Contrast
enhanced ultrasound, CEU
Nico A.M. Schellart, Dept. of Med. Physics, AMC
Principle
CEU is
administrating gas-filled microbubbles
intravenously to the systemic circulation in echography. Microbubbles in fluid and
subjected to an ultrasound
field show compressions and rarefactions, so they oscillate strongly and
consequently reflect the waves. They are highly echogenetic, due to the large acoustic impedance
difference between gas and liquid. There characteristic echo generates the
strong and unique echogram in contrast enhanced ultrasound. CEU can be used to
image blood perfusion and flow rate in organs.
Bubbles in blood are thought to be covered by a surfactant of blood-macromolecules. However, often bubbles
with an artificial skin (coating, e.g. phospholipids) are injected. This
coating also improves stability and prevents dissolution.
The gas core, the contrast
agents, is the most important part of the ultrasound contrast signal and determines
the echogenicity. They lower the threshold for cavitation (the collapse of the
bubble during rarefaction). The reflected signal as well as the signal emitted
during cavitation can be used.
Common practiced gases are of N2, or heavy gases like
sulfurhexafluoride (F6S), perfuorocarbon and octafluoropropane,
which are all inert. Heavy gases are less water-soluble so they leak less to
the medium, guarantying long lasting echogenicity. Regardless of the shell or
gas core composition, microbubble size is fairly uniform, ranging 1-4 μm in diameter. F6S
bubbles have a mean of 2,5 μm and 90%<6 μm. With these sizes, they
flow easily through the microcirculation.
Selection of shell material determines how easily the microbubble is
taken up and how long the bubbles survive.
Targeting ligands that bind to receptors
characteristic of intravascular diseases can be conjugated to themicrobubble
skin, enabling the microbubble complex to accumulate selectively in areas of
interest. However, the targeted technique has not yet been approved for
clinical use; it is currently under preclinical research and development.
Genetic drugs can incorporated into
ultrasound contrast agents. Genebearing microbubbles can be injected IV and
ultrasound energy applied to the target region. As the microbubbles enter the
region of insonation, the microbubbles cavitate, locally releasing DNA. Cavitation
also likely causes a local shockwave that improves cellular uptake of DNA. By
manipulating ultrasound energy, cavitation and so delivery can be visualized in
the vessels with bubbles. Imaging can be performed before, just after IV and
during cavitation, each with a different energy, to control the process of
delivery.
Applications
Untargeted
CEU is currently applied in echocardiography.
Microbubbles
can enhance the contrast at the interface between the tissue and blood. When
used in conjunction with Doppler (see Doppler principle)
Ultrasound, microbubbles can measure myocardial flow rate to diagnose valve
problems. The relative intensity of the microbubble echoes can also provide a
quantitative estimate on blood volume.
In vascular medicine, bubbles visualize perfusion. Therefore this
technique is crucial for tracking down a
and so stenosis.
Targeted CEU is being developed for a variety of
medical applications. Microbubbles targeted with ligands are injected
systemically in a small bolus. The ligands bind to certain molecular markers
that are expressed by the area of imaging interest Microbubbles theoretically
travel through the circulatory system, eventually finding their respective
targets and binding specifically. Ultrasound waves can then be directed on the
area of interest.
Specific applications are to visualize for instance inflammatory
organs (Crohn’s disease, arteriosclerosis, heart attacks).
Microbubbles-targeted ligands can bind receptors like VEGF to depress
angiogenesis in areas of cancer. Detection of bound targeted microbubbles may
show the area of expression. This can be indicative of a certain disease state,
or may identify particular cells in the area of interest.
Drugs
can be incorporated into the microbubble’s lipid shell. The microbubble’s large
size relative to other drug delivery vehicles like liposomes may allow a
greater amount of drug to be delivered per vehicle. By targeted the drug-loaded
microbubble with ligands that bind to a specific cell type, microbubble will
not only deliver the drug specifically, but can also provide verification that
the drug is delivered if the area is imaged using ultrasound. Local drug delivery
is used for angiogenesis, vascular remodeling andr tumor destruction.
The
force associated with the bursting may temporarily permeabilize surrounding
tissues and allow the DNA to more easily enter the cells. This can further be
facilitated by coating materials of the
shell, e.g. liposomes, positively charged polymers, and viruses (as they do
already for millions of years for delivering genetic materials into living
cells).
