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Ultrasonic technologies in imaging and drug delivery

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Abstract

Ultrasonic technologies show great promise for diagnostic imaging and drug delivery in theranostic applications. The development of functional and molecular ultrasound imaging is based on the technical breakthrough of high frame–rate ultrasound. The evolution of shear wave elastography, high-frequency ultrasound imaging, ultrasound contrast imaging, and super-resolution blood flow imaging are described in this review. Recently, the therapeutic potential of the interaction of ultrasound with microbubble cavitation or droplet vaporization has become recognized. Microbubbles and phase-change droplets not only provide effective contrast media, but also show great therapeutic potential. Interaction with ultrasound induces unique and distinguishable biophysical features in microbubbles and droplets that promote drug loading and delivery. In particular, this approach demonstrates potential for central nervous system applications. Here, we systemically review the technological developments of theranostic ultrasound including novel ultrasound imaging techniques, the synergetic use of ultrasound with microbubbles and droplets, and microbubble/droplet drug-loading strategies for anticancer applications and disease modulation. These advancements have transformed ultrasound from a purely diagnostic utility into a promising theranostic tool.

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References

  1. Leighton TG (2007) What is ultrasound? Prog Biophys Mol Biol 93:3–83. https://doi.org/10.1016/j.pbiomolbio.2006.07.026

    Article  PubMed  Google Scholar 

  2. Shung KK (2006) Diagnostic Ultrasound: Imaging and blood flow measurement. CRC Press, Boca Raton

    Google Scholar 

  3. Ignee A, Atkinson NS, Schuessler G, Dietrich CF (2016) Ultrasound contrast agents. Endosc Ultrasound 5:355–362. https://doi.org/10.4103/2303-9027.193594

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bercoff J (2011) Ultrafast ultrasound imaging. IntechOpen

  5. Lentacker I, De Cock I, Deckers R, De Smedt SC, Moonen CT (2014) Understanding ultrasound induced sonoporation: definitions and underlying mechanisms. Adv Drug Deliv Rev 72:49–64. https://doi.org/10.1016/j.addr.2013.11.008

    Article  CAS  PubMed  Google Scholar 

  6. Deprez J, Lajoinie G, Engelen Y, De Smedt SC, Lentacker I (2021) Opening doors with ultrasound and microbubbles: Beating biological barriers to promote drug delivery. Adv Drug Deliv Rev 172:9–36. https://doi.org/10.1016/j.addr.2021.02.015

    Article  CAS  PubMed  Google Scholar 

  7. Liu HL, Fan CH, Ting CY, Yeh CK (2014) Combining microbubbles and ultrasound for drug delivery to brain tumors: current progress and overview. Theranostics 4:432–444. https://doi.org/10.7150/thno.8074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Meng Y, Hynynen K, Lipsman N (2021) Applications of focused ultrasound in the brain: from thermoablation to drug delivery. Nat Rev Neurol 17:7–22. https://doi.org/10.1038/s41582-020-00418-z

    Article  PubMed  Google Scholar 

  9. Kripfgans OD, Fowlkes JB, Miller DL, Eldevik OP, Carson PL (2000) Acoustic droplet vaporization for therapeutic and diagnostic applications. Ultrasound Med Biol 26:1177–1189

    Article  CAS  Google Scholar 

  10. Huynh E, Rajora MA, Zheng G (2016) Multimodal micro, nano, and size conversion ultrasound agents for imaging and therapy. Wiley Interdiscip Rev Nanomed Nanobiotechnol 8:796–813. https://doi.org/10.1002/wnan.1398

    Article  PubMed  Google Scholar 

  11. Ho YJ, Wang TC, Fan CH, Yeh CK (2017) Current progress in antivascular tumor therapy. Drug Discov Today 22:1503–1515. https://doi.org/10.1016/j.drudis.2017.06.001

    Article  PubMed  Google Scholar 

  12. Lea-Banks H, O’Reilly MA, Hynynen K (2019) Ultrasound-responsive droplets for therapy: A review. J Control Release 293:144–154. https://doi.org/10.1016/j.jconrel.2018.11.028

    Article  CAS  PubMed  Google Scholar 

  13. Wells PNT (1977) Biomedical ultrasonics. Academic Press, London

    Google Scholar 

  14. Shung KK, Smith M, Tsui BMW (1992) Principles of Medical Imaging. Academic Press, San Diego

    Google Scholar 

  15. Shung KK, Thieme GA (1993) Biological tissues as ultrasonic scattering media. CRC Press, Boca Raton

    Google Scholar 

  16. Hill JC, Palma RA (2005) Doppler tissue imaging for the assessment of left ventricular diastolic function: a systematic approach for the sonographer. J Am Soc Echocardiogr 18:80–88. https://doi.org/10.1016/j.echo.2004.09.007

    Article  PubMed  Google Scholar 

  17. Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM et al (2000) Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation 102:1788–1794. https://doi.org/10.1161/01.cir.102.15.1788

    Article  CAS  PubMed  Google Scholar 

  18. Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BH et al (1997) Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 30:474–480. https://doi.org/10.1016/s0735-1097(97)88335-0

    Article  CAS  PubMed  Google Scholar 

  19. Greenleaf JA (1986) Tissue characterization with ultrasound. CRC Press, Boca Raton

    Google Scholar 

  20. Tanter M, Fink M (2014) Ultrafast imaging in biomedical ultrasound. IEEE Trans Ultrason Ferroelectr Freq Control 61:102–119. https://doi.org/10.1109/TUFFC.2014.6689779

    Article  PubMed  Google Scholar 

  21. Fink M (1983) Ultrasound imaging. Revue De Physique Appliquee 18:527–556. https://doi.org/10.1051/rphysap:01983001809052700

    Article  Google Scholar 

  22. Lu JY, Greenleaf JF (1991) Pulse-echo imaging using a nondiffracting beam transducer. Ultrasound Med Biol 17:265–281. https://doi.org/10.1016/0301-5629(91)90048-2

    Article  CAS  PubMed  Google Scholar 

  23. Tanter M, Bercoff J, Sandrin L, Fink M (2002) Ultrafast compound imaging for 2-D motion vector estimation: application to transient elastography. IEEE Trans Ultrason Ferroelectr Freq Control 49:1363–1374. https://doi.org/10.1109/tuffc.2002.1041078

    Article  PubMed  Google Scholar 

  24. Huang CC, Chen PY, Peng PH, Lee PY (2017) 40 MHz high-frequency ultrafast ultrasound imaging. Med Phys 44:2185–2195. https://doi.org/10.1002/mp.12244

    Article  PubMed  Google Scholar 

  25. Ophir J, Alam SK, Garra B, Kallel F, Konofagou E, Krouskop T et al (1999) Elastography: ultrasonic estimation and imaging of the elastic properties of tissues. Proc Inst Mech Eng H 213:203–233. https://doi.org/10.1243/0954411991534933

    Article  CAS  PubMed  Google Scholar 

  26. Nightingale K, Soo MS, Nightingale R, Trahey G (2002) Acoustic radiation force impulse imaging: in vivo demonstration of clinical feasibility. Ultrasound Med Biol 28:227–235. https://doi.org/10.1016/s0301-5629(01)00499-9

    Article  PubMed  Google Scholar 

  27. Gao L, Parker KJ, Lerner RM, Levinson SF (1996) Imaging of the elastic properties of tissue–a review. Ultrasound Med Biol 22:959–977. https://doi.org/10.1016/s0301-5629(96)00120-2

    Article  CAS  PubMed  Google Scholar 

  28. Nightingale KR, Palmeri ML, Nightingale RW, Trahey GE (2001) On the feasibility of remote palpation using acoustic radiation force. J Acoust Soc Am 110:625–634. https://doi.org/10.1121/1.1378344

    Article  CAS  PubMed  Google Scholar 

  29. Nightingale KR, Kornguth PJ, Trahey GE (1999) The use of acoustic streaming in breast lesion diagnosis: A clinical study. Ultrasound Med Biol 25:75–87. https://doi.org/10.1016/S0301-5629(98)00152-5

    Article  CAS  PubMed  Google Scholar 

  30. Walker WF (1999) Internal deformation of a uniform elastic solid by acoustic radiation force. J Acoust Soc Am 105:2508–2518. https://doi.org/10.1121/1.426854

    Article  CAS  PubMed  Google Scholar 

  31. Fatemi M, Greenleaf JF (1999) Vibro-acoustography: an imaging modality based on ultrasound-stimulated acoustic emission. Proc Natl Acad Sci U S A 96:6603–6608. https://doi.org/10.1073/pnas.96.12.6603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huang CC, Shih CC, Liu TY, Lee PY (2011) Assessing the viscoelastic properties of thrombus using a solid-sphere-based instantaneous force approach. Ultrasound Med Biol 37:1722–1733. https://doi.org/10.1016/j.ultrasmedbio.2011.06.026

    Article  PubMed  Google Scholar 

  33. Fahey BJ, Nightingale KR, Stutz DL, Trahey GE (2004) Acoustic radiation force impulse imaging of thermally- and chemically-induced lesions in soft tissues: preliminary ex vivo results. Ultrasound Med Biol 30:321–328. https://doi.org/10.1016/j.ultrasmedbio.2003.11.012

    Article  PubMed  Google Scholar 

  34. Shih CC, Huang CC, Zhou Q, Shung KK (2013) High-resolution acoustic-radiation-force-impulse imaging for assessing corneal sclerosis. IEEE Trans Med Imag 32:1316–1324. https://doi.org/10.1109/TMI.2013.2256794

    Article  Google Scholar 

  35. Gennisson JL, Deffieux T, Mace E, Montaldo G, Fink M, Tanter M (2010) Viscoelastic and anisotropic mechanical properties of in vivo muscle tissue assessed by supersonic shear imaging. Ultrasound Med Biol 36:789–801. https://doi.org/10.1016/j.ultrasmedbio.2010.02.013

