Nucleation, mapping and control of cavitation for drug delivery

Abstract

Acoustically driven bubbles produce a range of mechanical, thermal and chemical effects that can be exploited in drug delivery applications. Significant improvements in the targeting, distribution and efficacy of both current and emerging therapeutics can be achieved, from small molecules to biologics and nucleic-acid-based drugs. This Review describes how specially designed cavitation nuclei in the form of solid, liquid or gas particles can enable the triggered release of drugs, promote the permeabiliziation of challenging biological barriers and enhance drug delivery through tissue regions where diffusion alone is inadequate. Scalable strategies for mapping and controlling cavitation activity to harness its therapeutic potential at depth within the body are discussed, alongside current and emerging applications for the treatment of diseases, including cancer and stroke.

Key points

  • A major challenge in the treatment of diseases such as cancer and stroke is achieving a sufficient concentration of a drug throughout the target region without producing toxic side effects elsewhere in the body.

  • Oscillating microbubbles driven by ultrasound produce a range of mechanical, thermal and chemical effects that can be used to enable both localized delivery and improved distribution of drugs in tissue.

  • This approach can be used to deliver both conventional small-molecule drugs and more recent biological therapeutics to areas of the body that are normally inaccessible, including across the blood–brain barrier and into solid tumours.

  • Ultrasound-responsive microparticles and nanoparticles can either be used as drug carriers or co-administered with a free drug into the bloodstream, providing cavitation nuclei that reduce the ultrasound pressures required to achieve effective drug delivery.

  • The production of strong acoustic emissions during cavitation-enhanced delivery enables acoustic localization and mapping of bubble activity in real time for treatment monitoring.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Schematic of barriers to drug delivery from the tissue to the intracellular scale.
Fig. 2: Illustration of key cavitation-mediated phenomena exploited in drug delivery.
Fig. 3: Schematic of the different mechanisms of cavitation nucleation.
Fig. 4: Oncological, brain, cardiovascular and transdermal applications of microbubble-enhanced drug delivery.
Fig. 5: Challenges and future directions for applications of acoustic cavitation.

References

  1. 1.

    Lohse, D., Schmitz, B. & Versluis, M. Snapping shrimp make flashing bubbles. Nature 413, 477–478 (2001).

    ADS  Article  Google Scholar 

  2. 2.

    Suslick, K. S. Sonochemistry. Science 247, 1439–1445 (1990).

    ADS  Article  Google Scholar 

  3. 3.

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

    Article  Google Scholar 

  4. 4.

    Lehmann, J. F. & Herrick, J. F. Biologic reactions to cavitation, a consideration for ultrasonic therapy. Arch. Phys. Med. Rehabil. 34, 86–98 (1953).

    Google Scholar 

  5. 5.

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

    Article  Google Scholar 

  6. 6.

    Crum, L. A. Cavitation microjets as a contributory mechanism for renal calculi disintegration in ESWL. J. Urol. 140, 1587–1590 (1988).

    Article  Google Scholar 

  7. 7.

    Kennedy, J. E. High-intensity focused ultrasound in the treatment of solid tumours. Nat. Rev. Cancer 5, 321–327 (2005).

    Article  Google Scholar 

  8. 8.

    Fechheimer, M. et al. Transfection of mammalian-cells with plasmid DNA by scrape loading and sonication loading. Proc. Natl Acad. Sci. USA 84, 8463–8467 (1987).

    ADS  Article  Google Scholar 

  9. 9.

    McDannold, N., Vykhodtseva, N. & Hynynen, K. Targeted disruption of the blood–brain barrier with focused ultrasound: association with cavitation activity. Phys. Med. Biol. 51, 793–807 (2006).

    Article  Google Scholar 

  10. 10.

    Langer, R. Drug delivery and targeting. Nature 392 (Suppl.), 5–10 (1998).

    Google Scholar 

  11. 11.

    Husseini, G. A. & Pitt, W. G. Micelles and nanoparticles for ultrasonic drug and gene delivery. Adv. Drug Deliv. Rev. 60, 1137–1152 (2008).

    Article  Google Scholar 

  12. 12.

    Evjen, T. J. et al. In vivo monitoring of liposomal release in tumours following ultrasound stimulation. Eur. J. Pharm. Biopharm. 84, 526–531 (2013).

    Article  Google Scholar 

  13. 13.

    Graham, S. M. et al. Inertial cavitation to non-invasively trigger and monitor intratumoral release of drug from intravenously delivered liposomes. J. Control. Release 178, 101–107 (2014).

    Article  Google Scholar 

  14. 14.

    Kolb, J. & Nyborg, W. L. Small-scale acoustic streaming in liquids. J. Acoust. Soc. Am. 28, 1237–1242 (1956).

    ADS  Article  Google Scholar 

  15. 15.

    Nyborg, W. L. Acoustic streaming near a boundary. J. Acoust. Soc. Am. 30, 329–339 (1958).

    ADS  MathSciNet  Article  Google Scholar 

  16. 16.

    Elder, S. & Nyborg, W. L. Acoustic streaming resulting from a resonant bubble. J. Acoust. Soc. Am. 28, 155–155 (1956).

    Article  Google Scholar 

  17. 17.

    Marmottant, P. & Hilgenfeldt, S. Controlled vesicle deformation and lysis by single oscillating bubbles. Nature 423, 153–156 (2003).

    ADS  Article  Google Scholar 

  18. 18.

