1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Biomedical Engineering
  4. Volume 23, 2021
  5. Article

Annual Review of Biomedical Engineering

Volume 23, 2021

Therapeutic Agent Delivery Across the Blood–Brain Barrier Using Focused Ultrasound

Abstract

Specialized features of vasculature in the central nervous system greatly limit therapeutic treatment options for many neuropathologies. Focused ultrasound, in combination with circulating microbubbles, can be used to transiently and noninvasively increase cerebrovascular permeability with a high level of spatial precision. For minutes to hours following sonication, drugs can be administered systemically to extravasate in the targeted brain regions and exert a therapeutic effect, after which permeability returns to baseline levels. With the wide range of therapeutic agents that can be delivered using this approach and the growing clinical need, focused ultrasound and microbubble (FUS+MB) exposure in the brain has entered human testing to assess safety. This review outlines the use of FUS+MB-mediated cerebrovascular permeability enhancement as a drug delivery technique, details several technical and biological considerations of this approach, summarizes results from the clinical trials conducted to date, and discusses the future direction of the field.

Keyword(s): blood–brain barrier, brain, drug delivery, image-guided therapy, therapy, ultrasound
Loading

Article metrics loading...

/content/journals/10.1146/annurev-bioeng-062117-121238
2021-07-13
2024-04-16
Loading full text...

Full text loading...

/deliver/fulltext/bioeng/23/1/annurev-bioeng-062117-121238.html?itemId=/content/journals/10.1146/annurev-bioeng-062117-121238&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Feigin VL, Nichols E, Alam T, Bannick MS, Beghi E et al. 2019. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 18:5459–80
     [Google Scholar]
  2. 2. 
    Pardridge WM. 2012. Drug transport across the blood-brain barrier. J. Cereb. Blood Flow Metab. 32:111959–72
     [Google Scholar]
  3. 3. 
    Pardridge WM. 2005. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2:13–14
     [Google Scholar]
  4. 4. 
    Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. 2019. Blood-brain barrier: from physiology to disease and back. Physiol. Rev. 99:121–78
     [Google Scholar]
  5. 5. 
    Abbott NJ, Rönnbäck L, Hansson E. 2006. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7:141–53
     [Google Scholar]
  6. 6. 
    Wong AD, Ye M, Levy AF, Rothstein JD, Bergles DE, Searson PC. 2013. The blood-brain barrier: an engineering perspective. Front. Neuroeng. 6:7
     [Google Scholar]
  7. 7. 
    Engelhardt B, Vajkoczy P, Weller RO. 2017. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18:2123–31
     [Google Scholar]
  8. 8. 
    Frisella WA, O'Connor LH, Vogler CA, Roberts M, Walkley S et al. 2001. Intracranial injection of recombinant adeno-associated virus improves cognitive function in a murine model of mucopolysaccharidosis type VII. Mol. Ther. 3:3351–58
     [Google Scholar]
  9. 9. 
    Muir KW, Sinden J, Miljan E, Dunn L. 2011. Intracranial delivery of stem cells. Transl. Stroke Res. 2:3266–71
     [Google Scholar]
  10. 10. 
    Evans BK, Armstrong S, Singer G, Cook RD, Burnstock G. 1975. Intracranial injection of drugs: comparison of diffusion of 6-OHDA and guanethidine. Pharmacol. Biochem. Behav. 3:2205–28
     [Google Scholar]
  11. 11. 
    Dhuria SV, Hanson LR, Frey WH 2nd 2010. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J. Pharm. Sci. 99:41654–73
     [Google Scholar]
  12. 12. 
    Pardridge WM. 2011. Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS 8:17
     [Google Scholar]
  13. 13. 
    Neuwelt EA, Howieson J, Frenkel EP, Specht HD, Weigel R et al. 1986. Therapeutic efficacy of multiagent chemotherapy with drug delivery enhancement by blood-brain barrier modification in glioblastoma. Neurosurgery 19:4573–82
     [Google Scholar]
  14. 14. 
    Suzuki M, Iwasaki Y, Yamamoto T, Konno H, Kudo H. 1988. Sequelae of the osmotic blood-brain barrier opening in rats. J. Neurosurg. 69:3421–28
     [Google Scholar]
  15. 15. 
    Marchi N, Angelov L, Masaryk T, Fazio V, Granata T et al. 2007. Seizure-promoting effect of blood-brain barrier disruption. Epilepsia 48:4732–42
     [Google Scholar]
  16. 16. 
    Killian DM, Hermeling S, Chikhale PJ. 2007. Targeting the cerebrovascular large neutral amino acid transporter (LAT1) isoform using a novel disulfide-based brain drug delivery system. Drug Deliv 14:125–31
     [Google Scholar]
  17. 17. 
    Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. 2009. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol. 27:159–65
     [Google Scholar]
  18. 18. 
    Afergan E, Epstein H, Dahan R, Koroukhov N, Rohekar K et al. 2008. Delivery of serotonin to the brain by monocytes following phagocytosis of liposomes. J. Control. Release 132:284–90
     [Google Scholar]
  19. 19. 
