contrast agents for enhanced ultrasound imaging and for ... · a pulse of ultrasound is applied (c)...

UNIVERSITETET I OSLO

Contrast Agents for gEnhanced Ultrasound Imaging and for

Drug DeliveryDrug DeliverySverre Holm

INSTITUTT FOR INFORMATIKK SH, 1


Mi b bbl ( hit )Microbubbles (white) –red blood cells (black)( )

• 2-6 m diameter• Shell of biocompatible

material• Filled with gas

• Quaia 2007



Contrast agents classified according to the filling gas (Quaia 2007)to the filling gas (Quaia 2007)



ApplicationsApplications• Enhanced Imaging• Gene and Drug Delivery



Linear and non-linear responseLinear and non linear response

• Microbubbles show a non-linear response if the• Microbubbles show a linear physical • Microbubbles show a non-linear response if the acoustic power of insonation is progressively increased at the resonance frequency (b) and the degree of microbubble expansion is greater than its compression. This nonlinear response to the

• Microbubbles show a linear physical behavior at very low acoustic power since the microbubble radius presents a degree of compression during the positive phase that is equal to the degree of expansion


insonation determines the production of harmonic frequencies,

• Quaia 2007

during the negative phase (a).


Contrast-specific ultrasound techniquesContrast specific ultrasound techniques• Pulse Inversion• Cadence Contrast Pulse Sequencing



Pulse InversionPulse Inversion• Principle of Pulse Inversion. Two

sequential US waves that aresequential US waves that are inverted replicas of each other are transmitted into tissue (a), and the resulting echoes are summed.

• For a linear medium (b) the echoes from the two waves are inverted copies of each other, and the

lti iresulting sum is zero. • For non-linear media (c) such as

microbubbles, the echoes will not be inverted copies and the sum isbe inverted copies, and the sum is not zero

• Quaia 2007


UNIVERSITETET I OSLO Pulse InversionPulse Inversion

(Ferrara et al, 2007)



Cadence Contrast Pulse SequencingCadence Contrast Pulse Sequencing• Principle of Cadence Contrast Pulse

Sequencing. Three pulses are Seque c g ee pu ses a etransmitted along each line (a), and the first and the third are half in the amplitude in comparison with the second pulse, presenting ansecond pulse, presenting an opposed phase with respect to the others, and the returning echoes are summed. F li di (b) th lti• For a linear medium (b) the resulting sum is zero,

• while for a non-linear medium such as microbubbles the sum is not zero both for the non-linear fundamental (c) and non-linear harmonic frequencies (d)



Liver – hepatocellular carcinoma (Quaia 2007)


UNIVERSITETET I OSLO Liver – metastatis (Quaia 2007)Liver metastatis (Quaia 2007)



Spleen nodularlymphomalymphomaQuaia 2007• Lymfekreft


UNIVERSITETET I OSLO Kidney carcinomaKidney - carcinoma

Contrast enhancement after 30 secLoss of intensity after 90 sec


UNIVERSITETET I OSLO Kidney, power Dopplery, p pp

• (a) B-mode ultrasound image of the left kidney of a 9-week-old mouse (bar=0 5 cm) (b) The same kidney as in (a) isold mouse (bar=0.5 cm). (b) The same kidney as in (a) is shown following intravenous administration of ultrasound contrast and application of power Doppler. Notice that the kidney vasculature is visualized to the level of the


kidney vasculature is visualized to the level of the interlobular vessels (arrows). A=aorta. Ferrara et al, 2007


Destruction-l i h treplenishment

Ult d t t t i• Ultrasound contrast agent is freely circulating in the vasculature.

• In a destruction replenishment• In a destruction-replenishment scheme, a strong ultrasound pulse destroys the agent in the imaging plane. g g p

• Low-pressure pulses are then used to observe the contrast agent returning to the imaging plane.



Kidney: Destruction - replenishmentKidney: Destruction replenishment• (a) A destructive pulse destroys

all contrast agents in this rat a co as age s s akidney.

• (b) Contrast cadence pulse sequencing (CPS) visualizes contrast replenishment into thecontrast replenishment into the kidney at 2 s while negating most signal from regional tissue.

• (c) Contrast is refilling the kidney ( ) g yvasculature at 12 s and

• (d ) 30 s after the destructive pulse. Ti i t it b• Time-intensity curves can be generated from any part of the kidney.


UNIVERSITETET I OSLO Abdominal aorta (Quaia 2007)Abdominal aorta (Quaia, 2007)

Imaging of contrast leakage in aortic aneurysm rupture

d d l kand endoleaks (Fig. 11) after endovascularendovascular abdominal aorta repairrepair


UNIVERSITETET I OSLO Local drug delivery

(a) Ultrasound contrast agents are freely circulating in small vessels along with drug particles (blue). Once a sufficiently strong ultrasound

(b) Drug-laden ultrasound contrastagents are freely circulating throughout the vasculature. A pulse of ultrasound is applied

(c) Drug-laden ultrasound contrast agents baring surface ligands targeted to specific endothelial receptors are freely circulating. The ligand preferentially binds the ultrasoundsufficiently strong ultrasound

pulse is applied to the area, the contrast agent expands rupturing the endothelial lining. Drug is then able to extravasate.

and ruptures the contrast agent, thereby liberating the drug payload. Because ultrasound is only applied in the region of interest drug is preferentially

The ligand preferentially binds the ultrasound contrast agent in the target region, increasing local agent accumulation. An ultrasound pulse is then applied liberating the drug payload.

F t l 2007


interest, drug is preferentially delivered locally.

Ferrara et al 2007


ReferencesReferences• Emilio Quaia, "Microbubble ultrasound contrast agents: an

update " European radiology 17 8 (2007): 1995 2008update. European radiology 17.8 (2007): 1995-2008.• Katherine Ferrara, Rachel Pollard, and Mark Borden.

"Ultrasound microbubble contrast agents: fundamentals and li ti t d d d li " A R Bi dapplication to gene and drug delivery." Annu. Rev. Biomed.

Eng. 9 (2007): 415-447. • Shengping Qin, Charles F. Caskey, and Katherine W.

Ferrara. "Ultrasound contrast microbubbles in imaging and therapy: physical principles and engineering." Physics in medicine and biology 54.6 (2009): R27.


contrast agents for enhanced ultrasound imaging and for ... · a pulse of ultrasound is applied (c)...

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