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Photoacoustic Tomography: Principles and applications

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Photoacoustic Tomography :
Principles and applications
Etienne De Montigny
Département de génie physique, École Polytechnique de Montréal,
2500 Chemin de Polytechnique, Montréal, QC H3T 1J4, Canada
etienne.de-montigny@polymtl.ca

Abstract: An overview of photoacoustic tomography (PAT) in


biomedical imaging is provided. This modality effectively combines
optical contrast with high resolution in-depth ultrasound imaging.
PAT allows visualization of the three dimensional distribution of light
absorption in the sample. Applications of photoacoustic tomography
in cancer detection, particularly in breast cancer screening, and
identification of atherosclerotic plaques are discussed.
© 2011 École Polytechnique de Montréal
OCIS codes: (170.5120) Photoacoustic imaging.

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1. Introduction
The photoacoustic (PA), also referred as optoacoustic, effect was first introduced by
Alexander Graham Bell in 1880. He found that absorption of electromagnetic waves
by a medium generated sound waves. Even though the PA effect was known for a long
time, it was not until 1994 that Kruger [1] demonstrated application of this phenomenon
in highly scattering media. It was applied a few years later to biomedical imaging [2].
The PA effect explains how electromagnetic energy can be absorbed and converted into
acoustic waves. PA imaging benefits from the advantages of pure optical or ultrasound
imaging, without the major disadvantages of each technique [3]. PAT combines the
high contrast from absorption of light with the high resolution and penetration depth
of ultrasound imaging.
Optical modalities benefit from high contrast due to electromagnetic interaction with
materials, particularly absorption. Absorption in a biological tissue can be modeled
with the well-known Beer-Lambert law:

I = I0 × exp(−µa L) (1)

where I is the intensity after light has traveled L meters, I0 is the initial intensity and
µa is the absorption coefficient.
High resolution (1 − 10µm) can be obtained in optical imaging because of the short
wavelengths used, typically between 650 and 1350 nm. The major problem in optical
imaging is the penetration depth. Biological tissue scatters light a lot. By replacing µa
by µs , the Beer-Lambert law presented in Eq:1 can also be used to model scattering.
This coefficient (µs )is around 1-10 mm−1 [4] in biological tissue. This means that the
major part of the incident light has scattered after one millimeter. Scattering increases
with shorter wavelengths, this is why near infrared (NIR) light is mostly used in optical
biomedical imaging. Since photons that have not scattered form the signal of interest,
maximal imaging depth rarely exceeds 3 mm. Diffuse optical tomography extends the
penetration depth by detecting diffuse photons. This requires complex algorithms and
suffers from poor spatial resolution [4].
On the other hand, ultrasound imaging, also known as echography, relies on acous-
tic waves to study a tissue. High resolution (100µm)can also be obtained with short
wavelengths, because they can resolve smaller details. In addition, penetration depth
is in the order of centimeters to a few tens of centimeters [5]. The down side is that
the signal of interest is reflected waves due to changes in the speed of sound and these
changes are relatively small. Therefore, contrast is poor in ultrasound imaging. Func-
tional information is provided by Doppler imaging, where the velocity of fluids such as
blood is imaged.
Photoacoustic tomography (PAT) aims to use the advantages of both optical and
ultrasound imaging, without the disadvantages. This is done by illuminating the sam-
ple with diffuse, short pulses and collecting the ultrasound waves generated by the
PA effect. This review article covers the basis of the PA effect and the generation,
propagation and detection of the photoacoustic waves. The third section describes the
inverse source problem in PAT and shows how a reconstruction algorithm can solve it.
Finally, biomedical applications of this new imaging modality in cancer detection and
atherosclerosis study are discussed.

2. Generation of photoacoustic waves


This section covers the basics of photoacoustic imaging: the photoacoustic effect, the
requirements for the light source and absorption by blood.

2.1. Principle of the photoacoustic effect


The basic idea of the photoacoustic effect is simple. Light is shone on a sample which
absorbs a fraction of the incident energy. This energy is converted into heat. The tem-
perature rise leads to thermoelastic expansion of the object. This sudden pressure rise
propagates as a sound wave, which can be detected. By detecting the pressure waves,
we can localize their source (i.e., where light was absorbed) and obtain important in-
formation about the studied sample. This is schematized in Fig. 1.
Photoacoustic waves

Piezoelectric transducer
Incident light (detector)

Photoacoustic source

Fig. 1. Basic principle of the photoacoustic effect. Incident light is absorbed and
converted in acoustic waves by thermal expansion. The acoustic waves are de-
tected by a piezoelectric transducer.