    Article  PubMed  Google Scholar 

  36. Muller M, Gennisson JL, Deffieux T, Tanter M, Fink M (2009) Quantitative viscoelasticity mapping of human liver using supersonic shear imaging: preliminary in vivo feasibility study. Ultrasound Med Biol 35:219–229. https://doi.org/10.1016/j.ultrasmedbio.2008.08.018

    Article  PubMed  Google Scholar 

  37. Tanter M, Bercoff J, Athanasiou A, Deffieux T, Gennisson JL, Montaldo G et al (2008) Quantitative assessment of breast lesion viscoelasticity: initial clinical results using supersonic shear imaging. Ultrasound Med Biol 34:1373–1386. https://doi.org/10.1016/j.ultrasmedbio.2008.02.002

    Article  PubMed  Google Scholar 

  38. Nomikou N, Tiwari P, Trehan T, Gulati K, McHale AP (2012) Studies on neutral, cationic and biotinylated cationic microbubbles in enhancing ultrasound-mediated gene delivery in vitro and in vivo. Acta Biomater 8:1273–1280. https://doi.org/10.1016/j.actbio.2011.09.010

    Article  CAS  PubMed  Google Scholar 

  39. Cebi Olgun D, Korkmazer B, Kilic F, Dikici AS, Velidedeoglu M, Aydogan F et al (2014) Use of shear wave elastography to differentiate benign and malignant breast lesions. Diagn Interv Radiol 20:239–244. https://doi.org/10.5152/dir.2014.13306

    Article  PubMed  Google Scholar 

  40. Balleyguier C, Ciolovan L, Ammari S, Canale S, Sethom S, Al Rouhbane R et al (2013) Breast elastography: the technical process and its applications. Diagn Interv Imag 94:503–513. https://doi.org/10.1016/j.diii.2013.02.006

    Article  CAS  Google Scholar 

  41. Samir AE, Dhyani M, Vij A, Bhan AK, Halpern EF, Mendez-Navarro J et al (2015) Shear-wave elastography for the estimation of liver fibrosis in chronic liver disease: determining accuracy and ideal site for measurement. Radiology 274:888–896. https://doi.org/10.1148/radiol.14140839

    Article  PubMed  Google Scholar 

  42. Sande JA, Verjee S, Vinayak S, Amersi F, Ghesani M (2017) Ultrasound shear wave elastography and liver fibrosis: A Prospective Multicenter Study. World J Hepatol 9:38–47. https://doi.org/10.4254/wjh.v9.i1.38

    Article  PubMed  PubMed Central  Google Scholar 

  43. Park AY, Son EJ, Han K, Youk JH, Kim JA, Park CS (2015) Shear wave elastography of thyroid nodules for the prediction of malignancy in a large scale study. Eur J Radiol 84:407–412. https://doi.org/10.1016/j.ejrad.2014.11.019

    Article  PubMed  Google Scholar 

  44. Chen PY, Yang TH, Kuo LC, Shih CC, Huang CC (2020) Characterization of hand tendons through high-frequency ultrasound elastography. IEEE Trans Ultrason Ferroelectr Freq Control 67:37–48. https://doi.org/10.1109/Tuffc.2019.2938147

    Article  PubMed  Google Scholar 

  45. Chen PY, Shih CC, Lin WC, Ma T, Zhou QF, Shung KK et al (2018) High-resolution shear wave imaging of the human cornea using a dual-element transducer. Sensors. https://doi.org/10.3390/s18124244

    Article  PubMed  PubMed Central  Google Scholar 

  46. Shih CC, Qian XJ, Ma T, Han ZL, Huang CC, Zhou QF et al (2018) Quantitative assessment of thin-layer tissue viscoelastic properties using ultrasonic micro-elastography with lamb wave model. IEEE Trans Med Imag 37:1887–1898. https://doi.org/10.1109/Tmi.2018.2820157

    Article  Google Scholar 

  47. Tanter M, Touboul D, Gennisson JL, Bercoff J, Fink M (2009) High-resolution quantitative imaging of cornea elasticity using supersonic shear imaging. IEEE Trans Med Imag 28:1881–1893. https://doi.org/10.1109/TMI.2009.2021471

    Article  CAS  Google Scholar 

  48. Huang CC, Chen PY, Shih CC (2013) Estimating the viscoelastic modulus of a thrombus using an ultrasonic shear-wave approach. Med Phys 40:042901. https://doi.org/10.1118/1.4794493

    Article  PubMed  Google Scholar 

  49. Shih CC, Chen PY, Ma T, Zhou Q, Shung KK, Huang CC (2018) Development of an intravascular ultrasound elastography based on a dual-element transducer. R Soc Open Sci 5:180138. https://doi.org/10.1098/rsos.180138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sun L, Lien CL, Xu X, Shung KK (2008) In vivo cardiac imaging of adult zebrafish using high frequency ultrasound (45–75 MHz). Ultrasound Med Biol 34:31–39. https://doi.org/10.1016/j.ultrasmedbio.2007.07.002

    Article  CAS  PubMed  Google Scholar 

  51. Liu TY, Lee PY, Huang CC, Sun L, Shung KK (2013) A study of the adult zebrafish ventricular function by retrospective Doppler-gated ultrahigh-frame-rate echocardiography. IEEE Trans Ultrason Ferroelectr Freq Control 60:1827–1837. https://doi.org/10.1109/TUFFC.2013.2769

    Article  PubMed  PubMed Central  Google Scholar 

  52. Sun P, Zhang Y, Yu F, Parks E, Lyman A, Wu Q et al (2009) Micro-electrocardiograms to study post-ventricular amputation of zebrafish heart. Ann Biomed Eng 37:890–901. https://doi.org/10.1007/s10439-009-9668-3

    Article  PubMed  PubMed Central  Google Scholar 

  53. Huang CC, Su TH, Shih CC (2015) High-resolution tissue Doppler imaging of the zebrafish heart during its regeneration. Zebrafish 12:48–57. https://doi.org/10.1089/zeb.2014.1026

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ho-Chiang C, Huang H, Huang CC (2020) High-frequency ultrasound deformation imaging for adult zebrafish during heart regeneration. Quant Imaging Med Surg 10: 66–75. https://doi.org/10.21037/qims.2019.09.20

  55. Fei CL, Chiu CT, Chen XY, Chen ZY, Ma JG, Zhu BP et al (2016) Ultrahigh Frequency (100 MHz-300 MHz) Ultrasonic Transducers for Optical Resolution Medical Imagining. Sci Rep 6 ARTN 28360 https://doi.org/10.1038/srep28360

  56. Mohamed ETA, Declercq NF (2020) Giga-Hertz ultrasonic microscopy: Getting over the obscurity- A short review on the biomedical applications. Phys Med 9:100025. https://doi.org/10.1016/j.phmed.2020.100025

    Article  Google Scholar 

  57. Ingram N, Macnab SA, Marston G, Scott N, Carr IM, Markham AF et al (2013) The use of high-frequency ultrasound imaging and biofluorescence for in vivo evaluation of gene therapy vectors. BMC Med Imag 13:35. https://doi.org/10.1186/1471-2342-13-35

    Article  Google Scholar 

  58. Lakshman M, Needles A (2015) Screening and quantification of the tumor microenvironment with micro-ultrasound and photoacoustic imaging. Nat Methods 12:iii–v

    Article  Google Scholar 

  59. Huang CC, Cheng HF, Zhu BP, Chen PY, Beh ST, Kuo YM et al (2017) Studying arterial stiffness using high-frequency ultrasound in mice with alzheimer disease. Ultrasound Med Biol 43:2054–2064. https://doi.org/10.1016/j.ultrasmedbio.2017.04.029

    Article  PubMed  Google Scholar 

  60. Huang CC, Chen WT (2014) Developing high-frequency ultrasound tomography for testicular tumor imaging in rats: an in vitro study. Med Phys 41:012902. https://doi.org/10.1118/1.4852915

    Article  PubMed  Google Scholar 

  61. Chang CC, Chen PY, Huang H, Huang CC (2019) In Vivo Visualization of vasculature in adult zebrafish by using high-frequency ultrafast ultrasound imaging. IEEE Trans Biomed Eng 66:1742–1751. https://doi.org/10.1109/Tbme.2018.2878887

    Article  PubMed  Google Scholar 

  62. Hsiao YY, Yang TH, Chen PY, Hsu HY, Kuo LC, Su FC et al (2020) Characterization of the extensor digitorum communis tendon using high-frequency ultrasound shear wave elastography. Med Phys. https://doi.org/10.1002/mp.14061

    Article  PubMed  Google Scholar 

  63. Huang H, Chen PY, Huang CC (2020) 40-MHz high-frequency vector Doppler imaging for superficial venous valve flow estimation. Med Phys 47:4020–4031. https://doi.org/10.1002/mp.14362

    Article  PubMed  Google Scholar 

  64. Lay FY, Chen PY, Cheng HF, Kuo YM, Huang CC (2019) Ex vivo evaluation of mouse brain elasticity using high-frequency ultrasound elastography. IEEE Trans Biomed Eng 66:3426–3435. https://doi.org/10.1109/Tbme.2019.2905551

    Article  PubMed  Google Scholar 

  65. Li HC, Chen PY, Cheng HF, Kuo YM, Huang CC (2019) In Vivo visualization of brain vasculature in alzheimer’s disease mice by high-frequency micro-doppler imaging. IEEE Trans Biomed Eng 66:3393–3401. https://doi.org/10.1109/Tbme.2019.2904702

    Article  PubMed  Google Scholar 

  66. Wang MY, Yang TH, Huang H, Hsu HY, Kuo LC, Su FC et al (2020) Evaluation of hand tendon movement by using high-frequency ultrasound vector doppler imaging. IEEE Trans Biomed Eng 67:2945–2952. https://doi.org/10.1109/Tbme.2020.2974244

