Skip to main content

Advertisement

Log in

Microbubbles traversing the blood–brain barrier for imaging and therapy

  • Special Issue - Original Article
  • Published:
Medical & Biological Engineering & Computing Aims and scope Submit manuscript

Abstract

In the last several years great progress has been made in the field of ultrasound perfusion imaging of the brain. Different approaches have been assessed and shown to be capable of early detection of cerebral perfusion deficits. Real-time low mechanical index imaging simplifies the acquisition of perfusion parameters and alleviates many of the previous imaging problems related to shadowing, uniplanar analysis, and temporal resolution. With the advent of this new, highly sensitive contrast-specific imaging technique new possibilities of real-time visualization of brain infarctions and cerebral hemorrhages have emerged. Microbubbles that traverse the blood–brain barrier (BBB) can also elicit bioeffects that may be used to open the BBB for targeted delivery of macromolecular agents to the brain. Possible ways in which substances cross the BBB after application of this novel approach include transcytosis, passage through endothelial cell cytoplasmic openings, opening of tight junctions, and free passage through injured endothelium. Although relatively little tissue damage occurs at low acoustic intensities capable of opening the BBB, no investigation has demonstrated a total lack of BBB injury when using ultrasound and microbubbles. Further studies are necessary to address the effects of ultrasound and microbubbles upon the various transport mechanisms of the BBB. Moreover, investigations aimed at elucidating how ultrasound and microbubbles interact at the molecular level of the BBB are necessary. Results of such studies will increase our understanding of the mechanisms of BBB opening and also allow a better appraisal of the safety of this technique for future clinical applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Burns PN (1996) Harmonic imaging with ultrasound contrast agents. Clin Radiol 51(Suppl 1):50–55

    Google Scholar 

  2. Claudon M, Cosgrove D, Albrecht T, Bolondi L, Bosio M, Calliada F, Correas JM, Darge K, Dietrich C, D’Onofrio M, Evans DH, Filice C, Greiner L, Jager K, Jong N, Leen E, Lencioni R, Lindsell D, Martegani A, Meairs S, Nolsoe C, Piscaglia F, Ricci P, Seidel G, Skjoldbye B, Solbiati L, Thorelius L, Tranquart F, Weskott HP, Whittingham T (2008) Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS)—update 2008. Ultraschall Med 29:28–44. doi:10.1055/s-2007-963785

    Article  Google Scholar 

  3. Culp WC, Porter TR, Lowery J, Xie F, Roberson PK, Marky L (2004) Intracranial clot lysis with intravenous microbubbles and transcranial ultrasound in swine. Stroke 35:2407–2411. doi:10.1161/01.STR.0000140890.86779.79

    Article  Google Scholar 

  4. Dallasta LM, Pisarov LA, Esplen JE, Werley JV, Moses AV, Nelson JA, Achim CL (1999) Blood-brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis. Am J Pathol 155:1915–1927

    Google Scholar 

  5. Davson H, Spaziani E (1959) The blood-brain barrier and the extracellular space of brain. J Physiol 149:135–143

    Google Scholar 

  6. Della MA, Meyer-Wiethe K, Allemann E, Seidel G (2005) Ultrasound contrast agents for brain perfusion imaging and ischemic stroke therapy. J Neuroimaging 15:217–232. doi:10.1177/1051228405277342

    Article  Google Scholar 

  7. Diels A, Pettenpohl J, Kern R, Kablau M, Sick C, Hennerici M, Meairs S (2007) Real-time microbubble refill kinetics in patients with MCA infarction. Cerebrovasc Dis 23(suppl 1):1–76

    Google Scholar 

  8. Ehrlich P (1885) Das Sauerstoffbedürfnis des Organismus. Eine farbenanalytische Studie. Hirschwald, Berlin

    Google Scholar 

  9. Eyding J, Krogias C, Wilkening W, Postert T (2004) Detection of cerebral perfusion abnormalities in acute stroke using phase inversion harmonic imaging (PIHI): preliminary results. J Neurol Neurosurg Psychiatry 75:926–929. doi:10.1136/jnnp.2003.026195

    Article  Google Scholar 

  10. Eyding J, Krogias C, Schollhammer M, Eyding D, Wilkening W, Meves S, Schroder A, Przuntek H, Postert T (2006) Contrast-enhanced ultrasonic parametric perfusion imaging detects dysfunctional tissue at risk in acute MCA stroke. J Cereb Blood Flow Metab 26:576–582. doi:10.1038/sj.jcbfm.9600216

    Article  Google Scholar 

  11. Eyding J, Nolte-Martin A, Krogias C, Postert T (2007) Changes of contrast-specific ultrasonic cerebral perfusion patterns in the course of stroke; reliability of region-wise and parametric imaging analysis. Ultrasound Med Biol 33:329–334. doi:10.1016/j.ultrasmedbio.2006.08.013

