Microbubble-Assisted Ultrasound for Drug Delivery in the Brain and Central Nervous System

  • Alison Burgess
  • Kullervo HynynenEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 880)


The blood-brain barrier is a serious impediment to the delivery of pharmaceutical treatments for brain diseases, including cancer, neurodegenerative and neuropsychatric diseases. Focused ultrasound, when combined with microbubbles, has emerged as an effective method to transiently and locally open the blood-brain barrier to promote drug delivery to the brain. Focused ultrasound has been used to successfully deliver a wide variety of therapeutic agents to pre-clinical disease models. The requirement for clinical translation of focused ultrasound technology is considered.


Focused ultrasound Blood-brain barrier Drug delivery Alzheimer’s disease Glioblastoma 


  1. Abbott NK, Patabendige AA, Doman DE, Yusof SR, Begley DG (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37:13–25PubMedCrossRefGoogle Scholar
  2. Alkins R, Burgess A, Ganguly M, Francia G, Kerbel R, Wels WS, Hynynen K (2013) Focused ultrasound delivers targeted immune cells to metastatic brain tumors. Cancer Res 73:1892–1899PubMedCentralPubMedCrossRefGoogle Scholar
  3. Alonso A, Reinz E, Fatar M, Hennerici MG, Meairs S (2011) Clearance of albumin following ultrasound-induced blood-brain barrier opening is mediated by glial but not neuronal cells. Brain Res 1411:9–16PubMedGoogle Scholar
  4. Alonso A, Reinz E, Leuchs B, Kleinschmidt J, Fatar M, Geers B, Lentacker I, Hennerici MG, de Smedt SC, Meairs S (2013) Focal delivery of AAV2/1-transgene into the rat brain by localized ultrasound induced BBB opening. Mol Ther Nucleic Acids 2:e73PubMedCentralPubMedCrossRefGoogle Scholar
  5. Armulik A, Genové G, Mäe M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood-brain barrier. Nature 468:557–561PubMedCrossRefGoogle Scholar
  6. Arvanitis CD, Livingstone MS, Vykhodtseva N, McDannold N (2012) Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring. PLoS One 7:e45783PubMedCentralPubMedCrossRefGoogle Scholar
  7. Aryal M, Vykhodtseva N, Zhang YZ, 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 169:103–111PubMedCentralPubMedCrossRefGoogle Scholar
  8. Bakay L, Ballantine HT Jr, Hueter TF, Sosa D (1956) Ultrasonically produced changes in the blood-brain barrier. AMA Arch Neurol Psychiatry 76:457PubMedCrossRefGoogle Scholar
  9. Baseri B, Choi JJ, Deffieux T, Samiotaki G, Tung YS, Olumolade O, Small SA, Morrison B III, Konofagou EE (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 57:65–81CrossRefGoogle Scholar
  10. Bing KF, Howles GP, Qi Y, Palmeri ML, Nightingale KR (2009) Blood-brain barrier (BBB) disruption using a diagnostic ultrasound scanner and definity in mice. Ultrasound Med Biol 35:1298–1308PubMedCentralPubMedCrossRefGoogle Scholar
  11. 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:e27877PubMedCentralPubMedCrossRefGoogle Scholar
  12. 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 163:125–129PubMedCentralPubMedCrossRefGoogle Scholar
  13. Burgess A, Dubey S, Yeung S, Hough O, Eterman N, Aubert I, Hynynen K (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 273:736–745PubMedCentralPubMedCrossRefGoogle Scholar
  14. Chen H, Konofagou EE (2014) The size of blood-brain barrier opening induced by focused ultrasound is dictated by acoustic pressure. J Cereb Blood Flow Metab 34:1197–1204PubMedCentralPubMedCrossRefGoogle Scholar
  15. Chen PY, Liu HL, Hua MY, Yang HW, Huang CY, Chu PC, Lyu LA, Tseng IC, Feng LY, Tsai HC, Chen SM, Lu YJ, Wang JJ, Yen TC, Ma YH, Wu T, Chen JP, Chuang JI, Shin JW, Hseuh C, Wei KC (2010) Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma treatment. Neuro Oncol 12:1050–1060PubMedCentralPubMedCrossRefGoogle Scholar