    Article  PubMed  Google Scholar 

  67. Frinking P, Segers T, Luan Y, Tranquart F (2020) Three decades of ultrasound contrast agents: a review of the past, present and future improvements. Ultrasound Med Biol 46:892–908. https://doi.org/10.1016/j.ultrasmedbio.2019.12.008

    Article  PubMed  Google Scholar 

  68. Nguyen T, Davidson BP (2019) Contrast enhanced ultrasound perfusion imaging in skeletal muscle. J Cardiovasc Imaging 27:163–177. https://doi.org/10.4250/jcvi.2019.27.e31

    Article  PubMed  PubMed Central  Google Scholar 

  69. Rafailidis V, Huang DY, Yusuf GT, Sidhu PS (2020) General principles and overview of vascular contrast-enhanced ultrasonography. Ultrasonography 39: 22–42. https://doi.org/10.14366/usg.19022

  70. Schinkel AFL, Bosch JG, Staub D, Adam D, Feinstein SB (2020) Contrast-enhanced ultrasound to assess carotid intraplaque neovascularization. Ultrasound Med Biol 46:466–478. https://doi.org/10.1016/j.ultrasmedbio.2019.10.020

    Article  PubMed  Google Scholar 

  71. Christensen-Jeffries K, Couture O, Dayton PA, Eldar YC, Hynynen K, Kiessling F et al (2020) Super-resolution Ultrasound Imaging. Ultrasound Med Biol 46:865–891. https://doi.org/10.1016/j.ultrasmedbio.2019.11.013

    Article  PubMed  PubMed Central  Google Scholar 

  72. Dizeux A, Gesnik M, Ahnine H, Blaize K, Arcizet F, Picaud S et al (2019) Functional ultrasound imaging of the brain reveals propagation of task-related brain activity in behaving primates. Nat Commun 10:1400. https://doi.org/10.1038/s41467-019-09349-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Errico C, Pierre J, Pezet S, Desailly Y, Lenkei Z, Couture O et al (2015) Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging. Nature 527:499–502. https://doi.org/10.1038/nature16066

    Article  CAS  PubMed  Google Scholar 

  74. Couture O, Hingot V, Heiles B, Muleki-Seya P, Tanter M (2018) Ultrasound localization microscopy and super-resolution: a state of the art. IEEE Trans Ultrason Ferroelectr Freq Control 65:1304–1320. https://doi.org/10.1109/TUFFC.2018.2850811

    Article  PubMed  Google Scholar 

  75. Lin CY, Tsai CH, Feng LY, Chai WY, Lin CJ, Huang CY et al (2019) Focused ultrasound-induced blood brain-barrier opening enhanced vascular permeability for GDNF delivery in Huntington’s disease mouse model. Brain Stimul 12:1143–1150. https://doi.org/10.1016/j.brs.2019.04.011

    Article  PubMed  Google Scholar 

  76. Geers B, Lentacker I, Sanders NN, Demeester J, Meairs S, De Smedt SC (2011) Self-assembled liposome-loaded microbubbles: The missing link for safe and efficient ultrasound triggered drug-delivery. J Control Release 152:249–256. https://doi.org/10.1016/j.jconrel.2011.02.024

    Article  CAS  PubMed  Google Scholar 

  77. Ting CY, Fan CH, Liu HL, Huang CY, Hsieh HY, Yen TC et al (2012) Concurrent blood-brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment. Biomaterials 33:704–712. https://doi.org/10.1016/j.biomaterials.2011.09.096

    Article  CAS  PubMed  Google Scholar 

  78. Unger EC, McCreery TP, Sweitzer RH, Caldwell VE, Wu Y (1998) Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent. Invest Radiol 33:886–892. https://doi.org/10.1097/00004424-199812000-00007

    Article  CAS  PubMed  Google Scholar 

  79. Fan CH, Ting CY, Liu HL, Huang CY, Hsieh HY, Yen TC et al (2013) Antiangiogenic-targeting drug-loaded microbubbles combined with focused ultrasound for glioma treatment. Biomaterials 34:2142–2155. https://doi.org/10.1016/j.biomaterials.2012.11.048

    Article  CAS  PubMed  Google Scholar 

  80. Yeh JS, Sennoga CA, McConnell E, Eckersley R, Tang MX, Nourshargh S et al (2015) A targeting microbubble for ultrasound molecular imaging. PLoS ONE 10:e0129681. https://doi.org/10.1371/journal.pone.0129681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tinkov S, Coester C, Serba S, Geis NA, Katus HA, Winter G et al (2010) New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: in-vivo characterization. J Control Release 148:368–372. https://doi.org/10.1016/j.jconrel.2010.09.004

    Article  CAS  PubMed  Google Scholar 

  82. Shortencarier MJ, Dayton PA, Bloch SH, Schumann PA, Matsunaga TO, Ferrara KW (2004) A method for radiation-force localized drug delivery using gas-filled lipospheres. IEEE Trans Ultrason Ferroelectr Freq Control 51:822–831. https://doi.org/10.1109/tuffc.2004.1320741

    Article  PubMed  Google Scholar 

  83. Borden MA, Caskey CF, Little E, Gillies RJ, Ferrara KW (2007) DNA and polylysine adsorption and multilayer construction onto cationic lipid-coated microbubbles. Langmuir 23:9401–9408. https://doi.org/10.1021/la7009034

    Article  CAS  PubMed  Google Scholar 

  84. Melino S, Zhou M, Tortora M, Paci M, Cavalieri F, Ashokkumar M (2012) Molecular properties of lysozyme-microbubbles: towards the protein and nucleic acid delivery. Amino Acids 43:885–896. https://doi.org/10.1007/s00726-011-1148-z

    Article  CAS  PubMed  Google Scholar 

  85. Liao AH, Hung CR, Lin CF, Lin YC, Chen HK (2017) Treatment effects of lysozyme-shelled microbubbles and ultrasound in inflammatory skin disease. Sci Rep 7:41325. https://doi.org/10.1038/srep41325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lum AF, Borden MA, Dayton PA, Kruse DE, Simon SI, Ferrara KW (2006) Ultrasound radiation force enables targeted deposition of model drug carriers loaded on microbubbles. J Control Release 111:128–134. https://doi.org/10.1016/j.jconrel.2005.11.006

    Article  CAS  PubMed  Google Scholar 

  87. Ryu JY, Won EJ, Lee HAR, Kim JH, Hui E, Kim HP et al (2020) Ultrasound-activated particles as CRISPR/Cas9 delivery system for androgenic alopecia therapy. Biomaterials 232:119736. https://doi.org/10.1016/j.biomaterials.2019.119736

    Article  CAS  PubMed  Google Scholar 

  88. Ho YJ, Chu SW, Liao EC, Fan CH, Chan HL, Wei KC et al (2019) Normalization of tumor vasculature by oxygen microbubbles with ultrasound. Theranostics 9:7370–7383. https://doi.org/10.7150/thno.37750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ho YJ, Wang TC, Fan CH, Yeh CK (2018) Spatially uniform tumor treatment and drug penetration by regulating ultrasound with microbubbles. ACS Appl Mater Interfaces 10:17784–17791. https://doi.org/10.1021/acsami.8b05508

    Article  CAS  PubMed  Google Scholar 

  90. McEwan C, Owen J, Stride E, Fowley C, Nesbitt H, Cochrane D et al (2015) Oxygen carrying microbubbles for enhanced sonodynamic therapy of hypoxic tumours. J Control Release 203:51–56. https://doi.org/10.1016/j.jconrel.2015.02.004

    Article  CAS  PubMed  Google Scholar 

  91. Grishenkov D, Gonon A, Weitzberg E, Lundberg JO, Harmark J, Cerroni B et al (2015) Ultrasound contrast agent loaded with nitric oxide as a theranostic microdevice. Drug Des Devel Ther 9:2409–2419. https://doi.org/10.2147/DDDT.S77790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Huynh E, Leung BY, Helfield BL, Shakiba M, Gandier JA, Jin CS et al (2015) In situ conversion of porphyrin microbubbles to nanoparticles for multimodality imaging. Nat Nanotechnol 10:325–332. https://doi.org/10.1038/nnano.2015.25

    Article  CAS  PubMed  Google Scholar 

  93. Fan CH, Chang EL, Ting CY, Lin YC, Liao EC, Huang CY et al (2016) Folate-conjugated gene-carrying microbubbles with focused ultrasound for concurrent blood-brain barrier opening and local gene delivery. Biomaterials 106:46–57. https://doi.org/10.1016/j.biomaterials.2016.08.017

    Article  CAS  PubMed  Google Scholar 

  94. Luan Y, Lajoinie G, Gelderblom E, Skachkov I, van der Steen AF, Vos HJ et al (2014) Lipid shedding from single oscillating microbubbles. Ultrasound Med Biol 40:1834–1846. https://doi.org/10.1016/j.ultrasmedbio.2014.02.031

    Article  PubMed  Google Scholar 

  95. De Cock I, Lajoinie G, Versluis M, De Smedt SC, Lentacker I (2016) Sonoprinting and the importance of microbubble loading for the ultrasound mediated cellular delivery of nanoparticles. Biomaterials 83:294–307. https://doi.org/10.1016/j.biomaterials.2016.01.022

    Article  CAS  PubMed  Google Scholar 

  96. Roovers S, Lajoinie G, De Cock I, Brans T, Dewitte H, Braeckmans K et al (2019) Sonoprinting of nanoparticle-loaded microbubbles: Unraveling the multi-timescale mechanism. Biomaterials 217:119250. https://doi.org/10.1016/j.biomaterials.2019.119250