    Jia, C. et al. Generation of reactive oxygen species in heterogeneously sonoporated cells by microbubbles with single-pulse ultrasound. Ultrasound Med. Biol. 44, 1074–1085 (2018).

    Article  Google Scholar 

  19. 19.

    Nce, A. On the mechanism of cavitation damage by nonhemispherical cavities collapsing in contact with a solid boundary. J. Basic Eng. 83, 648–656 (1961).

    Article  Google Scholar 

  20. 20.

    Benjamin, T. B. & Ellis, A. T. The collapse of cavitation bubbles and the pressures thereby produced against solid boundaries. Phil. Trans. R. Soc. Lond. A 260, 221–240 (1966).

    ADS  Article  Google Scholar 

  21. 21.

    Enayati, M., Al Mohazey, D., Edirisinghe, M. & Stride, E. Ultrasound-stimulated drug release from polymer micro and nanoparticles. Bioinspir. Biomim. Nanobiomater. 2, 3–10 (2013).

    Article  Google Scholar 

  22. 22.

    Ahmed, S. E., Martins, A. M. & Husseini, G. A. The use of ultrasound to release chemotherapeutic drugs from micelles and liposomes. J. Drug Target. 23, 16–42 (2015).

    Article  Google Scholar 

  23. 23.

    Hilgenfeldt, S., Lohse, D. & Zomack, M. Response of bubbles to diagnostic ultrasound: a unifying theoretical approach. Eur. Phys. J. B 4, 247–255 (1998).

    ADS  Article  Google Scholar 

  24. 24.

    Holt, R. G. & Roy, R. A. Measurements of bubble-enhanced heating from focused, MHz-frequency ultrasound in a tissue-mimicking material. Ultrasound Med. Biol. 27, 1399–1412 (2001).

    Article  Google Scholar 

  25. 25.

    Hilgenfeldt, S. & Lohse, D. The acoustics of diagnostic microbubbles: dissipative effects and heat deposition. Ultrasonics 38, 99–104 (2000).

    Article  Google Scholar 

  26. 26.

    Hilgenfeldt, S., Lohse, D. & Zomack, M. Sound scattering and localized heat deposition of pulse-driven microbubbles. J. Acoust. Soc. Am. 107, 3530–3539 (2000).

    ADS  Article  Google Scholar 

  27. 27.

    Yudina, A. et al. Ultrasound-mediated intracellular drug delivery using microbubbles and temperature-sensitive liposomes. J. Control. Release 155, 442–448 (2011).

    Article  Google Scholar 

  28. 28.

    Coussios, C. C. & Roy, R. A. Applications of acoustics and cavitation to noninvasive therapy and drug delivery. Annu. Rev. Fluid Mech. 40, 395–420 (2008).

    ADS  MathSciNet  MATH  Article  Google Scholar 

  29. 29.

    Bader, K. B., Gruber, M. J. & Holland, C. K. Shaken and stirred: mechanisms of ultrasound-enhanced thrombolysis. Ultrasound Med. Biol. 41, 187–196 (2015).

    Article  Google Scholar 

  30. 30.

    Miller, D. L., Thomas, R. M. & Williams, A. R. Mechanisms for hemolysis by ultrasonic cavitation in the rotating exposure system. Ultrasound Med. Biol. 17, 171–178 (1991).

    Article  Google Scholar 

  31. 31.

    Prosperetti, A. Thermal effects and damping mechanisms in forced radial oscillations of gas-bubbles in liquids. J. Acoust. Soc. Am. 61, 17–27 (1977).

    ADS  Article  Google Scholar 

  32. 32.

    Flint, E. B. & Suslick, K. S. The temperature of cavitation. Science 253, 1397–1399 (1991).

    ADS  Article  Google Scholar 

  33. 33.

    Winterbourn, C. C. Reconciling the chemistry and biology of reactive oxygen species. Nat. Chem. Biol. 4, 278–286 (2008).

    Article  Google Scholar 

  34. 34.

    Kudo, N. & Kinoshita, Y. Effects of cell culture scaffold stiffness on cell membrane damage induced by sonoporation. J. Med. Ultrason. 41, 411–420 (2014).

    Article  Google Scholar 

  35. 35.

    McEwan, C. et al. Combined sonodynamic and antimetabolite therapy for the improved treatment of pancreatic cancer using oxygen loaded microbubbles as a delivery vehicle. Biomaterials 80, 20–32 (2016).

    Article  Google Scholar 

  36. 36.

    Lee, J. Y. et al. Ultrasound-enhanced siRNA delivery using magnetic nanoparticle-loaded chitosan-deoxycholic acid nanodroplets. Adv. Healthc. Mater. 6, 1601246 (2017).

    Article  Google Scholar 

  37. 37.

    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).

    Google Scholar 

  38. 38.

    Bohmer, M. R. et al. Focused ultrasound and microbubbles for enhanced extravasation. J. Control. Release 148, 18–24 (2010).

    Article  Google Scholar 

  39. 39.

    Carlisle, R. & Coussios, C.-C. Mechanical approaches to oncological drug delivery. Ther. Deliv. 4, 1213–1215 (2013).

    Article  Google Scholar 

  40. 40.

    Arvanitis, C. D., Bazan-Peregrino, M., Rifai, B., Seymour, L. W. & Coussios, C. C. Cavitation-enhanced extravasation for drug delivery. Ultrasound Med. Biol. 37, 1838–1852 (2011).

    Article  Google Scholar 

  41. 41.

