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HIFU Tissue Ablation: Concept

and Devices 1
Gail ter Haar

Abstract
High intensity focused ultrasound (HIFU) is rapidly gaining clinical
acceptance as a technique capable of providing non-invasive heating and
ablation for a wide range of applications. Usually requiring only a single
session, treatments are often conducted as day case procedures, with the
patient either fully conscious, lightly sedated or under light general anes-
thesia. HIFU scores over other thermal ablation techniques because of the
lack of necessity for the transcutaneous insertion of probes into the target
tissue. Sources placed either outside the body (for treatment of tumors or
abnormalities of the liver, kidney, breast, uterus, pancreas brain and
bone), or in the rectum (for treatment of the prostate), provide rapid heat-
ing of a target tissue volume, the highly focused nature of the field leav-
ing tissue in the ultrasound propagation path relatively unaffected.
Numerous extra-corporeal, transrectal and interstitial devices have been
designed to optimize application-specific treatment delivery for the wide-
ranging areas of application that are now being explored with HIFU. Their
principle of operation is described here, and an overview of their design
principles is given.

Keywords
5LTRASOUND THERAPY s 4HERMAL ABLATION s #ANCER s (EATING s (IGH )NTENSITY
&OCUSED 5LTRASOUND ()&5 s 5LTRASOUND TRANSDUCERS

G. ter Haar
Joint Department of Physics,
4HE )NSTITUTE OF #ANCER 2ESEARCH
Sutton, London, UK
e-mail: gail.terhaar@icr.ac.uk

© Springer International Publishing Switzerland 2016 3


J.-M. Escoffre, A. Bouakaz (eds.), Therapeutic Ultrasound, Advances in Experimental
Medicine and Biology, Vol. 880, DOI 10.1007/978-3-319-22536-4_1
4 G. ter Haar

1.1 Introduction histological section taken at the lesion’s edge.


The very sharp drop off in temperature is
As the name suggests, High Intensity Focused reflected in the sharp demarcation between live
Ultrasound, HIFU, is the term used to describe and dead cells.
the application of focused beams of high power
ultrasound for therapeutic benefit. The technique
is also sometimes referred to as focused ultra- 1.3 History of HIFU
sound surgery, FUS. The common feature of the
now many, and varied, HIFU treatments is the Since this use of high intensity focused beams
need to provide a beam in which the energy is was first proposed in ~1942 (Lynn et al. 1942), it
sufficient to produce biological change solely has been explored for a number of different
within the focal volume. With few exceptions, the potential medical applications. The aim in the
aim is to induce irreversible damage, although in 1940 and 1950s was to destroy regions of the
some applications, such as drug delivery, the goal brain selectively, in the quest for a better under-
is to produce more transient effects. standing of neurobehavior (Fry et al. 1954, 1958;
Fry 1953; Fry and Fry 1960). These early efforts
were hampered not only by the poor quality of
1.2 Principles of HIFU the ultrasound images used for targeting, but also
by the necessity of removing a portion of the
In the frequency range 0.8–5 MHz, the wave- skull to provide an acoustic window for the
length of ultrasound in tissue is ~2–0.3 mm. This focused beam into the brain. Despite these limita-
means that small regions of high pressure (inten- tions, it was possible to destroy pre-determined
sity) can be created at a distance from the source, regions of the brains of experimental animals
in the focal plane. In principle, therefore, if there with good selectivity, and some human treat-
is sufficient energy in the ultrasound beam travel- ments of Parkinson’s disease were also carried
ling through an absorbing medium, it is possible out (Ballantine et al. 1960). The early work
to obtain a biologically significant temperature achieved ‘focusing’ by using several plane trans-
rise solely in this region, with negligible rises ducers whose beams all crossed in the same
elsewhere. plane. The development of HIFU coincided with
A common analogy here is that of a magnify- the introduction of the drug L-dopa. From a
ing glass used to concentrate the sun’s rays, with patient’s perspective, L-dopa proved to be a more
the purpose of igniting dry kindling. This is only acceptable treatment for Parkinsonism, and from
successful when the fuel is placed where the a clinical viewpoint, was easier to administer.
bright spot is at its most intense, that is, in the HIFU did not really gain significant clinical
focal plane of the lens. When the spot is more acceptance until the 1990s, despite successful
diffuse, it is not possible to set fire to the kin- ophthalmological treatments before this date.
dling, as the fuel is no longer in the focal region. The first proposal to use focused ultrasound in
Similarly, when a HIFU focus is placed at depth ophthalmology came from Lavine et al. (1952)
inside soft tissue, it is possible to raise the tem- who demonstrated cataract formation when the
perature at the focus to levels at which thermal lens of the eye was targeted with a focused beam.
NECROSIS OCCURS  —# WHILE LEAVING THE TEM- Other studies demonstrated that HIFU can
peratures elsewhere close to their original lev- DECREASE INTRA OCULAR PRESSURE 2OSENBERG AND
els, including those of tissues lying in the beam Purnell 1967) and produce lesions in the vitreous,
path overlying the focal volume. Figure 1.1a LENS RETINA AND CHOROID #OLEMAN ET AL 1980,
shows the principle of this technique. The gross 1985a, b; Lizzi et al. 1978). The first human treat-
appearance of a HIFU lesion (the term used to ments of glaucoma, undertaken in 1982, gave
describe the region of damage induced) can be encouraging results. 79 % of the patient cohort
seen in Fig. 1.1b, while Fig. 1.1c shows a treated had a sustained lowered intra-ocular
1 HIFU Tissue Ablation: Concept and Devices 5