    Article  CAS  PubMed  Google Scholar 

  97. Roovers S, Deprez J, Priwitaningrum D, Lajoinie G, Rivron N, Declercq H et al (2019) Sonoprinting liposomes on tumor spheroids by microbubbles and ultrasound. J Control Release 316:79–92. https://doi.org/10.1016/j.jconrel.2019.10.051

    Article  CAS  PubMed  Google Scholar 

  98. De Temmerman ML, Dewitte H, Vandenbroucke RE, Lucas B, Libert C, Demeester J et al (2011) mRNA-Lipoplex loaded microbubble contrast agents for ultrasound-assisted transfection of dendritic cells. Biomaterials 32:9128–9135. https://doi.org/10.1016/j.biomaterials.2011.08.024

    Article  CAS  PubMed  Google Scholar 

  99. Helfield B, Chen X, Watkins SC, Villanueva FS (2016) Biophysical insight into mechanisms of sonoporation. Proc Natl Acad Sci U S A 113:9983–9988. https://doi.org/10.1073/pnas.1606915113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Apodaca G (2002) Modulation of membrane traffic by mechanical stimuli. Am J Physiol Renal Physiol 282:F179-190. https://doi.org/10.1152/ajprenal.2002.282.2.F179

    Article  PubMed  Google Scholar 

  101. Sutton JT, Haworth KJ, Pyne-Geithman G, Holland CK (2013) Ultrasound-mediated drug delivery for cardiovascular disease. Expert Opin Drug Deliv 10:573–592. https://doi.org/10.1517/17425247.2013.772578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kooiman K, Vos HJ, Versluis M, de Jong N (2014) Acoustic behavior of microbubbles and implications for drug delivery. Adv Drug Deliv Rev 72:28–48. https://doi.org/10.1016/j.addr.2014.03.003

    Article  CAS  PubMed  Google Scholar 

  103. Qin P, Han T, Yu ACH, Xu L (2018) Mechanistic understanding the bioeffects of ultrasound-driven microbubbles to enhance macromolecule delivery. J Control Release 272:169–181. https://doi.org/10.1016/j.jconrel.2018.01.001

    Article  CAS  PubMed  Google Scholar 

  104. Qin S, Caskey CF, Ferrara KW (2009) Ultrasound contrast microbubbles in imaging and therapy: physical principles and engineering. Phys Med Biol 54:R27-57. https://doi.org/10.1088/0031-9155/54/6/R01

    Article  PubMed  PubMed Central  Google Scholar 

  105. Zhao YZ, Luo YK, Lu CT, Xu JF, Tang J, Zhang M et al (2008) Phospholipids-based microbubbles sonoporation pore size and reseal of cell membrane cultured in vitro. J Drug Target 16:18–25. https://doi.org/10.1080/10611860701637792

    Article  CAS  PubMed  Google Scholar 

  106. Deng CX, Sieling F, Pan H, Cui J (2004) Ultrasound-induced cell membrane porosity. Ultrasound Med Biol 30:519–526. https://doi.org/10.1016/j.ultrasmedbio.2004.01.005

    Article  PubMed  Google Scholar 

  107. Hu Y, Wan JM, Yu AC (2013) Membrane perforation and recovery dynamics in microbubble-mediated sonoporation. Ultrasound Med Biol 39:2393–2405. https://doi.org/10.1016/j.ultrasmedbio.2013.08.003

    Article  PubMed  Google Scholar 

  108. Lionetti V, Fittipaldi A, Agostini S, Giacca M, Recchia FA, Picano E (2009) Enhanced caveolae-mediated endocytosis by diagnostic ultrasound in vitro. Ultrasound Med Biol 35:136–143. https://doi.org/10.1016/j.ultrasmedbio.2008.07.011

    Article  PubMed  Google Scholar 

  109. Zeghimi A, Escoffre JM, Bouakaz A (2015) Role of endocytosis in sonoporation-mediated membrane permeabilization and uptake of small molecules: a electron microscopy study. Phys Biol 12:066007. https://doi.org/10.1088/1478-3975/12/6/066007

    Article  CAS  PubMed  Google Scholar 

  110. Fekri F, Delos Santos RC, Karshafian R, Antonescu CN (2016) Ultrasound microbubble treatment enhances clathrin-mediated endocytosis and fluid-phase uptake through distinct mechanisms. PLoS ONE 11:e0156754. https://doi.org/10.1371/journal.pone.0156754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Davies PF, Dewey CF Jr, Bussolari SR, Gordon EJ, Gimbrone MA Jr (1984) Influence of hemodynamic forces on vascular endothelial function. In vitro studies of shear stress and pinocytosis in bovine aortic cells. J Clin Invest 73:1121–1129. https://doi.org/10.1172/JCI111298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ho YJ, Chang HC, Lin CW, Fan CH, Lin YC, Wei KC et al (2021) Oscillatory behavior of microbubbles impacts efficacy of cellular drug delivery. J Control Release 333:316–327. https://doi.org/10.1016/j.jconrel.2021.03.044

    Article  CAS  PubMed  Google Scholar 

  113. Davies PF (1995) Flow-mediated endothelial mechanotransduction. Physiol Rev 75:519–560. https://doi.org/10.1152/physrev.1995.75.3.519

    Article  CAS  PubMed  Google Scholar 

  114. Wu J (2002) Theoretical study on shear stress generated by microstreaming surrounding contrast agents attached to living cells. Ultrasound Med Biol 28:125–129. https://doi.org/10.1016/s0301-5629(01)00497-5

    Article  PubMed  Google Scholar 

  115. Caskey CF, Qin S, Dayton PA, Ferrara KW (2009) Microbubble tunneling in gel phantoms. J Acoust Soc Am 125:183–189. https://doi.org/10.1121/1.3097679

    Article  Google Scholar 

  116. Arvanitis CD, Bazan-Peregrino M, Rifai B, Seymour LW, Coussios CC (2011) Cavitation-enhanced extravasation for drug delivery. Ultrasound Med Biol 37:1838–1852. https://doi.org/10.1016/j.ultrasmedbio.2011.08.004

    Article  PubMed  Google Scholar 

  117. Heath CH, Sorace A, Knowles J, Rosenthal E, Hoyt K (2012) Microbubble therapy enhances anti-tumor properties of cisplatin and cetuximab in vitro and in vivo. Otolaryngol Head Neck Surg 146:938–945. https://doi.org/10.1177/0194599812436648

    Article  PubMed  PubMed Central  Google Scholar 

  118. Sakakima Y, Hayashi S, Yagi Y, Hayakawa A, Tachibana K, Nakao A (2005) Gene therapy for hepatocellular carcinoma using sonoporation enhanced by contrast agents. Cancer Gene Ther 12:884–889. https://doi.org/10.1038/sj.cgt.7700850

    Article  CAS  PubMed  Google Scholar 

  119. Zolochevska O, Xia X, Williams BJ, Ramsay A, Li S, Figueiredo ML (2011) Sonoporation delivery of interleukin-27 gene therapy efficiently reduces prostate tumor cell growth in vivo. Hum Gene Ther 22:1537–1550. https://doi.org/10.1089/hum.2011.076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Suzuki R, Namai E, Oda Y, Nishiie N, Otake S, Koshima R et al (2010) Cancer gene therapy by IL-12 gene delivery using liposomal bubbles and tumoral ultrasound exposure. J Control Release 142:245–250. https://doi.org/10.1016/j.jconrel.2009.10.027

    Article  CAS  PubMed  Google Scholar 

  121. Suzuki R, Oda Y, Utoguchi N, Namai E, Taira Y, Okada N et al (2009) A novel strategy utilizing ultrasound for antigen delivery in dendritic cell-based cancer immunotherapy. J Control Release 133:198–205. https://doi.org/10.1016/j.jconrel.2008.10.015

    Article  CAS  PubMed  Google Scholar 

  122. Oda Y, Suzuki R, Otake S, Nishiie N, Hirata K, Koshima R et al (2012) Prophylactic immunization with Bubble liposomes and ultrasound-treated dendritic cells provided a four-fold decrease in the frequency of melanoma lung metastasis. J Control Release 160:362–366. https://doi.org/10.1016/j.jconrel.2011.12.003

    Article  CAS  PubMed  Google Scholar 

  123. Kotopoulis S, Delalande A, Popa M, Mamaeva V, Dimcevski G, Gilja OH et al (2014) Sonoporation-enhanced chemotherapy significantly reduces primary tumour burden in an orthotopic pancreatic cancer xenograft. Mol Imag Biol 16:53–62. https://doi.org/10.1007/s11307-013-0672-5

    Article  Google Scholar 

  124. Couture O, Foley J, Kassell NF, Larrat B, Aubry JF (2014) Review of ultrasound mediated drug delivery for cancer treatment: updates from pre-clinical studies. Trans Cancer Res 3:494–511. https://doi.org/10.3978/j.issn.2218-676X.2014.10.01

    Article  CAS  Google Scholar 

  125. Dimcevski G, Kotopoulis S, Bjånes T, Hoem D, Schjøtt J, Gjertsen BT et al (2016) A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer. J Control Release 243:172–181. https://doi.org/10.1016/j.jconrel.2016.10.007

    Article  CAS  PubMed  Google Scholar 

  126. Khokhlova TD, Haider Y, Hwang JH (2015) Therapeutic potential of ultrasound microbubbles in gastrointestinal oncology: recent advances and future prospects. Therap Adv Gastroenterol 8:384–394. https://doi.org/10.1177/1756283X15592584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J et al (2004) Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 351:2170–2178. https://doi.org/10.1056/NEJMoa041175