    Carlisle, R. et al. Enhanced tumor uptake and penetration of virotherapy using polymer stealthing and focused ultrasound. J. Natl Cancer Inst. 105, 1701–1710 (2013).

    Article  Google Scholar 

  42. 42.

    Rifai, B., Arvanitis, C. D., Bazan-Peregrino, M. & Coussios, C. C. Cavitation-enhanced delivery of macromolecules into an obstructed vessel. J. Acoust. Soc. Am. 128, El310–El315 (2010).

    ADS  Article  Google Scholar 

  43. 43.

    van Wamel, A. et al. Vibrating microbubbles poking individual cells: drug transfer into cells via sonoporation. J. Control. Release 112, 149–155 (2006).

    Article  Google Scholar 

  44. 44.

    Kudo, N. High-speed in situ observation system for sonoporation of cells with size- and position-controlled microbubbles. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 64, 273–280 (2017).

    Article  Google Scholar 

  45. 45.

    Abbott, N. J. Blood–brain barrier structure and function and the challenges for CNS drug delivery. J. Inherit. Metab. Dis. 36, 437–449 (2013).

    Article  Google Scholar 

  46. 46.

    Kooiman, K., van der Steen, A. F. & de Jong, N. Role of intracellular calcium and reactive oxygen species in microbubble-mediated alterations of endothelial layer permeability. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 60, 1811–1815 (2013).

    Article  Google Scholar 

  47. 47.

    Juffermans, L. J., Kamp, O., Dijkmans, P. A., Visser, C. A. & Musters, R. J. Low-intensity ultrasound-exposed microbubbles provoke local hyperpolarization of the cell membrane via activation of BK(Ca) channels. Ultrasound Med. Biol. 34, 502–508 (2008).

    Article  Google Scholar 

  48. 48.

    Helfield, B. L., Chen, X. C., Qin, B., Watkins, S. C. & Villanueva, F. S. Mechanistic insight into sonoporation with ultrasound-stimulated polymer microbubbles. Ultrasound Med. Biol. 43, 2678–2689 (2017).

    Article  Google Scholar 

  49. 49.

    Acconcia, C. N., Leung, B. Y. & Goertz, D. E. The microscale evolution of the erosion front of blood clots exposed to ultrasound stimulated microbubbles. J. Acoust. Soc. Am. 139, EL135–EL141 (2016).

    ADS  Article  Google Scholar 

  50. 50.

    Caskey, C. F., Qin, S., Dayton, P. A. & Ferrara, K. W. Microbubble tunneling in gel phantoms. J. Acoust. Soc. Am. 125, EL183–EL189 (2009).

    ADS  Article  Google Scholar 

  51. 51.

    Samiotaki, G. & Konofagou, E. E. Dependence of the reversibility of focused- ultrasound-induced blood-brain barrier opening on pressure and pulse length in vivo. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 60, 2257–2265 (2013).

    Article  Google Scholar 

  52. 52.

    Plesset, M. S. & Prosperetti, A. Bubble dynamics and cavitation. Annu. Rev. Fluid Mech. 9, 145–185 (1977).

    ADS  MATH  Article  Google Scholar 

  53. 53.

    Lajoinie, G. et al. Non-spherical oscillations drive the ultrasound-mediated release from targeted microbubbles. Commun. Phys. 1, 22 (2018).

  54. 54.

    Chen, H., Brayman, A. A., Kreider, W., Bailey, M. R. & Matula, T. J. Observations of translation and jetting of ultrasound-activated microbubbles in mesenteric microvessels. Ultrasound Med. Biol. 37, 2139–2148 (2011).

    Article  Google Scholar 

  55. 55.

    Martynov, S., Kostson, E., Saffari, N. & Stride, E. Forced vibrations of a bubble in a liquid-filled elastic vessel. J. Acoust. Soc. Am. 130, 2700–2708 (2011).

    ADS  Article  Google Scholar 

  56. 56.

    Chen, X., Wang, J., Pacella, J. J. & Villanueva, F. S. Dynamic behavior of microbubbles during long ultrasound tone-burst excitation: mechanistic insights into ultrasound-microbubble mediated therapeutics using high-speed imaging and cavitation detection. Ultrasound Med. Biol. 42, 528–538 (2016).

    Article  Google Scholar 

  57. 57.

    Lentacker, I., De Cock, I., Deckers, R., De Smedt, S. C. & Moonen, C. T. Understanding ultrasound induced sonoporation: definitions and underlying mechanisms. Adv. Drug Deliv. Rev. 72, 49–64 (2014).

    Article  Google Scholar 

  58. 58.

    Qin, P., Han, T., Yu, A. C. H. & Xu, L. Mechanistic understanding the bioeffects of ultrasound-driven microbubbles to enhance macromolecule delivery. J. Control. Release 272, 169–181 (2018).

    Article  Google Scholar 

  59. 59.

    Hebdm, W. Bubble formation in animals. J. Cell. Comp. Physiol. 24, 1–22 (1944).

    Article  Google Scholar 

  60. 60.

    Briggs, L. J. Limiting negative pressure of water. J. Appl. Phys. 21, 721–722 (1950).

    ADS  Article  Google Scholar 

  61. 61.

    Morch, K. A. Cavitation inception from bubble nuclei. Interface Focus 5, 20150006 (2015).

    Article  Google Scholar 

  62. 62.

    Strasberg, M. Onset of ultrasonic cavitation in tap water. J. Acoust. Soc. Am. 31, 163–176 (1959).

    ADS  Article  Google Scholar 

  63. 63.

