case, re spec tively. (g, h, i) Rel a tive pres sure am pli tude at a depth of 2 cm for each case, re spec tively.

Fab ri cat ing the in te grated ar ray in volved adapt ing the flex cir cuit (Fig. 4a), which was ini -tially de signed for a ma trix ar ray alone.42 A 0.35-mm-thick piece of PZT-5H was bonded tothe flex cir cuit with sil ver ep oxy, slightly over lap ping the grid of el e ment con tacts onto thebor der ing ground con tact. This piece was diced on a 0.2 mm pitch both ver ti cally and hor i -zon tally to cre ate the ma trix ar ray on a 19 × 11 el e ment grid. The lin ear ar ray was then builtin the ad ja cent spaces: first, each space was filled with sil ver ep oxy and cured to cre ate a levelback side con tact; then, a piece of PZT-5H was bonded to each side and diced (0.2 mm pitch), phys i cally sep a rat ing the nine el e ments on each end. MicroFlat ca bles from W.L. Gore &As so ci ates, Inc. (New ark, DE, USA) were sol dered with ap pro pri ate spac ing to the ex posedbor der con tact and these sol der joints were re in forced with UV-cur ing ep oxy be fore care -fully re-dic ing the lin ear ar ray to en sure elec tri cal sep a ra tion of the lin ear ar ray chan nels(fig ure 4b shows the com ple tion of these steps: the 8.4 mm × 2.3 mm to tal ap er ture).

A layer of dou ble-sided metallized liq uid crys tal poly mer (LCP) was at tached to the faceof the trans ducer for a front ground ing con tact and over all elec tronic shield ing for the trans -ducer. There was no acous tic match ing layer for this pro to type. MicroFlat ca bles were sol -dered to the pads of the flex cir cuit to con nect the ma trix ar ray chan nels and an acous ticback ing was at tached be fore bend ing the flex cir cuit into a side-view ing con fig u ra tion and


FIG. 4 (a) Bare flex cir cuit above a ruler with mm mark ings. (b) Diced ma trix and lin ear ar rays with MicroFlatca bles sol dered to lin ear ar ray con tacts. (c) Com pleted 12 Fr dual-mode cath e ter trans ducer.

pack ag ing the trans ducer into the 12 Fr cath e ter lu men. The prox i mal ends of the ca bleswere sol dered to cus tom cir cuit boards fit ted with Samtek, Inc. (New Al bany, IN, USA) con -nec tors (model # BSH-060-01-F-D-A) to link with the ul tra sound sys tem han dle. The com -plete, pack aged trans ducer is shown in fig ure 4c (on a larger scale than fig ures 4a,b).

In vi tro tem per a ture mea sure ment

For mea sure ments as sess ing the hyperthermia ca pa bil ity of the pro to type dual-mode cath -e ter trans ducer, tis sue-mim ick ing ma te rial from Na tional Phys i cal Lab o ra tory (Teddington,UK) was used as a model, hav ing ther mal prop er ties sim i lar to brain tis sue.58, 59 Be cause thedual-mode pro to type had a smaller ap er ture than the 50-chan nel lin ear ar ray used in our pre -lim i nary ex per i ment, a 2 cm fo cus was cho sen in stead of 3 cm to in crease fo cal gain. A hy -po der mic nee dle ther mo cou ple was in serted ap prox i mately 2 mm be neath the sur face andplaced at the fo cus to mea sure the achiev able tem per a ture rise. As be fore, the wa ter path be -tween the trans ducer and the tar get served to iso late the tis sue from con duc tive heat ing. Inor der to com pare hyperthermia ex per i ments and as sess whether the heat ing was a re sult ofcon duc tion or ul tra sound ab sorp tion, the max i mum heat ing rate was cal cu lated by di vid ingby the amount of time taken to achieve the ini tial 2.0°C of the to tal tem per a ture rise.

