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Novel preparation techniques for controlling microbubble uniformity: a comparison

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Abstract

In recent years, there has been increasing interest in the use of coated microbubbles as vehicles for ultrasound mediated targeted drug delivery. This application requires a high degree of control over the size and uniformity of microbubbles, in order to ensure accurate dosing of a given drug and to maximise delivery efficiency. Similarly, as more advanced imaging techniques are developed which exploit the complex nonlinear features of the microbubble signal and/or enable quantification of tissue perfusion, the ability to predetermine the acoustic response of a microbubble suspension is becoming increasingly important. Consequently, a number of new preparation technologies have been developed to meet the demand for improved control over microbubble characteristics. The aim of the work described in this paper was to compare a conventional microbubble preparation technique, sonication, with two more recent methods: coaxial electrohydrodynamic atomisation and microfluidic (T-junction) processing, in terms of their ability to produce bubbles which are sufficiently small and stable for in vivo use, microbubble uniformity, relative production rates and other practical and economic considerations.

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Notes

  1. As shown in [25], Eq. 1 represents the limiting case of an infinitely thin microbubble coating derived from a model for a bubble surrounded by a coating of finite thickness [8]. Hence, the shear viscosity, modulus and thickness have been referred to here as effective quantities since they are being applied to a two-dimensional structure. In other models, e.g. [11] the fractional terms in the expressions for b and k are represented as single “shell parameters” in order to avoid the apparent paradox. Mathematically, however, the treatments are equivalent.

  2. The calculations for the microbubbles prepared by sonication were based on the size distribution for a filtered suspension (R o < 10 μm) in Fig. 4, since this would be more relevant for biomedical applications.

References

  1. Ahmad Z, Zhang H, Farook U, Edirisinghe M, Stride E, Colombo P (2008) Generation of multi-layered structures for biomedical applications using a novel tri-needle co-axial device and electrohydrodynamic flow. J R Soc Interface 5:1255–1261

    Article  Google Scholar 

  2. Albrecht T, Blomley MJK, Heckemann RA, Cosgrove DO, Jayaram V, Butler-Barnes J, Eckersley RJ, Hoffmann CW, Bauer A (2000) Stimulated acoustic emission with the ultrasound contrast agent levovist: a clinically useful contrast effect with liver-specific properties. Rofo-Fortschritte Auf dem Gebiet der Rontgenstrahlen und der Bildgebenden Verfahren 172:61–67

    Article  Google Scholar 

  3. Al-Mansour HA, Mulvagh SL, Pumper GM, Klarich KW, Foley DA (2000) Usefulness of harmonic imaging for left ventricular opacification and endocardial border delineation by Optison. Am J Cardiol 85:795–799

    Google Scholar 

  4. Anna SL, Bontoux N, Stone HA (2003) Formation of dispersions using “flow focusing” in microchannels. Appl Phys Lett 82:364–366

    Article  Google Scholar 

  5. Borden MA, Longo ML (2002) Dissolution behavior of lipid monolayer-coated, air-filled microbubbles: effect of lipid hydrophobic chain length. Langmuir 18:9225–9233

    Article  Google Scholar 

  6. Bull JL (2007) The application of microbubbles for targeted drug delivery. Expert Opin Drug Deliv 4:475–493

    Article  Google Scholar 

  7. Christiansen C, Kryvi H, Sontum PC, Skotland T (1994) Physical and biochemical-characterization of Albunex(Tm), a new ultrasound contrast agent consisting of air-filled albumin microspheres suspended in a solution of human albumin. Biotechnol Appl Biochem 19:307–320

    Google Scholar 

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

    Article  Google Scholar 

  9. Cosgrove D (2006) Ultrasound contrast agents: an overview. Eur J Radiol 60:324–330

    Article  Google Scholar 

  10. Coussios CC, Farny CH, Ter Haar G, Roy RA (2007) Role of acoustic cavitation in the delivery and monitoring of cancer treatment by high-intensity focused ultrasound (HIFU). Int J Hyperthermia 23:105–120

    Article  Google Scholar 

  11. de Jong N, Hoff L, Skotland T, Bom N (1992) Absorption and scatter of encapsulated gas filled microspheres—theoretical considerations and some measurements. Ultrasonics 30:95–103

    Article  Google Scholar 

  12. Dollet B, van Hoeve W, Raven JP, Marmottant P, Versluis M (2008) Role of the channel geometry on the bubble pinch-off in flow-focusing devices. Phys Rev Lett 1:034504-1–034504-4