    Kreuter J, Alyautdin RN, Kharkevich DA, Ivanov AA. 1995. Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles). Brain Res 674:1171–74
     [Google Scholar]
  20. 20. 
    Fry WJ, Fry FJ. 1960. Fundamental neurological research and human neurosurgery using intense ultrasound. IRE Trans. Med. Electron ME-7:166–81
     [Google Scholar]
  21. 21. 
    Fry FJ, Barger JE. 1978. Acoustical properties of the human skull. J. Acoust. Soc. Am. 63:1576–90
     [Google Scholar]
  22. 22. 
    Pichardo S, Sin VW, Hynynen K. 2011. Multi-frequency characterization of the speed of sound and attenuation coefficient for longitudinal transmission of freshly excised human skulls. Phys. Med. Biol. 56:219–50
     [Google Scholar]
  23. 23. 
    Carpentier A, Canney M, Vignot A, Reina V, Beccaria K et al. 2016. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci. Transl. Med. 8:343343re2
     [Google Scholar]
  24. 24. 
    Aubry JF, Tanter M, Pernot M, Thomas JL, Fink M. 2003. Experimental demonstration of noninvasive transskull adaptive focusing based on prior computed tomography scans. J. Acoust. Soc. Am. 113:84–93
     [Google Scholar]
  25. 25. 
    Hynynen K, Jolesz FA. 1998. Demonstration of potential noninvasive ultrasound brain therapy through an intact skull. Ultrasound Med. Biol. 24:2275–83
     [Google Scholar]
  26. 26. 
    Clement GT, Hynynen K. 2002. Correlation of ultrasound phase with physical skull properties. Ultrasound Med. Biol. 28:5617–24
     [Google Scholar]
  27. 27. 
    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 121:4901–7
     [Google Scholar]
  28. 28. 
    Yang F-Y, Fu W-M, Yang R-S, Liou H-C, Kang K-H, Lin W-L 2007. Quantitative evaluation of focused ultrasound with a contrast agent on blood-brain barrier disruption. Ultrasound Med. Biol. 33:91421–27
     [Google Scholar]
  29. 29. 
    Maimbourg G, Houdouin A, Deffieux T, Tanter M, Aubry J-F. 2018. 3D-printed adaptive acoustic lens as a disruptive technology for transcranial ultrasound therapy using single-element transducers. Phys. Med. Biol. 63:025026
     [Google Scholar]
  30. 30. 
    Lewin PA, Bjørnø L. 1982. Acoustically induced shear stresses in the vicinity of microbubbles in tissue. J. Acoust. Soc. Am. 71:3728–34
     [Google Scholar]
  31. 31. 
    Leighton TG. 1994. The Acoustic Bubble London: Academic
  32. 32. 
    McDannold N, Vykhodtseva N, Hynynen K. 2006. Targeted disruption of the blood–brain barrier with focused ultrasound: association with cavitation activity. Phys. Med. Biol. 51:4793
     [Google Scholar]
  33. 33. 
    Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA. 2001. Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 220:3640–46
     [Google Scholar]
  34. 34. 
    McDannold N, Vykhodtseva N, Hynynen K. 2008. Blood-brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index. Ultrasound Med. Biol. 34:5834–40
     [Google Scholar]
  35. 35. 
    McDannold N, Vykhodtseva N, Hynynen K. 2008. Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood-brain barrier disruption. Ultrasound Med. Biol. 34:6930–37
     [Google Scholar]
  36. 36. 
    Choi JJ, Feshitan JA, Baseri B, Wang S, Tung YS et al. 2010. Microbubble-size dependence of focused ultrasound-induced blood-brain barrier opening in mice in vivo. IEEE Trans. Biomed. Eng. 57:1145–54
     [Google Scholar]
  37. 37. 
    Chopra R, Vykhodtseva N, Hynynen K. 2010. Influence of exposure time and pressure amplitude on blood-brain-barrier opening using transcranial ultrasound exposures. ACS Chem. Neurosci. 1:5391–98
     [Google Scholar]
  38. 38. 
    Goertz DE, Wright C, Hynynen K. 2010. Contrast agent kinetics in the rabbit brain during exposure to therapeutic ultrasound. Ultrasound Med. Biol. 36:6916–24
     [Google Scholar]
  39. 39. 
    Apfel RE, Holland CK. 1991. Gauging the likelihood of cavitation from short-pulse, low-duty cycle diagnostic ultrasound. Ultrasound Med. Biol. 17:2179–85
     [Google Scholar]
  40. 40. 
    O'Reilly MA, Muller A, Hynynen K. 2011. Ultrasound insertion loss of rat parietal bone appears to be proportional to animal mass at submegahertz frequencies. Ultrasound Med. Biol. 37:111930–37
     [Google Scholar]
  41. 41. 
    Gerstenmayer M, Fellah B, Magnin R, Selingue E, Larrat B. 2018. Acoustic transmission factor through the rat skull as a function of body mass, frequency and position. Ultrasound Med. Biol. 44:112336–44
     [Google Scholar]
  42. 42. 