2.2. Laser excitation


The first thing to consider is the laser excitation. To generate high frequency (short
wavelength) sound waves in the sample and thus obtain a high resolution, the laser pulse
must be shorter than both the thermal relaxation time τth and the stress relaxation time
τs respectively defined by Eqs.2 and 3.
dc2
τth = (2)
αth
where dc is the characteristic dimension of the structure of interest and αth is the thermal
diffusivity.
dc
τs = (3)
vs
where vs is the speed of sound in the tissue (≈ 1500m/s).
Considering a 15µm structure, we find τth = 1.4 × 10−3 s and τs = 1 × 10−8 s. Thus,
the excitation duration has to be shorter than 10 ns to see a 15µm object. Usual light
sources include Q-switched Nd:YAG lasers emitting at 1064 nm and frequency-doubled
Nd:YAG lasers emitting at half the wavelength, 532 nm. Typical pulse durations are 5
ns, with energy per pulse in the range of mJ. Optical Parametric Oscillators (OPO) are
also used for spectroscopic imaging, because the wavelength can be tuned. The goal is
to provide a uniform incident energy distribution, so that each section of the sample
receives the same amount of energy. To achieve this, the laser beam is widened to match
the region of interest. Usually, the beam is a few centimeters wide. Optical scattering
inside the tissue helps homogenizing the incident light distribution over the volume of
the sample.

2.3. Absorption
Blood is the major absorbent in biological tissues, as depicted in Fig. 2(b). Therefore,
the signal comes mainly from regions where there is a high concentration of blood.
Since hemoglobin linked with oxygen (oxyhemoglobin) and hemoglobin without oxygen
(deoxyhemoglobin) have different absorption spectra, careful selection of the excitation
wavelength can bring important information of the oxygenation ratio. Their respective
absorption spectra are presented in Fig. 2(a). Fig. 2(b) shows the absorption spectra of
the major absorbents in biological tissues : water, melanin and blood. This figure shows
why NIR is preferred over other wavelengths : absorption by water is minimal in this
region of the spectra, and absorption by blood is large.

Fig. 2. (a) Absorption spectra of oxyhemoglobin (HbO2) and deoxyhemoglobin


(Hb). (b) Absorption coefficients of blood, melanosomes and water.(Ref. [6],
Fig.(1).

3. Ultrasound propagation and detection


3.1. Acoustic wave propagation
Acoustic waves present many advantages compared to optical waves when propagating
in a biological tissue. Scattering is less important for acoustic waves, so the major aspect
to consider is attenuation of the sound waves. Attenuation in a medium can be modeled
by the following formula :
α = a f b [dB/cm] (4)
where a is a tissue dependent constant, 1 ≤ b ≤ 2 and f is the frequency expressed in
MHz. Many authors consider b = 1 [5], which is close to reality in many biological tissues.
It is around 1 dB cm−1 MHz−1 for most tissues, but can reach 20 dB cm−1 MHz−1
for bone, assuming b = 1. This form of attenuation affects more the higher frequency
components, and thus acts as a low-pass filter, reducing overall resolution. This presents
a trade off between resolution (high frequency) and penetration depth, which favors
lower frequencies who are less attenuated. The compromise that has to be done has
lead Ku et al. to present a multiple bandwidth system [7]. This system uses different
central frequency transducers to benefit from the different advantages. They showed
that low frequencies provide a better signal to noise ratio and that higher frequencies
lead to better resolution.
Velocity of ultrasound waves is pretty much constant at 1500m/s. Variations are typ-
ically less than 10%, and are usually not accounted for, unless the sample is highly het-
erogenous. These variations of the speed of sound are modeled by acoustic impedance,
which is related to pressure amplitude and sound velocity. Changes in velocity , even
though they are small, are responsible for reflections at interfaces and refraction. This
shows why contrast is usually poor in echography, where reflected sound waves form
the signal of interest. Large reflections occur at the interface between the crystal and
the tissue, which is why an impedance matching gel is used in echography.