    Atchley, A. A. & Prosperetti, A. The crevice model of bubble nucleation. J. Acoust. Soc. Am. 86, 1065–1084 (1989).

    ADS  Article  Google Scholar 

  64. 64.

    Borkent, B. M., Gekle, S., Prosperetti, A. & Lohse, D. Nucleation threshold and deactivation mechanisms of nanoscopic cavitation nuclei. Phys. Fluids 21, 102003 (2009).

  65. 65.

    Fox, F. E. & Herzfeld, K. F. Gas bubbles with organic skin as cavitation nuclei. J. Acoust. Soc. Am. 26, 984–989 (1954).

    ADS  Article  Google Scholar 

  66. 66.

    Yount, D. E. Skins of varying permeability — stabilization mechanism for gas cavitation nuclei. J. Acoust. Soc. Am. 65, 1429–1439 (1979).

    ADS  Article  Google Scholar 

  67. 67.

    Blake, F. G. Technical Memo. 12 (Acoustics Research Laboratory, Harvard University, 1949).

  68. 68.

    Hsieh, D. Y. & Plesset, M. S. Theory of rectified diffusion of mass into gas bubbles. J. Acoust. Soc. Am. 33, 206–20 (1961).

    ADS  MathSciNet  Article  Google Scholar 

  69. 69.

    Church, C. C. The effects of an elastic solid-surface layer on the radial pulsations of gas-bubbles. J. Acoust. Soc. Am. 97, 1510–1521 (1995).

    ADS  Article  Google Scholar 

  70. 70.

    Carugo, D. et al. Modulation of the molecular arrangement in artificial and biological membranes by phospholipid-shelled microbubbles. Biomaterials 113, 105–117 (2017).

    Article  Google Scholar 

  71. 71.

    Lentacker, I., De Smedt, S. C. & Sanders, N. N. Drug loaded microbubble design for ultrasound triggered delivery. Soft Matter 5, 2161–2170 (2009).

    ADS  Article  Google Scholar 

  72. 72.

    Mulvana, H. et al. Characterization of contrast agent microbubbles for ultrasound imaging and therapy research. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 64, 232–251 (2017).

    Article  Google Scholar 

  73. 73.

    Tinkov, S. et al. New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: in-vivo characterization. J. Control. Release 148, 368–372 (2010).

    Article  Google Scholar 

  74. 74.

    Geers, B. et al. Self-assembled liposome-loaded microbubbles: the missing link for safe and efficient ultrasound triggered drug-delivery. J. Control. Release 152, 249–256 (2011).

    Article  Google Scholar 

  75. 75.

    Geers, B., Dewitte, H., De Smedt, S. C. & Lentacker, I. Crucial factors and emerging concepts in ultrasound-triggered drug delivery. J. Control. Release 164, 248–255 (2012).

    Article  Google Scholar 

  76. 76.

    Vlaskou, D. et al. Magnetic microbubbles: magnetically targeted and ultrasound-triggered vectors for gene delivery in vitro. Hum. Gene Ther. 21, 1191–1191 (2010).

    Google Scholar 

  77. 77.

    Sheng, Y. J. et al. Magnetically responsive microbubbles as delivery vehicles for targeted sonodynamic and antimetabolite therapy of pancreatic cancer. J. Control. Release 262, 192–200 (2017).

    Article  Google Scholar 

  78. 78.

    McEwan, C. et al. Oxygen carrying microbubbles for enhanced sonodynamic therapy of hypoxic tumours. J. Control. Release 203, 51–56 (2015).

    Article  Google Scholar 

  79. 79.

    Grishenkov, D. et al. Ultrasound contrast agent loaded with nitric oxide as a theranostic microdevice. Drug Des. Dev. Ther. 9, 2409–2419 (2015).

    Article  Google Scholar 

  80. 80.

    Morel, D. R. et al. Human pharmacokinetics and safety evaluation of SonoVue, a new contrast agent for ultrasound imaging. Invest. Radiol. 35, 80–85 (2000).

    Article  Google Scholar 

  81. 81.

    Rapoport, N., Gao, Z. & Kennedy, A. Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. J. Natl Cancer Inst. 99, 1095–1106 (2007).

    Article  Google Scholar 

  82. 82.

    Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

  83. 83.

    Sheeran, P. S., Luois, S., Dayton, P. A. & Matsunaga, T. O. Formulation and acoustic studies of a new phase-shift agent for diagnostic and therapeutic ultrasound. Langmuir 27, 10412–10420 (2011).

    Article  Google Scholar 

  84. 84.

    Javadi, M., Pitt, W. G., Belnap, D. M., Tsosie, N. H. & Hartley, J. M. Encapsulating nanoemulsions inside eLiposomes for ultrasonic drug delivery. Langmuir 28, 14720–14729 (2012).

    Article  Google Scholar 

  85. 85.

    Wang, C. H. et al. Aptamer-conjugated and drug-loaded acoustic droplets for ultrasound theranosis. Biomaterials 33, 1939–1947 (2012).

    Article  Google Scholar 

  86. 86.

    Yu, J. S. et al. Echogenic chitosan nanodroplets for spatiotemporally controlled gene delivery. J. Biomed. Nanotechnol. 14, 1287–1297 (2018).

    Article  Google Scholar 

  87. 87.

    Moyer, L. C. et al. High-intensity focused ultrasound ablation enhancement in vivo via phase-shift nanodroplets compared to microbubbles. J. Ther. Ultrasound 3, 7 (2015).

    Article  Google Scholar 

  88. 88.