Large an i mal study pro to col

The In sti tu tional An i mal Care and Use Com mit tee at Duke Uni ver sity ap proved the fol low ing pro ce dure used on two ca nine sub jects — one for a RT3D im ag ing study us ing an ear lier ma -trix ar ray cath e ter pro to type, and one for a com bined RT3D im ag ing and hyper thermia studyus ing the in te grated ma trix and lin ear ar ray pro to type.60 In each study, an in tra ve nous (IV) linewas es tab lished in a pe riph eral vein and the dog was se dated with thiopental so dium, 20 mg/kgad min is tered in tra ve nously. An es the sia was in duced with in ha la tion of isoflurane gas 1% to 5 % de liv ered through a nose cone. The an i mal was intubated, placed on a wa ter heated ther -mal pad and started on a ven ti la tor. A fem o ral ar te rial line was placed via a percutaneouspunc ture or cutdown. Elec tro lyte and ven ti la tor ad just ments were made based on se rial elec -tro lyte and ar te rial blood gas mea sure ments. An IV main te nance drip of D-5 lac tatedRinger’s so lu tion was started and main tained at 5 mL/kg/min. Blood pres sure, lead II elec -tro car dio gram and tem per a ture were con tin u ously mon i tored through out the pro ce dure. The an i mal was placed in a prone po si tion, the top of the head was shorn and a scalp in ci sionwas made near the skull midline. The skin and mus cle were dis sected free and re tracted toex pose the skull. A 1 cm burr hole was care fully drilled through the bone just above the ex -ter nal oc cip i tal pro tu ber ance to ex pose the dura ma ter en cas ing the su pe rior sagittal ve noussi nus. An in ci sion in the dura was made and a cath e ter de vice was in serted into the su pe riorsagittal si nus; the cath e ter was ad vanced and ro tated in the ves sel to ori ent and op ti mize thefield of view and iden tify struc tures in the cra nial cav ity us ing both B-mode and Dopp ler im -ag ing. For the cath e ter hyperthermia por tion of the study, a sec ond 1 cm burr hole was madeap prox i mately 1.5 cm lat eral to the midline and the po si tion of the in serted trans ducer. Atype T, 33 gauge, stain less steel hy po der mic nee dle ther mo cou ple was in serted through theex posed dura into the ce re brum to mon i tor tem per a ture dur ing hyper thermia tri als.

RE SULTS

Pre lim i nary ex per i ment: hyperthermia with RT3D scan ner

With the 50-chan nel lin ear ar ray trans mit ting to a 3 cm fo cal depth in a wa ter tank, a spa -tial-peak, tem po ral-av er age in ten sity (ISPTA) of 6.88 W/cm2 was mea sured with our mem -

88 HERICKHOFF ET AL

brane hydrophone. Us ing iden ti cal scan ner set tings, we mea sured a tem per a ture rise of5.0°C in de gassed, ex cised pork mus cle. The in ter nal tem per a ture of the scan ner re mained at an ac cept able level as the power out put was main tained for sev eral min utes. Fig ure 5a is aphoto of the cen ter of the lin ear ar ray used in this ex per i ment; note that a gap was left wherethe ma trix ar ray would be ac cord ing to the in te grated de sign given in fig ure 2. The data infig ure 5b show the tem per a ture rise over 4°C within one min ute af ter turn-on, lev el ing off atabout 5°C above the am bi ent tem per a ture.

In vi tro im ag ing and ther mal per for mance tests

The dual-mode RT3D/hyperthermia pro to type cath e ter con struc tion yielded 153 ma trixar ray el e ments (77% el e ment yield) and 11 lin ear ar ray el e ments (61% yield). El e ment yield


FIG. 5 (a) Cen ter of lin ear ar ray trans ducer used in in vi tro hyperthermia ex per i ment with Volu met rics RT3Dscan ner and match ing cir cuits. (b) Ther mo cou ple data show ing a 5.0ºC tem per a ture rise at 3 cm fo cus in de gassed,ex cised pork mus cle.