3.2. Ultrasound detection


There are two main ways to detect ultrasound waves : piezoelectric crystals and optical
pressure sensors. While optical sensors provide an interesting alternative to piezoelectric
crystals, they will not be covered in this review. Complementary reading is provided in
Refs. [8, 9]. Piezoelectricity is a property of certain crystals in which a mechanical strain
generates a voltage. Therefore, piezoelectric crystals can detect the pressure variation
on a surface due to a sound wave. The voltage produced by the crystal is proportional to
the product of the amplitude of the wave and the receiving constant of the crystal. The
receiving constant g is the potential produced by a unit strain. Piezoelectric transducers
used for ultrasound imaging are mostly made of lead zirconate titanate (PZT). The
receiving constant is g = 2.5 × 10−2V m N −1 [5]. Polyvinylidene fluoride (PVDF), a
polymer film, is also used because its receiving constant g is about five times larger.
Piezoelectric crystals exhibit resonance. This resonance occurs when the wavelength
of the generated wave is half the length of the crystal LT as seen in Eq:5:
λ
LT = (5)
2
The resonant frequency can be extracted with knowledge of the velocity of sound cT in
the crystal:
cT
fT = (6)
2LT
Typical frequencies for ultrasound imaging are in the range of 1-25 MHz. Since pure
ultrasound imaging also relies on the detection of acoustic waves, significant improve-
ment has been made in this field, which can be reused for PAT. Ultrasound transducers
are designed to have a definite resonant frequency and wide band detection. This means
they are sensible to a large range of frequencies around the resonant frequency. Acoustic
waves detection can be done in two ways. A single transducer can be used and moved
along a certain detection geometry (plane, cylinder, sphere) to detect generated waves.
Alternatively, an array of transducers can eliminate the need for a mechanical move-
ment. Using an array allows faster imaging since no mechanical movement is required,
as shown by Yin et al. [10].

4. Reconstruction
4.1. Inverse problem definition
The major challenge in PAT resides in image reconstruction. Reconstruction algorithms
used in PAT mostly have already been used in other imaging modalities such as com-
puted tomography (CT), magnetic resonance imaging (MRI) and ultrasound [6]. This
challenge arises from the fact that the location of the source of the acoustic waves is
unknown. It is in fact what we wish to know. To illustrate this source problem, let’s
examine the following example [11]. How can we identify where thunder originated in
a lightning storm? Knowing the time delay between the flash of light and the hearing
of the thunder can help restrain the source in a circle. The radius of this circle is the
product of the time delay and the speed of sound. It would take three measurements to
triangulate the exact source. When many lightnings strike at the same time, it becomes
increasingly difficult to localize each source. The same inverse problem is the basis of
photoacoustic imaging. This can be seen in Fig. 3(a) where the detector sees signals
coming from a circle of radius vst. In Fig. 3(b), the N-shape of the signal shows the
densification and rarefaction sections of the pressure wave. PAT uses a reconstruction
algorithm to correlate the measurements taken with the source of the signal.

Fig. 3. (a) Source location ambiguity arises from the fact that only the time
between the laser pulse and the arrival of the pressure waves to the detector is
known. (b) Typical N-shape of the pressure waves. (Ref. [6], Fig. 2).

4.2. Reconstruction
Many different approaches have been suggested to solve the inverse problem of PAT. An-
alytic back-projection algorithm [12], finite-elements [13], Radon transform [14], Fourier
domain analysis [15, 16], diffusion equation based reconstruction [17] are all successful
methods, but they require extensive mathematical analysis to be explained. In this sec-
tion, an explanation of a widely used method named weighted delay-and-sum [18], or
synthetic aperture, is provided. The first section explains dynamic focusing with an
array of transducers. The second part explains how to use focusing to reconstruct an
image of the PA source.

4.2.1. Focusing
A flat linear array of transducers can be used to produce a focused beam or alternatively,
detect signal coming from a particular region. The obvious way to do this is to fire all
transducers at the same time and use an acoustic lens, which will act the same way as
an optical lens and focus the waves at the focal spot. The other way to do this is to
fire each transducer in the array separately with a variable delay. When the distance
between the transducer and the desired focal spot shortens, the induced delay increases.
In this way, all pulses emitted by the transducers arrive at the same time at the focal
spot. This is called electronic focusing. Reciprocally, adding a delay to the detected
signals can lead to a greater sensitivity to a particular area of the sample. This is the
basis of the delay and sum reconstruction algorithm. Focused detection is illustrated in
figure 4.