    Ho, Y. J. & Yeh, C. K. Theranostic performance of acoustic nanodroplet vaporization-generated bubbles in tumor intertissue. Theranostics 7, 1477–1488 (2017).

    Article  Google Scholar 

  89. 89.

    Chen, C. C. et al. Targeted drug delivery with focused ultrasound-induced blood–brain barrier opening using acoustically-activated nanodroplets. J. Control. Release 172, 795–804 (2013).

    Article  Google Scholar 

  90. 90.

    Sheeran, P. S., Matsunaga, T. O. & Dayton, P. A. Phase-transition thresholds and vaporization phenomena for ultrasound phase-change nanoemulsions assessed via high-speed optical microscopy. Phys. Med. Biol. 58, 4513–4534 (2013).

    Article  Google Scholar 

  91. 91.

    Shpak, O,. et al. Acoustic droplet vaporization is initiated by superharmonic focusing. Proc. Natl Acad. Sci. USA 111, 1697–1702 (2014).

    ADS  Article  Google Scholar 

  92. 92.

    Wang, Y. et al. Stable encapsulated air nanobubbles in water. Angew. Chem. Int. Ed. 54, 14291–14294 (2015).

    Article  Google Scholar 

  93. 93.

    Hernandez, C., Nieves, L., de Leon, A. C., Advincula, R. & Exner, A. A. Role of surface tension in gas nanobubble stability under ultrasound. ACS Appl. Mater. Interfaces 10, 9949–9956 (2018).

    Article  Google Scholar 

  94. 94.

    Paris, J. L. et al. Ultrasound-mediated cavitation-enhanced extravasation of mesoporous silica nanoparticles for controlled-release drug delivery. Chem. Eng. J. 340, 2–8 (2018).

    Article  Google Scholar 

  95. 95.

    Delogu, L. G. et al. Functionalized multiwalled carbon nanotubes as ultrasound contrast agents. Proc. Natl Acad. Sci. USA 109, 16612–16617 (2012).

    ADS  Article  Google Scholar 

  96. 96.

    Straub, J. A. et al. Porous PLGA microparticles: AI-700, an intravenously administered ultrasound contrast agent for use in echocardiography. J. Control. Release 108, 21–32 (2005).

    Article  Google Scholar 

  97. 97.

    Kwan, J. et al. Ultrasound-induced inertial cavitation from gas-stabilizing nanoparticles. Phys. Rev. E 92, 023019 (2015).

    ADS  Article  Google Scholar 

  98. 98.

    Mannaris, C. et al. Gas-stabilizing gold nanocones for acoustically mediated drug delivery. Adv. Healthc. Mater. 7, 1800184 (2018).

    Article  Google Scholar 

  99. 99.

    Kang, E. et al. Nanobubbles from gas-generating polymeric nanoparticles: ultrasound imaging of living subjects. Angew. Chem. Int. Ed. 49, 524–528 (2010).

    Article  Google Scholar 

  100. 100.

    Toyokuni, S. Genotoxicity and carcinogenicity risk of carbon nanotubes. Adv. Drug Deliv. Rev. 65, 2098–2110 (2013).

    Article  Google Scholar 

  101. 101.

    Prosperetti, A., Crum, L. A. & Commander, K. W. Nonlinear bubble dynamics. J. Acoust. Soc. Am. 83, 502–514 (1988).

    ADS  Article  Google Scholar 

  102. 102.

    Flynn, H. G. Cavitation dynamics. 2. Free pulsations and models for cavitation bubbles. J. Acoust. Soc. Am. 58, 1160–1170 (1975).

    ADS  Article  Google Scholar 

  103. 103.

    Church, C. C. & Carstensen, E. L. “Stable” inertial cavitation. Ultrasound Med. Biol. 27, 1435–1437 (2001).

    Article  Google Scholar 

  104. 104.

    Neppiras, E. A. Acoustic cavitation. Phys. Rep. 61, 159–251 (1980).

    ADS  MathSciNet  Article  Google Scholar 

  105. 105.

    Apfel, R. E. & Holland, C. K. Gauging the likelihood of cavitation from short-pulse, low-duty cycle diagnostic ultrasound. Ultrasound Med. Biol. 17, 179–185 (1991).

    Article  Google Scholar 

  106. 106.

    Madanshetty, S. I., Roy, R. & Apfel, R. E. Acoustic microcavitation: its active and passive acoustic detection. J. Acoust. Soc. Am. 90, 1515–1526 (1991).

    ADS  Article  Google Scholar 

  107. 107.

    Rabkin, B. A., Zderic, V. & Vaezy, S. Hyperecho in ultrasound images of HIFU therapy: involvement of cavitation. Ultrasound Med. Biol. 31, 947–956 (2005).

    Article  Google Scholar 

  108. 108.

    Coussios, C. C., Farny, C. H., Haar, G. T. & Roy, R. A. Role of acoustic cavitation in the delivery and monitoring of cancer treatment by high-intensity focused ultrasound (HIFU). Int. J. Hyperthermia 23, 105–120 (2007).

    Article  Google Scholar 

  109. 109.

    Arnal, B., Baranger, J., Demene, C., Tanter, M. & Pernot, M. In vivo real-time cavitation imaging in moving organs. Phys. Med. Biol. 62, 843–857 (2017).

    Article  Google Scholar 

  110. 110.

    Gateau, J., Aubry, J.-F., Pernot, M., Fink, M. & Tanter, M. Combined passive detection and ultrafast active imaging of cavitation events induced by short pulses of high-intensity ultrasound. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 58, 517–532 (2011).