will steadily im prove with prac tice and re fine ment of fab ri ca tion tech niques. The dual- mode cath e ter and Volu met rics scan ner were com pared with a Siemens 10 Fr AcuNav andSONOLINE AnteresTM sys tem as a gold stan dard to as sess im ag ing ca pa bil ity and ther a peu -tic po ten tial. Var i ous wire, tu mor, and cyst phan toms were im aged with each probe. Fig ure6 shows im ages of a test phan tom con tain ing a 1.5 cm di am e ter cyst, 4 cm deep: fig ure 6a isan im age taken with the AcuNav at 5.33 MHz, fig ure 6b is sin gle-B scan us ing both the ma -trix and lin ear ar ray el e ments of the in te grated cath e ter ar ray at 3.64 MHz and fig ures 6c, 6dand 6e are si mul ta neously-ac quired co ro nal, ax ial and sagittal planes, re spec tively, of a 3Dscan us ing only the ma trix ar ray el e ments.

It should be noted that the con cen tric ring pat tern of the ax ial im age (Fig. 6d) is an ar ti factof the sys tem’s scan con verter. The speckle pat terns in these im ages show that the pro to typedual-mode cath e ter yielded poorer spa tial res o lu tion than the AcuNav due to the re duced ap -er ture and band width of the ma trix ar ray for 3D im ag ing. In ad di tion, the AcuNav showedsu pe rior color Dopp ler sen si tiv ity (Fig. 9b).

To as sess the po ten tial of the cath e ters to cre ate hyperthermia, the max i mum spa tial-peak,tem po ral-av er age in ten sity was mea sured in a wa ter tank with our mem brane hydrophone. At a trans mit fo cus of 2 cm, the Volu met rics scan ner de liv ered an ISPTA = 2.43 W/cm2 us ing a12-cy cle, 3.64 MHz pulse at a 6.6 kHz PRF with the dual-mode cath e ter. An ISPTA = 4.54W/cm2 was also mea sured at 1 cm for the case of the unfocused lin ear ar ray el e ments drivenat 4.6 MHz by a 25-Watt power am pli fier. Fi nally, the AcuNav could de liver a 10-cy cle,5.33 MHz pulse at 6.6 kHz PRF and 55% sys tem volt age as pro jected max i mum set tings safe for the sys tem. To avoid po ten tially-dam ag ing self-heat ing in the AcuNav, ISPTA mea sure -ments were taken for lower volt age set tings on the Siemens sys tem and we ex trap o lated to55% yield ing an es ti mate of ISPTA = 4.10 W/cm2.

Us ing the same set tings as for the ISPTA = 2.43 W/cm2 data, the dual-mode cath e ter pro to typecre ated a tem per a ture rise of 3.5°C ( Fig. 7) at a 2 cm trans mit fo cus in tis sue-mim ick ing ma te rial.

90 HERICKHOFF ET AL

FIG. 6 (a) AcuNav im age of 4-cm deep, 1.5-cm di am e ter cyst phan tom. (b) Dual-mode cath e ter sin gle-B scan ofcyst phan tom. (c, d, e) Dual-mode cath e ter 3D scan of cyst phan tom: co ro nal, ax ial and sagittal im age planes.

This was achieved in less than 2.5 min utes, at which time trans mis sion was halted be causesome of the scan ner’s in ter nal elec tronic com po nents were over heat ing (above 85°C). Ittook sev eral min utes for the tis sue-mim ick ing ma te rial to dis si pate the added heat and re turnto equi lib rium tem per a ture. To avoid risk ing dam age to the scan ner, fur ther ther apy ex per i -ments were car ried out with the dual-mode pro to type by driv ing only the lin ear ar ray el e -ments as a sin gle chan nel (unfocused) us ing an ex ter nal, 25-Watt rf power am pli fiercon nected to a wave form gen er a tor. Ta ble 1 shows a com plete chart of ex per i men tal re sults.


FIG. 7 Ther mo cou ple data show ing 3.5ºC tem per a ture rise in tis sue-mim ick ing ma te rial us ing the dual-modecath e ter fo cused at 2 cm.

TA BLE 1 In ten sity and ther mal ex per i ment re sults for three ar rays and five con fig u ra tions.