  16. Chen H, Kreider W, Brayman AA, Bailey MR, Matula TJ (2011) Blood vessel deformations on microsecond time scales by ultrasonic cavitation. Phys Rev Lett 106:034301PubMedCentralPubMedCrossRefGoogle Scholar
  17. Cho CW, Liu W, Cobb N, Henthorn TK, Lillehei K, Christians U (2002) Ultrasound induced mild hyperthermia as a novel approach to increase drug uptake in brain microvessel endothelial cells. Pharm Res 19:1123–1129PubMedCrossRefGoogle Scholar
  18. 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 31:1852–1862PubMedCentralPubMedCrossRefGoogle Scholar
  19. Choi JJ, Pernot M, Small SA, Konofagou EE (2007) Noninvasive transcranial and localized opening of the blood-brain barrier using focused ultrasound in mice. Ultrasound Med Biol 33:95–104PubMedCrossRefGoogle Scholar
  20. Choi JJ, Wang S, Brown TR, Small SA, Duff KE, Konofagou EE (2008) Noninvasive and transient blood-brain barrier opening in the hippocampus of Alzheimer’s double transgenic mice using focused ultrasound. Ultrason Imaging 30:189–200PubMedCentralPubMedCrossRefGoogle Scholar
  21. Choi JJ, Feshitan JA, Baseri B, Wang S, Tung YS, Borden MA, Konofagou EE (2010) Microbubble-size dependence of focused ultrasound-induced blood-brain barrier opening in mice in vivo. IEEE Trans Biomed Eng 57:145–154PubMedCentralPubMedCrossRefGoogle Scholar
  22. Choi JJ, Selert K, Gao Z, Baseri B, Konofagou EE (2011) Noninvasive and localized blood-brain barrier disruption using focused ultrasound can be achieved at short pulses lengths and low repetition frequencies. J Cereb Blood Flow Metab 31:725–737PubMedCentralPubMedCrossRefGoogle Scholar
  23. Clement GT, Sun J, Hynynen K (2001) The role of internal reflection in transskull phase distortion. Ultrasonics 39:109–113PubMedCrossRefGoogle Scholar
  24. Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468:562–566PubMedCentralPubMedCrossRefGoogle Scholar
  25. Deng CX, Sieling F, Pan H, Cui J (2004) Ultrasound-induced cell membrane porosity. Ultrasound Med Biol 30:519–526PubMedCrossRefGoogle Scholar
  26. Deng J, Huang Q, Wang F, Liu Y, Wang Z, Wang Z, Zhang Q, Lei B, Cheng Y (2012) The role of caveolin-1 in blood-brain barrier disruption induced by focused ultrasound combined with microbubbles. J Mol Neurosci 46:677–687PubMedCrossRefGoogle Scholar
  27. Diaz RJ, McVeigh PZ, O’Reilly MA, Burrell K, Bebenek M, Smith C, Etame AB, Zadeh G, Hynynen K, Wilson BC, Rutka JT (2014) Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier potential for targeting experimental brain tumours. Nanomedicine 10:1075–1087PubMedCentralPubMedCrossRefGoogle Scholar
  28. Etame AB, Diaz RJ, O’Reilly MA, Smith CA, Mainprize TG, Hynynen K, Rutka JT (2012) Enhanced delivery of gold nanoparticles with therapeutic potential into the brain using MRI-guided focused ultrasound. Nanomedicine 8:1133–1142PubMedCentralPubMedCrossRefGoogle Scholar
  29. Fan CH, Ting CY, Lin HJ, Wang CH, Liu HL, Yen TC, Yeh CK (2013a) SPIO-conjugated, doxorubicin-loaded microbubbles for concurrent MRI and focused-ultrasound enhanced brain-tumor drug delivery. Biomaterials 34:3706–3715PubMedCrossRefGoogle Scholar
  30. Fan CH, Ting CY, Liu HL, Huang CY, Hsieh HY, Yen TC, Wei KC, Yeh CK (2013b) Antiangiogenic-targeting drug-loaded microbubbles combined with focused ultrasound for glioma treatment. Biomaterials 34:2142–2155PubMedCrossRefGoogle Scholar
  31. Fenstermacher J, Gross P, Sposito N, Acuff V, Pettersen S, Gruber K (1988) Structural and functional variations in capillary systems within the brain. Ann N Y Acad Sci 529:21–30PubMedCrossRefGoogle Scholar
  32. Fry WJ, Fry FJ (1960) Fundamental neurological research and human neurosurgery using intense ultrasound. IRE Trans Med Electron 7:166–181PubMedCrossRefGoogle Scholar