    Google Scholar 

  13. Epstein PS, Plesset MS (1950) On the stability of gas bubbles in liquid–gas solutions. J Chem Phys 18:1505–1509

    Article  Google Scholar 

  14. Farook U, Zhang HB, Edirisinghe MJ, Stride E, Saffari N (2007) Preparation of microbubble suspensions by co-axial electrohydrodynamic atomization. Med Eng Phys 29:749–754

    Article  Google Scholar 

  15. Farook U, Stride E, Edirisinghe MJ, Moaleji R (2007) Microbubbling by co-axial electrohydrodynamic atomization. Med Biol Eng Comput 45:781–789

    Article  Google Scholar 

  16. Farook U, Stride E, Edirisinghe M (2009) Preparation of suspensions of phospholipid-coated microbubbles by coaxial electrohydrodynamic atomisation. J R Soc Interface 6:271–277

    Article  Google Scholar 

  17. Farook U, Stride E, Edirisinghe MJ (2009) Stability of microbubbles prepared by co-axial electrohydrodynamic atomisation. Eur Biophys J. doi:10.1007/s00249-008-0391-z

  18. Feshitan JA, Chen CC, Kwan JJ, Borden MA (2009) Microbubble size isolation by differential centrifugation. J Colloid Interface Sci 329:316–324

    Article  Google Scholar 

  19. Garstecki P, Gitlin I, DiLuzio W, Whitesides GM, Kumacheva E, Stone HA (2004) Formation of monodisperse bubbles in a microfluidic flow-focusing device. Appl Phys Lett 85:2649–2651

    Article  Google Scholar 

  20. Grinstaff MW, Suslick KS (1991) Air-filled proteinaceous microbubbles: synthesis of an Echo-contrast agent. Proc Natl Acad Sci USA 88:7708–7710

    Article  Google Scholar 

  21. Heppner P, Lindner JR (2005) Contrast ultrasound assessment of angiogenesis by perfusion and molecular imaging. Expert Rev Mol Diagn 5:447–455

    Article  Google Scholar 

  22. Hettiarachchi K, Talu E, Longo ML, Dayton PA, Lee AP (2007) On-chip generation of microbubbles as a practical technology for manufacturing contrast agents for ultrasonic imaging. Lab Chip 7:463–468

    Article  Google Scholar 

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

    Article  Google Scholar 

  24. Hill CR, Bamber J, Ter Haar G (2004) Physical principles of medical ultrasound, Chap 3, 2nd edn. Wiley/Blackwell, Chichester, UK

  25. Hoff L, Sontum PC, Hovem JM (2000) Oscillations of polymeric microbubbles: effect of the encapsulating shell. J Acoust Soc Am 107:2272–2280

    Article  Google Scholar 

  26. Kaneko Y, Maruyama T, Takegami K, Watanabe T, Mitsui H, Hanajiri K, Nagawa HA, Matsumoto Y (2005) Use of a microbubble agent to increase the effects of high intensity focused ultrasound on liver tissue. Eur Radiol 15:1415–1420

    Article  Google Scholar 

  27. Klibanov AL (2006) Microbubble contrast agents—targeted ultrasound imaging and ultrasound-assisted drug-delivery applications. Invest Radiol 41:354–362

    Article  Google Scholar 

  28. Leen E, Ceccotti P, Kalogeropoulou C, Angerson WJ, Moug SJ, Horgan PG (2006) Prospective multicenter trial evaluating a novel method of characterizing focal liver lesions using contrast-enhanced sonography. Am J Roentgenol 186:1551–1559

    Article  Google Scholar 

  29. Lepper W, Belcik T, Wei K, Lindner JR, Sklenar J, Kaul S (2004) Myocardial contrast echocardiography. Circulation 109:3132–3135

    Article  Google Scholar 

  30. Loscertales IG, Barrero A, Guerrero I et al (2002) Micro/nano encapsulation via electrified coaxial liquid jets. Science 295:1695–1698

    Article  Google Scholar 

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

    Article  Google Scholar 

  32. Marmottant P, van der Meer S, Emmer M, Versluis M, de Jong N, Hilgenfeldt S, Lohse D (2005) A model for large amplitude oscillations of coated bubbles accounting for buckling and rupture. J Acoust Soc Am 118:3499–3505

    Article  Google Scholar 

  33. McDonald DM, Choyke PL (2003) Imaging of angiogenesis: from microscope to clinic. Nat Med 9:713–725

    Article  Google Scholar 

  34. Mor-Avi V, Bednarz J, Weinert L, Sugeng L, Lang RM (2000) Power Doppler imaging as a basis for automated endocardial border detection during left ventricular contrast enhancement. Echocardiogr A J Cardiovasc Ultrasound Allied Tech 17:529–537