    Article  Google Scholar 

  12. Fatar M, Stroick M, Griebe M, Alonso A, Kreisel S, Kern R, Hennerici M, Meairs S (2008) Effect of combined ultrasound and microbubbles treatment in an experimental model of cerebral ischemia. Ultrasound Med Biol 34:1414–1420. doi:10.1016/j.ultrasmedbio.2008.02.008

    Article  Google Scholar 

  13. Federlein J, Postert T, Meves S, Weber S, Przuntek H, Buttner T (2000) Ultrasonic evaluation of pathological brain perfusion in acute stroke using second harmonic imaging. J Neurol Neurosurg Psychiatry 69:616–622. doi:10.1136/jnnp.69.5.616

    Article  Google Scholar 

  14. Harrer JU, Mayfrank L, Mull M, Klotzsch C (2003) Second harmonic imaging: a new ultrasound technique to assess human brain tumour perfusion. J Neurol Neurosurg Psychiatry 74:333–338. doi:10.1136/jnnp.74.3.333

    Article  Google Scholar 

  15. Hawkins BT, Davis TP (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173–185. doi:10.1124/pr.57.2.4

    Article  Google Scholar 

  16. Holscher T, Wilkening W, Draganski B, Meves SH, Eyding J, Voit H, Bogdahn U, Przuntek H, Postert T (2005) Transcranial ultrasound brain perfusion assessment with a contrast agent-specific imaging mode: results of a two-center trial. Stroke 36:2283–2285. doi:10.1161/01.STR.0000179038.63109.b0

    Article  Google Scholar 

  17. Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA (2001) Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 220:640–646. doi:10.1148/radiol.2202001804

    Article  Google Scholar 

  18. 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. doi:10.1016/S0301-5629(02)00741-X

    Article  Google Scholar 

  19. 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. doi:10.1016/j.neuroimage.2004.06.046

    Article  Google Scholar 

  20. Kern R, Perren F, Schoeneberger K, Gass A, Hennerici M, Meairs S (2004) Ultrasound microbubble destruction imaging in acute middle cerebral artery stroke. Stroke 35:1665–1670. doi:10.1161/01.STR.0000129332.10721.7e

    Article  Google Scholar 

  21. Kern R, Perren F, Kreisel S, Szabo K, Hennerici M, Meairs S (2005) Multi-planar transcranial ultrasound imaging—standards, landmarks and correlation with magnetic resonance imaging. Ultrasound Med Biol 31:311–315. doi:10.1016/j.ultrasmedbio.2004.12.006

    Article  Google Scholar 

  22. 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. doi:10.1016/j.bbrc.2005.12.112

    Article  Google Scholar 

  23. Kirk J, Plumb J, Mirakhur M, McQuaid S (2003) Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination. J Pathol 201:319–327. doi:10.1002/path.1434

    Article  Google Scholar 

  24. Lewandowsky M (1900) Zur Lehre von der Cerebrospinalflussigkeit. Z Klin Med 40:480–494

    Google Scholar 

  25. 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. doi:10.1016/j.ultrasmedbio.2005.07.010

    Article  Google Scholar 

  26. McDannold N, Vykhodtseva N, Hynynen K (2006) Targeted disruption of the blood-brain barrier with focused ultrasound: association with cavitation activity. Phys Med Biol 51:793–807. doi:10.1088/0031-9155/51/4/003

    Article  Google Scholar 

  27. Meairs S, Daffertshofer M, Neff W, Eschenfelder C, Hennerici M (2000) Pulse-inversion contrast harmonic imaging: ultrasonographic assessment of cerebral perfusion. Lancet 355:550–551. doi:10.1016/S0140-6736(99)04361-5

    Article  Google Scholar 

  28. 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 28:389–400. doi:10.1016/S0301-5629(01)00521-X

    Article  Google Scholar 

  29. Meyer-Wiethe K, Cangur H, Seidel GU (2005) Comparison of different mathematical models to analyze diminution kinetics of ultrasound contrast enhancement in a flow phantom. Ultrasound Med Biol 31:93–98. doi:10.1016/j.ultrasmedbio.2004.05.006

    Article  Google Scholar 

  30. Molina CA, Ribo M, Rubiera M, Montaner J, Santamarina E, Delgado-Mederos R, Arenillas JF, Huertas R, Purroy F, Delgado P, Alvarez-Sabin J (2006) Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 37:425–429. doi:10.1161/01.STR.0000199064.94588.39

    Article  Google Scholar 

  31. Ogawa K, Tachibana K, Uchida T, Tai T, Yamashita N, Tsujita N, Miyauchi R (2001) High-resolution scanning electron microscopic evaluation of cell-membrane porosity by ultrasound. Med Electron Microsc 34:249–253. doi:10.1007/s007950100022

    Article  Google Scholar 

  32. Pardridge WM (2005) The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2:3–14. doi:10.1602/neurorx.2.1.3

    Article  Google Scholar 

  33. Pettenpohl J, Diels A, Kablau M, Kern R, Sick C, Hennerici M, Meairs S (2007) Dynamic microvascular perfusion maps for assessement of brain infarction. Cerebrovasc Dis 23(Suppl 1):1–76