a b

HIFU

Beam axis

HIFU lesion HIFU lesion

HIFU transducer HIFU transducer


Focal plane Focal plane

Skin Skin

c d
Mechanical translation of the HIFU source

HIFU lesion array

HIFU transducer
Focal plane

Skin

Fig. 1.1 (a) Schematic diagram showing the principle of and unablated cells (Hematoxylin and Eosine staining).
high intensity focused ultrasound (HIFU). (b) Slice of (d) Schematic diagram showing the formation of conflu-
ex-vivo bovine showing a HIFU lesion. (c) Histological ent regions of ablation
section showing the sharp demarcation between ablated

pressure after 1 year (Silverman et al. 1991). of opportunity for HIFU which can only be used
Although HIFU showed considerable promise in to full advantage when the tissue volume to be
these, and other, ophthalmological applications, destroyed can be precisely targeted. Both ultra-
laser surgery has enjoyed wider success and SOUND AND -2) HAVE BEEN USED TO GUIDE AND
application, presumably because of its apparently monitor HIFU treatments. Each method comes
simpler technology and application. It is only WITH ITS ADVANTAGES AND DISADVANTAGES -2) GIVES
now that the use of HIFU in the treatment of anatomical images, and can provide thermometry
glaucoma is being revisited, with considerable sequences that allow the tissue temperature to be
success (Aptel et al. 2014). mapped, thus providing information not only
about the success of ablation in the target, but
Overview of clinical usage The realization of also about the safety of critical regions outside
the full potential of HIFU treatments is only pos- this volume. While ultrasound thermometry has
sible now that precise targeting and good treat- not yet found clinical implementation, this
ment follow-up techniques, (with anatomical and modality offers superior spatial and temporal
functional imaging), are available with modern RESOLUTION FOR IMAGING #ONlRMATION OF SUCCESS-
diagnostic ultrasound scanning and magnetic ful ablation under ultrasound guidance relies on
RESONANCE IMAGING -2) METHODOLOGIES 4HE the appearance of bright echoes on an ultrasound
provision of real-time images with excellent spa- scan, The ability of HIFU to ablate subcutaneous
tial resolution and contrast has opened a window tissue volumes non-invasively has made it an
6 G. ter Haar

attractive potential therapy for deep-seated soft with either hemi-ablation, or focal ablations
tissue tumors. Malignant tumors of the liver, kid- #ROUZET ET AL 2014; Baco et al. 2014; Valerio
ney, breast and pancreas have been successfully et al. 2014). There is little in the way of conven-
targeted (Al-Bataineh et al. 2012; Orsi et al. tional therapy to offer patients whose prostate
2010; Wu et al. 2004, 2005a, b). While ultra- cancer recurs after radiation therapy. High inten-
sound does not significantly penetrate bone, sity focused ultrasound may be able to fulfill this
many osteosarcomas break through the bone cor- role as it offers selective tissue destruction with-
tex, and thus are also good candidates for HIFU out side effect. Early trials for this application
treatment (Li et al. 2010 #HEN AND :HOU 2005). have shown encouraging results (Ahmed et al.
The successful palliation of pain resulting from 2012; Gelet et al. 2004).
bone tumors has also been reported, with the
treatment here being aimed at destroying the
nerves lying on the peri-osteum (Liberman et al. 1.4 Exposure Dosimetry
2009; Hurwitz et al. 2014  #ARE MUST BE EXER-
cised to avoid bowel gas that lies in the propaga- In imaging and therapies that use ionizing radia-
tion path. In some treatment orientations this gas tion, a distinction is clearly made between “expo-
may be successfully displaced by applying pres- sure” and “dose”, with exposure for these energy
sure from a water balloon placed against the forms being the amount of ionization produced in
abdomen. HIFU has proved to be an attractive air by X- or γ-rays. The unit of exposure is the
technique for the treatment of uterine fibroids. 2OENTGEN 2 %XPOSURE DESCRIBES THE AMOUNT OF
4HESE MAY BE CLEARLY VISUALIZED ON EITHER -2 OR radiation that reaches the body, but does not
Ultrasound images (Froeling et al. 2013; Hesley describe the fraction of that incident energy that
et al. 2013; Quinn et al. 2015). is absorbed within tissue. A second parameter is
Trans-rectal HIFU treatment of prostate used for this, the “absorbed dose” (commonly
tumors has also been widely investigated. Both referred to as “dose”). Dose characterizes the
benign prostate hyperplasia (BPH) and prostate amount of energy deposited per kilogram and has
CANCER HAVE BEEN TARGETED #ROUZET ET AL 2015; units of the gray (Gy) and the rad, where
4HÓROFF AND #HAUSSY 2015). Initial results from 1 rad = 100 Gy. A weighting factor (relative bio-
clinical trials for treatment of BPH (Gelet et al. LOGICAL EFFECT 2"% IS USED IN AN ATTEMPT TO COM-
1993; Sullivan et al. 1997) were encouraging, pare the biological effects of different forms of
with increase in flow rate and decreases in post- ionizing radiation. This leads to a “dose equiva-
void residual volume. However, the long-term lent” parameter, whose units are the rem or
results of Madersbacher et al. (2000) were disap- Sievert, Sv, (1 rem = 100 Sv). These parameters
pointing, with 44 % of patients requiring a sal- are related by the equation: Dose equivalent
vage trans-urethral resection of the prostate 3V  DOSE 'Y X 2"% 8 RAYS γ-rays and ß par-
4520 WITHIN  YEARS ()&5 HAS THUS NOT PROVED TICLES HAVE AN 2"% OF  WHEREAS α particles
to be significantly better than the “gold standard” HAVE AN 2"% OF 
TREATMENT 4520  4REATMENT OF CANCER IN THE The terms “exposure” and “dose” are used
prostate presents different problems from those interchangeably in medical ultrasound, although
ASSOCIATED WITH THE TREATMENT OF "0( #ROUZET a convincing case for drawing the distinction can
et al. 2015 4HÓROFF AND #HAUSSY 2015). Prostate be made. Different biological effects result from
cancer is a multi-focal disease, the foci of which different modes of ultrasonic energy delivery. For
are difficult to detect with diagnostic ultrasound. example, two exposures that use the same total
It is important for its control that all foci are acoustic energy over an identical time span,
destroyed. Initially HIFU treatments were aimed where one is delivered in continuous mode, and
AT ABLATION OF THE WHOLE GLAND #HAUSSY ET AL the other in short pulses at low repetition rate and
2001; Dickinson et al. 2013). More recently, high amplitude may result in very different
there has been a move towards partial ablation, effects in tissue. The first is more likely to induce
1 HIFU Tissue Ablation: Concept and Devices 7

