European Radiology

, Volume 16, Issue 7, pp 1557–1563 | Cite as

Microbubbles assist goat liver ablation by high intensity focused ultrasound

  • Tinghe YuEmail author
  • Xionglin Fan
  • Shuhua Xiong
  • Kai Hu
  • Zhibiao Wang


High intensity focused ultrasound (HIFU) has been introduced to treat cancers. However, this therapy is a time-consuming procedure; destructing a deeper volume is also difficult as ultrasonic energy attenuates exponentially with increasing depth in tissues. The aim of the present study was to investigate the effects of introducing microbubbles on liver HIFU ablation. Seventeen goats were divided into groups A (n=8) and B (n=9). The livers in both groups were ablated using HIFU (1.0 MHz, 22,593 W/cm2) performed in the manner of a clinical regime using a clinical device. A microbubble agent was bolus-injected intravenously before HIFU exposure in group B. All animals in group A and seven goats in group B were euthanased to evaluate the ablation efficiency 24 h after HIFU. The necrosis rate (mm3/s), which was the volume of necrosis tissue per second of HIFU exposure, was used to judge the ablation efficiency. Pathological examinations were performed to determine whether there were residual intact tissues within the exposed volume. The other two goats in group B were used to determine the delayed pathological changes 7 days after ultrasonic ablation. The necrosis rate (mm3/s) was increased in group B (14.4647±4.1960 versus 33.5302±12.4484, P=0.0059). Pathological examinations confirmed that there were no residual unaffected tissue focuses within the exposed volume. Two remarkable changes occurred in the other two goats in group B 7 days after HIFU: there were ghost-cell islands at the periphery of the ablated tissues, and surrounding adjacent tissues outside the reactive zone necrotized. These findings showed that microbubbles could be used to assist liver HIFU ablation.


High intensity focused ultrasound Liver Microbubble Ablation efficiency Delayed necrosis 



This work was funded with grants from State Ministry of Education (NCET) and Chongqing Medical University (CX 200314).

We express our sincere thanks to Ms. Tao Cheng for helping preparing the Figs. 1, 2.


