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Abdominal Radiology

, Volume 43, Issue 4, pp 762–772 | Cite as

Imaging with ultrasound contrast agents: current status and future

  • Wui K. Chong
  • Virginie Papadopoulou
  • Paul A. Dayton
Pictorial essay
  • 656 Downloads

Abstract

Microbubble ultrasound contrast agents (UCAs) were recently approved by the Food and Drug administration for non-cardiac imaging. The physical principles of UCAs, methods of administration, dosage, adverse effects, and imaging techniques both current and future are described. UCAs consist of microbubbles in suspension which strongly interact with the ultrasound beam and are readily detectable by ultrasound imaging systems. They are confined to the blood pool when administered intravenously, unlike iodinated and gadolinium contrast agents. UCAs have a proven safety record based on over two decades of use, during which they have been used in echocardiography in the U.S. and for non-cardiac imaging in the rest of the world. Adverse effects are less common with UCAs than CT/MR contrast agents. Compared to CT and MR, contrast-enhanced ultrasound has the advantages of real-time imaging, portability, and reduced susceptibility to metal and motion artifact. UCAs are not nephrotoxic and can be used in renal failure. High acoustic amplitudes can cause microbubbles to fragment in a manner that can result in short-term increases in capillary permeability or capillary rupture. These bioeffects can be beneficial and have been used to enhance drug delivery under appropriate conditions. Imaging with a mechanical index of < 0.4 preserves the microbubbles and is not typically associated with substantial bioeffects. Molecularly targeted ultrasound contrast agents are created by conjugating the microbubble shell with a peptide, antibody, or other ligand designed to target an endothelial biomarker associated with tumor angiogenesis or inflammation. These microbubbles then accumulate in the microvasculature at target sites where they can be imaged. Ultrasound contrast agents are a valuable addition to the diagnostic imaging toolkit. They will facilitate cross-sectional abdominal imaging in situations where contrast-enhanced CT and MR are contraindicated or impractical.