    Article  CAS  Google Scholar 

  128. Hu J, Zhang N Jr, Li L, Zhang N Sr, Ma Y, Zhao C et al (2018) The synergistic bactericidal effect of vancomycin on UTMD treated biofilm involves damage to bacterial cells and enhancement of metabolic activities. Sci Rep 8:192. https://doi.org/10.1038/s41598-017-18496-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Lattwein KR, Shekhar H, Kouijzer JJP, van Wamel WJB, Holland CK, Kooiman K (2020) Sonobactericide: an emerging treatment strategy for bacterial infections. Ultrasound Med Biol 46:193–215. https://doi.org/10.1016/j.ultrasmedbio.2019.09.011

    Article  PubMed  Google Scholar 

  130. Lattwein KR, Shekhar H, van Wamel WJB, Gonzalez T, Herr AB, Holland CK et al (2018) An in vitro proof-of-principle study of sonobactericide. Sci Rep 8:3411. https://doi.org/10.1038/s41598-018-21648-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Dong Y, Li J, Li P, Yu J (2018) Ultrasound microbubbles enhance the activity of vancomycin against staphylococcus epidermidis biofilms in vivo. J Ultrasound Med 37:1379–1387. https://doi.org/10.1002/jum.14475

    Article  PubMed  Google Scholar 

  132. Zhu X, Guo J, He C, Geng H, Yu G, Li J et al (2016) Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles. Sci Rep 6:21683. https://doi.org/10.1038/srep21683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kilroy JP, Dhanaliwala AH, Klibanov AL, Bowles DK, Wamhoff BR, Hossack JA (2015) Reducing neointima formation in a swine model with IVUS and sirolimus microbubbles. Ann Biomed Eng 43:2642–2651. https://doi.org/10.1007/s10439-015-1315-6

    Article  PubMed  PubMed Central  Google Scholar 

  134. Nomikou N, Fowley C, Byrne NM, McCaughan B, McHale AP, Callan JF (2012) Microbubble-sonosensitiser conjugates as therapeutics in sonodynamic therapy. Chem Commun (Camb) 48:8332–8334. https://doi.org/10.1039/c2cc33913g

    Article  CAS  Google Scholar 

  135. McEwan C, Fowley C, Nomikou N, McCaughan B, McHale AP, Callan JF (2014) Polymeric microbubbles as delivery vehicles for sensitizers in sonodynamic therapy. Langmuir 30:14926–14930. https://doi.org/10.1021/la503929c

    Article  CAS  PubMed  Google Scholar 

  136. Yang H, Sun Y, Wei J, Xu L, Tang Y, Yang L et al (2019) The effects of ultrasound-targeted microbubble destruction (UTMD) carrying IL-8 monoclonal antibody on the inflammatory responses and stability of atherosclerotic plaques. Biomed Pharmacother 118:109161. https://doi.org/10.1016/j.biopha.2019.109161

    Article  CAS  PubMed  Google Scholar 

  137. Horsley H, Owen J, Browning R, Carugo D, Malone-Lee J, Stride E et al (2019) Ultrasound-activated microbubbles as a novel intracellular drug delivery system for urinary tract infection. J Control Release 301:166–175. https://doi.org/10.1016/j.jconrel.2019.03.017

    Article  CAS  PubMed  Google Scholar 

  138. Un K, Kawakami S, Suzuki R, Maruyama K, Yamashita F, Hashida M (2011) Suppression of melanoma growth and metastasis by DNA vaccination using an ultrasound-responsive and mannose-modified gene carrier. Mol Pharm 8:543–554. https://doi.org/10.1021/mp100369n

    Article  CAS  PubMed  Google Scholar 

  139. Un K, Kawakami S, Suzuki R, Maruyama K, Yamashita F, Hashida M (2010) Development of an ultrasound-responsive and mannose-modified gene carrier for DNA vaccine therapy. Biomaterials 31:7813–7826. https://doi.org/10.1016/j.biomaterials.2010.06.058

    Article  CAS  PubMed  Google Scholar 

  140. Dewitte H, Van Lint S, Heirman C, Thielemans K, De Smedt SC, Breckpot K et al (2014) The potential of antigen and TriMix sonoporation using mRNA-loaded microbubbles for ultrasound-triggered cancer immunotherapy. J Control Release 194:28–36. https://doi.org/10.1016/j.jconrel.2014.08.011

    Article  CAS  PubMed  Google Scholar 

  141. Lentacker I, De Geest BG, Vandenbroucke RE, Peeters L, Demeester J, De Smedt SC et al (2006) Ultrasound-responsive polymer-coated microbubbles that bind and protect DNA. Langmuir 22:7273–7278. https://doi.org/10.1021/la0603828

    Article  CAS  PubMed  Google Scholar 

  142. Geis NA, Mayer CR, Kroll RD, Hardt SE, Katus HA, Bekeredjian R (2009) Spatial distribution of ultrasound targeted microbubble destruction increases cardiac transgene expression but not capillary permeability. Ultrasound Med Biol 35:1119–1126. https://doi.org/10.1016/j.ultrasmedbio.2009.01.008

    Article  PubMed  Google Scholar 

  143. Bekeredjian R, Kroll RD, Fein E, Tinkov S, Coester C, Winter G et al (2007) Ultrasound targeted microbubble destruction increases capillary permeability in hepatomas. Ultrasound Med Biol 33:1592–1598. https://doi.org/10.1016/j.ultrasmedbio.2007.05.003

    Article  PubMed  Google Scholar 

  144. Liu H, Chang S, Sun J, Zhu S, Pu C, Zhu Y et al (2014) Ultrasound-mediated destruction of LHRHa-targeted and paclitaxel-loaded lipid microbubbles induces proliferation inhibition and apoptosis in ovarian cancer cells. Mol Pharm 11:40–48. https://doi.org/10.1021/mp4005244

    Article  CAS  PubMed  Google Scholar 

  145. Yan F, Li X, Jin Q, Jiang C, Zhang Z, Ling T et al (2011) Therapeutic ultrasonic microbubbles carrying paclitaxel and LyP-1 peptide: preparation, characterization and application to ultrasound-assisted chemotherapy in breast cancer cells. Ultrasound Med Biol 37:768–779. https://doi.org/10.1016/j.ultrasmedbio.2011.02.006

    Article  PubMed  Google Scholar 

  146. Zhou Y, Gu H, Xu Y, Li F, Kuang S, Wang Z et al (2015) Targeted antiangiogenesis gene therapy using targeted cationic microbubbles conjugated with CD105 antibody compared with untargeted cationic and neutral microbubbles. Theranostics 5:399–417. https://doi.org/10.7150/thno.10351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Crake C, Owen J, Smart S, Coviello C, Coussios CC, Carlisle R et al (2016) Enhancement and passive acoustic mapping of cavitation from fluorescently tagged magnetic resonance-visible magnetic microbubbles in vivo. Ultrasound Med Biol 42:3022–3036. https://doi.org/10.1016/j.ultrasmedbio.2016.08.002

    Article  PubMed  Google Scholar 

  148. Chertok B, Langer R (2018) Circulating magnetic microbubbles for localized real-time control of drug delivery by ultrasonography-guided magnetic targeting and ultrasound. Theranostics 8:341–357. https://doi.org/10.7150/thno.20781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Beguin E, Bau L, Shrivastava S, Stride E (2019) Comparing strategies for magnetic functionalization of microbubbles. ACS Appl Mater Interfaces 11:1829–1840. https://doi.org/10.1021/acsami.8b18418

    Article  CAS  PubMed  Google Scholar 

  150. 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 24:12–20. https://doi.org/10.1016/j.neuroimage.2004.06.046

    Article  PubMed  Google Scholar 

  151. Hynynen K, McDannold N, Martin H, Jolesz FA, Vykhodtseva N (2003) The threshold for brain damage in rabbits induced by bursts of ultrasound in the presence of an ultrasound contrast agent (Optison). Ultrasound Med Biol 29:473–481. https://doi.org/10.1016/s0301-5629(02)00741-x

    Article  PubMed  Google Scholar 

  152. McDannold N, Vykhodtseva N, Raymond S, Jolesz FA, Hynynen K (2005) MRI-guided targeted blood-brain barrier disruption with focused ultrasound: histological findings in rabbits. Ultrasound Med Biol 31:1527–1537. https://doi.org/10.1016/j.ultrasmedbio.2005.07.010

    Article  PubMed  Google Scholar 

  153. Liu HL, Wai YY, Chen WS, Chen JC, Hsu PH, Wu XY et al (2008) Hemorrhage detection during focused-ultrasound induced blood-brain-barrier opening by using susceptibility-weighted magnetic resonance imaging. Ultrasound Med Biol 34:598–606. https://doi.org/10.1016/j.ultrasmedbio.2008.01.011

    Article  PubMed  Google Scholar 

  154. Fan CH, Liu HL, Huang CY, Ma YJ, Yen TC, Yeh CK (2012) Detection of intracerebral hemorrhage and transient blood-supply shortage in focused-ultrasound-induced blood-brain barrier disruption by ultrasound imaging. Ultrasound Med Biol 38:1372–1382. https://doi.org/10.1016/j.ultrasmedbio.2012.03.013

    Article  PubMed  Google Scholar 

  155. Wei KC, Chu PC, Wang HY, Huang CY, Chen PY, Tsai HC et al (2013) Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study. PLoS ONE 8:e58995. https://doi.org/10.1371/journal.pone.0058995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Liu HL, Huang CY, Chen JY, Wang HY, Chen PY, Wei KC (2014) Pharmacodynamic and therapeutic investigation of focused ultrasound-induced blood-brain barrier opening for enhanced temozolomide delivery in glioma treatment. PLoS ONE 9:e114311. https://doi.org/10.1371/journal.pone.0114311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Liu HL, Hua MY, Chen PY, Chu PC, Pan CH, Yang HW et al (2010) Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology 255:415–425. https://doi.org/10.1148/radiol.10090699

    Article  PubMed  Google Scholar 

  158. Treat LH, McDannold N, Vykhodtseva N, Zhang Y, Tam K, Hynynen K (2007) Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int J Cancer 121:901–907. https://doi.org/10.1002/ijc.22732

