Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Innovation
  • Published:

Healing sound: the use of ultrasound in drug delivery and other therapeutic applications

Abstract

Ultrasound, which is routinely used for diagnostic imaging applications, is now being adopted in various drug delivery and other therapeutic applications. Ultrasound has been shown to facilitate the delivery of drugs across the skin, promote gene therapy to targeted tissues, deliver chemotherapeutic drugs into tumours and deliver thrombolytic drugs into blood clots. In addition, ultrasound has also been shown to facilitate the healing of wounds and bone fractures. This article reviews the principles and current status of ultrasound-based treatments.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A partial summary of ultrasound frequencies used for medical applications.
Figure 2: Mechanisms of cavitation-based ultrasound therapies.
Figure 3: Schematic representation of a few ultrasound-mediated therapies.

Similar content being viewed by others

Zixuan Zhao, Xinyi Chen, … Hanry Yu

References

  1. Moore, C. & Promes, S. B. Ultrasound in pregnancy. Emerg. Med. Clin. North Am. 22, 697–722 (2004).

    Article  Google Scholar 

  2. Lindner, J. R. Microbubbles in medical imaging: current applications and future directions. Nature Rev. Drug Discov. 3, 527–532 (2004).

    Article  CAS  Google Scholar 

  3. Suslick, K. S. Ultrasound: Its Chemical, Physical and Biological Effects (VCH, New York, 1988).

    Google Scholar 

  4. Pecha, R. & Gompf, B. Microimplosions: cavitation collapse and shock wave emission on a nanosecond time scale. Phys. Rev. Lett. 84, 1328–1330 (2000).

    Article  CAS  Google Scholar 

  5. Riesz, P. & Christman, C. L. Sonochemical free radical formation in aqueous solutions. Fed. Proc. 45, 2485–2492 (1986).

    CAS  PubMed  Google Scholar 

  6. Fellinger, K. & Schmidt, J. Klinik and therapies des chromischen gelenkreumatismus. Maudrich Vienna, Austria 549–552 (1954).

  7. Tezel, A., Sens, A., Tuscherer, J. & Mitragotri, S. Frequency dependence of sonophoresis. Pharm. Res. 18, 1694–1700 (2001).

    Article  CAS  Google Scholar 

  8. Mitragotri, S., Blankschtein, D. & Langer, R. Ultrasound-mediated transdermal protein delivery. Science 269, 850–853 (1995).

    Article  CAS  Google Scholar 

  9. Boucaud, A., Garrigue, M. A., Machet, L., Vaillant, L. & Patat, F. Effect of sonication parameters on transdemral delivery of insulin to hairless rats. J. Pharm. Sci. 91, 113–119 (2002).

    Google Scholar 

  10. Mitragotri, S. & Kost, J. Low-frequency sonophoresis: a review. Adv. Drug Deliv. Rev. 56, 589–601 (2004).

    Article  CAS  Google Scholar 

  11. Mitragotri, S., Edwards, D. A., Blankschtein, D. & Langer, R. A mechanistic study of ultrasonically-enhanced transdermal drug delivery. J. Pharm. Sci. 84, 697–706 (1995).

    Article  CAS  Google Scholar 

  12. Tezel, A. & Mitragotri, S. Interactions of inertial cavitation bubbles with stratum corneum lipid bilayers during low-frequency sonophoresis. Biophys. J. 85, 3502–3512 (2003).

    Article  CAS  Google Scholar 

  13. Kost, J., Mitragotri, S., Gabbay, R. A., Pishko, M. & Langer, R. Transdermal monitoring of glucose and other analytes using ultrasound. Nature Med. 6, 347–350 (2000).

    Article  CAS  Google Scholar 

  14. van Wamel, A., Bouakaz, A., Bernard, B., ten Cate, F. & de Jong, N. Radionuclide tumour therapy with ultrasound contrast microbubbles. Ultrasonics 42, 903–906 (2004).

    Article  CAS  Google Scholar 

  15. Tachibana, K. et al. Enhanced cytotoxic effect of Ara-C by low intensity ultrasound to HL-60 cells. Cancer Lett. 149, 189–194 (2000).