    Google Scholar 

  35. Nyborg W (2007) WFUMB safety symposium on echo-contrast agents: mechanisms for the interaction of ultrasound. Ultrasound Med Biol 33:224–232

    Article  Google Scholar 

  36. Pancholi K, Stride E, Edirisinghe M (2008) Dynamics of bubble formation in highly viscous liquids. Langmuir 24:4388–4393

    Article  Google Scholar 

  37. Pancholi KP, Farook U, Moaleji R, Stride E, Edirisinghe MJ (2008) Novel methods for preparing phospholipid coated microbubbles. Eur Biophys J Biophys Lett 37:515–520

    Google Scholar 

  38. Pancholi K, Stride E, Edirisinghe M (2008) Generation of microbubbles for diagnostic and therapeutic applications using a novel device. J Drug Target 16:494–501

    Article  Google Scholar 

  39. Postema M, van Wamel A, Lancee CT, de Jong N (2004) Ultrasound-induced encapsulated microbubble phenomena. Ultrasound Med Biol 30:827–840

    Article  Google Scholar 

  40. Schneider M (2008) Molecular imaging and ultrasound-assisted drug delivery. J Endourol 22:795–801

    Article  Google Scholar 

  41. Stride E (2008) The influence of surface adsorption on microbubble dynamics. Philos Transact R Soc A Math Phys Eng Sci 366:2103–2115

    Article  Google Scholar 

  42. Stride E, Edirisinghe M (2008) Novel microbubble preparation technologies. Soft Matter 4:2350–2359

    Article  Google Scholar 

  43. Stride E, Tang M, Eckersley RJ (2008) Physical phenomena affecting quantitative imaging of ultrasound contrast agents. Appl Acoust doi:10.1016/j.apacoust.2008.10.003

  44. Suslick KS, Didenko Y, Fang MM, Hyeon T, Kolbeck KJ, McNamara WB, Mdleleni MM, Wong M (1999) Acoustic cavitation and its chemical consequences. Philos Trans R Soc Lond Ser A Math Phys Eng Sci 357:335–353

    Article  Google Scholar 

  45. Talu E, Hettiarachchi K, Zhao S, Powell RL, Lee AP, Longo ML, Dayton PA (2007) Tailoring the size distribution of ultrasound contrast agents: Possible method for improving sensitivity in molecular imaging. Mol Imaging 6:384–392

    Google Scholar 

  46. Talu E, Hettiarachchi K, Powell RL, Lee AP, Dayton PA, Longo ML (2008) Maintaining monodispersity in a microbubble population formed by flow-focusing. Langmuir 24:1745–1749

    Article  Google Scholar 

  47. Unger EC, McCreery TP, Sweitzer RH, Caldwell VE, Wu YQ (1998) Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent. Invest Radiol 33:886–892

    Article  Google Scholar 

  48. Wang WH, Moser CC, Wheatley MA (1996) Langmuir trough study of surfactant mixtures used in the production of a new ultrasound contrast agent consisting of stabilized microbubbles. J Phys Chem 100:13815–13821

    Article  Google Scholar 

  49. Xu S, Nie Z, Seo M, Lewis P, Kumacheva E, Stone HA, Garstecki P, Weibel DB, Gitlin I, Whitesides GM (2005) Generation of monodisperse particles by using microfluidics: control over size, shape, and composition (vol 44, pg 724, 2005). Angew Chem Int Ed 44:3799

    Article  Google Scholar 

  50. Zhao YZ, Liang HD, Mei XG, Halliwell M (2005) Preparation, characterization and in vivo observation of phospholipid-based gas-filled microbubbles containing hirudin. Ultrasound Med Biol 31:1237–1243

    Article  Google Scholar 

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Acknowledgments

This work was supported by the Engineering and Physical Sciences Research Council (Grants EP/E012434/1 and EP/E 045839/1) and The Royal Academy of Engineering.

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  1. Department of Mechanical Engineering, University College London, Torrington Place, London, WC1E 7JE, UK

    Eleanor Stride & Mohan Edirisinghe

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  1. Eleanor Stride
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Correspondence to Eleanor Stride.

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Stride, E., Edirisinghe, M. Novel preparation techniques for controlling microbubble uniformity: a comparison. Med Biol Eng Comput 47, 883–892 (2009). https://doi.org/10.1007/s11517-009-0490-8

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