    Vlachos F, Tung Y-S, Konofagou E. 2011. Permeability dependence study of the focused ultrasound-induced blood-brain barrier opening at distinct pressures and microbubble diameters using DCE-MRI. Magn. Reson. Med. 66:3821–30
     [Google Scholar]
  43. 43. 
    Song K-H, Fan AC, Hinkle JJ, Newman J, Borden MA, Harvey BK. 2017. Microbubble gas volume: a unifying dose parameter in blood-brain barrier opening by focused ultrasound. Theranostics 7:1144–52
     [Google Scholar]
  44. 44. 
    Hosseinkhah N, Goertz DE, Hynynen K. 2015. Microbubbles and blood-brain barrier opening: a numerical study on acoustic emissions and wall stress predictions. IEEE Trans. Biomed. Eng. 62:51293–304
     [Google Scholar]
  45. 45. 
    McDannold N, Zhang Y, Vykhodtseva N. 2017. The effects of oxygen on ultrasound-induced blood-brain barrier disruption in mice. Ultrasound Med. Biol. 43:2469–75
     [Google Scholar]
  46. 46. 
    Mullin L, Gessner R, Kwan J, Kaya M, Borden MA, Dayton PA. 2011. Effect of anesthesia carrier gas on in vivo circulation times of ultrasound microbubble contrast agents in rats. Contrast Media Mol. Imaging 6:3126–31
     [Google Scholar]
  47. 47. 
    O'Reilly MA, Hynynen K. 2012. Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller. Radiology 263:196–106
     [Google Scholar]
  48. 48. 
    Sun T, Zhang Y, Power C, Alexander PM, Sutton JT et al. 2017. Closed-loop control of targeted ultrasound drug delivery across the blood-brain/tumor barriers in a rat glioma model. PNAS 114:48E10281–90
     [Google Scholar]
  49. 49. 
    Çavuşoğlu M, Zhang J, Ielacqua GD, Pellegrini G, Signorell RD et al. 2019. Closed-loop cavitation control for focused ultrasound-mediated blood-brain barrier opening by long-circulating microbubbles. Phys. Med. Biol. 64:045012
     [Google Scholar]
  50. 50. 
    Jones RM, Deng L, Leung K, McMahon D, O'Reilly MA, Hynynen K. 2018. Three-dimensional transcranial microbubble imaging for guiding volumetric ultrasound-mediated blood-brain barrier opening. Theranostics 8:112909–26
     [Google Scholar]
  51. 51. 
    Baseri B, Choi JJ, Tung Y-S, Konofagou EE. 2010. Multi-modality safety assessment of blood-brain barrier opening using focused ultrasound and definity microbubbles: a short-term study. Ultrasound Med. Biol. 36:91445–59
     [Google Scholar]
  52. 52. 
    McDannold N, Arvanitis CD, Vykhodtseva N, Livingstone MS. 2012. Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques. Cancer Res 72:143652–63
     [Google Scholar]
  53. 53. 
    Thévenot E, Jordão JF, O'Reilly MA, Markham K, Weng Y-Q et al. 2012. Targeted delivery of self-complementary adeno-associated virus serotype 9 to the brain, using magnetic resonance imaging-guided focused ultrasound. Hum. Gene Ther. 23:111144–55
     [Google Scholar]
  54. 54. 
    Kovacs ZI, Tu T-W, Sundby M, Qureshi F, Lewis BK et al. 2018. MRI and histological evaluation of pulsed focused ultrasound and microbubbles treatment effects in the brain. Theranostics 8:174837–55
     [Google Scholar]
  55. 55. 
    Kobus T, Vykhodtseva N, Pilatou M, Zhang Y, McDannold N. 2016. Safety validation of repeated blood-brain barrier disruption using focused ultrasound. Ultrasound Med. Biol. 42:2481–92
     [Google Scholar]
  56. 56. 
    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. 31:111527–37
     [Google Scholar]
  57. 57. 
    Hynynen K, McDannold N, Vykhodtseva N, Raymond S, Weissleder R et al. 2006. Focal disruption of the blood-brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery. J. Neurosurg. 105:3445–54
     [Google Scholar]
  58. 58. 
    Leinenga G, Götz J. 2015. Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer's disease mouse model. Sci. Transl. Med. 7:278278ra33
     [Google Scholar]
  59. 59. 
    Kovacs ZI, Kim S, Jikaria N, Qureshi F, Milo B et al. 2017. Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation. PNAS 114:1E75–84
     [Google Scholar]
  60. 60. 
    Liu H-L, Wai Y-Y, Hsu P-H, Lyu L-A, Wu J-S et al. 2010. In vivo assessment of macrophage CNS infiltration during disruption of the blood-brain barrier with focused ultrasound: a magnetic resonance imaging study. J. Cereb. Blood Flow Metab. 30:1177–86
     [Google Scholar]
  61. 61. 
    Sheikov N, McDannold N, Vykhodtseva N, Jolesz F, Hynynen K. 2004. Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles. Ultrasound Med. Biol. 30:7979–89
     [Google Scholar]
  62. 62. 