    Article  CAS  PubMed  Google Scholar 

  159. Beccaria K, Canney M, Goldwirt L, Fernandez C, Piquet J, Perier MC et al (2016) Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits. J Neurosurg 124:1602–1610. https://doi.org/10.3171/2015.4.Jns142893

    Article  CAS  PubMed  Google Scholar 

  160. Zhang DY, Dmello C, Chen L, Arrieta VA, Gonzalez-Buendia E, Kane JR et al (2020) Ultrasound-mediated delivery of paclitaxel for glioma: a comparative study of distribution, toxicity, and efficacy of albumin-bound versus cremophor formulations. Clin Cancer Res 26:477–486. https://doi.org/10.1158/1078-0432.Ccr-19-2182

    Article  CAS  PubMed  Google Scholar 

  161. Treat LH, McDannold N, Zhang Y, Vykhodtseva N, Hynynen K (2012) Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma. Ultrasound Med Biol 38:1716–1725. https://doi.org/10.1016/j.ultrasmedbio.2012.04.015

    Article  PubMed  PubMed Central  Google Scholar 

  162. Aryal M, Vykhodtseva N, Zhang YZ, McDannold N (2015) Multiple sessions of liposomal doxorubicin delivery via focused ultrasound mediated blood-brain barrier disruption: a safety study. J Control Release 204:60–69. https://doi.org/10.1016/j.jconrel.2015.02.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Sun T, Zhang YZ, Power C, Alexander PM, Sutton JT, Aryal M et al (2017) Closed-loop control of targeted ultrasound drug delivery across the blood-brain/tumor barriers in a rat glioma model. Proc Natl Acad Sci USA 114:E10281–E10290. https://doi.org/10.1073/pnas.1713328114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. McDannold N, Zhang YZ, Supko JG, Power C, Sun T, Peng CG et al (2019) Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model. Theranostics 9:6284–6299. https://doi.org/10.7150/thno.35892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chen PY, Hsieh HY, Huang CY, Lin CY, Wei KC, Liu HL (2015) Focused ultrasound-induced blood-brain barrier opening to enhance interleukin-12 delivery for brain tumor immunotherapy: a preclinical feasibility study. J Transl Med 13:93. https://doi.org/10.1186/s12967-015-0451-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Kinoshita M, McDannold N, Jolesz FA, Hynynen K (2006) Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc Natl Acad Sci U S A 103:11719–11723. https://doi.org/10.1073/pnas.0604318103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kinoshita M, McDannold N, Jolesz FA, Hynynen K (2006) Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound. Biochem Biophys Res Commun 340:1085–1090. https://doi.org/10.1016/j.bbrc.2005.12.112

    Article  CAS  PubMed  Google Scholar 

  168. Liu HL, Hsu PH, Lin CY, Huang CW, Chai WY, Chu PC et al (2016) Focused ultrasound enhances central nervous system delivery of bevacizumab for malignant glioma treatment. Radiology 281:99–108. https://doi.org/10.1148/radiol.2016152444

    Article  PubMed  Google Scholar 

  169. Park EJ, Zhang YZ, Vykhodtseva N, McDannold N (2012) Ultrasound-mediated blood-brain/blood-tumor barrier disruption improves outcomes with trastuzumab in a breast cancer brain metastasis model. J Control Release 163:277–284. https://doi.org/10.1016/j.jconrel.2012.09.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Carpentier A, Canney M, Vignot A, Reina V, Beccaria K, Horodyckid C et al (2016) Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med 8:343re342. https://doi.org/10.1126/scitranslmed.aaf6086

    Article  CAS  Google Scholar 

  171. Idbaih A, Canney M, Belin L, Desseaux C, Vignot A, Bouchoux G et al (2019) Safety and feasibility of repeated and transient blood-brain barrier disruption by pulsed ultrasound in patients with recurrent glioblastoma. Clin Cancer Res 25:3793–3801. https://doi.org/10.1158/1078-0432.CCR-18-3643

    Article  CAS  PubMed  Google Scholar 

  172. Raymond SB, Treat LH, Dewey JD, McDannold NJ, Hynynen K, Bacskai BJ (2008) Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer’s disease mouse models. PLoS ONE 3:e2175. https://doi.org/10.1371/journal.pone.0002175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Jordao JF, Ayala-Grosso CA, Markham K, Huang Y, Chopra R, McLaurin J et al (2010) Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer’s disease. PLoS ONE 5:e10549. https://doi.org/10.1371/journal.pone.0010549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Burgess A, Dubey S, Yeung S, Hough O, Eterman N, Aubert I et al (2014) Alzheimer disease in a mouse model: MR imaging-guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior. Radiology 273:736–745. https://doi.org/10.1148/radiol.14140245

    Article  PubMed  Google Scholar 

  175. Nisbet RM, Van der Jeugd A, Leinenga G, Evans HT, Janowicz PW, Gotz J (2017) Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain 140:1220–1230. https://doi.org/10.1093/brain/awx052

    Article  PubMed  PubMed Central  Google Scholar 

  176. Dubey S, Heinen S, Krantic S, McLaurin J, Branch DR, Hynynen K et al (2020) Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer’s disease. Proc Natl Acad Sci USA 117:32691–32700. https://doi.org/10.1073/pnas.1908658117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Leinenga G, Gotz J (2015) Scanning ultrasound removes amyloid-beta and restores memory in an Alzheimer’s disease mouse model. Sci Transl Med 7:278ra233. https://doi.org/10.1126/scitranslmed.aaa2512

    Article  CAS  Google Scholar 

  178. Meng Y, Shirzadi Z, MacIntosh B, Heyn C, Smith GS, Aubert I et al (2019) Blood-brain barrier opening in alzheimer’s disease using mr-guided focused ultrasound. Neurosurgery 66:65–65

    Article  Google Scholar 

  179. Meng Y, MacIntosh BJ, Shirzadi Z, Kiss A, Bethune A, Heyn C et al (2019) Resting state functional connectivity changes after MR-guided focused ultrasound mediated blood-brain barrier opening in patients with Alzheimer’s disease. Neuroimage 200:275–280. https://doi.org/10.1016/j.neuroimage.2019.06.060

    Article  PubMed  Google Scholar 

  180. Burgess A, Huang Y, Querbes W, Sah DW, Hynynen K (2012) Focused ultrasound for targeted delivery of siRNA and efficient knockdown of Htt expression. J Control Release 163:125–129. https://doi.org/10.1016/j.jconrel.2012.08.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Hsu PH, Wei KC, Huang CY, Wen CJ, Yen TC, Liu CL et al (2013) Noninvasive and targeted gene delivery into the brain using microbubble-facilitated focused ultrasound. PLoS ONE 8:e57682. https://doi.org/10.1371/journal.pone.0057682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Noroozian Z, Xhima K, Huang Y, Kaspar BK, Kugler S, Hynynen K et al (2019) MRI-guided focused ultrasound for targeted delivery of rAAV to the brain. Methods Mol Biol 1950:177–197. https://doi.org/10.1007/978-1-4939-9139-6_10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Lin CY, Hsieh HY, Pitt WG, Huang CY, Tseng IC, Yeh CK et al (2015) Focused ultrasound-induced blood-brain barrier opening for non-viral, non-invasive, and targeted gene delivery. J Control Release 212:1–9. https://doi.org/10.1016/j.jconrel.2015.06.010

    Article  CAS  PubMed  Google Scholar 

  184. Fan CH, Ting CY, Lin CY, Chan HL, Chang YC, Chen YY et al (2016) Noninvasive, targeted, and non-viral ultrasound-mediated GDNF-plasmid delivery for treatment of Parkinson’s disease. Sci Rep 6:19579. https://doi.org/10.1038/srep19579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Lin CY, Hsieh HY, Chen CM, Wu SR, Tsai CH, Huang CY et al (2016) Non-invasive, neuron-specific gene therapy by focused ultrasound-induced blood-brain barrier opening in Parkinson’s disease mouse model. J Control Release 235:72–81. https://doi.org/10.1016/j.jconrel.2016.05.052

    Article  CAS  PubMed  Google Scholar 

  186. Long L, Cai XD, Guo RM, Wang P, Wu LL, Yin TH et al (2017) Treatment of Parkinson’s disease in rats by Nrf2 transfection using MRI-guided focused ultrasound delivery of nanomicrobubbles. Biochem Biophys Res Commun 482:75–80. https://doi.org/10.1016/j.bbrc.2016.10.141

    Article  CAS  PubMed  Google Scholar 

  187. Gasca-Salas C, Fernandez-Rodriguez B, Pineda-Pardo JA, Rodriguez-Rojas R, Hernandez F, Obeso I et al (2020) Blood-brain barrier opening with focused ultrasound in Parkinson's disease dementia: a safety and feasibility study. Neurology 94(15)

  188. Gasca-Salas C, Fernandez-Rodriguez B, Pineda-Pardo JA, Rodriguez-Rojas R, Obeso I, Hernandez-Fernandez F et al (2021) Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia. Nature Commun. https://doi.org/10.1038/s41467-021-21022-9

    Article  Google Scholar 

  189. McDannold N, Zhang YZ, Power C, Arvanitis CD, Vykhodtseva N, Livingstone M (2015) Targeted, noninvasive blockade of cortical neuronal activity. Sci Rep. https://doi.org/10.1038/srep16253

    Article  PubMed  PubMed Central  Google Scholar 

  190. Chu PC, Liu HL, Lai HY, Lin CY, Tsai HC, Pei YC (2015) Neuromodulation accompanying focused ultrasound-induced blood-brain barrier opening. Sci Rep 5:15477. https://doi.org/10.1038/srep15477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Todd N, Zhang YZ, Arcaro M, Becerr L, Borsook D, Livingstone M et al (2018) Focused ultrasound induced opening of the blood-brain barrier disrupts inter-hemispheric resting state functional connectivity in the rat brain. Neuroimage 178:414–422. https://doi.org/10.1016/j.neuroimage.2018.05.063