thermal effects, while the second may stimulate for the short times required above this tempera-
cavitation activity and its associated characteris- ture, since very fast heating and cooling rates are
tic cell damage (ter Haar 2010). required. An alternative parameter related to the
Ultrasound exposures are most usually char- heating potential of the HIFU beam is the product
acterized in terms of the acoustic field determined of intensity and time (a measure of the total
under “free field conditions” in water. Here, “free energy), but this concept has not gained wide-
field” is taken to describe the conditions in which spread acceptance in the therapy ultrasound lit-
the ultrasound beam propagates freely, without ERATURE #LINICALLY A T43 of 240 min is used as the
influence from boundaries or other obstacles. A threshold for successful thermal ablation
full description of HIFU exposures requires (MacDannold et al. 2006). It is now well accepted
knowledge of frequency, exposure time, trans- that cavitation can enhance the heating in a HIFU
ducer characteristics, total power, acoustic pres- lELD (OLT AND 2OY 2001; Khokhlova et al. 2006).
sure and/or intensity (energy flux in Watts.cm−2) However, there is, as yet, no validated method of
and mode of energy delivery (single shots, quantifying cavitation activity, nor accepted
scanned exposures, etc.) (ter Haar et al. 2011). METHOD FOR DElNING hCAVITATION DOSEv #HEN
In order to make the transition from exposure et al. 2003; Hwang et al. 2006).
to dose in an ultrasound field, it is necessary to
know the acoustic characteristics of the propaga-
tion medium. The parameters of most importance 1.5 HIFU Treatment Delivery
are the attenuation and absorption coefficients,
the speed of sound and the nonlinearity parame- The devices used to deliver HIFU clinically are
ter B/A. There are large gaps in knowledge about broadly divided into two classes, extra-corporeal
these parameters for both normal and malignant and interstitial. The basic components however,
human tissues, although many have been tabu- do not differ much, comprising as they do, the
lated (Goss et al. 1980; Duck 2013). Generally transducer, a signal generator, amplifier, match-
HIFU exposures are described in terms of free ing circuitry to maximize the electro-acoustic
field water measurements, but in some cases, an efficiency, a power meter, and in some cases a
attempt is made to calculate an in-situ intensity method of cooling the transducer. These are con-
by estimating the total attenuation in the beam nected to an operator console that allows move-
path. Spatial peak (focal peak) intensities and ment and positioning of the source, and also
spatially averaged intensities are also sometimes provides a means of monitoring the treatment.
quoted. The focusing required for HIFU treatments
Two dose parameters related solely to thermal can be achieved in a number of ways. The sim-
effects have been proposed. Sapareto and Dewey plest is to use a single element transducer: most
(1984) proposed a thermal dose parameter. This commonly, either in the form of a planar disc
has been used extensively to describe hyperther- fronted by a lens, or shaped as a spherical bowl.
mic cancer treatments. The temperature-time his- Such transducers are limited in that they can only
tory for a particular tissue volume is integrated provide a fixed focus, and if clinically relevant
and reduced to a biologically equivalent exposure volumes are to be treated, the whole transducer
TIME AT  —# T43. This equivalent time is given by assembly must be physically moved in order to
the equation: place lesions side by side (Fig. 1.1d). The more
common alternative is to use multi-element trans-
t43 = R (T − 43) Δt (1.1) ducer arrays. Electronic phasing of the signal to
individual elements allows both flexibility in
WHERE 2 IS  ABOVE  —# AND  BELOW  —# shaping the focal volume, and some dynamic
and T is the average temperature over a time Δt. control of its position, both axially and trans-
This has been shown to be valid up to about axially (Gavrilov et al. 2000; Gavrilov and Hand
 —# BUT IS DIFlCULT TO VALIDATE EXPERIMENTALLY 2000; Daum and Hynynen 1999). The geometry
8 G. ter Haar