    Sheikov N, McDannold N, Jolesz F, Zhang Y-Z, Tam K, Hynynen K 2006. Brain arterioles show more active vesicular transport of blood-borne tracer molecules than capillaries and venules after focused ultrasound-evoked opening of the blood-brain barrier. Ultrasound Med. Biol. 32:91399–409
     [Google Scholar]
  63. 63. 
    Sheikov N, McDannold N, Sharma S, Hynynen K. 2008. Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med. Biol. 34:71093–104
     [Google Scholar]
  64. 64. 
    Raymond SB, Skoch J, Hynynen K, Bacskai BJ. 2007. Multiphoton imaging of ultrasound/Optison mediated cerebrovascular effects in vivo. J. Cereb. Blood Flow Metab. 27:2393–403
     [Google Scholar]
  65. 65. 
    Cho EE, Drazic J, Ganguly M, Stefanovic B, Hynynen K. 2011. Two-photon fluorescence microscopy study of cerebrovascular dynamics in ultrasound-induced blood–brain barrier opening. J. Cereb. Blood Flow Metab. 31:91852–62
     [Google Scholar]
  66. 66. 
    Nhan T, Burgess A, Cho EE, Stefanovic B, Lilge L, Hynynen K. 2013. Drug delivery to the brain by focused ultrasound induced blood-brain barrier disruption: quantitative evaluation of enhanced permeability of cerebral vasculature using two-photon microscopy. J. Control. Release 172:1274–80
     [Google Scholar]
  67. 67. 
    Burgess A, Nhan T, Moffatt C, Klibanov AL, Hynynen K. 2014. Analysis of focused ultrasound-induced blood-brain barrier permeability in a mouse model of Alzheimer's disease using two-photon microscopy. J. Control. Release 192:243–48
     [Google Scholar]
  68. 68. 
    Marty B, Larrat B, Van Landeghem M, Robic C, Robert P et al. 2012. Dynamic study of blood-brain barrier closure after its disruption using ultrasound: a quantitative analysis. J. Cereb. Blood Flow Metab. 32:101948–58
     [Google Scholar]
  69. 69. 
    Alkins R, Burgess A, Ganguly M, Francia G, Kerbel R et al. 2013. Focused ultrasound delivers targeted immune cells to metastatic brain tumors. Cancer Res 73:61892–99
     [Google Scholar]
  70. 70. 
    Park J, Zhang Y, Vykhodtseva N, Jolesz FA, McDannold NJ. 2012. The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound. J. Control. Release 162:1134–42
     [Google Scholar]
  71. 71. 
    Chu P-C, Chai W-Y, Tsai C-H, Kang S-T, Yeh C-K, Liu H-L. 2016. Focused ultrasound-induced blood-brain barrier opening: association with mechanical index and cavitation index analyzed by dynamic contrast-enhanced magnetic-resonance imaging. Sci. Rep. 6:33264
     [Google Scholar]
  72. 72. 
    McMahon D, Oakden W, Hynynen K. 2020. Investigating the effects of dexamethasone on blood-brain barrier permeability and inflammatory response following focused ultrasound and microbubble exposure. Theranostics 10:41604–18
     [Google Scholar]
  73. 73. 
    Samiotaki G, Vlachos F, Tung Y-S, Konofagou EE. 2012. A quantitative pressure and microbubble-size dependence study of focused ultrasound-induced blood-brain barrier opening reversibility in vivo using MRI. Magn. Reson. Med. 67:3769–77
     [Google Scholar]
  74. 74. 
    Arvanitis CD, Askoxylakis V, Guo Y, Datta M, Kloepper J et al. 2018. Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption. PNAS 115:37E8717–26
     [Google Scholar]
  75. 75. 
    Curley CT, Mead BP, Negron K, Kim N, Garrison WJ et al. 2020. Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection. Sci. Adv. 6:18eaay1344
     [Google Scholar]
  76. 76. 
    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. 7:45657
     [Google Scholar]
  77. 77. 
    Cho H, Lee H-Y, Han M, Choi J-R, Ahn S et al. 2016. Localized down-regulation of P-glycoprotein by focused ultrasound and microbubbles induced blood-brain barrier disruption in rat brain. Sci. Rep. 6:31201
     [Google Scholar]
  78. 78. 
    Aryal M, Fischer K, Gentile C, Gitto S, Zhang Y-Z, McDannold N. 2017. Effects on P-glycoprotein expression after blood-brain barrier disruption using focused ultrasound and microbubbles. PLOS ONE 12:1e0166061
     [Google Scholar]
  79. 79. 
    Schinkel AH. 1999. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv. Drug Deliv. Rev. 36:179–94
     [Google Scholar]
  80. 80. 
    Pacia CP, Zhu L, Yang Y, Yue Y, Nazeri A et al. 2020. Feasibility and safety of focused ultrasound-enabled liquid biopsy in the brain of a porcine model. Sci. Rep. 10:17449
     [Google Scholar]
  81. 81. 
    Zhu L, Cheng G, Ye D, Nazeri A, Yue Y et al. 2018. Focused ultrasound-enabled brain tumor liquid biopsy. Sci. Rep. 8:16553
     [Google Scholar]
  82. 82. 
    Zhu L, Nazeri A, Pacia CP, Yue Y, Chen H. 2020. Focused ultrasound for safe and effective release of brain tumor biomarkers into the peripheral circulation. PLOS ONE 15:6e0234182
     [Google Scholar]
  83. 83. 
    Wu S-K, Chu P-C, Chai W-Y, Kang S-T, Tsai C-H et al. 2017. Characterization of different microbubbles in assisting focused ultrasound-induced blood-brain barrier opening. Sci. Rep. 7:46689
     [Google Scholar]
  84. 84. 
    Jordão JF, Thévenot E, Markham-Coultes K, Scarcelli T, Weng Y-Q et al. 2013. Amyloid-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp. Neurol. 248:16–29
     [Google Scholar]
  85. 85. 
    McMahon D, Hynynen K. 2017. Acute inflammatory response following increased blood-brain barrier permeability induced by focused ultrasound is dependent on microbubble dose. Theranostics 7:163989–4000
     [Google Scholar]
  86. 86. 
    Zheng Z, Yenari MA. 2004. Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol. Res. 26:8884–92
     [Google Scholar]
  87. 87. 
    McMahon D, Hynynen K. 2018. Reply to Kovacs et al.: Concerning acute inflammatory response following focused ultrasound and microbubbles in the brain. Theranostics 8:82249–50
     [Google Scholar]
  88. 88. 
    Pekny M, Pekna M. 2014. Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol. Rev. 94:41077–98
     [Google Scholar]
  89. 89. 
    Scarcelli T, Jordão JF, O'Reilly MA, Ellens N, Hynynen K, Aubert I 2014. Stimulation of hippocampal neurogenesis by transcranial focused ultrasound and microbubbles in adult mice. Brain Stimul 7:2304–7
     [Google Scholar]
  90. 90. 
    Mooney SJ, Shah K, Yeung S, Burgess A, Aubert I, Hynynen K 2016. Focused ultrasound-induced neurogenesis requires an increase in blood-brain barrier permeability. PLOS ONE 11:7e0159892
     [Google Scholar]
  91. 91. 
    Burgess A, Dubey S, Yeung S, Hough O, Eterman N 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 273:3736–45
     [Google Scholar]
  92. 92. 
    Shin J, Kong C, Lee J, Choi BY, Sim J et al. 2019. Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model. Alzheimer's Res. Ther. 11:1110
     [Google Scholar]
  93. 93. 
    McMahon D, Mah E, Hynynen K. 2018. Angiogenic response of rat hippocampal vasculature to focused ultrasound-mediated increases in blood-brain barrier permeability. Sci. Rep. 8:112178
     [Google Scholar]
  94. 94. 
    Song J, Qi M, Kaul S, Price RJ. 2002. Stimulation of arteriogenesis in skeletal muscle by microbubble destruction with ultrasound. Circulation 106:121550–55
     [Google Scholar]
  95. 95. 
    Chappell JC, Klibanov AL, Price RJ. 2005. Ultrasound-microbubble-induced neovascularization in mouse skeletal muscle. Ultrasound Med. Biol. 31:101411–22
     [Google Scholar]
  96. 96. 
    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. 38:101716–25
     [Google Scholar]
  97. 97. 
    Yang F-Y, Wang H-E, Liu R-S, Teng M-C, Li J-J et al. 2012. Pharmacokinetic analysis of 111In-labeled liposomal doxorubicin in murine glioblastoma after blood-brain barrier disruption by focused ultrasound. PLOS ONE 7:9e45468
     [Google Scholar]
  98. 98. 
    Fan C-H, Ting C-Y, Lin H-J, Wang C-H, Liu H-L et al. 2013. SPIO-conjugated, doxorubicin-loaded microbubbles for concurrent MRI and focused-ultrasound enhanced brain-tumor drug delivery. Biomaterials 34:143706–15
     [Google Scholar]
  99. 99. 
    Aryal M, Vykhodtseva N, Zhang Y-Z, Park J, McDannold N 2013. Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood-tumor and blood-brain barriers improve outcomes in a rat glioma model. J. Control. Release 169:1–2103–11
     [Google Scholar]
  100. 100. 
    Kovacs Z, Werner B, Rassi A, Sass JO, Martin-Fiori E, Bernasconi M. 2014. Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models. J. Control. Release 187:74–82
     [Google Scholar]
  101. 101. 
    Park J, Aryal M, Vykhodtseva N, Zhang Y-Z, McDannold N. 2017. Evaluation of permeability, doxorubicin delivery, and drug retention in a rat brain tumor model after ultrasound-induced blood-tumor barrier disruption. J. Control. Release 250:77–85
     [Google Scholar]
  102. 102. 
    Mei J, Cheng Y, Song Y, Yang Y. 2009. Experimental study on targeted methotrexate delivery to the rabbit brain via magnetic resonance imaging-guided focused ultrasound. J. Ultrasound Med. 28:871–80
     [Google Scholar]
  103. 103. 
    Liu H-L, Hua M-Y, Chen P-Y, Chu P-C, Pan C-H et al. 2010. Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology 255:2415–25
     [Google Scholar]
  104. 104. 
    Fan C-H, Ting C-Y, Liu H-L, Huang C-Y, Hsieh H-Y et al. 2013. Antiangiogenic-targeting drug-loaded microbubbles combined with focused ultrasound for glioma treatment. Biomaterials 34:82142–55
     [Google Scholar]
  105. 105. 
    Ting C-Y, Fan C-H, Liu H-L, Huang C-Y, Hsieh H-Y et al. 2012. Concurrent blood-brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment. Biomaterials 33:2704–12
     [Google Scholar]
  106. 106. 
    Wei K-C, Chu P-C, Wang H-YJ, Huang C-Y, Chen P-Y et al. 2013. Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study. PLOS ONE 8:3e58995
     [Google Scholar]
  107. 107. 
    Dong Q, He L, Chen L, Deng Q 2018. Opening the blood-brain barrier and improving the efficacy of temozolomide treatments of glioblastoma using pulsed, focused ultrasound with a microbubble contrast agent. Biomed. Res. Int. 2018:6501508
     [Google Scholar]
  108. 108. 
    McDannold N, Zhang Y, Supko JG, Power C, Sun T 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 9:216284–99
     [Google Scholar]
  109. 109. 
    Zeng H-Q, Lü L, Wang F, Luo Y, Lou S-F. 2012. Focused ultrasound-induced blood-brain barrier disruption enhances the delivery of cytarabine to the rat brain. J. Chemother. 24:6358–63
     [Google Scholar]
  110. 110. 
    McDannold N, Zhang Y, Supko JG, Power C, Sun T et al. 2020. Blood-brain barrier disruption and delivery of irinotecan in a rat model using a clinical transcranial MRI-guided focused ultrasound system. Sci. Rep. 10:18766
     [Google Scholar]
  111. 111. 
    Chan KY, Jang MJ, Yoo BB, Greenbaum A, Ravi N et al. 2017. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20:81172–79
     [Google Scholar]
  112. 112. 
    Weber-Adrian D, Thévenot E, O'Reilly MA, Oakden W, Akens MK et al. 2015. Gene delivery to the spinal cord using MRI-guided focused ultrasound. Gene Ther 22:7568–77
     [Google Scholar]
  113. 113. 
    Weber-Adrian D, Kofoed RH, Chan JWY, Silburt J, Noroozian Z et al. 2019. Strategy to enhance transgene expression in proximity of amyloid plaques in a mouse model of Alzheimer's disease. Theranostics 9:268127–37
     [Google Scholar]
  114. 114. 
    Hsu P-H, Wei K-C, Huang C-Y, Wen C-J, Yen T-C et al. 2013. Noninvasive and targeted gene delivery into the brain using microbubble-facilitated focused ultrasound. PLOS ONE 8:2e57682
     [Google Scholar]
  115. 115. 
    Stavarache MA, Petersen N, Jurgens EM, Milstein ER, Rosenfeld ZB et al. 2018. Safe and stable noninvasive focal gene delivery to the mammalian brain following focused ultrasound. J. Neurosurg. 130:989–98
     [Google Scholar]
  116. 116. 
    Wang S, Olumolade OO, Sun T, Samiotaki G, Konofagou EE. 2015. Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus. Gene Ther 22:1104–10
     [Google Scholar]
  117. 117. 
    Xhima K, Nabbouh F, Hynynen K, Aubert I, Tandon A 2018. Noninvasive delivery of an α-synuclein gene silencing vector with magnetic resonance-guided focused ultrasound. Mov. Disord. 33:101567–79
     [Google Scholar]
  118. 118. 
    Wang S, Kugelman T, Buch A, Herman M, Han Y et al. 2017. Non-invasive, focused ultrasound-facilitated gene delivery for optogenetics. Sci. Rep. 7:39955
     [Google Scholar]
  119. 119. 
    Szablowski JO, Lee-Gosselin A, Lue B, Malounda D, Shapiro MG. 2018. Acoustically targeted chemogenetics for the non-invasive control of neural circuits. Nat. Biomed. Eng. 2:7475–84
     [Google Scholar]
  120. 120. 
    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 163:2125–29
     [Google Scholar]
  121. 121. 
    Zhao G, Huang Q, Wang F, Zhang X, Hu J et al. 2018. Targeted shRNA-loaded liposome complex combined with focused ultrasound for blood brain barrier disruption and suppressing glioma growth. Cancer Lett 418:147–58
     [Google Scholar]
  122. 122. 
    Huang Q, Deng J, Wang F, Chen S, Liu Y et al. 2012. Targeted gene delivery to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Exp. Neurol. 233:1350–56
     [Google Scholar]
  123. 123. 
    Wang H-B, Yang L, Wu J, Sun L, Wu J et al. 2014. Reduced ischemic injury after stroke in mice by angiogenic gene delivery via ultrasound-targeted microbubble destruction. J. Neuropathol. Exp. Neurol. 73:6548–58
     [Google Scholar]
  124. 124. 
    Mead BP, Mastorakos P, Suk JS, Klibanov AL, Hanes J, Price RJ. 2016. Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound. J. Control. Release 223:109–17
     [Google Scholar]
  125. 125. 
    Burgess A, Ayala-Grosso CA, Ganguly M, Jordão JF, Aubert I, Hynynen K 2011. Targeted delivery of neural stem cells to the brain using MRI-guided focused ultrasound to disrupt the blood-brain barrier. PLOS ONE 6:11e27877
     [Google Scholar]
  126. 126. 
    Jordão JF, Ayala-Grosso CA, Markham K, Huang Y, Chopra R et al. 2010. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-β plaque load in the TgCRND8 mouse model of Alzheimer's disease. PLOS ONE 5:5e10549
     [Google Scholar]
  127. 127. 
    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. 340:41085–90
     [Google Scholar]
  128. 128. 
    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. PNAS 103:3111719–23
     [Google Scholar]
  129. 129. 
    Chen P-Y, Hsieh H-Y, Huang C-Y, Lin C-Y, Wei K-C, Liu H-L. 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
     [Google Scholar]
  130. 130. 
    Wu S-K, Yang M-T, Kang K-H, Liou H-C, Lu D-H et al. 2014. Targeted delivery of erythropoietin by transcranial focused ultrasound for neuroprotection against ischemia/reperfusion-induced neuronal injury: a long-term and short-term study. PLOS ONE 9:2e90107
     [Google Scholar]
  131. 131. 
    Baseri B, Choi JJ, Deffieux T, Samiotaki G, Tung Y-S et al. 2012. Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles. Phys. Med. Biol. 57:7N65–81
     [Google Scholar]
  132. 132. 
    Meng Y, Abrahao A, Heyn CC, Bethune AJ, Huang Y et al. 2019. Glymphatics visualization after focused ultrasound induced blood-brain barrier opening in humans. Ann. Neurol. 86:975–80
     [Google Scholar]
  133. 133. 
    Poon CT, Shah K, Lin C, Tse R, Kim KK et al. 2018. Time course of focused ultrasound effects on β-amyloid plaque pathology in the TgCRND8 mouse model of Alzheimer's disease. Sci. Rep. 8:114061
     [Google Scholar]
  134. 134. 
    Pandit R, Leinenga G, Götz J. 2019. Repeated ultrasound treatment of tau transgenic mice clears neuronal tau by autophagy and improves behavioral functions. Theranostics 9:133754–67
     [Google Scholar]
  135. 135. 
    Leinenga G, Götz J. 2018. Safety and efficacy of scanning ultrasound treatment of aged APP23 mice. Front. Neurosci. 12:55
     [Google Scholar]
  136. 136. 
    Nisbet RM, Van der Jeugd A, Leinenga G, Evans HT, Janowicz PW, Götz J. 2017. Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain 140:51220–30
     [Google Scholar]
  137. 137. 
    Karakatsani ME, Kugelman T, Ji R, Murillo M, Wang S et al. 2019. Unilateral focused ultrasound-induced blood-brain barrier opening reduces phosphorylated tau from the rTg4510 mouse model. Theranostics 9:185396–411
     [Google Scholar]
  138. 138. 
    Tung Y-S, Vlachos F, Choi JJ, Deffieux T. 2010. In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice. Phys. Med. Biol. 55:6141–55
     [Google Scholar]
  139. 139. 
    O'Reilly MA, Huang Y, Hynynen K. 2010. The impact of standing wave effects on transcranial focused ultrasound disruption of the blood-brain barrier in a rat model. Phys. Med. Biol. 55:5251–67
     [Google Scholar]
  140. 140. 
    Arvanitis CD, Livingstone MS, Vykhodtseva N, McDannold N. 2012. Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring. PLOS ONE 7:9e45783
     [Google Scholar]
  141. 141. 
    Tsai C-H, Zhang J-W, Liao Y-Y, Liu H-L. 2016. Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual-frequency piezoelectric transducers. Phys. Med. Biol. 61:2926–46
     [Google Scholar]
  142. 142. 
    Bing C, Hong Y, Hernandez C, Rich M, Cheng B et al. 2018. Characterization of different bubble formulations for blood-brain barrier opening using a focused ultrasound system with acoustic feedback control. Sci. Rep. 8:17986
     [Google Scholar]
  143. 143. 
    Kamimura HAS, Flament J, Valette J, Cafarelli A, Badin RA et al. 2019. Feedback control of microbubble cavitation for ultrasound-mediated blood-brain barrier disruption in non-human primates under magnetic resonance guidance. J. Cereb. Blood Flow Metab. 39:1191–203
     [Google Scholar]
  144. 144. 
    Lipsman N, Meng Y, Bethune AJ, Huang Y, Lam B et al. 2018. Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound. Nat. Commun. 9:12336
     [Google Scholar]
  145. 145. 