  1. 1.
    Kennedy JE, Wu F, ter Haar GR, Gleeson FV, Phillips RR, Middleton MR, Cranston D (2004) High-intensity focused ultrasound for the treatment of liver tumours. Ultrasonics 42:931–935CrossRefPubMedGoogle Scholar
  2. 2.
    Wu F, Wang ZB, Chen WZ, Zhu H, Bai J, Zou JZ, Li KQ, Jin CB, Xie FL, Su HB (2004) Extracorporeal high intensity focused ultrasound ablation in the treatment of patients with large hepatocellular carcinoma. Ann Surg Oncol 11:1061–1069CrossRefPubMedGoogle Scholar
  3. 3.
    Wu F, Wang ZB, Chen WZ, Zou JZ, Bai J, Zhu H, Li KQ, Jin CB, Xie FL, Su HB (2005) Advanced hepatocellular carcinoma: treatment with high-intensity focused ultrasound ablation combined with transcatheter arterial embolization. Radiology 235:659–667PubMedCrossRefGoogle Scholar
  4. 4.
    Kennedy JE, ter Haar GR, Cranston D (2003) High intensity focused ultrasound: surgery of the future? Br J Radiol 76:590–599CrossRefPubMedGoogle Scholar
  5. 5.
    Halpern EJ (2005) High-intensity focused ultrasound ablation: will image-guided therapy replace conventional surgery? Radiology 235:345–346PubMedCrossRefGoogle Scholar
  6. 6.
    Kennedy JE (2005) High-intensity focused ultrasound in the treatment of solid tumours. Nat Rev Cancer 5:321–327CrossRefPubMedGoogle Scholar
  7. 7.
    ter Haar G (2001) Acoustic surgery. Phys Today 54(12):29–34CrossRefGoogle Scholar
  8. 8.
    Blomley MJK, Cooke JC, Unger EC, Monaghan MJ (2001) Microbubble contrast agents: a new era in ultrasound. BMJ 322:1222–1225CrossRefPubMedGoogle Scholar
  9. 9.
    Stride E, Saffari A (2003) Microbubble ultrasound agents: a review. Proc Inst Mech Eng [H] 217:429–447Google Scholar
  10. 10.
    Lindner JR (2004) Microbubbles in medical imaging: current applications and future directions. Nat Rev Drug Discov 3:527–532CrossRefPubMedGoogle Scholar
  11. 11.
    Feinstein SB (2004) The powerful microbubble: from bench to bedside, from intravascular indicator to therapeutic deliver system, and beyond. Am J Physiol Heart Circ Physiol 287:H450–H457CrossRefPubMedGoogle Scholar
  12. 12.
    Dijkmansa PA, Juffermansa LJM, Mustersb RJP, van Wamelc A, ten Catec FJ, van Gilstd W, Vissera CA, de Jong N, Kamp O (2004) Microbubbles and ultrasound: from diagnosis to therapy. Eur J Echocardiography 5:245–256CrossRefGoogle Scholar
  13. 13.
    Yu T, Wang G, Hu K, Ma P, Bai J, Wang Z (2004) A microbubble agent improves the therapeutic efficiency of high intensity focused ultrasound: a rabbit kidney study. Urol Res 32:14–19CrossRefPubMedGoogle Scholar
  14. 14.
    Yu T, Xiong S, Mason TJ, Wang Z (2006) The use of a microbubbble agent to enhance rabbit liver destruction using high intensity focused ultrasound. Ultrason Sonochem 13:143–149CrossRefPubMedGoogle Scholar
  15. 15.
    Takegami K, Kaneko Y, Watanabe T, Maruyama T, Matsumoto Y, Nagawa H (2005) Erythrocytes, as well as microbubble contrast agents, are important factors in improving thermal and therapeutic effects of high-intensity focused ultrasound. Ultrasound Med Biol 31:385–390CrossRefPubMedGoogle Scholar
  16. 16.
    Kaneko Y, Maruyama T, Takegami K, Watanabe T, Mitsui H, Hanajiri K, Nagawa H, Matsumota Y (2005) Use of a microbubble agent to increase the effects of high intensity focused ultrasound on liver tissue. Eur Radiol 15:1415–1420CrossRefPubMedGoogle Scholar
  17. 17.
    Wang W, Zhou J, Liu W, Bai L, Ye H, Gai L, Tan Y, Yang T (2002) Treatment of unresectable nodular hepatocellular carcinoma with high-intensity focused ultrasound combined transarterial oily chemoembolization: preliminary clinical outcomes. In: Andrew MA, Crum LA, Vaezy A (eds) Proceedings of 2nd International Symposium on Therapeutic Ultrasound, University of Washington, pp 44–50Google Scholar
  18. 18.
    Chen L, ter Haar G, Hill CR (1997) Influence of ablated tissue on the formation of high-intensity focused ultrasound lesions. Ultrasound Med Biol 23:921–931CrossRefPubMedGoogle Scholar