20 mm in Z
No.of Array 20 mm in Y (to
No steering (away from
elements configuration source left)
source)

64

128

256

512

Fig. 1.2 Effect of changing number of elements. 20 cm radius of curvature, 20 cm diameter, 1.7 MHz, 5 cm diameter
central aperture

of the elements determines its capabilities. For randomness and sparsity into their arrangement
example, if the array is comprised of concentric (Hutchinson et al. 1996; Goss et al. 1996;
elements (an annular array) it is only possible to Gavrilov et al. 1997; Filonenko et al. 2004; Hand
move the focus electronically to different posi- et al. 2009  2ANDOM ARRAYS TYPICALLY ALLOW LAT-
tions along the beam axis (Hynynen et al. 1996; eral movement in the focal plane by distances of
Dupenloup et al. 1996). ~10 % of the geometric focal length. Pernot et al.
When the individual elements are placed on a (2003) compared the steering capabilities and
spherical shell, focusing is achieved using both appearance of side lobes at a frequency of
the transducer’s geometry, and dynamic control 0.9 MHz for three sparse array geometries (hex-
of phase and amplitude. For the safe application agonal, annular and quasi-random), each with
of HIFU it is important to minimize the grating 52 % coverage of the 180 mm diameter, 120 mm
lobes that can occur when elements are uniformly geometrical focal length spherical surface on
spaced. These, and other secondary maxima that which they were mounted. They showed by sim-
can be present in the acoustic field, may lead to ulation that the quasi-random design gave the
unwanted local heating in tissue away from the best beam steering capability while maintaining
target volume. A number of solutions for reduc- sufficient peak pressure amplitude. Their results
ing grating lobes have been suggested. In the were validated by experiment. In Figs. 1.2, 1.3
main, these involve destroying the regular peri- and 1.4, field simulations for a 256 element ran-
odicity of the element spacing, and introducing dom array are displayed, showing the influence
1 HIFU Tissue Ablation: Concept and Devices 9

20 mm in Z
RoC No steering 20 mm in Y
(away from
(cm) 5.22 cm width (to source left)
source)

15.0

20.0

50.0

Fig. 1.3 %FFECT OF CHANGING RADIUS OF CURVATURE 2O#   ELEMENTS  CM DIAMETER  -(Z  CM DIAMETER CENTRAL
aperture

of the beam pattern of the number of array ele- results in a lower spatial resolution and cavitation
ments (Fig. 1.2), the radius of curvature of the threshold, and increases the probability of heating
bowl on which they are placed (Fig. 1.3), and the post-focally. At this lower frequency, the ultra-
drive frequency (Fig. 1.4). sound absorption is reduced, and more acoustic
A disadvantage of the sparse array is that power is required to achieve the desired tempera-
energy is deposited incoherently in the near field tures than for the 1–3 MHz frequency range that is
(Payne et al. 2011). This leads to a low level of more commonly used. This illustrates the neces-
heating that becomes problematic when focal sity, common to all designs, of making trade offs
lesions are to be placed side by side (to gain con- and compromises Hill et al. 1994.
fluent ablation volumes) with their near fields It is not possible here to describe in detail the
overlapping, since the temperature may rise to many different transducer geometries available,
biologically significant levels. This is avoided by but Table 1.1 summarizes the many different
introducing a cooling time between “shots”, but designs, their steering capabilities, and their
this in turn lengthens the treatment time. In order advantages and disadvantages.
to reduce these problems, a 500 kHz flat phased When tissue targets lie behind the ribcage
array with elements space λ/2 apart has been (such as those in liver, kidney or pancreas) or
proposed (Ellens et al. 2015). While this reduces under the skull, approaches that avoid overheating
the effects of near field heating, and avoids the the bone surface are required if an acoustic win-
problem of grating lobes, this lower frequency dow is not to be created by surgical removal of
(necessary if the λ/2 separation is to be achieved), some skull or ribs. For the rib cage, simple ray
10 G. ter Haar