    Article  PubMed  Google Scholar 

  192. Cui ZW, Li DP, Feng Y, Xu TQ, Wu S, Li YB et al (2019) Enhanced neuronal activity in mouse motor cortex with microbubbles’ oscillations by transcranial focused ultrasound stimulation. Ultrason Sonochem. https://doi.org/10.1016/j.ultsonch.2019.104745

    Article  PubMed  Google Scholar 

  193. Todd N, Zhang Y, Power C, Becerra L, Borsook D, Livingstone M et al (2019) Modulation of brain function by targeted delivery of GABA through the disrupted blood-brain barrier. Neuroimage 189:267–275. https://doi.org/10.1016/j.neuroimage.2019.01.037

    Article  CAS  PubMed  Google Scholar 

  194. Ibsen S, Tong A, Schutt C, Esener S, Chalasani SH (2015) Sonogenetics is a non-invasive approach to activating neurons in Caenorhabditis elegans. Nat Commun 6:8264. https://doi.org/10.1038/ncomms9264

    Article  CAS  PubMed  Google Scholar 

  195. Huang YS, Fan CH, Hsu N, Chiu NH, Wu CY, Chang CY et al (2020) Sonogenetic modulation of cellular activities using an engineered auditory-sensing protein. Nano Lett 20:1089–1100. https://doi.org/10.1021/acs.nanolett.9b04373

    Article  CAS  PubMed  Google Scholar 

  196. Kovacs ZI, Kim S, Jikaria N, Qureshi F, Milo B, Lewis BK et al (2017) Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation. Proc Natl Acad Sci U S A 114:E75–E84. https://doi.org/10.1073/pnas.1614777114

    Article  CAS  PubMed  Google Scholar 

  197. McMahon D, Bendayan R, Hynynen K (2017) Acute effects of focused ultrasound-induced increases in blood-brain barrier permeability on rat microvascular transcriptome. Sci Rep. https://doi.org/10.1038/srep45657

    Article  PubMed  PubMed Central  Google Scholar 

  198. McMahon D, Hynynen K (2017) Acute inflammatory response following increased blood-brain barrier permeability induced by focused ultrasound is dependent on microbubble dose. Theranostics 7:3989–4000. https://doi.org/10.7150/thno.21630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Liu HL, Hsieh HY, Lu LA, Kang CW, Wu MF, Lin CY (2012) Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response. J Transl Med 10:221. https://doi.org/10.1186/1479-5876-10-221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Chen PY, Wei KC, Liu HL (2015) Neural immune modulation and immunotherapy assisted by focused ultrasound induced blood-brain barrier opening. Hum Vaccin Immunother 11:2682–2687. https://doi.org/10.1080/21645515.2015.1071749

    Article  PubMed  PubMed Central  Google Scholar 

  201. Chen KT, Chai WY, Lin YJ, Lin CJ, Chen PY, Tsai HC et al (2021) Neuronavigation-guided focused ultrasound for transcranial blood-brain barrier opening and immunostimulation in brain tumors. Sci Adv. https://doi.org/10.1126/sciadv.abd0772

    Article  PubMed  PubMed Central  Google Scholar 

  202. Williams R, Wright C, Cherin E, Reznik N, Lee M, Gorelikov I et al (2013) Characterization of submicron phase-change perfluorocarbon droplets for extravascular ultrasound imaging of cancer. Ultrasound Med Biol 39:475–489. https://doi.org/10.1016/j.ultrasmedbio.2012.10.004

    Article  PubMed  Google Scholar 

  203. Phillips LC, Puett C, Sheeran PS, Wilson Miller G, Matsunaga TO, Dayton PA (2013) Phase-shift perfluorocarbon agents enhance high intensity focused ultrasound thermal delivery with reduced near-field heating. J Acoust Soc Am 134:1473–1482. https://doi.org/10.1121/1.4812866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Rapoport N, Gao Z, Kennedy A (2007) Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. J Natl Cancer Inst 99:1095–1106. https://doi.org/10.1093/jnci/djm043

    Article  CAS  PubMed  Google Scholar 

  205. Zhang G, Harput S, Lin ST, Christensen-Jeffries K, Leow CH, Brown J et al (2018) Acoustic wave sparsely activated localization microscopy (AWSALM): Super-resolution ultrasound imaging using acoustic activation and deactivation of nanodroplets. Appl Phys Lett. https://doi.org/10.1063/1.5029874

    Article  PubMed  PubMed Central  Google Scholar 

  206. Zhang G, Harput S, Hu H, Christensen-Jeffries K, Zhu J, Brown J et al (2019) Fast acoustic wave sparsely activated localization microscopy (fast-AWSALM): ultrasound super-resolution using plane-wave activation of nanodroplets. IEEE Trans Ultrason Ferroelectr Freq Control. https://doi.org/10.1109/TUFFC.2019.2906496

    Article  PubMed  Google Scholar 

  207. Shpak O, Verweij M, de Jong N, Versluis M (2016) Droplets, bubbles and ultrasound interactions. Adv Exp Med Biol 880:157–174. https://doi.org/10.1007/978-3-319-22536-4_9

    Article  CAS  PubMed  Google Scholar 

  208. Wu Q, Mannaris C, May JP, Bau L, Polydorou A, Ferri S et al (2021) Investigation of the acoustic vaporization threshold of lipid-coated perfluorobutane nanodroplets using both high-speed optical imaging and acoustic methods. Ultrasound Med Biol. https://doi.org/10.1016/j.ultrasmedbio.2021.02.019

    Article  PubMed  Google Scholar 

  209. Wang CH, Kang ST, Lee YH, Luo YL, Huang YF, Yeh CK (2012) Aptamer-conjugated and drug-loaded acoustic droplets for ultrasound theranosis. Biomaterials 33:1939–1947. https://doi.org/10.1016/j.biomaterials.2011.11.036

    Article  CAS  PubMed  Google Scholar 

  210. Seda R, Li DS, Fowlkes JB, Bull JL (2015) Characterization of bioeffects on endothelial cells under acoustic droplet vaporization. Ultrasound Med Biol 41:3241–3252. https://doi.org/10.1016/j.ultrasmedbio.2015.07.019

    Article  PubMed  PubMed Central  Google Scholar 

  211. Harmon JS, Kabinejadian F, Seda R, Fabiilli ML, Kuruvilla S, Kuo CC et al (2019) Minimally invasive gas embolization using acoustic droplet vaporization in a rodent model of hepatocellular carcinoma. Sci Rep. https://doi.org/10.1038/s41598-019-47309-y

    Article  PubMed  PubMed Central  Google Scholar 

  212. Feng Y, Qin D, Zhang J, Zhang L, Bouakaz A, Wan MX (2018) Occlusion and rupture of ex vivo capillary bifurcation due to acoustic droplet vaporization. Appl Phys Lett. https://doi.org/10.1063/15025594

    Article  Google Scholar 

  213. Kripfgans OD, Fabiilli ML, Carson PL, Fowlkes JB (2004) On the acoustic vaporization of micrometer-sized droplets. J Acoust Soc Am 116:272–281. https://doi.org/10.1121/1.1755236

    Article  CAS  PubMed  Google Scholar 

  214. Kang ST, Huang YL, Yeh CK (2014) Characterization of acoustic droplet vaporization for control of bubble generation under flow conditions. Ultrasound Med Biol 40:551–561. https://doi.org/10.1016/j.ultrasmedbio.2013.10.020

    Article  PubMed  Google Scholar 

  215. Rapoport NY, Kennedy AM, Shea JE, Scaife CL, Nam KH (2009) Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles. J Control Release 138:268–276. https://doi.org/10.1016/j.jconrel.2009.05.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Airan RD, Meyer RA, Ellens NP, Rhodes KR, Farahani K, Pomper MG et al (2017) Noninvasive targeted transcranial neuromodulation via focused ultrasound gated drug release from nanoemulsions. Nano Lett 17:652–659. https://doi.org/10.1021/acs.nanolett.6b03517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Lea-Banks H, O’Reilly MA, Hamani C, Hynynen K (2020) Localized anesthesia of a specific brain region using ultrasound-responsive barbiturate nanodroplets. Theranostics 10:2849–2858. https://doi.org/10.7150/thno.41566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Fabiilli ML, Haworth KJ, Fakhri NH, Kripfgans OD, Carson PL, Fowlkes JB (2009) The role of inertial cavitation in acoustic droplet vaporization. IEEE Trans Ultrason Ferroelectr Freq Control 56:1006–1017. https://doi.org/10.1109/TUFFC.2009.1132

    Article  PubMed  PubMed Central  Google Scholar 

  219. Lo AH, Kripfgans OD, Carson PL, Rothman ED, Fowlkes JB (2007) Acoustic droplet vaporization threshold: effects of pulse duration and contrast agent. IEEE Trans Ultrason Ferroelectr Freq Control 54:933–946. https://doi.org/10.1109/tuffc.2007.339

    Article  PubMed  Google Scholar 

  220. Sheeran PS, Matsunaga TO, Dayton PA (2013) Phase-transition thresholds and vaporization phenomena for ultrasound phase-change nanoemulsions assessed via high-speed optical microscopy. Phys Med Biol 58:4513–4534. https://doi.org/10.1088/0031-9155/58/13/4513

    Article  PubMed  PubMed Central  Google Scholar 

  221. Sheeran PS, Yoo K, Williams R, Yin M, Foster FS, Burns PN (2016) More than bubbles: creating phase-shift droplets from commercially available ultrasound contrast agents. Ultrasound Med Biol 43:531–540. https://doi.org/10.1016/j.ultrasmedbio.2016.09.003

    Article  PubMed  Google Scholar 

  222. Sheeran PS, Luois S, Dayton PA, Matsunaga TO (2011) Formulation and acoustic studies of a new phase-shift agent for diagnostic and therapeutic ultrasound. Langmuir 27:10412–10420. https://doi.org/10.1021/la2013705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Sheeran PS, Wong VP, Luois S, McFarland RJ, Ross WD, Feingold S et al (2011) Decafluorobutane as a phase-change contrast agent for low-energy extravascular ultrasonic imaging. Ultrasound Med Biol 37:1518–1530. https://doi.org/10.1016/j.ultrasmedbio.2011.05.021

    Article  PubMed  PubMed Central  Google Scholar 

  224. Sheeran PS, Luois SH, Mullin LB, Matsunaga TO, Dayton PA (2012) Design of ultrasonically-activatable nanoparticles using low boiling point perfluorocarbons. Biomaterials 33:3262–3269. https://doi.org/10.1016/j.biomaterials.2012.01.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Fan CH, Lin YT, Ho YJ, Yeh CK (2018) Spatial-temporal cellular bioeffects from acoustic droplet vaporization. Theranostics 8:5731–5743. https://doi.org/10.7150/thno.28782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Kang ST, Yeh CK (2011) Intracellular acoustic droplet vaporization in a single peritoneal macrophage for drug delivery applications. Langmuir 27:13183–13188. https://doi.org/10.1021/la203212p

    Article  CAS  PubMed  Google Scholar 

  227. Fan CH, Lee YH, Ho YJ, Wang CH, Kang ST, Yeh CK (2018) Macrophages as drug delivery carriers for acoustic phase-change droplets. Ultrasound Med Biol 44:1468–1481. https://doi.org/10.1016/j.ultrasmedbio.2018.03.009

    Article  PubMed  Google Scholar 

  228. Gorelikov I, Martin AL, Seo M, Matsuura N (2011) Silica-coated quantum dots for optical evaluation of perfluorocarbon droplet interactions with cells. Langmuir 27:15024–15033. https://doi.org/10.1021/la202679p

    Article  CAS  PubMed  Google Scholar 

  229. Ho YJ, Chiang YJ, Kang ST, Fan CH, Yeh CK (2018) Camptothecin-loaded fusogenic nanodroplets as ultrasound theranostic agent in stem cell-mediated drug-delivery system. J Control Release 278:100–109. https://doi.org/10.1016/j.jconrel.2018.04.001

    Article  CAS  PubMed  Google Scholar 

  230. Samuel S, Duprey A, Fabiilli ML, Bull JL, Fowlkes JB (2012) In vivo microscopy of targeted vessel occlusion employing acoustic droplet vaporization. Microcirculation 19:501–509. https://doi.org/10.1111/j.1549-8719.2012.00176.x

    Article  PubMed  PubMed Central  Google Scholar 

  231. Sontum P, Kvale S, Healey AJ, Skurtveit R, Watanabe R, Matsumura M et al (2015) Acoustic cluster therapy (ACT)–A novel concept for ultrasound mediated, targeted drug delivery. Int J Pharm 495:1019–1027. https://doi.org/10.1016/j.ijpharm.2015.09.047

    Article  CAS  PubMed  Google Scholar 

  232. Kripfgans OD, Orifici CM, Carson PL, Ives KA, Eldevik OP, Fowlkes JB (2005) Acoustic droplet vaporization for temporal and spatial control of tissue occlusion: a kidney study. IEEE Trans Ultrason Ferroelectr Freq Control 52:1101–1110. https://doi.org/10.1109/tuffc.2005.1503996

    Article  PubMed  Google Scholar 

  233. Ho YJ, Chang YC, Yeh CK (2016) Improving nanoparticle penetration in tumors by vascular disruption with acoustic droplet vaporization. Theranostics 6:392–403. https://doi.org/10.7150/thno.13727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Fang J, Nakamura H, Maeda H (2011) The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 63:136–151. https://doi.org/10.1016/j.addr.2010.04.009

    Article  CAS  PubMed  Google Scholar 

  235. Rapoport N, Kennedy AM, Shea JE, Scaife CL, Nam KH (2010) Ultrasonic nanotherapy of pancreatic cancer: lessons from ultrasound imaging. Mol Pharm 7:22–31. https://doi.org/10.1021/mp900128x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Rapoport N, Nam KH, Gupta R, Gao Z, Mohan P, Payne A et al (2011) Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions. J Control Release 153:4–15. https://doi.org/10.1016/j.jconrel.2011.01.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Helfield BL, Yoo K, Liu J, Williams R, Sheeran PS, Goertz DE et al (2020) Investigating the accumulation of submicron phase-change droplets in tumors. Ultrasound Med Biol 46:2861–2870. https://doi.org/10.1016/j.ultrasmedbio.2020.06.021

    Article  PubMed  Google Scholar 

  238. Lea-Banks H, Meng Y, Wu SK, Belhadjhamida R, Hamani C, Hynynen K (2021) Ultrasound-sensitive nanodroplets achieve targeted neuromodulation. J Control Release 332:30–39. https://doi.org/10.1016/j.jconrel.2021.02.010

    Article  CAS  PubMed  Google Scholar 

  239. Hu YX, Xue S, Long T, Lyu P, Zhang XY, Chen JQ et al (2020) Opto-acoustic synergistic irradiation for vaporization of natural melanin-cored nanodroplets at safe energy levels and efficient sono-chemo-photothermal cancer therapy. Theranostics 10:10448–10465. https://doi.org/10.7150/thno.44879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Mountford PA, Thomas AN, Borden MA (2015) Thermal activation of superheated lipid-coated perfluorocarbon drops. Langmuir 31:4627–4634. https://doi.org/10.1021/acs.langmuir.5b00399

    Article  CAS  PubMed  Google Scholar 

  241. Hannah AS, Luke GP, Emelianov SY (2016) Blinking phase-change nanocapsules enable background-free ultrasound imaging. Theranostics 6:1866–1876. https://doi.org/10.7150/thno.14961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Hallam KA, Donnelly EM, Karpiouk AB, Hartman RK, Emelianov SY (2018) Laser-activated perfluorocarbon nanodroplets: a new tool for blood brain barrier opening. Biomed Opt Express 9:4527–4538. https://doi.org/10.1364/BOE.9.004527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Harmon JS, Celingant-Copie CA, Kabinejadian F, Bull JL (2020) Lipid shell retention and selective binding capability following repeated transient acoustic microdroplet vaporization. Langmuir 36:6626–6634. https://doi.org/10.1021/acs.langmuir.0c00320

    Article  CAS  PubMed  Google Scholar 

  244. Aliabouzar M, Kripfgans OD, Wang WY, Baker BM, Brian Fowlkes J, Fabiilli ML (2021) Stable and transient bubble formation in acoustically-responsive scaffolds by acoustic droplet vaporization: theory and application in sequential release. Ultrason Sonochem 72:105430. https://doi.org/10.1016/j.ultsonch.2020.105430

    Article  CAS  PubMed  Google Scholar 

  245. Fan CH, Wang TW, Hsieh YK, Wang CF, Gao Z, Kim A et al (2019) Enhancing boron uptake in brain glioma by a boron-polymer/microbubble complex with focused ultrasound. ACS Appl Mater Interfaces 11:11144–11156. https://doi.org/10.1021/acsami.8b22468

    Article  CAS  PubMed  Google Scholar 

  246. Cai X, Jiang Y, Lin M, Zhang J, Guo H, Yang F et al (2019) Ultrasound-responsive materials for drug/gene delivery. Front Pharmacol 10:1650. https://doi.org/10.3389/fphar.2019.01650

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors gratefully acknowledge the support of the Ministry of Science and Technology, Taiwan under Grant No. MOST 108-2221-E-007-040-MY3, 108-2221-E-007-041-MY3, 108-2638-M-002-001-MY2, 107-2628-E-006-004-MY3, 107-2221-E-006-024-MY3, 109-2636-E-006-024-, 110-2321-B-002-010-, 108-2221-E-002-176-MY3, and 108-2221-E-002-175-MY3; National Tsing Hua University under Grant No. 110Q2510E1. The authors also thank to support from Higher Education Sprout Project, Ministry of Education to the Headquarters of University Advancement at NCKU.

Funding

This work was supported by the Ministry of Science and Technology, Taiwan (Grant No. MOST 108-2221-E-007-040-MY3, 108-2221-E-007-041-MY3, 108-2638-M-002-001-MY2, 107-2628-E-006-004-MY3, 107-2221-E-006-024-MY3, 109-2636-E-006-024-, 110-2321-B-002-010-, 108-2221-E-002-176-MY3, and 108-2221-E-002-175-MY3), National Tsing Hua University (Grant No. 110Q2510E1), and Headquarters of University Advancement at NCKU.

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  1. Yi-Ju Ho and Chih-Chung Huang both are contributed equally.

Authors and Affiliations

  1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan

    Yi-Ju Ho & Chih-Kuang Yeh

  2. Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan

    Chih-Chung Huang & Ching-Hsiang Fan

  3. Medical Device Innovation Center, National Cheng Kung University, Tainan, Taiwan

    Chih-Chung Huang & Ching-Hsiang Fan

  4. Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan

    Hao-Li Liu

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Y.J. H and C.K. Y conceptualised the manuscript, Y.J. H, C.C. H, C.H. F, and H. L. L wrote the manuscript, C.C. H, C.H. F and H. L. L designed and prepared the tables and figures. All authors reviewed and edited the final version of the text and approved the final manuscript.

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Ho, YJ., Huang, CC., Fan, CH. et al. Ultrasonic technologies in imaging and drug delivery. Cell. Mol. Life Sci. 78, 6119–6141 (2021). https://doi.org/10.1007/s00018-021-03904-9

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