  33. Goertz DE, Wright C, Hynynen K (2010) Contrast agent kinetics in the rabbit brain during exposure to therapeutic ultrasound. Ultrasound Med Biol 36:916–924PubMedCentralPubMedCrossRefGoogle Scholar
  34. Goldmann EE (1909) Die aussere und innere Sekretion des gesunden und kranken Organismus im Lichte det ‘vitalenFarbung’. Beitraege Klinischen Chirurgie 64:192–265Google Scholar
  35. Gross ME, Nelson ET, Mone MC, Hansen HJ, Sklow B, Glasgow RE, Scaife CL (2011) A comparison of postoperative outcomes utilizing a continuous preperitoneal infusion versus epidural for midline laparotomy. Am J Surg 202:765–770PubMedCrossRefGoogle Scholar
  36. Hawkins BT, Davis TP (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173–185PubMedCrossRefGoogle Scholar
  37. Hosseinkhah N, Hynynen K (2012) A three-dimensional model of an ultrasound contrast agent gas bubble and its mechanical effects on microvessels. Phys Med Biol 57:785–808PubMedCentralPubMedCrossRefGoogle Scholar
  38. Hsu PH, Wei KC, Huang CY, Wen CJ, Yen TC, Liu CL, Lin YT, Chen JC, Shen CR, Liu HL (2013) Noninvasive and targeted gene delivery into the brain using microbubble-facilitated focused ultrasound. PLoS One 8:e57682PubMedCentralPubMedCrossRefGoogle Scholar
  39. Hynynen K, Jolesz FA (1998) Demonstration of potential noninvasive ultrasound brain therapy through an intact skull. Ultrasound Med Biol 24:275–283PubMedCrossRefGoogle Scholar
  40. Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA (2001) Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 220:640–646PubMedCrossRefGoogle Scholar
  41. Hynynen K, Clement GT, McDannold N, Vykhodtseva N, King R, White PJ, Vitek S, Jolesz FA (2004) 500-element ultrasound phased array system for noninvasive focal surgery of the brain: a preliminary rabbit study with ex vivo human skulls. Magn Reson Med 52:100–107PubMedCrossRefGoogle Scholar
  42. Hynynen K, McDannold N, Sheikov NA, Jolesz FA, Vyhodtseva N (2005) Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. Neuroimage 24:12–20PubMedCrossRefGoogle Scholar
  43. Hynynen K, McDannold N, Vykhodtseva N, Raymond S, Weissleder R, Jolesz FA, Sheikov N (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 105:445–454PubMedCrossRefGoogle Scholar
  44. Jalali S, Huang Y, Dumont DJ, Hynynen K (2010) Focused ultrasound-mediated bbb disruption is associated with an increase in activation of AKT: experimental study in rats. BMC Neurol 10:114PubMedCentralPubMedCrossRefGoogle Scholar
  45. Janzer RC, Raff MC (1987) Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325:253–257PubMedCrossRefGoogle Scholar
  46. Jordão JF, Ayala-Grosso CA, Markham K, Huang Y, Chopra R, McLaurin J, Hynynen K, Aubert I (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:e10549PubMedCentralPubMedCrossRefGoogle Scholar
  47. Jordão JF, Thévenot E, Markham-Coultes K, Scarcelli T, Weng YQ, Xhima K, O’Reilly M, Huang Y, McLaurin J, Hynynen K, Aubert I (2013) Amyloid-ß plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp Neurol 248:16–29PubMedCentralPubMedCrossRefGoogle Scholar
  48. 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 14:25–31PubMedCrossRefGoogle Scholar
  49. 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 103:11719–11723PubMedCentralPubMedCrossRefGoogle Scholar
  50. Kniesel U, Wolburg H (2000) Tight junctions of the blood-brain barrier. Cell Mol Neurobiol 20:1347–1357CrossRefGoogle Scholar
  51. Krizanac-Bengez L, Mayberg MR, Janigro D (2004) The cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in vascular homeostatis and pathophysiology. Neurol Res 26:846–853PubMedCrossRefGoogle Scholar
  52. 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 35:136–143PubMedCrossRefGoogle Scholar