4.2.2. Delay and sum


The first part of the algorithm is to divide the imaged volume in small elements of
volume, or voxels. The distance between the detector plane and the voxel determines
the time it takes for sound to travel from the source to the detector. The time-domain
Fig. 4. The delay applied to each signal depends on the distance between the
focal spot and the transducer. Signals are coherently summed after the delay is
applied. Weighting is not shown. Delays are generally applied in post-processing.
(Ref. [10], Fig. 1).

detected signal is used to determine whether a potential PA source is present in each


voxel. The contribution of each transducer in the array is calculated for each voxel,
based on the delay and the traveling time. Each contribution receives a weighting factor
based on the directivity of the transducer [18]. Then, each weighted signal is summed
for each voxel. This forms the reconstructed volume in PAT. Directivity comes from the
fact that the detector is not equally sensible to waves depending on their direction of
propagation. This is mostly due to interference and refraction. The directivity is also
depth dependent. Optimizing the weight factors can lead to optimal signal to noise ratio
(SNR).

5. Applications
This section reviews the most promising applications of photoacoustic tomography in
medical imaging. The main application is cancer detection, which will be covered in the
first section, with a focus on breast cancer. The next section covers the identification of
atherosclerotic plaques by intravascular PAT.

5.1. Cancer detection and angiogenesis


Absorption of light by hemoglobin was previously covered in section 2.3. This mechanism
is the basis of cancer detection in PAT. To fully understand how blood vessel imaging is
useful, the mechanisms of cancerous tumors growth have to be explained. A cancerous
cell is formed when it undergoes several mutations that modify its behavior. When some
critical genes are modified, the cell does not respond to signals from other cells and can
replicate indefinitely. Generally, cell population is controlled by the body with certain
factors that cause the cells to suicide (apoptosis) when they are not needed. By not
responding to these signals, the cancerous cell will be uncontrollable. If it can replicate
indefinitely, which is not the case for most cells, it will grow to become a cancer. A
large number of cancerous cells is called a tumor. But to fuel this exponential growth,
the tumor needs nutrients and oxygen. Thus, the cancer will need more blood vessels to
supply this abnormal number of cells. The process involving the creation of new blood
vessels is called angiogenesis. This results in a large amount of blood vessels in and
around the tumor. Another important aspect to note is that, in general, there are not
enough blood vessels to fuel the entire tumor. Therefore, the overall oxygenation ratio
is lower, meaning there is more deoxyhemoglobin. This higher concentration of blood
around the cancer is used to efficiently detect it. The proof that a large signal is due to
blood was first shown by Hoelen et al. in 1998 [2]. Study of angiogenesis on rats was
performed by Siphanto et al.[19] and Ku et al.[20]. They studied the growth of a tumor
with the associated angiogenesis. As predicted, the signal intensity increases with the
growth of the tumor. Results from [19] are shown in Fig. 5. We can clearly see the
development of the tumor in the thin 150 µm slices (1-10) of the volume after 3, 7, 8
and 10 days(a-d).

Fig. 5. Thin slices of a 3D volume (1-10) performed 3 days (a), 7 days (b), 8 days
(c) and 10 days (d) after inoculation of cancerous cells on a rat. The evolution
of the tumor and associated angiogenesis can be clearly seen in (b), (c) and (d).
(Ref. [19], Fig. 3).

The use of contrast agents has also shown promising results in cancer detection. The
contrast can be enhanced by using particles that bind selectively to cancerous cells such
as nanorods [21] and carbon nanotubes [22] which show high absorption at the laser
wavelength.