    Cheng B, Bing C, Xi Y, Shah B, Exner AA, Chopra R. 2019. Influence of nanobubble concentration on blood-brain barrier opening using focused ultrasound under real-time acoustic feedback control. Ultrasound Med. Biol. 45:2174–87
     [Google Scholar]
  146. 146. 
    Maimbourg G, Houdouin A, Santin M, Lehericy S, Tanter M, Aubry J-F. 2018. Inside/outside the brain binary cavitation localization based on the lowpass filter effect of the skull on the harmonic content: a proof of concept study. Phys. Med. Biol. 63:135012
     [Google Scholar]
  147. 147. 
    Norton SJ, Won IJ. 2000. Time exposure acoustics. IEEE Trans. Geosci. Remote Sens. 38:31337–43
     [Google Scholar]
  148. 148. 
    Coviello C, Kozick R, Choi J, Gyöngy M, Jensen C et al. 2015. Passive acoustic mapping utilizing optimal beamforming in ultrasound therapy monitoring. J. Acoust. Soc. Am. 137:2573–85
     [Google Scholar]
  149. 149. 
    Lyka E, Coviello CM, Paverd C, Gray MD, Coussios CC. 2018. Passive acoustic mapping using data-adaptive beamforming based on higher order statistics. IEEE Trans. Med. Imaging 37:2582–92
     [Google Scholar]
  150. 150. 
    Arvanitis CD, Livingstone MS, McDannold N. 2013. Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain. Phys. Med. Biol. 58:4749–61
     [Google Scholar]
  151. 151. 
    O'Reilly MA, Jones RM, Hynynen K. 2014. Three-dimensional transcranial ultrasound imaging of microbubble clouds using a sparse hemispherical array. IEEE Trans. Biomed. Eng. 61:41285–94
     [Google Scholar]
  152. 152. 
    Deng L, O'Reilly MA, Jones RM, An R, Hynynen K 2016. A multi-frequency sparse hemispherical ultrasound phased array for microbubble-mediated transcranial therapy and simultaneous cavitation mapping. Phys. Med. Biol. 61:248476–501
     [Google Scholar]
  153. 153. 
    Jones RM, McMahon D, Hynynen K. 2020. Ultrafast three-dimensional microbubble imaging in vivo predicts tissue damage volume distributions during nonthermal brain ablation. Theranostics 10:167211–30
     [Google Scholar]
  154. 154. 
    Crake C, Brinker ST, Coviello CM, Livingstone MS, McDannold NJ. 2018. A dual-mode hemispherical sparse array for 3D passive acoustic mapping and skull localization within a clinical MRI guided focused ultrasound device. Phys. Med. Biol. 63:6065008
     [Google Scholar]
  155. 155. 
    Mainprize T, Lipsman N, Huang Y, Meng Y, Bethune A et al. 2019. Blood-brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study. Sci. Rep. 9:1321
     [Google Scholar]
  156. 156. 
    Rezai AR, Ranjan M, D'Haese P-F, Haut MW, Carpenter J et al. 2020. Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound. PNAS 117:179180–82
     [Google Scholar]
  157. 157. 
    Abrahao A, Meng Y, Llinas M, Huang Y, Hamani C et al. 2019. First-in-human trial of blood-brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound. Nat. Commun. 10:14373
     [Google Scholar]
  158. 158. 
    Idbaih A, Canney M, Belin L, Desseaux C, Vignot A 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. 25:3793–801
     [Google Scholar]
  159. 159. 
    Huang Y, Alkins R, Schwartz ML, Hynynen K. 2017. Opening the blood-brain barrier with MR imaging-guided focused ultrasound: preclinical testing on a trans-human skull porcine model. Radiology 282:1123–30
     [Google Scholar]
  160. 160. 
    Meng Y, MacIntosh BJ, Shirzadi Z, Kiss A, Bethune A 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 200:275–80
     [Google Scholar]
  161. 161. 
    Chen K-T, Lin Y-J, Chai W-Y, Lin C-J, Chen P-Y et al. 2020. Neuronavigation-guided focused ultrasound (NaviFUS) for transcranial blood-brain barrier opening in recurrent glioblastoma patients: clinical trial protocol. Ann. Transl. Med. 8:673
     [Google Scholar]
  162. 162. 
    O'Reilly MA, Jones RM, Birman G, Hynynen K. 2016. Registration of human skull computed tomography data to an ultrasound treatment space using a sparse high frequency ultrasound hemispherical array. Med. Phys. 43:95063
     [Google Scholar]
  163. 163. 
    Hughes A, Hynynen K. 2017. Design of patient-specific focused ultrasound arrays for non-invasive brain therapy with increased trans-skull transmission and steering range. Phys. Med. Biol. 62:17L9–19
     [Google Scholar]
/content/journals/10.1146/annurev-bioeng-062117-121238
Loading
Therapeutic Agent Delivery Across the Blood–Brain Barrier Using Focused Ultrasound
Annual Review of Biomedical Engineering 23, 89 (2021); https://doi.org/10.1146/annurev-bioeng-062117-121238
/content/journals/10.1146/annurev-bioeng-062117-121238
/content/journals/10.1146/annurev-bioeng-062117-121238
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error