  53. Lipsman N, Schwartz ML, Huang Y, Lee L, Sankar T, Chapman M, Hynynen K, Lozano AM (2013) MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study. Lancet Neurol 12:462–468PubMedCrossRefGoogle Scholar
  54. Liu HL, Pan CH, Ting CY, Hsiao MJ (2010a) Opening of the blood-brain barrier by low-frequency (28 kHz) ultrasound: a novel pinhole assisted mechanical scanning device. Ultrasound Med Biol 36:325–335PubMedCrossRefGoogle Scholar
  55. Liu HL, Hua MY, Chen PY, Chu PC, Pan CH, Yang HW, Huang CY, Wang JJ, Yen TC, Wei KC (2010b) Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology 255:415–425PubMedCrossRefGoogle Scholar
  56. Lochhead JJ, Thorne RG (2012) Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 64:614–628PubMedCrossRefGoogle Scholar
  57. Marquet F, Tung YS, Teichert T, Ferrera VP, Konofagou EE (2011) Noninvasive, transient and selective blood-brain barrier opening in non-human primates in vivo. PLoS One 6:e22598PubMedCentralPubMedCrossRefGoogle Scholar
  58. McDannold N, Vykhodsteva N, Jolesz FA, Hynynen K (2004) MRI investigation of the threshold for thermally induced blood-brain barrier disruption and brain tissue damage in the rabbit. Magn Reson Med 51:913–923PubMedCrossRefGoogle Scholar
  59. McDannold N, Vykhodtseva N, Raymond S, Jolesz F, Hynynen K (2005) MRI-guided targeted blood-brain barrier disruption with focused ultrasound: histological findings in rabbits. Ultrasound Med Biol 31:1527–1537PubMedCrossRefGoogle Scholar
  60. McDannold N, Vykhodtseva N, Hynynen K (2006) Targeted disruption of the blood-brain barrier with focused ultrasound: association with cavitation activity. Phys Med Biol 51:793–807PubMedCrossRefGoogle Scholar
  61. McDannold N, Vykhodtseva N, Hynynen K (2007) Use of ultrasound pulses combined with definity for targeted blood-brain barrier disruption; a feasibility study. Ultrasound Med Biol 33:584–590PubMedCentralPubMedCrossRefGoogle Scholar
  62. McDannold N, Vykhodtseva N, Hynynen K (2008a) Blood-brain barrier disruption by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index. Ultrasound Med Biol 34:834–840PubMedCentralPubMedCrossRefGoogle Scholar
  63. McDannold N, Vykhodtseva N, Hynynen K (2008b) Effects of acoustic parameters and ultrasound. Ultrasound Med Biol 34:930–937PubMedCentralPubMedCrossRefGoogle Scholar
  64. McDannold N, Clement GT, Black P, Jolesz F, Hynynen K (2010) Transcranial magnetic resonance imaging – guided focused ultrasound surgery of brain tumors: initial findings in 3 patients. J Neurosurg 66:323–332CrossRefGoogle Scholar
  65. 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 72:3652–3663PubMedCentralPubMedCrossRefGoogle Scholar
  66. Mei J, Cheng Y, Song Y, Yang Y, Wang F, Liu Y, Wang Z (2009) Experimental study on targeted methotrexate delivery to the rabbit brain via magnetic resonance imaging-guided focused ultrasound. J Ultrasound Med 28:871–880PubMedGoogle Scholar
  67. Meijering BD, Juffermans LJ, van Wamel A, Henning RH, Zuhorn IS, Emmer M, Versteilen AM, Paulus WJ, van Gilst WH, Kooiman K, de Jong N, Musters RJ, Deelman LE, Kamp O (2009) Ultrasound and microbubble-targeted delivery of macromolecules is regulated by induction of endocytosis and pore formation. Circ Res 104:679–687PubMedCrossRefGoogle Scholar
  68. Mesiwala AH, Farrell L, Wenzel HJ, Silbergeld DL, Crum LA, Winn HR, Mourad PD (2002) High-intensity focused ultrasound selectively disrupts the blood-brain barrier in vivo. Ultrasound Med Biol 28:389–400PubMedCrossRefGoogle Scholar
  69. Musch MW, Walsh-Reitz MM, Chang EB (2006) Roles of ZO-1, occludin, and actin in oxidant-induced barrier disruption. Am J Physiol Gastrointest Liver Physiol 290:222–231CrossRefGoogle Scholar