    Article  CAS  Google Scholar 

  16. Carmen, J. C. et al. Ultrasonic-enhanced gentamicin transport through colony biofilms of Pseudomonas aeruginosa and Escherichia coli. J. Infect. Chemother. 10, 193–199 (2004).

    Article  Google Scholar 

  17. Griffin, J. E. & Touchstone, J. C. Low-intensity phonophoresis of cortisol in swine. Phys. Ther. 48, 1336–1344 (1968).

    Article  CAS  Google Scholar 

  18. Yu, T., Huang, X., Hu, K., Bai, J. & Wang, Z. Treatment of transplanted adriamycin-resistant ovarian cancers in mice by combination of adriamycin and ultrasound exposure. Ultrason. Sonochem. 11, 287–291 (2004).

    Article  CAS  Google Scholar 

  19. Mesiwala, A. H. et al. High-intensity focused ultrasound selectively disrupts the blood–brain barrier in vivo. Ultrasound Med. Biol. 28, 389–400 (2002).

    Article  Google Scholar 

  20. Hynynen, K., McDannold, N., Vykhodtseva, N. & Jolesz, F. A. Non-invasive opening of BBB by focused ultrasound. Acta Neurochir. Suppl. 86, 555–558 (2003).

    CAS  PubMed  Google Scholar 

  21. Zderic, V., Clark, J. I. & Vaezy, S. Drug delivery into the eye with the use of ultrasound. J. Ultrasound Med. 23, 1349–1359 (2004).

    Article  Google Scholar 

  22. Zderic, V., Vaezy, S., Martin, R. W. & Clark, J. I. Ocular drug delivery using 20-kHz ultrasound. Ultrasound Med. Biol. 28, 823–829 (2002).

    Article  Google Scholar 

  23. Rapoport, N. Y., Christensen, D. A., Fain, H. D., Barrows, L. & Gao, Z. Ultrasound-triggered drug targeting of tumors in vitro and in vivo. Ultrasonics 42, 943–950 (2004).

    Article  CAS  Google Scholar 

  24. Nelson, J. L., Roeder, B. L., Carmen, J. C., Roloff, F. & Pitt, W. G. Ultrasonically activated chemotherapeutic drug delivery in a rat model. Cancer Res. 62, 7280–7283 (2002).

    CAS  PubMed  Google Scholar 

  25. Huang, S. L. & MacDonald, R. C. Acoustically active liposomes for drug encapsulation and ultrasound-triggered release. Biochim. Biophys. Acta 1665, 134–141 (2004).

    Article  CAS  Google Scholar 

  26. Kwok, C. S., Mourad, P. D., Crum, L. A. & Ratner, B. D. Self-assembled molecular structures as ultrasonically-responsive barrier membranes for pulsatile drug delivery. J. Biomed. Mater. Res. 57, 151–164 (2001).

    Article  CAS  Google Scholar 

  27. Kost, J., Leong, K. & Langer, R. Ultrasound-enhanced polymer degradation and release of incorporated substances. Proc. Natl Acad. Sci. USA 86, 7663–7666 (1989).

    Article  CAS  Google Scholar 

  28. Guzman, H. R., Nguyen, D. X., McNamara, A. J. & Prausnitz, M. R. Equilibrium loading of cells with macromolecules by ultrasound: effects of molecular size and acoustic energy. J. Pharm. Sci. 91, 1693–1701 (2002).

    Article  CAS  Google Scholar 

  29. Keyhani, K., Guzman, H. R., Parsons, A., Lewis, T. N. & Prausnitz, M. R. Intracellular drug delivery using low-frequency ultrasound: quantification of molecular uptake and cell viability. Pharm. Res. 18, 1514–1520 (2001).

    Article  CAS  Google Scholar 

  30. Sundaram, J., Mellein, B. R. & Mitragotri, S. An experimental and theoretical analysis of ultrasound-induced permeabilization of cell membranes. Biophys. J. 84, 3087–3101 (2003).