More info
Gas bubbles in a liquid are characterized by a resonance frequency f,
which is directly related to their diameter R0. f can
by approximated (liquid surface tension not included; S. De, 1987) by:
(1)
with γ the specific heat ratio of the gas (=1.40 for N2;
see Gas laws), ρl the
liquid density (=1050 kg/m3 for blood) and P0 the ambient
pressure (here 114.7 kPa). With R0=2.5
μm, f is about
Fig. 1 Different MIs produce different reflected spectra.
Micro-bubbles oscillate (expand and contract) in the ultrasound field.
The pattern and nature of their oscillation, and thus the nature of the
backscatter signal, differs, depending on the transmitted acoustic power. The
power of the ultrasound field is expressed as the mechanical index (MI; see Ultrasound). With very low MI
(< 0.1), micro bubbles demonstrate linear oscillation (reflected frequency
equals impeding frequency). Low MIs (0.1 – 0.6), generates nonlinear oscillation of the
micro bubble whereby expansion is greater than contraction. In addition to the
usual backscatter of the fundamental frequency, the bubbles also produce
backscatter of harmonics (see Signal analysis and Fourier). When exposed to high MI
(> 0.6, i.e. the MI used for standard imaging) the bubbles oscillate wildly
and burst. Upon destruction, micro-bubbles produce a brief, high amplitude
signal, with good resolution, which is rich in harmonic signals, containing
backscatter at the second third and fourth harmonics etc (Fig.
1).
The most important limitation of this technique is motion artifact from
tissue, because tissue motion will be expressed like bubble destruction,
potentially showing perfusion when none is present (a false negative). If
Doppler frequency is increased, pulse separation is reduced, so tissue movement
between pulses can be minimized. However, if the pulses are too close, not all
the gas within the bubble will have dissipated before arrival of the next
pulse, so the difference between pulses is reduced, possibly leading to false
positive perfusion defects. Air-filled micro-bubbles are optimal for this
technique because of rapid dissipation of the gas, allowing closely spaced
pulses.
There are several high MI techniques, some developed for the moving
myocard.
Triggered harmonic imaging
Intermittent high power imaging can improve imaging, with the best
opacification obtained using intermittent harmonic imaging. During intermittent
high power imaging, high energy ultrasound is transmitted at specified
intermittent intervals, triggered to the ECG (e.g. 1 of 4 cardiac cycles). The time between destructive
pulses allows the micro-bubbles to replenish the myocardium. With each
destructive pulse, high amplitude backscatter rich in harmonics is returned to
the transducer, enabling static images of myocardial perfusion.
Fig. 2 From top to
bottom: Base imaging, no bubbles; contrast, bubbles; subtracted, echo’s
subtracted; gray-scale, color coded.
Pulse Inversion Doppler
Another grey scale high MI technique is pulse-inversion imaging whereby
two synchronized beams of pulses impinging onto the myocardium. The second
pulse sent is a mirror image of the first (i.e. 180° phase shift). The scanner
processes the echo’s of two types of pulses by adding them together. When the
bubbles generate a linear echo, the addition of one pulse to the other should
cancel out to zero and no signal is generated. However, micro-bubbles produce
non-linear echo signals at high MI and the summation of returning pulses will
not equal zero.
Using this technique, processing can theoretically be limited only to
signals generated by bubbles and not by other objects. However, tissue motion artefacts are a major
limitation, as movement of tissue also creates non-linear signals.
More specific applications can be found in ref. 5.
Physical advantages of CEU
Ø Ultrasonic
molecular imaging is safer than molecular imaging modalities such as radionuclide
imaging.
Ø Since
microbubbles can generate such strong signals, a lower intravenous dosage is
possible; micrograms compared to milligrams for other molecular imaging
modalities such as MRI contrast agents.
Physical disadvantages of CEU
Ø Ultrasound
produces more heat as f increases, so f must be carefully
monitored.
Ø Equipment
settings are subjected to safety indexes (see Ultrasound).
Increasing ultrasound energy increases image quality, but microbubbles can be
destructed, resulting in microvasculature ruptures and hemolysis.
Ø Low targeted
microbubble adhesion efficiency, which means a small fraction of injected
microbubbles bind to the area of interest.
Literature
1 De S. On the oscillations of bubbles in body fluids. J Acoust Soc.
Amer, 1987, 81, 56-567.
2 Postma, M., Bouakaz A., Versluis M. and de Jong, N. IEEE T Ultrason
Ferr, 2005,
3 http://en.wikipedia.org/wiki/Contrast_enhanced_ultrasound
4 http://e-collection.ethbib.ethz.ch/ecol-pool/diss/fulltext/eth15572.pdf
5 http://www.cardiovascularultrasound.com/content/