Fre quency(MHz)

Fo cus(cm)

ISPTA(W/cm2)

Temperature Rise(°C)

Max i mumheat ing rate

(°C/s)in vi tro in vivo

Lin ear ar ray(w/match ing cir cuits

4.4 3 6.88 5 n/a 0.509

AcuNav 5.33 2 4.10* n/a n/a n/a

AcuNav 5.33 1 n/a 3.5 4.5† 0.020

Dual-mode cath e ter(all el e ments)

3.64 2 2.43 n/a n/a 0.164

Dual-mode cath e ter(lin ear ar rays)

5.33 unfocused 4.54 n/a 0.87‡ 0.146

* ex trap o lated es ti mate † trans ducer self-heat ing, con duc tion ‡ weak ened el e ments

In vivo ca nine model – im ag ing

Each ul tra sound cath e ter was placed in the su pe rior sagittal si nus ac cord ing to the largean i mal pro to col. Fig ure 8 is a photo from the sur gi cal pro ce dure show ing the ex posed skull,with the dual-mode cath e ter in serted an te ri orly into the su pe rior sagittal si nus through theburr hole cre ated on the midline and the ther mo cou ple in serted me di ally into the ce re brumthrough the dura ma ter ex posed by an ad ja cent burr hole. Both echo and Dopp ler im ageswere ac quired with each probe. The AcuNav pro duced echo im ages with clear de lin ea tionof ce re bral gyri and sulci (Fig. 9a), as well as color Dopp ler im ages of the in ter nal ca rotid ar -tery (Fig. 9b) ac quired with out the use of con trast.

92 HERICKHOFF ET AL

FIG. 8 In vivo ca nine model: the dual-mode cath e ter (C) placed in the su pe rior sagittal si nus through a burr hole

cre ated in the skull and a ther mo cou ple (T) in serted into the ce re brum through the dura ma ter ex posed by a sec ondburr hole, for hyperthermia tri als.

The dual-mode cath e ter pro to type ac quired RT3D im age data from a py ram i dal vol umeex tend ing from the trans ducer face to ward the base of the cra nial cav ity. The Volu met ricsscan ner si mul ta neously dis played two per pen dic u lar B-mode sec tors (sagittal and co ro nalplanes) and two C-scans (ax ial plane, par al lel to the trans ducer face), which can be in clinedat any de sired an gle. The co ro nal plane im ages were found to be very use ful for ori ent ing the trans ducer’s field of view, en abling the op er a tor to iden tify struc tures more quickly, withgreater con fi dence and ac cu racy. The lat eral ven tri cles were the most prom i nent an a tom i calland mark, and could be clearly seen in all three or thogo nal im age planes. Due to the lim itedspa tial res o lu tion of the dual-mode cath e ter, the nar row lu men of the lat eral ven tri cles andthe highly-echogenic ven tric u lar walls in the ca nine, the ven tric u lar lu men does not ap pear


FIG. 9 Intracranial AcuNav im ages. (a) Echo im age show ing var i ous gyri and sulci of the ce re brum. (b) ColorDopp ler im age show ing the in ter nal ca rotid ar tery.

as an echo-free re gion. The tentorium cerebelli mem brane, which sep a rates the cer e bel lumfrom the ce re brum, and pul sa tions of ar ter ies at the base of the brain were also vis i ble. Fig -ures 10a, 10b, and 10c com pare si mul ta neous co ro nal, ax ial and sagittal planes, re spec tively, ver sus cor re spond ing an a tom i cal slices.61 The lat eral ven tri cles can be clearly seen in the co -ro nal and ax ial planes and the sagittal plane just ad ja cent to the midline shows the cer e bel -lum, the tentorium and a pos te rior horn of the lat eral ven tri cles.