    Article  Google Scholar 

  111. 111.

    Rabkin, B. A., Zderic, V., Crum, L. A. & Vaezy, S. Biological and physical mechanisms of HIFU-induced hyperecho in ultrasound images. Ultrasound Med. Biol. 32, 1721–1729 (2006).

    Article  Google Scholar 

  112. 112.

    Gyongy, M., Arora, M., Noble, J. A. & Coussios, C. C. Use of passive arrays for characterization and mapping of cavitation activity during HIFU exposure. In 2008 IEEE Ultrasonics Symposium 871–874 (IEEE, 2008).

  113. 113.

    Gyongy, M. & Coussios, C. C. Passive spatial mapping of inertial cavitation during HIFU exposure. IEEE Trans. Biomed. Eng. 57, 48–56 (2010).

    Article  Google Scholar 

  114. 114.

    Salgaonkar, V. A., Datta, S., Holland, C. K. & Mast, T. D. Passive cavitation imaging with ultrasound arrays. J. Acoust. Soc. Am. 126, 3071–3083 (2009).

    ADS  Article  Google Scholar 

  115. 115.

    Haworth, K. J. et al. Passive imaging with pulsed ultrasound insonations. J. Acoust. Soc. Am. 132, 544–553 (2012).

    ADS  Article  Google Scholar 

  116. 116.

    Arvanitis, C. D., Crake, C., McDannold, N. & Clement, G. T. Passive acoustic mapping with the angular spectrum method. IEEE Trans. Med. Imaging 36, 983–993 (2017).

    Article  Google Scholar 

  117. 117.

    Gyongy, M. & Coussios, C. C. Passive cavitation mapping for localization and tracking of bubble dynamics. J. Acoust. Soc. Am. 128, E175–E180 (2010).

    ADS  Article  Google Scholar 

  118. 118.

    Jensen, C. R. et al. Spatiotemporal monitoring of high-intensity focused ultrasound therapy with passive acoustic mapping. Radiology 262, 252–261 (2012).

    Article  Google Scholar 

  119. 119.

    Gray, M. D., Lyka, E. & Coussios, C. C. Diffraction effects and compensation in passive acoustic mapping. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 65, 258–268 (2018).

    Article  Google Scholar 

  120. 120.

    Coviello, C. et al. Passive acoustic mapping utilizing optimal beamforming in ultrasound therapy monitoring. J. Acoust. Soc. Am. 137, 2573–2585 (2015).

    ADS  Article  Google Scholar 

  121. 121.

    Choi, J. J., Carlisle, R. C., Coviello, C., Seymour, L. & Coussios, C.-C. Non-invasive and real-time passive acoustic mapping of ultrasound-mediated drug delivery. Phys. Med. Biol. 59, 4861–4877 (2014).

    Article  Google Scholar 

  122. 122.

    Kwan, J. J. et al. Ultrasound-propelled nanocups for drug delivery. Small 11, 5305–5314 (2015).

    Article  Google Scholar 

  123. 123.

    Miller, D. L. Overview of experimental studies of biological effects of medical ultrasound caused by gas body activation and inertial cavitation. Prog. Biophys. Mol. Biol. 93, 314–330 (2007).

    Article  Google Scholar 

  124. 124.

    Hobbs, S. K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95, 4607–4612 (1998).

    ADS  Article  Google Scholar 

  125. 125.

    Bazan-Peregrino, M., Arvanitis, C. D., Rifai, B., Seymour, L. W. & Coussios, C. C. Ultrasound-induced cavitation enhances the delivery and therapeutic efficacy of an oncolytic virus in an in vitro model. J. Control. Release 157, 235–242 (2012).

    Article  Google Scholar 

  126. 126.

    Bazan-Peregrino, M. et al. Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound. J. Control. Release 169, 40–47 (2013).

    Article  Google Scholar 

  127. 127.

    Lafond, M., Aptel, F., Mestas, J. L. & Lafon, C. Ultrasound-mediated ocular delivery of therapeutic agents: a review. Expert Opin. Drug Deliv. 14, 539–550 (2017).

    Article  Google Scholar 

  128. 128.

    Prieur, F. et al. Enhancement of fluorescent probe penetration into tumors in vivo using unseeded inertial cavitation. Ultrasound Med. Biol. 42, 1706–1713 (2016).

    Article  Google Scholar 

  129. 129.

    Li, T. et al. Pulsed high intensity focused ultrasound (pHIFU) enhances delivery of doxorubicin in a preclinical model of pancreatic cancer. Cancer Res. 75, 3738–3746 (2015).

    Article  Google Scholar 

  130. 130.

    Myers, R. et al. Polymeric cups for cavitation-mediated delivery of oncolytic vaccinia virus. Mol. Ther. 24, 1627–1633 (2016).

    Article  Google Scholar 

  131. 131.

    Dimcevski, G. et al. A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer. J. Control. Release 243, 172–181 (2016).

    Article  Google Scholar 

  132. 132.

    Hynynen, K., McDannold, N., Vykhodtseva, N. & Jolesz, F. A. Noninvasive MR imaging-guided focal opening of the blood–brain barrier in rabbits. Radiology 220, 640–646 (2001).

    Article  Google Scholar 

  133. 133.

    McDannold, N., Vykhodtseva, N. & Hynynen, K. Targeted disruption of the blood–brain barrier with focused ultrasound: association with cavitation activity. Phys. Med. Biol. 51, 793–807 (2006).