    Article  CAS  Google Scholar 

  31. Azuma, H. et al. Transfection of NFκB-decoy oligodeoxynucleotides using efficient ultrasound-mediated gene transfer into donor kidneys prolonged survival of rat renal allografts. Gene Ther. 10, 415–425 (2003).

    Article  CAS  Google Scholar 

  32. Huber, P. E. et al. Focused ultrasound (HIFU) induces localized enhancement of reporter gene expression in rabbit carotid artery. Gene Ther. 10, 1600–1607 (2003).

    Article  CAS  Google Scholar 

  33. Anwer, K. et al. Ultrasound enhancement of cationic lipid-mediated gene transfer to primary tumors following systemic administration. Gene Ther. 7, 1833–1839 (2000).

    Article  CAS  Google Scholar 

  34. Taniyama, Y. et al. Local delivery of plasmid DNA into rat carotid artery using ultrasound. Circulation 105, 1233–1239 (2002).

    Article  CAS  Google Scholar 

  35. Zarnitsyn, V. G. & Prausnitz, M. R. Physical parameters influencing optimization of ultrasound-mediated DNA transfection. Ultrasound Med. Biol. 30, 527–538 (2004).

    Article  Google Scholar 

  36. Yu, T., Wang, Z. & Mason, T. J. A review of research into the uses of low level ultrasound in cancer therapy. Ultrason. Sonochem. 11, 95–103 (2004).

    Article  CAS  Google Scholar 

  37. Tachibana, K., Uchida, T., Ogawa, K., Yamashita, N. & Tamura, K. Induction of cell-membrane porosity by ultrasound. Lancet 353, 1409 (1999).

    Article  CAS  Google Scholar 

  38. Tachibana, K., Uchida, T., Hisano, S. & Morioka, E. Eliminating adult T-cell leukaemia cells with ultrasound. Lancet 349, 325 (1997).

    Article  CAS  Google Scholar 

  39. Abe, H. et al. Targeted sonodynamic therapy of cancer using a photosensitizer conjugated with antibody against carcinoembryonic antigen. Anticancer Res. 22, 1575–1580 (2002).

    CAS  PubMed  Google Scholar 

  40. Yumita, N., Okuyama, N., Sasaki, K. & Umemura, S. Sonodynamic therapy on chemically induced mammary tumor: pharmacokinetics, tissue distribution and sonodynamically induced antitumor effect of porfimer sodium. Cancer Sci. 95, 765–769 (2004).

    Article  CAS  Google Scholar 

  41. Huang, D. et al. Ultrastructure of sarcoma 180 cells after ultrasound irradiation in the presence of sparfloxacin. Anticancer Res. 24, 1553–1559 (2004).

    CAS  PubMed  Google Scholar 

  42. Paliwal, S., Sundaram, J. & Mitragotri, S. Induction of selective cytotoxicity in skin and prostate cancer cells using quercetin and ultrasound. Br. J. Cancer 01 Feb 2005 (10.1038/sj.bjc.6602364).

  43. Rosenthal, I., Sostaric, J. Z. & Riesz, P. Sonodynamic therapy — a review of the synergistic effects of drugs and ultrasound. Ultrason. Sonochem. 11, 349–363 (2004).

    CAS  PubMed  Google Scholar 

  44. Alexandrov, A. V. et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N. Engl. J. Med. 351, 2170–2178 (2004).

    Article  CAS  Google Scholar 

  45. Daffertshofer, M. & Hennerici, M. Ultrasound in the treatment of ischaemic stroke. Lancet Neurol. 2, 283–290 (2003).

    Article  Google Scholar 

  46. Daffertshofer, M. & Fatar, M. Therapeutic ultrasound in ischemic stroke treatment: experimental evidence. Eur. J. Ultrasound 16, 121–130 (2002).

    Article  Google Scholar 

  47. Everbach, E. C. & Francis, C. W. Cavitational mechanisms in ultrasound-accelerated thrombolysis at 1 MHz. Ultrasound Med. Biol. 26, 1153–1160 (2000).

    Article  CAS  Google Scholar 

  48. Harpaz, D. Ultrasound enhancement of thrombolytic therapy: observations and mechanisms. Int. J. Cardiovasc. Intervent. 3, 81–89 (2000).