Keywords

Microbubble Ultrasound contrast Review 

Notes

Compliance with ethical standards

Disclosures

Paul A. Dayton is an inventor on several patents involving microbubble technology and acoustic angiography, and is a co-founder of SonoVol, Inc. and Triangle Biotechnology, Inc, which have licensed some of these patents. Wui K Chong is on the Lumason advisory board of Bracco Diagnostics.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Huang SF, Chang RF, Moon WK, et al. (2008) Analysis of tumor vascularity using three-dimensional power Doppler ultrasound images. IEEE Trans Med Imaging 27(3):320–330PubMedCrossRefGoogle Scholar
  2. 2.
    McDonald DM, Choyke PL (2003) Imaging of angiogenesis: from microscope to clinic. Nat Med 9(6):713–725PubMedCrossRefGoogle Scholar
  3. 3.
    Lassau N, Lamuraglia M, Vanel D, et al. (2005) Doppler US with perfusion software and contrast medium injection in the early evaluation of isolated limb perfusion of limb sarcomas: prospective study of 49 cases. Ann Oncol 16(7):1054–1060PubMedCrossRefGoogle Scholar
  4. 4.
    Lindner JR, Womack L, Barrett EJ, et al. (2008) Limb stress-rest perfusion imaging with contrast ultrasound for the assessment of peripheral arterial disease severity. JACC Cardiovasc Imaging 1(3):343–350PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Darge K, Moeller RT, Trusen A, et al. (2005) Diagnosis of vesicoureteric reflux with low-dose contrast-enhanced harmonic ultrasound imaging. Pediatr Radiol 35(1):73–78PubMedCrossRefGoogle Scholar
  6. 6.
    Prefumo F, Serafini G, Martinoli C, et al. (2002) The sonographic evaluation of tubal patency with stimulated acoustic emission imaging. Ultrasound Obstet Gynecol 20(4):386–389PubMedCrossRefGoogle Scholar
  7. 7.
    Society, I.C.U. CEUS Around the World. 2017 [cited 2017 October]; Available from: http://www.icus-society.org/attachments/article/103/ICUS%20-%20CEUS%20Around%20the%20World.pdf.
  8. 8.
    Claudon M, Dietrich CF, Choi BI, et al. (2013) Guidelines and good clinical practice recommendations for Contrast Enhanced Ultrasound (CEUS) in the liver-update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM. FLAUS and ICUS. Ultrasound Med Biol 39(2):187–210PubMedCrossRefGoogle Scholar
  9. 9.
    Piscaglia F, Nolsøe C, Dietrich CF, et al. (2012) The EFSUMB Guidelines and Recommendations on the Clinical Practice of Contrast Enhanced Ultrasound (CEUS): update 2011 on non-hepatic applications. Ultraschall Med 33(1):33–59PubMedCrossRefGoogle Scholar
  10. 10.
    D’Onofrio M, Romanini L, Serra C, et al. (2016) Contrast enhancement ultrasound application in focal liver lesions characterization: a retrospective study about guidelines application (SOCEUS-CEUS survey). J Ultrasound 19(2):99–106PubMedCrossRefGoogle Scholar
  11. 11.
    Dawson P, Cosgrove D, Grainger R (1999) Textbook of contrast media. Oxford: ISIS Medical MediaGoogle Scholar
  12. 12.
    Burns PN (1996) Harmonic imaging with ultrasound contrast agents. Clin Radiol 51(1):50–55PubMedGoogle Scholar
  13. 13.
    Forsberg F, Merton DA, Liu J, et al. (1998) Clinical applications of ultrasound contrast agents. Ultrasonics 36(1–5):695–701PubMedCrossRefGoogle Scholar
  14. 14.
    Schrope BA, Newhouse VL (1993) Second harmonic ultrasonic blood perfusion measurement. Ultrasound Med Biol 19(7):567–579PubMedCrossRefGoogle Scholar
  15. 15.
    Bouakaz A, Frigstad S, Ten Cate FJ, et al. (2002) Super harmonic imaging: a new imaging technique for improved contrast detection. Ultrasound Med Biol 28(1):59–68PubMedCrossRefGoogle Scholar
  16. 16.
    van Neer PL, Danilouchkine MG, Verweij MD, et al. (2011) Comparison of fundamental, second harmonic, and superharmonic imaging: a simulation study. J Acoust Soc Am 130(5):3148–3157PubMedCrossRefGoogle Scholar
  17. 17.
    Lindsey BD, Rojas JD, Dayton PA (2015) On the relationship between microbubble fragmentation, deflation and broadband superharmonic signal production. Ultrasound Med Biol 41(6):1711–1725PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Chomas J, Dayton P, May D, Ferrara K (2002) Nondestructive subharmonic imaging. IEEE Trans Ultrason Ferroelectr FreqControl 49(7):883–892CrossRefGoogle Scholar