    Article  Google Scholar 

  134. 134.

    Tung, Y.-S. et al. In vivo transcranial cavitation threshold detection during ultrasound-induced blood–brain barrier opening in mice. Phys. Med. Biol. 55, 6141–6155 (2010).

    MathSciNet  Article  Google Scholar 

  135. 135.

    Arvanitis, C. D., Livingstone, M. S. & McDannold, N. Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain. Phys. Med. Biol. 58, 4749–4761 (2013).

    Article  Google Scholar 

  136. 136.

    Jones, R. M. et al. Three-dimensional transcranial microbubble imaging for guiding volumetric ultrasound-mediated blood–brain barrier opening. Theranostics 8, 2909–2926 (2018).

    Article  Google Scholar 

  137. 137.

    Carpentier, A. et al. Clinical trial of blood–brain barrier disruption by pulsed ultrasound. Sci. Transl. Med. 8, 343re2 (2016).

    Article  Google Scholar 

  138. 138.

    Lipsman, N. et al. Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat. Commun. 9, 2336 (2018).

    ADS  Article  Google Scholar 

  139. 139.

    de Saint Victor, M., Crake, C., Coussios, C.-C. & Stride, E. Properties, characteristics and applications of microbubbles for sonothrombolysis. Expert Opin. Drug Deliv. 11, 187–209 (2014).

    Article  Google Scholar 

  140. 140.

    Mercado-Shekhar, K. P. et al. Effect of clot stiffness on recombinant tissue plasminogen activator lytic susceptibility in vitro. Ultrasound Med. Biol. 44, 2710–2727 (2018).

    Article  Google Scholar 

  141. 141.

    Datta, S. et al. Ultrasound-enhanced thrombolysis using Definity® as a cavitation nucleation agent. Ultrasound Med. Biol. 34, 1421–1433 (2008).

    Article  Google Scholar 

  142. 142.

    Datta, S. et al. Correlation of cavitation with ultrasound enhancement of thrombolysis. Ultrasound Med. Biol. 32, 1257–1267 (2006).

    Article  Google Scholar 

  143. 143.

    Molina, C. A. et al. Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 37, 425–429 (2006).

    Article  Google Scholar 

  144. 144.

    Mathias, W. et al. The effectiveness of microbubble-mediated sonothrombolysis for inducing early recanalization of different culprit coronary arteries in patients with acute ST-segment elevation myocardial infarction. J. Am. Coll. Cardiol. 71, A1460 (2018).

    Article  Google Scholar 

  145. 145.

    Mathias, W. et al. Diagnostic ultrasound impulses improve microvascular flow in patients with STEMI receiving intravenous microbubbles. J. Am. Coll. Cardiol. 67, 2506–2515 (2016).

    Article  Google Scholar 

  146. 146.

    Molina, C. A. et al. Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial. Ann. Neurol. 66, 28–38 (2009).

    Article  Google Scholar 

  147. 147.

    Owen, J. et al. Magnetic targeting of microbubbles against physiologically relevant flow conditions. Interface Focus 5, 20150001 (2015).

    Article  Google Scholar 

  148. 148.

    Vignon, F. et al. Microbubble cavitation imaging. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 60, 661–670 (2013).

    Article  Google Scholar 

  149. 149.

    Qiao, S., Coussios, C. & Cleveland, R. Characterization of modular arrays for transpinal ultrasound application. J. Acoust. Soc. Am. 141, 3954–3954 (2017).

    ADS  Article  Google Scholar 

  150. 150.

    Fletcher, S.-M. P. & O’Reilly, M. A. Analysis of multi-frequency and phase keying strategies for focusing ultrasound to the human vertebral canal. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 65, 2322–2331 (2018).

  151. 151.

    O’Reilly, M. A. et al. Preliminary investigation of focused ultrasound-facilitated drug delivery for the treatment of leptomeningeal metastases. Sci. Rep. 8, 9013 (2018).

    ADS  Article  Google Scholar 

  152. 152.

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

    Article  Google Scholar 

  153. 153.

    Tezel, A., Paliwal, S., Shen, Z. & Mitragotri, S. Low-frequency ultrasound as a transcutaneous immunization adjuvant. Vaccine 23, 3800–3807 (2005).

    Article  Google Scholar 

  154. 154.

    Polat, B. E., Hart, D., Langer, R. & Blankschtein, D. Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. J. Control. Release 152, 330–348 (2011).

    Article  Google Scholar 

  155. 155.

    Mitragotri, S., Blankschtein, D. & Langer, R. Transdermal drug delivery using low-frequency sonophoresis. Pharm. Res. 13, 411–420 (1996).

    Article  Google Scholar 

  156. 156.

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

    Article  Google Scholar 

  157. 157.

    Tezel, A., Sens, A. & Mitragotri, S. Investigations of the role of cavitation in low-frequency sonophoresis using acoustic spectroscopy. J. Pharm. Sci. 91, 444–453 (2002).

    Article  Google Scholar 

  158. 158.

    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  Google Scholar 

  159. 159.

    Rich, K. T., Hoerig, C. L., Rao, M. B. & Mast, T. D. Relations between acoustic cavitation and skin resistance during intermediate-and high-frequency sonophoresis. J. Control. Release 194, 266–277 (2014).

    Article  Google Scholar 

  160. 160.

    Bhatnagar, S., Schiffter, H. & Coussios, C. C. Exploitation of acoustic cavitation-induced microstreaming to enhance molecular transport. J. Pharm. Sci. 103, 1903–1912 (2014).