20 mm in Y 20 mm in Z
Freq.
No steering (to source (away from
(MHz)
left) source)

0.50

1.00

1.50

1.75

2.00

Fig. 1.4 Effect of changing frequency. 256 elements, 20 cm radius of curvature, 20 cm diameter, 5 cm diameter central
aperture

tracing may be used to “turn off” elements whose lying behind bone can be targeted, and clinically,
BEAM IMPINGES ON THE BONE #IVALE ET AL 2006) or, they have been used successfully in the treatment
more sophisticatedly, time reversal or adaptive of essential tremor and other neurological prob-
focusing techniques are used (Pernot et al. 2003; lems (Medel et al. 2012; Martin et al. 2009; Elias
Tanter et al. 1998, 2001; Thomas and Fink 1996; et al. 2013). The ultrasound field is severely dis-
#LEMENT AND (YNYNEN 2002a, b; Aubry et al. torted in amplitude and phase by passage through
2008). Using these techniques, selective regions the skull. Time reversal can correct the phase
1

Table 1.1 Summary of available transducer geometries, their advantages and disadvantages
Transducer geometry/ Significant grating #OVER PACKING #APABLE OF BONE
composition Steering capability lobes? fraction) sparing Application 2EFERENCES
Single element None, mechanical No 100 % No Abdomen, breast, prostate #HAN ET AL 2002),
Planar + lens translational only Abdomen, breast, prostate Fjeld et al. (1999),
Spherical bowl Liver – intra-operative #OUPPIS ET AL 2012),
Toroid Ophthalmology – Fry (1958 2IVENS
#YLINDER glaucoma et al. (1996), ter Haar
AND #OUSSIOS 2007),
Melodelima et al.
(2009), Aptel et al.
(2011)
HIFU Tissue Ablation: Concept and Devices

Multi-element Only in axial direction No ≈100 % No Abdomen, breast Hynynen et al.


Annular array (1996), Dupenloup
et al. (1996)
Multi-element Limited No ≈100 % No Liver – intra-operative Vincenot et al. (2013)
Toroid array
Multi-element Limited Yes High Yes Abdomen, breast, prostate Pernot et al. (2003),
Periodic array Filonenko et al.
(2004)
Multi-element Yes, limited No Variable Yes Abdomen, breast, prostate Ellens et al. (2015)
Periodic array λ/2 spacing
1.5D array Only in lateral Depends on High (variable) (Yes) Abdomen, breast, prostate #HEN ET AL 2012),
direction element spacing Urban et al. (2013)
Multi-element Yes No 2EDUCED Yes Abdomen, breast, prostate, Filonenko et al.
Aperiodic, random, sparse array ≈10 % focal length brain (2004), Hand et al.
laterally (2009), Gavrilov
et al. (2000)
Multi-element Yes No Variable (Yes) Abdomen, breast, prostate #IVALE ET AL 2006),
2ANDOMLY SIZED ELEMENTS Lafon et al. (2000),
(including sector arrays, strip Melodelima et al.
arrays) (2003)
11
12 G. ter Haar

Fig. 1.5 Multi-element pseudo-random array composed of 256 individual elements mounted in 3D printed shell

aberrations induced by the skull bone, and when transducer. Apart from the obvious necessity of
combined with amplitude correction, is used to the ability to produce high powers at frequencies
restore the desired focus at the brain target. The in the range 0.25–10 MHz (requiring high
time reversal technique relies on the reciprocity electro-acoustic conversion efficiency), they
property of the wave equation, and requires the must be reliable, able to deliver energy in pulsed
presence of a sensor at the anticipated focal point or continuous wave form, and be physically com-
in the brain to record the aberrations, which dis- patible with the chosen imaging methods.
rupt the focus. The implantation of such a sensor #OMPATIBILITY WITH THE HIGH MAGNETIC lELDS PRES-
is clinically unrealistic, but it has been shown that ENT DURING -2 GUIDED ()&5 IS CLEARLY A TECHNO-
it is possible to perform the required phase and logical challenge. When ultrasound is the
amplitude corrections using either magnetic reso- monitoring modality of choice, a central aperture
NANCE -2 OR COMPUTED TOMOGRAPHY #4 is usually required in the therapy transducer, into
images of the skull to model its ultrasonic proper- which an imaging probe can be inserted. There is
ties for use in numerical modeling of the wave increasingly a call for transducer elements that
front distortion (Hynynen and Sun 1999; Aubry are dual mode, that is, are capable of operating
et al. 2003). This allows the propagation of a wave both as therapy sources at high power, and of
front emanating from a virtual point-like source in being used in short pulse, imaging mode (Ebbini
the brain (the intended “target”) through the skull et al. 2006; Owen et al. 2010; Mari et al. 2013;
to be simulated and recorded by a set of virtual #ASPER ET AL 2013).
receivers outside the head. This wave front can be Multi-element arrays are most commonly
time reversed, and emitted by a real transducer constructed in one of two ways. Individual ele-
array. This, along with amplitude correction made ments can be cased in separate housings and then
possible by knowledge of the porosity of the bone mounted individually on a shell of the required
OBTAINED FROM THE #4 SCAN RESULTS IN A FOCUSED geometry. This allows easy replacement of fail-
beam at the brain “target” (Aubry et al. 2003). ing elements and gives flexibility in their arrange-
ment, but only allows for sparse arrays. An
example of such a multi-element array is shown
1.5.1 Transducer Materials in Fig. 1.5. The alternative is to create an array
by, for example, cutting deep grooves into a sin-
There are a number of constraints that must be gle piezo-ceramic sheet. This allows for denser
considered in the design of a therapy ultrasound packing of the elements, but can create a fragile
1 HIFU Tissue Ablation: Concept and Devices 13