  19. 19.
    ter Haar G (1995) Ultrasound focal beam surgery. Ultrasound Med Biol 21:1089–1100CrossRefPubMedGoogle Scholar
  20. 20.
    Fry FJ (1991) Intense focused ultrasound in medicine. Eur Urol 23 (Suppl 1):2–7Google Scholar
  21. 21.
    Chapelon JY, Margonari J, Theillere Y, Gorry F, Vernier F, Blanc E, Gelet A (1992) Effects of high-energy focused ultrasound on kidney tissue in the rat and the dog. Eur Urol 22:147–152PubMedGoogle Scholar
  22. 22.
    Chen WS, Lafon C, Matula TJ, Vaezy S, Crum LA (2003) Mechanisms of lesion formation in high intensity focused ultrasound therapy. Acoust Res Lett Online 4:41–46CrossRefGoogle Scholar
  23. 23.
    Holt RG, Roy RA (2001) Measurements of bubble-enhanced heating from focused, MHz-frequency ultrasound in a tissue-mimicking material. Ultrasound Med Biol 27:1399–1412CrossRefPubMedGoogle Scholar
  24. 24.
    Umemura S, Kawabata K, Sanghvi N, Sasaki K (2002) Enhancement of ultrasonic adsorption by microbubble agent for HIFU. In: Andrew MA, Crum LA, Vaezy A (eds). Proceedings of 2nd International Symposium on Therapeutic Ultrasound, University of Washington, pp 527–538Google Scholar
  25. 25.
    Unger EC, Matsunaga TO, McCreery T, Schumann P, Sweitzer R, Quigley R (2002) Therapeutic applications of microbubbles. Eur J Radiol 42:160–168CrossRefPubMedGoogle Scholar
  26. 26.
    Fry FJ, Sanghvi NT, Foster RS, Bihrle R, Hennige C (1995) Ultrasound and microbubbles: their generation, detection and potential utilization in tissue and organ therapy-experimental. Ultrasound Med Biol 21:1227–1237CrossRefPubMedGoogle Scholar
  27. 27.
    Bailey MR, Couret LN, Sapozhnikov OA, Khokhlova VA, ter Haar G, Vaezy S, Shi X, Martin R, Crum LA (2001) Use of overpressue to asses the role of bubbles in focused ultrasound lesion shape in vitro. Ultrasound Med Biol 27:695–708CrossRefPubMedGoogle Scholar
  28. 28.
    Sokka SD, King R, Hynynen K (2003) MRI-guided gas bubble enhanced ultrasound heating in in vivo rabbit thigh. Phys Med Biol 48:223–241CrossRefPubMedGoogle Scholar
  29. 29.
    Van Leenders GJLH, Beerlage HP, Ruijter ETh, de la Rosette JJMCH, van de Kaa CA (2000) Histopathological changes associated with high intensity focused ultrasound (HIFU) treatment for localised adenocarcinoma of the prostate. J Clin Pathol 53:391–394CrossRefPubMedGoogle Scholar
  30. 30.
    Chen L, ter Haar G, Robertson D, Bensted JP, Hill CR (1999) Histological study of normal and tumor-bearing liver treated with focused ultrasound. Ultrasound Med Biol 25:847–856CrossRefPubMedGoogle Scholar
  31. 31.
    Chen L, ter Haar G, Hill CR, Dworkin M, Carnochan P, Young H, Bensted JP (1993) Effects of blood perfusion on the ablation of liver parenchyma with high-intensity focused ultrasound. Phys Med Biol 38:1661–1673CrossRefPubMedGoogle Scholar
  32. 32.
    Huber PE, Debus J (2001) Tumor cytotoxicity in vivo and radical formation in vitro depend on the shock wave-induced cavitation dose. Radiat Res 156:301–309PubMedCrossRefGoogle Scholar
  33. 33.
    Hohmann J, Albrecht T, Oldenburg A, Skrok J, Wolf KJ (2004) Liver metastases in cancer: detection with contrast-enhanced ultrasonography. Abdom Imaging 29:669–681CrossRefPubMedGoogle Scholar
  34. 34.
    Nicolau C, Brú C (2004) Focal liver lesions: evaluation with contrast-enhanced ultrasonography. Abdom Imaging 29:348–359CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Tinghe Yu
    • 1
    Email author
  • Xionglin Fan
    • 2
  • Shuhua Xiong
    • 3
  • Kai Hu
    • 1
  • Zhibiao Wang
    • 1
  1. 1.Institute of Ultrasound Engineering in MedicineChongqing Medical UniversityChongqingPeople’s Republic of China
  2. 2.Department of MicrobiologyHuazhong University of Science and Technology, Tongji Medical SchoolWuhanPeople’s Republic of China
  3. 3.Department of Gynecological OncologyJiangxi Provincial Maternal and Children’s HospitalNanchangPeople’s Republic of China

Personalised recommendations