For 3D color Dopp ler im ag ing, a bolus of ag i tated sa line was needed for con trast and wasde liv ered into the left in ter nal ca rotid ar tery.62 Sev eral ves sels be came vis i ble im me di atelyaf ter the bolus in jec tion, in clud ing those that com prise the Cir cle of Wil lis. The con trast-en -hanced 3D color Dopp ler scans are shown in fig ure 11. To elim i nate ef fects of aliasing dueto undersampling, the color Dopp ler look-up ta ble was mod i fied to dis play only a sin gle hue, to better vi su al ize the ves sels (al beit elim i nat ing di rec tional flow in for ma tion). Fig ure 11a is the co ro nal plane of the scan, clearly show ing the an te rior com mu ni cat ing ar tery and leftmid dle ce re bral ar tery as well as the left and right in ter nal ca rotid ar ter ies. Fig ure 11b showsthe Cir cle of Wil lis, in clud ing the an te rior, mid dle and pos te rior ce re bral, an te rior and pos te -rior com mu ni cat ing ar ter ies, in an ax ial im age plane. Fig ure 11c is a sagittal plane of thescan, show ing the left in ter nal ca rotid, mid dle and pos te rior ce re bral, and pos te rior com mu -ni cat ing ar ter ies. Fig ure 11d is an an a tom i cal di a gram show ing a la tex-in jected sheep brainof sim i lar scale for ref er ence.63

In vivo ca nine model – hyperthermia

Af ter im ag ing, the sec ond burr hole was cre ated, and a hy po der mic nee dle ther mo cou plewas in serted. The ther mo cou ple was lo cated and aligned within 1 cm of the trans ducer byim ag ing and both were held in place. Fig ure 12a shows the ther mo cou ple aligned in an

94 HERICKHOFF ET AL

FIG. 10 (a, b, c) Intracranial RT3D echo im ages in co ro nal, ax ial and sagittal planes, re spec tively, com pared to

cor re spond ing an a tom i cal im ages (reproduced with per mis sion from Fletcher et al, Uni ver sity of Min ne sota Col -lege of Vet er i nary Med i cine). The lat eral ven tri cles (LV) are clearly seen in (a) and (b). The tentorium (T) and cer e -bel lum (C), as well as a pos te rior horn of the lat eral ven tri cle, are vis i ble in (c).

AcuNav scan. Scan ning was halted and high-power pulse se quences (10-cy cles at 5.33MHz, 6.6 kHz PRF and 55% sys tem volt age) were ini ti ated. As seen in fig ure 12e, af terabout 20 sec onds, the tem per a ture be gan to rise slowly and lin early with time for the next 3.5min utes up to 4.5°C above base line un til it was re ported that the AcuNav felt hot where itwas be ing held six inches from the trans ducer.

Af ter turn ing off power, the ther mo cou ple re corded a slow de cline in tem per a ture whilethe probe it self re mained warm. The cas ing around the trans ducer had melted and de formedand the probe could no lon ger ac quire im ages, in di cat ing that the mea sured heat ing was dueto en ergy dis si pa tion within the trans ducer and con duc tion through the tis sue rather than ul -tra sound ab sorp tion at the fo cus. Com par i son of the slow heat ing rate (0.020°C/s) withthose of our in vi tro ul tra sound hyperthermia ex per i ments (0.164-0.509°C/s) re in forces thisde ter mi na tion.

For the dual-mode cath e ter, we had de cided that driv ing the lin ear ar ray el e ments as a sin -gle chan nel (unfocused) with an ex ter nal, 25-Watt power am pli fier was pref er a ble to us ingthe Volu met rics scan ner at high power set tings that could po ten tially harm its in ter nal elec -tron ics. Here, the ther mo cou ple was aligned with one side of the lin ear ar ray at a depth of 0.5cm, where we ex pected max i mal heat ing ac cord ing to our sim u la tions (Fig. 3e). Fig ures12b, 12c and 12d show si mul ta neous co ro nal, ax ial and sagittal planes of the in serted ther -mo cou ple. 3D scan ning with the ma trix ar ray was paused as ther mo cou ple mon i tor ing wasac ti vated and the power am pli fier turned on to drive the lin ear ar ray at 4.6 MHz. The mea -