array when larger sizes are required. Hybrid in one dimension (a pillar) and the 3D continuity
combinations of these two methods are also of the embedding polymer.
possible. Polyvinylidene fluoride (PVDF) is another
With few exceptions (most notably for litho- commonly used piezo-electric material used in
tripsy), medical ultrasound transducers are made medical ultrasound applications. This may be
from piezo-electric materials. Early pioneers in manufactured as a thin (acoustically transparent)
this area used the naturally occurring material, membrane, and can be electroded to act as either
quartz (Fry 1953, 1977; Fry et al. 1954). Piezo- a sensor or a low power source. PVDF membrane
electricity was first discovered by Pierre and hydrophones are in common use as they only
*ACQUES #URIE IN THE S AND IS THE NAME GIVEN minimally distort the acoustic field during pres-
to the property of a crystalline material that devel- sure measurement (Shotton et al. 1980; Bacon
ops a charge when it is subjected to mechanical 1982; Bailey et al. 2011; Wear et al. 2014).
stress. The inverse effect is that when an electrical #APACITIVE MICROMACHINED ULTRASONIC TRANS-
charge is applied to such a material, it will change DUCERS #-54S HAVE UNTIL NOW NOT BEEN THOUGHT
its shape. An alternating current applied across a to be capable of producing sufficient power for
piezo-electric disc will cause rapid movement of HIFU applications, but recent publications indi-
its faces, creating a pressure wave in the medium cate that this limitation may be overcome (Wong
in which it sits. Naturally occurring piezo-electric et al. 2010; Khuri-Yakub and Oralkan 2011;
materials other than quartz include sucrose, tour- Yamaner et al. 2012; Lee et al. 2013).
maline, lead titanate and dry bone.
In medical ultrasound, the most commonly
used piezo-electric material is now lead zirconate 1.6 Clinical Devices
TITANATE 0B;:RxTi1-x]O3 0:4  ,OW LOSS 0:4
ceramic is cut into discs, the thickness of which The characteristics of transducers currently in
determines the resonant frequency, the higher the clinical use are shown in Table 1.2. This is neces-
frequency, the thinner the disc. In order to reduce sarily not a completely comprehensive list. The
fragility it is often convenient to drive these trans- aim for most systems is to deliver an in-situ
ducers at their third harmonic. For high power intensity greater than 103 W.cm−2 at the focus. For
APPLICATIONS 0:4 CERAMIC TRANSDUCERS ARE COM- extra-corporeal sources with long focal length,
monly air backed, to allow cooling and to reduce this is achieved using a high power wide aperture
damping of the pressure wave. While high- source. Wide aperture sources have the advantage
density arrays can be made from simple of distributing the incident energy over a large
piezo-electric materials, they operate in a narrow skin area, thus reducing the possibility of skin
bandwidth, and it is necessary to avoid cross talk burn. Trans-rectal and intra-cavitary sources
between adjacent elements of the array. operate at lower powers and higher frequencies
An alternative to using the piezo-ceramic as they can be placed close to the target volume.
crystals on their own is to incorporate them into a
PIEZO COMPOSITE STRUCTURE #HAPELON ET AL 2000).
Here, pillars of piezo-ceramic material are 1.6.1 Extracorporeal Devices
embedded in a polymer. The presence of the
polymer enhances the vibration in the thickness Tissue targets lying within the breast, abdomen,
mode used to generate the ultrasound wave, and brain or limbs are usually treated using an extra-
reduces cross talk between the elements. The corporeal HIFU source. This necessitates a suit-
transducer shell can be shaped, and a solid back- able acoustic window on the skin that allows
ing material can be used, rendering the transducer access to the treatment site that is free of gas or
less fragile. A common geometry for piezo- bone in the propagation path. It must also be pos-
composites used in therapy ultrasound is 1–3. sible to couple the ultrasound energy to the skin
This describes the continuity of the piezo-ceramic surface using coupling gel, a water balloon or
14