  19. 19.
    Forsberg F, Shi WT, Goldberg BB (2000) Subharmonic imaging of contrast agents. Ultrasonics 38(1–8):93–98PubMedCrossRefGoogle Scholar
  20. 20.
    Shankar PM, Krishna PD, Newhouse VL (1998) Advantages of subharmonic over second harmonic backscatter for contrast-to-tissue echo enhancement. Ultrasound Med Biol 24(3):395–399PubMedCrossRefGoogle Scholar
  21. 21.
    Abbott JG (1999) Rationale and derivation of MI and TI: a review. Ultrasound Med Biol 25(3):431–441PubMedCrossRefGoogle Scholar
  22. 22.
    Chomas JE, Dayton P, Allen J, et al. (2001) Mechanisms of contrast agent destruction. IEEE Trans Ultrason Ferroelectr Freq Control 48(1):232–248PubMedCrossRefGoogle Scholar
  23. 23.
    Lo AH, Kripfgans OD, Carson PL, et al. (2006) Spatial control of gas bubbles and their effects on acoustic fields. Ultrasound Med Biol 32(1):95–106PubMedCrossRefGoogle Scholar
  24. 24.
    Caskey CF, Kruse DE, Dayton PA, et al. (2006) Microbubble oscillation in tubes with diameters of 12, 25, and 195 μm. Appl Phys Lett 88(3):033902CrossRefGoogle Scholar
  25. 25.
    Thomas DH, Sboros V, Emmer M, et al. (2013) Microbubble oscillations in capillary tubes. IEEE Trans Ultrason Ferroelectr Freq Control 60(1):105–114PubMedCrossRefGoogle Scholar
  26. 26.
    Feingold S, Gessner R, Guracar IM, et al. (2010) Quantitative volumetric perfusion mapping of the microvasculature using contrast ultrasound. Invest Radiol 45(10):669–674PubMedCrossRefGoogle Scholar
  27. 27.
    Ghanem A, DeMaria AN, Lohmaier S, et al. (2007) Triggered replenishment imaging reduces variability of quantitative myocardial contrast echocardiography and allows assessment of myocardial blood flow reserve. Echocardiography 24(2):149–158PubMedCrossRefGoogle Scholar
  28. 28.
    Pollard RE, Sadlowski AR, Bloch SH, et al. (2002) Contrast-assisted destruction-replenishment ultrasound for the assessment of tumor microvasculature in a rat model. Technol Cancer Res Treat 1(6):459–470PubMedCrossRefGoogle Scholar
  29. 29.
    Cosgrove D, Eckersley R, Blomley M, et al. (2001) Quantification of blood flow. Eur Radiol 11(8):1338–1344PubMedCrossRefGoogle Scholar
  30. 30.
    Wei K, Jayaweera AR, Firoozan S, et al. (1998) Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation 97(5):473–483PubMedCrossRefGoogle Scholar
  31. 31.
    Jakobsen JA, Oyen R, Thomsen HS, Morcos SK, Members of Contrast Media Safety Committee of European Society of Urogenital Radiolog (2005) Safety of ultrasound contrast agents. Eur Radiol 15(5):941–945PubMedCrossRefGoogle Scholar
  32. 32.
    Wei K, Mulvagh SL, Carson L, et al. (2008) The safety of deFinity and Optison for ultrasound image enhancement: a retrospective analysis of 78,383 administered contrast doses. J Am Soc Echocardiogr 21(11):1202–1206PubMedCrossRefGoogle Scholar
  33. 33.
    Hynynen K, McDannold N, Sheikov NA, Jolesz FA, Vykhodtseva N (2005) Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. Neuroimage 24(1):12–20PubMedCrossRefGoogle Scholar
  34. 34.
    Piscaglia F, Bolondi L (2006) The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations. Ultrasound Med Biol 32(9):1369–1375PubMedCrossRefGoogle Scholar
  35. 35.
    Kusnetzky LL, Khalid A, Khumri TM, et al. (2008) Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent: results in 18,671 consecutive studies. J Am Coll Cardiol 51(17):1704–1706PubMedCrossRefGoogle Scholar
  36. 36.
    Main ML, Ryan AC, Davis TE, et al. (2008) Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients). Am J Cardiol 102(12):1742–1746PubMedCrossRefGoogle Scholar
  37. 37.
    Abdelmoneim SS, Bernier M, Scott CG, et al. (2009) Safety of contrast agent use during stress echocardiography: a 4-year experience from a single-center cohort study of 26,774 patients. JACC Cardiovasc Imaging 2(9):1048–1056PubMedCrossRefGoogle Scholar
  38. 38.
    Parker JM, Weller MW, Feinsteinz LM, et al. (2013) Safety of ultrasound contrast agents in patients with known or suspected cardiac shunts. Am J Cardiol 112(7):1039–1045PubMedCrossRefGoogle Scholar
  39. 39.
    Bracco Diagnostics (2017) Lumason Prescribing informationGoogle Scholar
  40. 40.
    GE Healthcare (2012) Optison Prescribing informationGoogle Scholar
  41. 41.
    Haqshenas SR, Ford IJ, Saffari N (2016) Modelling the effect of acoustic waves on nucleation. J Chem Phys 145(2):024315PubMedCrossRefGoogle Scholar
  42. 42.
    Marquet F, Teichert T, Wu SY, et al. (2014) Real-time, transcranial monitoring of safe blood-brain barrier opening in non-human primates. PLoS ONE 9(2):e84310PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Karshafian R, Bevan PD, Williams R, Samac S, Burns PN (2009) Sonoporation by ultrasound-activated microbubble contrast agents: effect of acoustic exposure parameters on cell membrane permeability and cell viability. Ultrasound Med Biol 35(5):847–860PubMedCrossRefGoogle Scholar
  44. 44.
    Ferrara K, Pollard R, Borden M (2007) Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery. Annu Rev Biomed Eng 9:415–447PubMedCrossRefGoogle Scholar
  45. 45.
    Price RJ, Skyba DM, Kaul S, Skalak TC (1998) Delivery of colloidal, particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound. Circulation 98(13):1264–1267PubMedCrossRefGoogle Scholar
  46. 46.
    Miller DL, Quddus J (2000) Diagnostic ultrasound activation of contrast agent gas bodies induces capillary rupture in mice. Proc Natl Acad Sci USA 97(18):10179–10184PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Shigeta K, Itoh K, Ookawara S, Taniguchi N, Omoto K (2004) Endothelial cell injury and platelet aggregation induced by contrast ultrasonography in the rat hepatic sinusoid. J Ultrasound Med 23(1):29–36PubMedCrossRefGoogle Scholar
  48. 48.
    Burgess A, Hynynen K (2016) Microbubble-assisted ultrasound for drug delivery in the brain and central nervous system. Adv Exp Med Biol 880:293–308PubMedCrossRefGoogle Scholar
  49. 49.
    Caskey CF (2017) Ultrasound molecular imaging and drug delivery. Mol Imaging Biol 19(3):336–340PubMedCrossRefGoogle Scholar
  50. 50.
    Dimcevski G, Kotopoulis S, Bjånes T, et al. (2016) A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer. J Control Release 243:172–181PubMedCrossRefGoogle Scholar
  51. 51.
    Alexandrov AV (2006) Ultrasound enhanced thrombolysis for stroke. Int J Stroke 1(1):26–29PubMedCrossRefGoogle Scholar
  52. 52.
    Kutty S, Xie F, Gao S, et al. (2010) Sonothrombolysis of intra-catheter aged venous thrombi using microbubble enhancement and guided three-dimensional ultrasound pulses. J Am Soc Echocardiogr 23(9):1001–1006PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Jiang N, Xie B, Zhang X, et al. (2014) Enhancing ablation effects of a microbubble-enhancing contrast agent (“SonoVue”) in the treatment of uterine fibroids with high-intensity focused ultrasound: a randomized controlled trial. Cardiovasc Intervent Radiol 37(5):1321–1328PubMedCrossRefGoogle Scholar
  54. 54.
    Kopechek JA, Park EJ, Zhang YZ, et al. (2014) Cavitation-enhanced MR-guided focused ultrasound ablation of rabbit tumors in vivo using phase shift nanoemulsions. Phys Med Biol 59(13):3465–3481PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Moyer LC, Timbie KF, Sheeran PS, et al. (2015) High-intensity focused ultrasound ablation enhancement in vivo via phase-shift nanodroplets compared to microbubbles. J Ther Ultrasound 3:7PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    ter Haar G (2009) Safety and bio-effects of ultrasound contrast agents. Med Biol Eng Comput 47(8):893–900PubMedCrossRefGoogle Scholar
  57. 57.
    AIUM (2015) Statement on Mammalian Biological Effects in Tissues with Naturally Occurring Gas BodiesGoogle Scholar
  58. 58.
    B.M.S. (2008) Definity package insertGoogle Scholar
  59. 59.
    Sontum PC (2008) Physicochemical characteristics of Sonazoid, a new contrast agent for ultrasound imaging. Ultrasound Med Biol 34(5):824–833PubMedCrossRefGoogle Scholar
  60. 60.
    Gessner R, Dayton PA (2010) Advances in molecular imaging with ultrasound. Mol Imaging 9(3):117–127PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Lindner JR (2004) Molecular imaging with contrast ultrasound and targeted microbubbles. J Nucl Cardiol 11(2):215–221PubMedCrossRefGoogle Scholar