FIG. 11 (a , b, c) Intracranial RT3D color Dopp ler im ages in co ro nal, ax ial and sagittal planes, re spec tively (note: the color Dopp ler look-up ta ble was mod i fied, elim i nat ing di rec tional flow in for ma tion). (d) La tex-in jected sheepbrain vasculature for an a tom i cal ref er ence (re pro duced with per mis sion from R.R. Miselis, Uni ver sity of Penn syl -va nia School of Vet er i nary Med i cine). The in ter nal ca rotid ar ter ies (ICA), left mid dle ce re bral ar tery (MCA) andan te rior com mu ni cat ing ar tery (ACoA) are vis i ble in (a). The Cir cle of Wil lis is shown in (b), with the an te rior ce re -bral ar ter ies (ACeA), pos te rior ce re bral ar ter ies (PCeA) and pos te rior com mu ni cat ing ar ter ies (PCoA) also in di -cated.

sured tem per a ture rise was just over 0.85°C (Fig. 12f); how ever, it was found later that thetrans mit ef fi ciency of the lin ear ar ray el e ments had been con sid er ably weak ened dur ing theex per i ment, in di cat ing that this mea sure ment did not give the max i mum pos si ble tem per a -ture rise achiev able by a dual-mode probe of this de sign. For this ex per i ment, be cause wedid not ex ceed 2.0°C of heat ing, the max i mum heat ing rate (0.146°C/s) was cal cu lated by di -vid ing by the amount of time taken to achieve the ini tial 0.685°C of the to tal tem per a turerise. This da tum was in agree ment with our in vi tro heat ing-rate mea sure ments.

SUM MARY AND DIS CUS SION

We suc cess fully cre ated a tem per a ture rise of 5°C in ex cised pork mus cle us ing the Volu -met rics RT3D scan ner and cus tom ized, chan nel-spe cific im ped ance match ing cir cuits witha 50 chan nel lin ear ar ray, dem on strat ing that hyperthermia might be achiev able in brain tis -sue us ing cath e ter ar rays. An in te grated ma trix and lin ear ar ray cath e ter trans ducer pro to -type was de signed and fab ri cated. When com pared to a Siemens AcuNav probe, thisdual-mode cath e ter de vice ex hib ited sat is fac tory RT3D im age qual ity and cre ated a 3.5°Ctem per a ture rise in tis sue-mim ick ing ma te rial at a depth of 2 cm with out us ing elec tri cal im -ped ance-match ing cir cuits. We be lieve that achiev ing a higher el e ment yield and add ing match -ing cir cuits at the prox i mal end of the cath e ter to max i mize power out put ef fi ciency would makea 4.0°C or greater tem per a ture rise pos si ble us ing the Volu met rics scan ner with this ar ray de sign.

To our knowl edge, we have shown the first intracranial ul tra sound im ages in the brain us -ing cath e ter probes. In an in vivo ca nine model, the AcuNav and dual-mode pro to type each

96 HERICKHOFF ET AL

FIG. 12 (a) AcuNav im age of ther mo cou ple (ar row) placed at 1 cm depth in ce re brum. (b, c, d) RT3D co ro nal,ax ial and sagittal im ages, re spec tively, of in serted ther mo cou ple (ar rows), ac quired with dual-mode cath e ter. (e)Tem per a ture rise achieved us ing the AcuNav (trans ducer self-heat ing and con duc tion). (f) Tem per a ture riseachieved by driv ing the dual-mode cath e ter’s lin ear ar ray el e ments as a sin gle chan nel (unfocused) with an rf poweram pli fier.

were placed in the su pe rior sagittal ve nous si nus to im age the brain vol ume and at tempt tocre ate hyperthermia. The higher sen si tiv ity and Dopp ler res o lu tion of the AcuNav was ap -par ent in 2D scans of ce re bral gyri and sulci and of an in ter nal ca rotid ar tery; these im agesdem on strate the im me di ate clin i cal im ag ing po ten tial of intracranial cath e ters. The dual- mode cath e ter pro to type in ter ro gated a 3D py ram i dal vol ume in real-time, which made iteas ier to rec og nize struc tures within the cra nial cav ity. The lat eral ven tri cles were eas ily dis -tin guish able in echo im ages and in jec tion of an ag i tated sa line bolus for ves sel con trast al -lowed vi su al iza tion of the Cir cle of Wil lis and sev eral con nect ing ar ter ies.