Table 1.2 Summary of devices currently in use clinically


Transducer Focal Acoustic Intensity
Device Application Guidance Freq. (MHz) aperture (cm) length (mm) power (W) (W.cm−2) 2EFERENCES
%# Liver cancer US 0.8/1.6 12 135 – 5–20·103 Wu et al. (2005a)
%# Kidney cancer US 0.8/1.6 12 13.5 <300 – Illing et al. (2005)
%# Breast cancer US 1.6 12 90 – 5–15·103 Wu et al. (2005a, b)
%# Uterine fibroid -2 0.96–1.14 12 Variable 100–140 – Tempany et al. (2003)
%# Osteosarcoma US 0.8 12 135 80–160 2–8·103 #HEN ET AL 2002)
%# Pancreatic cancer US 0.8 12 135 <300 5–10·103 Wu et al. (2005b)
42 Prostate BPH US 4 3.0 × 2.2 30–40 – 1.3–2·103 Sanghvi et al. (1999)
42 Prostate cancer US 4 – 30–50 – 1.3–2.2·103 Dickinson et al. (2013)
42 Prostate cancer US 3 6.1 × 3.9 45 26–35 – #HAUSSY ET AL 2001)
) # 2HINITIS None 5–8 0.5 2–3 10–20 –
) # Biliary duct cancer US 10 0.3 × 1.0 n/a 14 Prat et al. (1999)
H/H Gynaecology None 5–8 1.2 5 10–30 – Li et al. (2004)
%# Ophthalmology Visual 21 6 × cylindrical 10.2 2 – Aptel et al. (2011)
segment, 10.2 mm
radius, 4.5 mm
width and a 7 mm
length
I/O Liver metastases US 3 Toroid 70 mm 70, 86 – – Dupré et al. (2015)
%# Breast, thyroid US 3 – – 125 – Kovatcheva et al. (2014,
2015)
E/C extra-corporeal, T/R trans-rectal, H/H hand held, I/O intra-operative, (−) signifies that information in not available
G. ter Haar
1 HIFU Tissue Ablation: Concept and Devices 15

other suitable path of a material of similar acous- tissue gas. The stiffness of tissue is altered by the
tic impedance to that of the skin. Extracorporeal ablation process, and so elastographic techniques
HIFU treatments are guided using either US or should allow treatments to be monitored in real
-2) 4HESE METHODS HAVE BEEN REVIEWED BY time, although this technique has not yet achieved
2IVENS ET AL 2007). When treatments are carried widespread clinical use.
OUT UNDER -2 GUIDANCE CARE MUST BE TAKEN ABOUT
the magnetic compatibility of the treatment head.
0:4 CONTAINS .ICKEL WHICH HELPS WITH THE HIGH 1.6.2 Trans-rectal Devices
levels of electrical excitation and mechanical
stress induced. Nickel causes magnetic field dis- Trans-rectal devices have been developed for the
tortion, and eddy currents may be set up when the treatment of benign and malignant prostate dis-
transducers are given a conductive silver coating. ease. These have probes that can be inserted per
These eddy currents may cause local magnetic rectum and which incorporate both imaging and
field inhomogeneities, and significant image arti- therapy transducers in one unit. The clinical
facts. It is possible to reduce these currents by acceptance of these devices was made easier by
segmenting the transducer face into a number of TRANS RECTAL ULTRASOUND IMAGING 4253 BEING
areas (Wharton et al. 2007). The piezo-composite the diagnostic investigation of choice for many
materials discussed above reduce these problems, urologists. There are two commercially available
and have been used by the commercial clinical devices, which are very similar in concept. In
systems now available. both systems the therapy transducer takes the
-2 GUIDANCE HAS THE ADVANTAGE THAT THER- form of a truncated spherical bowl.
mometry sequences are available that allow
temperature mapping in soft tissue. This enables
the superimposition of either the temperature, 1.6.3 Interstitial Devices
or the calculated thermal dose, on the anatomi-
CAL -2 IMAGE 5SING THIS TYPE OF DISPLAY THE There has been some interest in the development
entire target region can be “painted” out during of high intensity ultrasound probes for interstitial
TREATMENT 4HE TWO MOST COMMONLY USED -2 use. In the main, these use plane transducers
guided clinical HIFU systems achieve volume rather than focusing elements, and volume
ablation in different ways. Both systems aim to destruction is obtained by rotation of the probe.
minimize treatment times. In one, the focus is Prat et al. (1999) have described a probe designed
swept electronically in concentric circles, with for the intra-ductal treatment of biliary tumors. A
the user able to choose the maximum diameter 3 × 10 mm 10 MHz plane transducer is mounted
of this sweep, and in the other, the phase and on a stainless steel shaft that is passed through a
amplitude applied to the multi-element array is jumbo fiberduodenoscope. The probe can be
designed to produce multiple focal peaks in the positioned under fluoroscopic guidance. An
focal plane. ultrasound intensity at the transducer face of 14
Where US is used to guide and monitor HIFU Wcm−2 IS USED FOR n S BURSTS #IRCUMFERENTIAL
treatments, the diagnostic transducer is incorpo- ablation is achieved by rotation of the flexible
rated into the treatment head. This allows real probe. The transducer is rotated by 18° after each
time imaging of the ablation process. The ther- “shot”. Once 360° of damage has been achieved,
mally ablated region is not visible on standard the probe is repositioned under fluoroscopic
B-mode images in the absence of contrast media, guidance to create adjacent rings. This has been
unless gas bubbles have been induced. HIFU used clinically with some encouraging results
exposures levels are therefore often adjusted until (Prat et al. 2001  !N -2 COMPATIBLE DEVICE
a hyperechoic region is seen on the US image, working on similar principles has been created
indicating that bubbles are present in this region. for the treatment of esophageal tumors
These are generated by thermal exsolution of (Melodelima et al. 2005).
16 G. ter Haar