    Google Scholar 

  34. Petty MA, Lo EH (2002) Junctional complexes of the blood-brain barrier: permeability changes in neuroinflammation. Prog Neurobiol 68:311–323. doi:10.1016/S0301-0082(02)00128-4

    Article  Google Scholar 

  35. Postert T, Muhs A, Meves S, Federlein J, Przuntek H, Buttner T (1998) Transient response harmonic imaging: an ultrasound technique related to brain perfusion. Stroke 29:1901–1907

    Google Scholar 

  36. Postert T, Hoppe P, Federlein J, Helbeck S, Ermert H, Przuntek H, Buttner T, Wilkening W (2000) Contrast agent specific imaging modes for the ultrasonic assessment of parenchymal cerebral echo contrast enhancement. J Cereb Blood Flow Metab 20:1709–1716. doi:10.1097/00004647-200012000-00010

    Article  Google Scholar 

  37. Reese T, Karnovsky M (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Biol Chem 34:207–217

    Google Scholar 

  38. Rim SJ, Leong-Poi H, Lindner JR, Couture D, Ellegala D, Mason H, Durieux M, Kassel NF, Kaul S (2001) Quantification of cerebral perfusion with “Real-Time” contrast-enhanced ultrasound. Circulation 104:2582–2587. doi:10.1161/hc4601.099400

    Article  Google Scholar 

  39. Schlachetzki F, Holscher T, Koch HJ, Draganski B, May A, Schuierer G, Bogdahn U (2002) Observation on the integrity of the blood-brain barrier after microbubble destruction by diagnostic transcranial color-coded sonography. J Ultrasound Med 21:419–429

    Google Scholar 

  40. Seidel G, Greis C, Sonne J, Kaps M (1999) Harmonic grey scale imaging of the human brain. J Neuroimaging 9:171–174

    Google Scholar 

  41. Seidel G, Algermissen C, Christoph A, Claassen L, Vidal-Langwasser M, Katzer T (2000) Harmonic imaging of the human brain. Visualization of brain perfusion with ultrasound. Stroke 31:151–154

    Google Scholar 

  42. Seidel G, Meyer-Wiethe K, Berdien G, Hollstein D, Toth D, Aach T (2004) Ultrasound perfusion imaging in acute middle cerebral artery infarction predicts outcome. Stroke 35:1107–1111. doi:10.1161/01.STR.0000124125.19773.40

    Article  Google Scholar 

  43. 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 30:979–989. doi:10.1016/j.ultrasmedbio.2004.04.010

    Article  Google Scholar 

  44. 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 34:1093–1104. doi:10.1016/j.ultrasmedbio.2007.12.015

    Article  Google Scholar 

  45. Sobesky J, Zaro WO, Lehnhardt FG, Hesselmann V, Thiel A, Dohmen C, Jacobs A, Neveling M, Heiss WD (2004) Which time-to-peak threshold best identifies penumbral flow? A comparison of perfusion-weighted magnetic resonance imaging and positron emission tomography in acute ischemic stroke. Stroke 35:2843–2847. doi:10.1161/01.STR.0000147043.29399.f6

    Article  Google Scholar 

  46. Stroick M, Alonso A, Fatar M, Griebe M, Kreisel S, Kern R, Gaud E, Arditi M, Hennerici M, Meairs S (2006) Effects of simultaneous application of ultrasound and microbubbles on intracerebral hemorrhage in an animal model. Ultrasound Med Biol 32:1377–1382. doi:10.1016/j.ultrasmedbio.2006.05.027

    Article  Google Scholar 

  47. Taniyama Y, Tachibana K, Hiraoka K, Namba T, Yamasaki K, Hashiya N, Aoki M, Ogihara T, Yasufumi K, Morishita R (2002) Local delivery of plasmid DNA into rat carotid artery using ultrasound. Circulation 105:1233–1239. doi:10.1161/hc1002.105228

    Article  Google Scholar 

  48. Wardlaw JM, Sandercock PA, Dennis MS, Starr J (2003) Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke 34:806–812. doi:10.1161/01.STR.0000058480.77236.B3

    Article  Google Scholar 

  49. Wiesmann M, Meyer K, Albers T, Seidel G (2004) Parametric perfusion imaging with contrast-enhanced ultrasound in acute ischemic stroke. Stroke 35:508–513. doi:10.1161/01.STR.0000114877.58809.3D

    Article  Google Scholar 

  50. Xie F, Tsutsui JM, Lof J, Unger EC, Johanning J, Culp WC, Matsunaga T, Porter TR (2005) Effectiveness of lipid microbubbles and ultrasound in declotting thrombosis. Ultrasound Med Biol 31:979–985. doi:10.1016/j.ultrasmedbio.2005.03.008

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephen Meairs.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meairs, S., Alonso, A., Fatar, M. et al. Microbubbles traversing the blood–brain barrier for imaging and therapy. Med Biol Eng Comput 47, 839–849 (2009). https://doi.org/10.1007/s11517-009-0468-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11517-009-0468-6

Keywords

Navigation