  62. 62.
    Smeenge M, Tranquart F, Mannaerts CK, et al. (2017) First-in-human ultrasound molecular imaging with a VEGFR2-specific ultrasound molecular contrast agent (BR55) in prostate cancer: a safety and feasibility pilot study. Invest Radiol 52(7):419–427PubMedCrossRefGoogle Scholar
  63. 63.
    Willmann JK, Bonomo L, Testa AC, et al. (2017) Ultrasound molecular imaging with BR55 in patients with breast and ovarian lesions: first-in-human results. J Clin Oncol 35(19):2133–2140PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Zhou J, Wang H, Zhang H, et al. (2016) VEGFR2-targeted three-dimensional ultrasound imaging can predict responses to antiangiogenic therapy in preclinical models of colon cancer. Cancer Res 76(14):4081–4089PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Streeter JE, Gessner RC, Tsuruta J, et al. (2011) Assessment of molecular imaging of angiogenesis with three-dimensional ultrasonography. Mol Imaging 10(6):7290CrossRefGoogle Scholar
  66. 66.
    Sirsi SR, Flexman ML, Vlachos F, et al. (2012) Contrast ultrasound imaging for identification of early responder tumor models to anti-angiogenic therapy. Ultrasound Med Biol 38(6):1019–1029PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Deshpande N, Lutz AM, Ren Y, et al. (2012) Quantification and monitoring of inflammation in murine inflammatory bowel disease with targeted contrast-enhanced US. Radiology 262(1):172–180PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Villanueva FS, Lu E, Bowry S, et al. (2007) Myocardial ischemic memory imaging with molecular echocardiography. :Circulation 115(3):345–352PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Abou-Elkacem L, Bachawal SV, Willmann JK (2015) Ultrasound molecular imaging: moving toward clinical translation. Eur J Radiol 84(9):1685–1693PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Gessner R, Lukacs M, Lee M, et al. (2010) High-resolution, high-contrast ultrasound imaging using a prototype dual-frequency transducer: in vitro and in vivo studies. Trans Ultrason Ferroelectr Freq Control 57(8):1772–1781CrossRefGoogle Scholar
  71. 71.
    Hu X, Zheng H, Kruse DE, et al. (2010) A sensitive TLRH targeted imaging technique for ultrasonic molecular imaging. IEEE Trans Ultrason Ferroelectr Freq Control 57(2):305–316PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Shelton SE, Lee YZ, Lee M, et al. (2015) Quantification of microvascular tortuosity during tumor evolution using acoustic angiography. Ultrasound Med Biol 41(7):1896–1904PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Shelton SE, Lindsey BD, Dayton PA, Lee YZ (2017) First-in-human study of acoustic angiography in the breast and peripheral vasculature. Ultrasound Med Biol 43(12):2939–2946PubMedCrossRefGoogle Scholar
  74. 74.
    Leow CH, Bazigou E, Eckersley RJ, et al. (2015) Flow velocity mapping using contrast enhanced high-frame-rate plane wave ultrasound and image tracking: methods and initial in vitro and in vivo evaluation. Ultrasound Med Biol 41(11):2913–2925PubMedCrossRefGoogle Scholar
  75. 75.
    Lin F, Shelton SE, Espíndola D, et al. (2017) 3-D ultrasound localization microscopy for identifying microvascular morphology features of tumor angiogenesis at a resolution beyond the diffraction limit of conventional ultrasound. Theranostics 7(1):196–204PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Errico C, Pierre J, Pezet S, et al. (2015) Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging. Nature 527(7579):499–502PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Wui K. Chong
    • 1
  • Virginie Papadopoulou
    • 3
  • Paul A. Dayton
    • 2
    • 3
  1. 1.Department of Diagnostic RadiologyUniversity of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.UNC Biomedical Research Imaging CenterChapel HillUSA
  3. 3.UNC-NC State Joint Department of Biomedical EngineeringChapel HillUSA

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