  70. 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 172:274–280PubMedCrossRefGoogle Scholar
  71. Nyborg WL (2001) Biological effects of ultrasound: development of safety guidelines. Part II: general review. Ultrasound Med Biol 27:301–333PubMedCrossRefGoogle Scholar
  72. O’Reilly MA, Hynynen K (2012) Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller. Radiology 263:96–106PubMedCentralPubMedCrossRefGoogle Scholar
  73. O’Reilly MA, Hynynen K (2013) A super-resolution ultrasound method for brain vascular mapping. Med Phys 40:100701CrossRefGoogle Scholar
  74. O’Reilly MA, Waspe AC, Ganguly M, Hynynen K (2010) Focused ultrasound disruption of the blood-brain barrier using closely-timed short pulses: influence of sonication parameters and injection rate. Ultrasound Med Biol 37:587–594CrossRefGoogle Scholar
  75. Pardridge WM (2005) The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2:3–14PubMedCentralPubMedCrossRefGoogle Scholar
  76. Pardridge WM (2012) Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab 32:1959–1972PubMedCentralPubMedCrossRefGoogle Scholar
  77. Pardridge WM, Boado RJ (2012) Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier. Methods Enzymol 503:269–292PubMedCrossRefGoogle Scholar
  78. 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 163:277–284PubMedCentralPubMedCrossRefGoogle Scholar
  79. Patrick JT, Nolting MN, Goss SA, Dines KA, Clendenon JL, Rea MA, Heimburger RF (1990) Ultrasound and the blood-brain barrier. Adv Exp Med Biol 267:369–381PubMedCrossRefGoogle Scholar
  80. Pires A, Fortuna A, Alves G, Falcao A (2009) Intranasal drug delivery: how, why and what for? J Pharm Pharm Sci 12:288–311PubMedGoogle Scholar
  81. Rapoport SI (2001) Advances in osmotic opening of the blood-brain barrier to enhance CNS chemotherapy. Expert Opin Investig Drugs 10:1809–1818PubMedCrossRefGoogle Scholar
  82. Raymond SB, Skoch J, Hynynen K, Bacskai BJ (2007) Multiphoton imaging of ultrasound/optison mediated cerebrovascular effects in vivo. J Cereb Blood Flow Metab 27:393–403.Google Scholar
  83. 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:e2175PubMedCentralPubMedCrossRefGoogle Scholar
  84. Samiotaki G, Konofagou EE (2013) Dependence of the reversibility of focused- ultrasound-induced blood-brain barrier opening on pressure and pulse length in vivo. IEEE Trans Ultrason Ferr 60:2257–2265CrossRefGoogle Scholar
  85. Samiotaki G, Vlachos F, Tung YS, 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 67:769–777PubMedCentralPubMedCrossRefGoogle Scholar
  86. Scarcelli T, Jordao 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 7:304–307PubMedCentralPubMedCrossRefGoogle Scholar
  87. Sedlakova R, Shivers RR, Del Maestro RF (1999) Ultrastructure of the blood-brain barrier in the rabbit. J Submicrosc Cytol Pathol 31:149–161PubMedGoogle Scholar
  88. Shealy CN, Crafts D (1965) Selective alteration of the blood-brain barrier. J Neurosurg 23:484–487PubMedCrossRefGoogle Scholar
  89. 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 30:979–989PubMedCrossRefGoogle Scholar
  90. Sheikov N, Mcdannold NJ, 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 34:1093–1104PubMedCentralPubMedCrossRefGoogle Scholar
  91. Thévenot E, Jordão JF, O’Reilly MA, Markham K, Weng YQ, Foust KD, Kaspar BK, Hynynen K, Aubert I (2012) Targeted delivery of scAAV9 to the brain using MRI-guided focused ultrasound. Human Gene Ther 23:1144–1155CrossRefGoogle Scholar
  92. Tilling T, Engelbertz C, Decker S, Korte D, Hüwel S, Galla HJ (2002) Expression and adhesive properties of basement membrane proteins in cerebral capillary endothelial cells cultures. Cell Tissue Res 310:19–29PubMedCrossRefGoogle Scholar
  93. Ting CY, Fan CH, Liu HL, Huang CY, Hsieh HY, Yen TC, Wei KC, Yeh CK (2012) Concurrent blood-brain barrier opening and local drug delivery using drug carrying microbubbles and focused ultrasound for brain glioma treatment. Biomaterials 33:704–712PubMedCrossRefGoogle Scholar
  94. Traub O, Ishida T, Ishida M, Tupper JC, Berk BC (1999) Shear-stress-mediated extracellular signal-related kinase activation is regulated by sodium in endothelial cells. Potential role for a voltage-dependent sodium channel. J Biol Chem 274:20144–20150PubMedCrossRefGoogle Scholar
  95. 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 121:901–907PubMedCrossRefGoogle Scholar
  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 38:1716–1725PubMedCentralPubMedCrossRefGoogle Scholar
  97. Tufail Y, Matyushov A, Baldwin N, Tauchmann ML, Georges J, Yoshihiro A, Tillery SIH, Tyler WJ (2010) Transcranial pulsed ultrasound stimulates intact brain circuits. Neuron 66:681–694PubMedCrossRefGoogle Scholar
  98. Tung YS, Marquet F, Teichert T, Ferrera V, Konofagou EE (2011) Feasibility of noninvasive cavitation-guided blood-brain barrier opening using focused ultrasound and microbubbles in nonhuman primates. Appl Phys Lett 98:163704PubMedCentralPubMedCrossRefGoogle Scholar
  99. van Wamel A, Kooiman K, Harteveld M, Emmer M, ten Cate FJ, Versluis M, de Jong N (2006) Vibrating microbubbles poking individual cells: drug transfer into cells via sonoporation. J Control Release 112:149–155PubMedCrossRefGoogle Scholar
  100. Vlachos F, Tung YS, Konofagou EE (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 66:821–830PubMedCentralPubMedCrossRefGoogle Scholar
  101. Vykhodtseva N, Hynynen K, Damianou C (1995) Histologic effects of high intensity pulsed ultrasound exposure with subharmonic emission in rabbit brain in vivo. Ultrasound Med Biol 21:969–979PubMedCrossRefGoogle Scholar
  102. Vykhodtseva N, McDannold N, Hynynen K (2008) Progress and problems in the application of focused ultrasound for blood–brain barrier disruption. Ultrasonics 48:279–296PubMedCentralPubMedCrossRefGoogle Scholar
  103. Wang F, Shi Y, Lu L, Liu L, Cai Y, Zheng H, Liu X, Yan F, Zou C, Sun C, Shi J, Lu S, Chen Y (2012) Targeted delivery of GDNF through the blood–brain barrier by MRI-guided focused ultrasound. PLoS One 7:e52925PubMedCentralPubMedCrossRefGoogle Scholar
  104. Wang S, Samiotaki G, Olumolade O, Feshitan JA, Konofagou EE (2014) Microbubble type and distribution dependence of focused ultrasound-induced blood-brain barrier opening. Ultrasound Med Biol 40:130–137PubMedCentralPubMedCrossRefGoogle Scholar
  105. Weng JC, Wu SK, Yang FY, Tseng WY (2010) Pulse sequence and timing of contrast-enhanced MRI for assessing blood-brain barrier disruption after transcranial focused ultrasound in the presence of haemorrhage. J Magn Reson Imaging 31:1323–1330PubMedCrossRefGoogle Scholar
  106. White E, Woolley M, Bienemann A, Johnson DE, Wyatt M, Murray G, Taylor H, Gill SS (2010) A robust MRI-compatible system to facilitate highly accurate stereotactic administration of therapeutic agents to targets within the brain of a large animal model. J Neurosci Methods 195:78–87PubMedCrossRefGoogle Scholar
  107. Yang FY, Fu WM, Chen WS, Yeh WL, Lin WL (2008) Quantitative evaluation of the use of microbubbles with transcranial focused ultrasound on blood-brain barrier disruption. Ultrason Sonochem 15:636–643PubMedCrossRefGoogle Scholar
  108. Yang FY, Lin YS, Kang KH, Chao TK (2011) Reversible blood-brain barrier disruption by repeated transcranial focused ultrasound allows enhanced extravasation. J Control Release 150:111–116PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Physical SciencesSunnybrook Research InstituteTorontoCanada
  2. 2.Medical BiophysicsUniversity of TorontoTorontoCanada

Personalised recommendations