    Article  Google Scholar 

  49. Francis, C. W., Blinc, A., Lee, S. & Cox, C. Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots. Ultrasound Med. Biol. 21, 419–424 (1995).

    Article  CAS  Google Scholar 

  50. Hart, J. The use of ultrasound therapy in wound healing. J. Wound Care 7, 25–28 (1998).

    Article  CAS  Google Scholar 

  51. Mourad, P. D. et al. Ultrasound accelerates functional recovery after peripheral nerve damage. Neurosurgery 48, 1136–1140 (2001).

    CAS  PubMed  Google Scholar 

  52. Hadjiargyrou, M., McLeod, K., Ryaby, J. P. & Rubin, C. Enhancement of fracture healing by low intensity ultrasound. Clin. Orthop. 355, S216–229 (1998).

    Article  Google Scholar 

  53. Cook, S. D. et al. Improved cartilage repair after treatment with low-intensity pulsed ultrasound. Clin. Orthop. 391, S231–243 (2001).

    Article  Google Scholar 

  54. Carvalho, D. C. & Cliquet, A. The action of low-intensity pulsed ultrasound in bones of osteopenic rats. Artif. Organs 28, 114–118 (2004).

    Article  Google Scholar 

  55. Doan, N., Reher, P., Meghji, S. & Harris, M. In vitro effects of therapeutic ultrasound on cell proliferation, protein synthesis, and cytokine production by human fibroblasts, osteoblasts, and monocytes. J. Oral Maxillofac. Surg. 57, 409–419 (1999).

    Article  CAS  Google Scholar 

  56. Lagneaux, L. et al. Ultrasonic low-energy treatment: a novel approach to induce apoptosis in human leukemic cells. Exp. Hematol. 30, 1293–12301 (2002).

    Article  Google Scholar 

  57. Fitzgerald, P. J. et al. Intravascular sonotherapy decreases neointimal hyperplasia after stent implantation in swine. Circulation 103, 1828–1831 (2001).

    Article  CAS  Google Scholar 

  58. Siegel, R. J. et al. Use of therapeutic ultrasound in percutaneous coronary angioplasty. Experimental in vitro studies and initial clinical experience. Circulation 89, 1587–1592 (1994).

    Article  CAS  Google Scholar 

  59. Mourad, P. D. & Crum, L. A. A review and examination of ultrasound for lipoplasty. Clin. Plast. Surg. 26, 409–422 (1999).

    CAS  PubMed  Google Scholar 

  60. Blana, A., Walter, B., Rogenhofer, S. & Wieland, W. F. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology 63, 297–300 (2004).

    Article  Google Scholar 

  61. Kohrmann, K. U., Michel, M. S., Gaa, J., Marlinghaus, E. & Alken, P. High intensity focused ultrasound as noninvasive therapy for multilocal renal cell carcinoma: case study and review of the literature. J. Urol. 167, 2397–2403 (2002).

    Article  Google Scholar 

  62. Vaezy, S., Martin, R. & Crum, L. High intensity focused ultrasound: a method of hemostasis. Echocardiography 18, 309–315 (2001).

    Article  CAS  Google Scholar 

  63. Nyborg, W. L. Biological effects of ultrasound: development of safety guidelines. Part II: general review. Ultrasound Med. Biol. 27, 301–333 (2001).

    Article  CAS  Google Scholar 

  64. O'Brien, W. D. & Zachary, J. F. Lung damage assessment from exposure to pulsed-wave ultrasound in the rabbit, mouse, and pig. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 44, 473–448 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

S.M. acknowledges funding from Whitaker Foundation.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

S.M. is a stockholder in Sontra Medical Inc. and scientific advisor to CytoDome Inc.

Related links

Related links

FURTHER INFORMATION

American Institute of Ultrasound in Medicine

Internet Portal for Drug Delivery Information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mitragotri, S. Healing sound: the use of ultrasound in drug delivery and other therapeutic applications. Nat Rev Drug Discov 4, 255–260 (2005). https://doi.org/10.1038/nrd1662

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1662

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing