Nonlinear Ultrasonic Contrast Imaging: History and Modern Applications

1. Ultrasonic Nonlinear Imaging-Contrast Imaging

2. History • 1968 Gramiak et al published observation of echo signal from LV injection of indocyanine dye • Subsequent research showed this phenomenon occurred with just about any liquid injected through small needle

3. More History • First work was with free gas bubbles • bubbles didn’t last very long • size too big to go through lungs, needed intra-arterial injection • Late ‘80’s - early ‘90’s - development of numerous agents • more stable • smaller size

4. Motivation • X-ray, CT, nuclear, and MR all need it. • Enhance backscatter signal from blood • Blood signal typically 40dB below tissue • Provide visualization of low velocity flow normally masked by tissue motion • measure of microvasculature important in many disease states

5. Desired Properties • Non-toxic/easily eliminated • Able to be injected intravenously • Small enough to pass through microcirculation • Physically stable • Acoustically active

6. Contrast Imaging • Contrast agents are used to provide higher contrast. The three commonly seen contrast agents are backscatter, attenuation and sound velocity. • Contrast agents could be solid particles, emulsion, gas bubbles, encapsulated gas, or liquid.

7. Contrast Imaging • Primary clinical benefits: • Enhanced contrast resolution between normal and diseased tissues. • Outline of vessels or heart chambers. • Tissue characterization by using tissue specific agents. • Increasing blood flow signals. • Dynamic study using washout curve.

8. After injection Before injection Harmonic imaging Harmonic Doppler Example

9. More Examples Bubbles & Physiology Portovenous phase at 45-90 seconds Parenchymal phase at 90-120 seconds, can be up to 5 min Arterial phase starts 20-45 seconds after injection

10. Tumor Detection Liver Metastases- primary Breast Ca Post Pre High MI, Harmonic B-mode using Levovist

11. Tumor Characterization Focal Nodular Hyperplasia Coded Harmonic Angio using Levovist

12. Tumor Characterization Hepatocellular Carcinoma (HCC) Coded Harmonic Angio using Levovist

13. Tumor Characterization Low MI Harmonic using Sonovue* * Images with non-approved agents for internal GE training only

14. Tumor Detection Late Phase Early Phase Low MI Harmonic - 2 using Definity* * Images with non-approved agents for internal GE training only

15. Tumor Detection/Characterization Hemangioma Pre Post High MI Fundamental Color using Levovist

16. Tumor Detection Hemangioma?, Adenomatous Nodule? High MI Harmonic Color using Levovist

17. Clinical Values (I) • Tumor Detection • presence or absence of liver, kidney or pancreatic masses • Tumor Characterization • avascular- cyst • hypovascular- metastasis, hemangioma • hypervascular- primary carcinoma, hypervascular met • Others • enhances vessels for RAS, Carotid stenosis, TCD, etc • better visualization of thrombus (IVC, TIPS) • post ablation follow up • trauma assessment

18. Clinical Values (II) • Endocardial border detection. • Left ventricle (LV) function. • Valvular regurgitation quantification. • LV flow patterns. • Perfusion area of coronary artery. • Assessment of surgery for ventricular septal defect.

19. Clinical Values (III) • Liver tumor enhancement. • Uro-dynamics and kidney functions. • Tubal function and placenta perfusion. • Transcranial Doppler enhancement. • LV pressure measurements.

20. Current Contrast Agents • Aerosomes (ImaRx, Tucson, AZ) • Albunex (MBI, San Diego, CA) • BY963 (Byk Gulden, Konstanz, Germany) • Echovist (Schering, Berlin, Germany) • EchoGen (Sonus, Bothell, WA) • DMP115 (DuPont-Merck, N. Billerica, MA) • Imagent US (Alliance, San Diego, CA) • Levovist (Schering, Berlin, Germany) • NC100-100 (Nycomed, Oslo, Norway)

21. Current Contrast Agents (Cont.) • Optison (MBI, San Diego, CA) approved in US for cardiac • Oralex (MBI, San Diego, CA) • PESDA (Univ of Nebraska, Omaha, NE) • SonoRx (Bracco, Princeton, NJ) US approved oral agent • Sonovist (Schering, Berlin, Germany) • Sonovue (Bracco, Milan, Italy) • ST68 (Drexel Univ, Philadelphia, PA) • Quantison (Andaris, Nottingham, UK) • Quantison Depot (Andaris, Nottingham, UK) • Many more,…

22. Contrast Mechanisms • Strong backscattering produced by air bubbles. • The backscatter increases roughly linearly with the number of micro-bubbles. • A bubble in liquid acts as a harmonic oscillator. Acoustic resonance provides the major echo enhancement. In addition, strong harmonics are produced.

23. Contrast Mechanisms • Acoustic attenuation of soft tissues is typically represented by a constant (e.g., 0.5dB/cm/MHz). • Since contrast agents significantly change the scattering properties, attenuation measurements can also be used for contrast enhancement.

24. Contrast Mechanisms • Sound velocity is primarily determined by density and compressibility. Apparently, micro-bubble based contrast agents alter sound velocity. • Contrast enhancement based on sound velocity variations is still academic.

25. Contrast Mechanisms • Micro-bubbles produce strong harmonics when insonified near the resonance frequency. • If such harmonics are stronger than tissue harmonics, contrast can be improved. • Second harmonic signal is most useful due to limited transducer and system bandwidth.

26. (Encapsulated) Gas Bubbles

27. Microbubble 2–8 µm RBC 6–8 µm Bubble Characteristics • Size • Shell for stabilization • tune for desired acoustic properties • Gas • use high molecular weight, less soluble gas

28. Ultrasound-Induced Encapsulated Microbubble Phenomena • Oscillation • Translation • Coalescence • Fragmentation • Sonic cracking • Jetting • ,…

29. Optical Measurements

30. Optical Measurements

31. Optical Measurements 100 Mframes/s camera

32. Examples

33. Pressure Dependence of Expansion MI = 0.089 MI = 0.15 MI = 0.25 MI = 0.39

34. Variations in Bubbles Reaction

35. Variations in Bubbles Reaction

36. Bubble Oscillation

37. Ultrasound-Induced Oscillation • Moderate: Alternate expansions and contractions with the same amplitude and duration at low driving pressures (stable cavitation). • Violent: At higher pressures, greater bubble expansion amplitude than contraction amplitude, and relatively slow expansion followed rapid contraction (inertial or transient cavitation). • Cavitation threshold: Above which the bubble’s maximum radius is larger than twice the equilibrium radius.

38. For a particle of volume V in homogenous medium k = compressibility r = mass density p = particle m = surrounding medium Modeling • Strength of backscatter signal depends on difference in acoustic properties between two materials...

39. Modeling • Now need to include shell effects... For a shell encapsulated gas bubble of instantaneous radius R: Keff ~ elasticity of shell r = density of surrounding media dtot = total damping coefficient P(t) = incident acoustic energy Accurate only at low pressures

40. Simulations

41. Simulations Free Encapsulated

42. Simulations

43. Measurements

44. Optical Measurements MI = 0.09 MI = 0.67

45. Translation

46. Translation • Resulted from primary radiation force (pressure gradient across the bubble surface). • Maximal in contraction phase. • Used for active targeting.

47. Translation

48. Translation • Secondary radiation force: The microbubbles translate toward each other (oscillating bubbles generate spatially varying pressure fields).

49. Coalescence

50. Coalescence • Fusion of two or more bubbles. • As bubbles expand, bubble surfaces flattens and thinning occurs. • When critical thickness is reached (around 0.1 micron), bubbles rupture and merge with each other.