The AcuNav was able to cre ate a tem per a ture rise of 4.5°C in ca nine brain tis sue but it wasev i dent that this was pri mar ily, if not ex clu sively, due to trans ducer self-heat ing and the re -sult ing heat con duc tion through out the tis sue vol ume, not ab sorp tion of en ergy from ul tra -sound waves. This il lus trates the im por tance of con sid er ing the con duc tion of in ter nal heataway from the trans ducer el e ments when de sign ing a dual-mode de vice: we sus pect that thepoly mer cas ing en cap su lat ing the AcuNav may have been ef fec tively trap ping ther mal en -ergy and ex ac er bat ing the self-heat ing of the probe.

The dual-mode pro to type was able to cre ate an in vivo tem per a ture rise less than one de -gree Cel sius by driv ing the lin ear ar ray el e ments as a sin gle chan nel at 4.6 MHz us ing a25-Watt power am pli fier. Post-ex per i ment as sess ment of the trans ducer’s per for mance re -vealed that the acous tic power out put had been de graded by a fac tor of 30 dur ing use in theca nine brain model; there fore, the in vivo re sult is not con clu sive. The max i mum heat ingrate for the dual-mode pro to type in vivo was com pa ra ble to the in vi tro mea sure ment, whichin di cates that the heat ing was due to ul tra sound ab sorp tion and sug gests that a 4°C in vivotem per a ture rise may be achiev able with this probe de sign. Fur ther test ing is needed to de -ter mine the op ti mal tis sue heat ing method (fo cused or unfocused beam) and trans mit cir -cuitry set tings and the ad di tion of match ing cir cuits to max i mize power out put ef fi ciencyshould en hance the de po si tion of ther mal en ergy as well.

As a whole, the re sults from these ex per i ments, in par tic u lar the in vivo RT3D im ages andmea sured in-vi tro tem per a ture rises, lead us to be lieve that the de vel op ment of an intracranialul tra sound cath e ter com bin ing RT3D im ag ing and hyperthermia ca pa bil ity is fea si ble. Inad di tion to at tain ing a higher el e ment yield, build ing elec tri cal im ped ance match ing cir cuitsand op ti miz ing the driv ing cir cuitry, the cath e ter it self must be built to man age the curves itmust make through the vasculature for the in tended, min i mally-in va sive pro ce dure (Fig. 1). This will re quire a smaller, more flex i ble cath e ter for a next-gen er a tion de vice, per haps sim i -lar to the 4.8 Fr de sign pre vi ously de scribed by Light and Smith for 3D intra vascular im ag ing.40

This 4.8 Fr de vice con tains con duc tors for 100 chan nels and may be ad e quate to re pro duce ourar ray de sign in a smaller size while achiev ing suf fi cient acous tic out put for heat ing.

In our long term plan, a brain tu mor will be lo cal ized by CT or MR im ag ing. Fluoroscopicangiography/venography will be used to guide the 3D ul tra sound cath e ter ret ro grade fromthe jug u lar vein to the dural ve nous si nuses so that the cath e ter is ad ja cent to or in close prox -im ity to the tu mor. A microbubble or liposomal agent mo lec u larly tar geted to re gions of tu -mor angiogenesis will be ad min is tered via in tra ve nous in jec tion. The dual-mode cath e terwill pro duce RT3D ul tra sound im ages with 3D color Dopp ler of the le sion and an ul tra sound hyperthermia beam will suf fi ciently warm the given agent, trig ger ing the re lease of achemotherapeutic drug at the tu mor site.

AC KNOWL EDGE MENTS

The au thors would like to thank El len Dixon-Tulloch and Ste phen J. Hsu for their as sis -tance. This re search was sup ported by a 2008 Chandran Fam ily Foun da tion Re searchAward and NIH grant EB001040.


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