5.1.1. Breast cancer detection


One woman in nine is expected to develop breast cancer in Canada [23]. Early detection
greatly increases the chances of survival. This is why mammograms are recommended
for screening and diagnosis. But the x-ray mammogram is not fail proof, and a tumor
may remain undetected. This is especially the case in dense breasts, where there is little
contrast between the breast and the actual tumor [24]. Use of ionizing radiation and
patient discomfort are unfavorable for x-ray mammography. Doppler ultrasonography is
also used to assess whether a cancer is present, but to a lesser extent. The gold standard
in cancer detection is still biopsy, but this process is long and costly. This is why it is
only used to confirm mammography results. Recent studies have reported promising
results in breast cancer detection [25, 26, 24, 27, 28] with PAT. PAT has the advantages
of being non-ionizing and requires no or mild breast compression which can make the
process more comfortable for the patients.
Oraevsky et al. [28, 29] have built an imaging system that can use two different
lasers, a Nd:YAG laser operating at 1064 nm and an alexandrite laser operating at 755
nm, and a hemicylindrical array of transducers. The choice of the laser is founded on
the difference in absorption by blood and penetration depth. As already mentionned,
NIR light can penetrate more deeply in the tissue. Deoxyhemoglobin absorbs more
in the range of 755 nm, while oxyhemoglobin absorbs more the 1064 nm light. By
imaging with these two wavelengths, quantitative information of the oxygenation ratio
can be extracted from the images. This information can be used to determine the stage
of the cancer. The hemicylindrical array was used to detect acoustic waves from a
large area on the breast. Their clinical studies involved standard mammography and
Doppler ultrasonography, followed by PAT and finally a biopsy. Fig. 6 shows in I(a) the
mammography image of a dense breast where no tumor can be seen. In I(b), we can see a
Doppler image showing enhanced blood flow in the top. (c) shows the reconstructed PA
image which clearly shows an increase in absorption, identified as a cancerous tumor.
This information was confirmed by biopsy. Fig. 6 II a), b) and c) show the presence of
a tumor confirmed by the three imaging modalities. These results show that PAT can
improve the screening process and can detect cancers that would have been missed by
X-ray mammography.

Fig. 6. I :(a) X-ray mammography of a dense breast does not show signs of a tumor;
(b) Doppler ultrasonography shows an increased blood flow(c) PAT clearly shows
a tumor; II a) X-ray mammography shows a tumor which is confirmed by the two
other imaging modalities ((b) and (c))(Ref. [29], Fig. 16-17).
5.2. Identification of atherosclerotic plaques
Atherosclerosis is a systemic disease in which lipid accumulates in arterial walls and
form atherosclerotic plaques. Inflammation also occurs and leads to an increase in blood
content in the plaque. The major complication of atherosclerosis is a rupture of the
plaque which will form a thrombus that can block blood flow in the artery, leading
to the death of the tissue fed by the artery. The vulnerability of a plaque to rupture
depends on the content of the plaque. Thus, information on the content of the plaque
will allow identification of the vulnerable plaques and take action before it ruptures. In
[30, 31, 32], a group from the University of Texas showed a new device for intravascular
photoacoustic (IVPA) using a commercial intravascular ultrasound probe, usually used
for ultrasound imaging. This probe consists of a catheter with a high frequency (40
MHz) transducer at the tip. Such high frequency can be used because the required
imaging depth is small since the plaques are usually a few millimeters thick. Ex vivo
studies on cholesterol fed rabbits show that PAT can be used to identify atherosclerotic
plaques. An artery was taken from the rabbit and immersed in water. The catheter
was inserted in the artery and laser pulses were sent on the artery from the outside.
An integrated system using an optical fiber to deliver light was proposed by Hsieh
et al. [33]. By using a frequency-doubled Nd:YAG, a decrease in signal was observed
in the lipid rich region [31]. Complementary structural information was provided by
using the probe in ultrasound mode. Further study [32] using an OPO to change the
wavelength between 680 and 900 nm showed that spectroscopic PA imaging can provide
more information. The transducer could also be used for standard ultrasound imaging.
Thus, structural and functional information can be retrieved.

6. Conclusion
A review of photoacoustic tomography was presented. While the photoacoustic phe-
nomenon has been known for a long time, photoacoustic medical imaging is a recent
domain and we have yet to see all of the possible applications. Breast cancer detection
and identification of atherosclerotic plaques are but a few of the pathologies PAT can be
applied to. PAT is being extended to the study of a number of pathologies such as trau-
matic brain injury [34], retinal diseases [35] and arthritis [36]. Furthermore, multimodal
imaging seems to be the way to improve overall diagnosis efficiency. Since no technique
is perfect, combining the advantages and contrast mechanisms of different technolo-
gies leads to more relevant information. PAT retrieves functional information related
mostly to blood concentration. Combining this with a structural imaging technique such
as ultrasound or X-ray, or novel techniques such as optical coherence tomography and
confocal microscopy will provide more efficient, faster and earlier diagnosis, all for the
well-being of the patient.

Acknowledgments
The author thanks Dr. Guy Lamouche for invaluable advices and remarks.

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