    Article  Google Scholar 

  161. 161.

    Bhatnagar, S., Kwan, J. J., Shah, A. R., Coussios, C. C. & Carlisle, R. C. Exploitation of sub-micron cavitation nuclei to enhance ultrasound-mediated transdermal transport and penetration of vaccines. J. Control. Release 238, 22–30 (2016).

    Article  Google Scholar 

  162. 162.

    Feiszthuber, H., Bhatnagar, S., Gyöngy, M. & Coussios, C.-C. Cavitation-enhanced delivery of insulin in agar and porcine models of human skin. Phys. Med. Biol. 60, 2421–2434 (2015).

    Article  Google Scholar 

  163. 163.

    Tran, D. M. et al. Prolonging pulse duration in ultrasound-mediated gene delivery lowers acoustic pressure threshold for efficient gene transfer to cells and small animals. J. Control. Release 279, 345–354 (2018).

    Article  Google Scholar 

  164. 164.

    Lee, J. Y. et al. Nanoparticle-loaded protein-polymer nanodroplets for improved stability and conversion efficiency in ultrasound imaging and drug delivery. Adv. Mater. 27, 5484–5492 (2015).

    Article  Google Scholar 

  165. 165.

    Haworth, K. J., Bader, K. B., Rich, K. T., Holland, C. K. & Mast, T. D. Quantitative frequency-domain passive cavitation imaging. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 64, 177–191 (2017).

    Article  Google Scholar 

  166. 166.

    Lu, S. et al. Passive acoustic mapping of cavitation using eigenspace-based robust Capon beamformer in ultrasound therapy. Ultrason. Sonochem. 41, 670–679 (2018).

    Article  Google Scholar 

  167. 167.

    Hockham, N., Coussios, C. C. & Arora, M. A real-time controller for sustaining thermally relevant acoustic cavitation during ultrasound therapy. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57, 2685–2694 (2010).

    Article  Google Scholar 

  168. 168.

    O’Reilly, M. A. & Hynynen, K. Blood–brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions–based controller. Radiology 263, 96–106 (2012).

    Article  Google Scholar 

  169. 169.

    Deng, L., O’Reilly, M. A., Jones, R. M., An, R. & Hynynen, K. A multi-frequency sparse hemispherical ultrasound phased array for microbubble-mediated transcranial therapy and simultaneous cavitation mapping. Phys. Med. Biol. 61, 8476–8501 (2016).

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank The Engineering and Physical Sciences Research Council for supporting their work through grants EP/ EP/L024012/1 and EP/L024012.

Author information

Affiliations

Authors

Contributions

All authors researched data for the article, discussed the content, wrote the manuscript, and reviewed and edited it before submission.

Corresponding author

Correspondence to Eleanor Stride.

Ethics declarations

Competing interests

C.C. is a named inventor on several patents pertaining to cavitation nucleation, mapping, monitoring and control, and a founder, director, shareholder and consultant receiving consultancy income from OxSonics Ltd, a spin-out from the University of Oxford developing a commercial product to enable the clinical translation of cavitation-mediated drug delivery. E.S. is a named inventor on two patents relating to the use of microbubbles for therapeutic applications and a founder of SonoTarg Ltd, a spin-out company developing oxygen-loaded microbubbles for cancer treatment.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Lithotripsy

A medical procedure involving the physical destruction of solid masses such as kidney stones.

High-intensity focused ultrasound

In medicine, this refers to ultrasound with intensities typically exceeding 1,000 W cm−2 used for thermal ablation of tissue, for example, for cancer treatment.

Vascular

Relating to vessels, typically blood vessels.

Endothelium

The layer of cells lining the interior surface of blood or lymphatic vessels.

Microstreaming

The microscale circulation of a viscous fluid produced by an oscillating structure.

Tissue phantoms

Synthetic objects whose physical properties are similar to those of tissue, enabling experiments to be conducted in a realistic environment.

Transcytosis

A process by which material is transported through the interior of a cell by encapsulation within vesicles that are formed on one side of the cell and ejected on the other.

Secondary radiation force

The force generated between two objects as a result of their oscillation, which may be attractive or repulsive.

Echogenicity

Ability to produce strong echoes — reflections or scattering — of an incident ultrasound field.

Superharmonic focusing

The process by which a small acoustically responsive object acts as a lens focusing the high-frequency components of a nonlinearly propagated ultrasound wave.

Extravasation

The leakage of a fluid out of its container; in the context of drug delivery, the transport of material out of the bloodstream into the surrounding tissue.

Beamform

To combine signals with suitable delays to amplify information coming from the region of interest.

Stromal layer

A region of tissue containing cells that are not part of the specific function of the organ in which they reside. In a tumour, this layer consists of cells that are not themselves malignant but present a dense barrier to the diffusion of drugs.

Erythrocyte

Red blood cell whose primary function is the transport of oxygen throughout the bloodstream.

Ischaemic

Referring to restricted blood supply and hence a shortage of oxygen.

Recanalization

The process of restoring flow to a blocked vessel.

Epicardial

Referring to the membrane constituting the outer layer of the heart.

Langerhans cells

Immune cells present in all layers of the epidermis and stimulated during vaccination.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Stride, E., Coussios, C. Nucleation, mapping and control of cavitation for drug delivery. Nat Rev Phys 1, 495–509 (2019). https://doi.org/10.1038/s42254-019-0074-y

Download citation

Further reading