Contrast Agents for Enhanced Ultrasound Imaging and for

Transcription

1 Contrast Agents for Enhanced Ultrasound Imaging and for Drug Delivery Sverre Holm INSTITUTT FOR INFORMATIKK SH, 1

2 Microbubbles bbl (white) red blood cells (black) 2-6 m diameter Shell of biocompatible material Filled with gas Quaia 2007 INSTITUTT FOR INFORMATIKK SH, 2

3 Contrast agents classified according to the filling gas (Quaia 2007) INSTITUTT FOR INFORMATIKK SH, 3

4 Applications Enhanced Imaging Gene and Drug Delivery INSTITUTT FOR INFORMATIKK SH, 4

5 Linear and non-linear response Microbubbles show a linear physical Microbubbles show a non-linear response if the behavior at very low acoustic power since acoustic power of insonation is progressively the microbubble radius presents a degree increased at the resonance frequency (b) and the of compression during the positive phase degree of microbubble expansion is greater than that is equal to the degree of expansion its compression. This nonlinear response to the during the negative phase (a). insonation determines the production of harmonic frequencies, Quaia 2007 INSTITUTT FOR INFORMATIKK SH, 5

6 Contrast-specific specific ultrasound techniques Pulse Inversion Cadence Contrast Pulse Sequencing INSTITUTT FOR INFORMATIKK SH, 6

7 Pulse Inversion Principle of Pulse Inversion. Two sequential 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 resulting sum is zero. For non-linear media (c) such as microbubbles, the echoes will not be inverted copies, and the sum is not zero Quaia 2007 INSTITUTT FOR INFORMATIKK SH, 7

8 Pulse Inversion (Ferrara et al, 2007) INSTITUTT FOR INFORMATIKK SH, 8

9 Cadence Contrast Pulse Sequencing Principle of Cadence Contrast Pulse Sequencing. Three pulses are transmitted along each line (a), and the first and the third are half in the amplitude in comparison with the second pulse, presenting an opposed phase with respect to the others, and the returning echoes are summed. 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) INSTITUTT FOR INFORMATIKK SH, 9

10 Liver hepatocellular carcinoma (Quaia 2007) INSTITUTT FOR INFORMATIKK SH, 10

11 Liver metastatis (Quaia 2007) INSTITUTT FOR INFORMATIKK SH, 11

12 Spleen nodular lymphoma Quaia 2007 Lymfekreft INSTITUTT FOR INFORMATIKK SH, 12

13 Kidney - carcinoma Contrast enhancement after 30 sec Loss of intensity after 90 sec INSTITUTT FOR INFORMATIKK SH, 13

14 Kidney, power Doppler (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) 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 interlobular vessels (arrows). A=aorta. Ferrara et al, 2007 INSTITUTT FOR INFORMATIKK SH, 14

15 Destruction- replenishment Ultrasound contrast t agent is freely circulating in the vasculature. In a destruction-replenishment replenishment scheme, a strong ultrasound pulse destroys the agent in the imaging g plane. Low-pressure pulses are then used to observe the contrast agent returning to the imaging plane. INSTITUTT FOR INFORMATIKK SH, 15

16 Kidney: Destruction - replenishment (a) A destructive pulse destroys all contrast agents in this rat kidney. (b) Contrast cadence pulse sequencing (CPS) visualizes contrast replenishment into the kidney at 2 s while negating most signal from regional tissue. (c) ) Contrast is refilling the kidney vasculature at 12 s and (d ) 30 s after the destructive pulse. Time-intensity i it curves can be generated from any part of the kidney. INSTITUTT FOR INFORMATIKK SH, 16

17 Abdominal aorta (Quaia, 2007) Imaging of contrast leakage in aortic aneurysm rupture and endoleaks (Fig. 11) after endovascular abdominal aorta repair INSTITUTT FOR INFORMATIKK SH, 17

18 Local drug delivery (a) Ultrasound contrast agents are freely circulating in small vessels along with drug particles (blue). Once a sufficiently strong ultrasound pulse is applied to the area, the contrast agent expands rupturing the endothelial lining. Drug is then able to extravasate. (b) Drug-laden ultrasound contrast agents are freely circulating throughout the vasculature. A pulse of ultrasound is applied and ruptures the contrast agent, thereby liberating the drug payload. Because ultrasound is only applied in the region of interest, drug is preferentially delivered locally. (c) Drug-laden ultrasound contrast agents baring surface ligands targeted to specific endothelial receptors are freely circulating. 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. Ferrara et al 2007 INSTITUTT FOR INFORMATIKK SH, 18

19 References Emilio Quaia, "Microbubble ultrasound contrast agents: an update. " European radiology 17.8 (2007): Katherine Ferrara, Rachel Pollard, and Mark Borden. "Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery." Annu. Rev. Biomed. Eng. 9 (2007): 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. INSTITUTT FOR INFORMATIKK SH, 20