While the main clinical route for the HIFU !PTEL & $UPUY # 2OULAND *&  4REATMENT OF REFRAC-
tory open-angle glaucoma using ultrasonic circular
treatment of the prostate is trans-rectal, the trans-
CYCLOCOAGULATION A PROSPECTIVE CASE SERIES #URR -ED
urethral route has also been explored under ultra- 2ES /PIN n
SOUND AND -2 GUIDANCE 3OMMERS ET AL 2013; Aubry JF, Pernot M, Marquet F, Tanter M, Fink M (2008)
Siddiqui et al. 2010). This route reduces the risk Transcostal high-intensity-focused ultrasound: ex vivo
adaptive focusing feasibility study. Phys Med Biol
of damaging the rectal wall.
53:2937–2951
Aubry JF, Tanter M, Pernot M, Thomas JL, Fink M (2003)
Experimental demonstration of noninvasive trans-
1.7 Summary skull adaptive focusing based on prior computed
tomography scans. J Acoust Soc Am 113:84–93
"ACO % 'ELET ! #ROUZET 3 2UD % 2OUVIáRE / 4ONOLI‐
Modern medicine concentrates on developing #ATEZ ( %GGESB’ ("  (EMI SALVAGE HIGH‐
personalized treatments and techniques that intensity focused ultrasound (HIFU) in unilateral
minimize intervention to the patient and length radiorecurrent prostate cancer: a prospective two‐cen-
tre study. BJU Int 114:532–540
of hospital stay. HIFU fits excellently into this
"ACON $2  #HARACTERISTICS OF A 06$& MEMBRANE
philosophy. Thermal ablation therapies in gen- hydrophone for use in the range 1–100 MHz. IEEE
eral provide a minimally invasive approach to Trans Sonics Ultrasonics 29:18–25
cancer therapy that is gaining rapid clinical "AILEY -2 -AXWELL !$ 0ISHCHALNIKOV 9! 3APOZHNIKOV
OA (2011) Polyvinylidene fluoride membrane hydro-
acceptance. HIFU is the least invasive of the
phone low‐frequency response to medical shock-
available ablative techniques, and as such should waves. J Acoust Soc Am 129:2677–2677
be the most attractive. However, there remain Ballantine HT, Bell E, Manlapaz J (1960) Progress and
outstanding technical and treatment delivery problems in the neurological application of focused
ultrasound. J Neurosurg 17:858–876
questions to be addressed. The growing use of
#ASPER !* ,IU $ "ALLARD *2 %BBINI %3  2EAL TIME
multi-element phased array sources has increased implementation of a dual-mode ultrasound array sys-
the flexibility of HIFU delivery, and shortened tem: in vivo results. IEEE Trans Biomed Eng 60:
treatment times. Integration of therapy and diag- 2751–2759
#HAN !( &UJIMOTO 69 -OORE $% -ARTIN 27 6AEZY 3
nostic technique has improved treatment target-
(2002) An image-guided high intensity focused ultra-
ing and monitoring, thus rendering HIFU both sound device for uterine fibroids treatment. Med Phys
safer and more effective. It seems probable that, 29:2611–2620
as the evidence base for the clinical efficacy of #HAPELON *9 #ATHIGNOL $ #AIN # %BBINI % +LUIWSTRA
JU, Sapozhnikov OA, Guey JL (2000) New piezoelec-
HIFU improves, there will be a move towards
tric transducers for therapeutic ultrasound. Ultrasound
more application specific devices, as already Med Biol 26:153–159
seen for treatments in the brain, eye and #HAUSSY # 4HUROFF 3 DE LA 2OSETTE **-#  2ESULTS
thyroid. and side effects of high-intensity focused ultrasound
in localized prostate cancer. J Endourol 15:437–440
#HEN 7 7ANG : 7U & :HU ( :OU * "AI * ,I + 8IE &
Acknowledgements I should like to thank my team at (2002) High intensity focused ultrasound in the treat-
THE )#2 FOR PROVIDING ME WITH PHOTOGRAPHS AND lGURES MENT OF PRIMARY MALIGNANT BONE TUMOR :HONGHUA
MOST ESPECIALLY $RS )AN 2IVENS *OHN #IVALE $AVID :HONG ,IU :A :HI n
Sinden and Pierre Gelat. #HEN 73 "RAYMAN !! -ATULA 4* #RUM ,!  )NERTIAL
cavitation dose and hemolysis produced in vitro with or
without Optison®. Ultrasound Med Biol 29:725–737
#HEN 7 :HOU +  (IGH INTENSITY FOCUSED ULTRA-
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