AAPS PharmSciTech

, 20:147 | Cite as

A Thermoelectric Device for Coupling Fluid Temperature Regulation During Continuous Skin Sonoporation or Sonophoresis

  • Jeremy RobertsonEmail author
  • Marie Squire
  • Sid Becker
Research Article


During skin sonoporation and sonophoresis, time-consuming duty cycles or fluid replacement is often required to mitigate coupling fluid temperature increases. This study demonstrates an alternative method for temperature regulation: a circulating, thermoelectric system. Porcine skin samples were sonoporated continuously for 10 min at one of three intensities (23.8, 34.2, 39.4 W/m2). A caffeine solution was then applied to the skin and left to diffuse for 20 h. During sonoporation, the system was able to maintain the temperature between 10 and 16°C regardless of the intensity. No increase in transdermal transport was achieved with an intensity of 23.8 W/m2. Intensities of 34.2 and 39.4 W/m2 resulted in 3.5-fold (p < 0.05) and 3.7-fold (p < 0.05) increases in mean transport, relative to a control case with no ultrasound. From these results, it is concluded that a significant transport increase can be achieved with a system that circulates and cools the coupling fluid during ultrasound application. Relative to the previous methods of temperature control (duty cycles and fluid replacement), use of this circulation system will lead to significant time savings in future experimental studies.


skin sonoporation transdermal ultrasound cavitation temperature 



  1. 1.
    Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26(11):1261–8.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Boucaud A, Montharu J, Machet L, Arbeille B, Machet MC, Patat F, et al. Clinical, histologic, and electron microscopy study of skin exposed to low-frequency ultrasound. Anat Rec. 2001;264(1):114–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Ogura M, Paliwal S, Mitragotri S. Low-frequency sonophoresis: current status and future prospects. Adv Drug Deliv Rev. 2008;60(10):1218–23.PubMedCrossRefGoogle Scholar
  4. 4.
    Lee SE, Choi KJ, Menon GK, Kim HJ, Choi EH, Ahn SK, et al. Penetration pathways induced by low-frequency sonophoresis with physical and chemical enhancers: iron oxide nanoparticles versus lanthanum nitrates. J Invest Dermatol. 2010;130(4):1063–72.PubMedCrossRefGoogle Scholar
  5. 5.
    Merino G, Kalia YN, Delgado-Charro MB, Potts RO, Guy RH. Frequency and thermal effects on the enhancement of transdermal transport by sonophoresis. J Control Release. 2003;88(1):85–94.PubMedCrossRefGoogle Scholar
  6. 6.
    Polat BE, Deen WM, Langer R, Blankschtein D. A physical mechanism to explain the delivery of chemical penetration enhancers into skin during transdermal sonophoresis—insight into the observed synergism. J Control Release. 2012;158(2):250–60.PubMedCrossRefGoogle Scholar
  7. 7.
    Mitragotri S, Blankschtein D, Langer R. Transdermal drug delivery using low-frequency sonophoresis. Pharm Res. 1996;13(3):411–20.PubMedCrossRefGoogle Scholar
  8. 8.
    Morimoto Y, Mutoh M, Ueda H, Fang L, Hirayama K, Atobe M, et al. Elucidation of the transport pathway in hairless rat skin enhanced by low-frequency sonophoresis based on the solute–water transport relationship and confocal microscopy. J Control Release. 2005;103(3):587–97.PubMedCrossRefGoogle Scholar
  9. 9.
    Mitragotri S, Kost J. Low-frequency sonophoresis: a review. Adv Drug Deliv Rev. 2004;56(5):589–601.PubMedCrossRefGoogle Scholar
  10. 10.
    Zorec B, Jelenc J, Miklavčič D, Pavšelj N. Ultrasound and electric pulses for transdermal drug delivery enhancement: ex vivo assessment of methods with in vivo oriented experimental protocols. Int J Pharm. 2015;490(1–2):65–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Boucaud A, Garrigue MA, Machet L, Lc V, Patat F. Effect of sonication parameters on transdermal delivery of insulin to hairless rats. J Control Release. 2002;81(1):113–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Kushner J, Blankschtein D, Langer R. Experimental demonstration of the existence of highly permeable localized transport regions in low-frequency sonophoresis. J Pharm Sci. 2004;93(11):2733–45.PubMedCrossRefGoogle Scholar
  13. 13.
    Ueda H, Mutoh M, Seki T, Kobayashi D, Morimoto Y. Acoustic cavitation as an enhancing mechanism of low-frequency sonophoresis for transdermal drug delivery. Biol Pharm Bull. 2009;32(5):916–20.PubMedCrossRefGoogle Scholar
  14. 14.
    Rangsimawong W, Obata Y, Opanasopit P, Ngawhirunpat T, Takayama K. Enhancement of galantamine HBr skin permeation using sonophoresis and limonene-containing PEGylated liposomes. AAPS PharmSciTech. 2018;19(3):1093–104.PubMedCrossRefGoogle Scholar
  15. 15.
    Terahara T, Mitragotri S, Kost J, Langer R. Dependence of low-frequency sonophoresis on ultrasound parameters; distance of the horn and intensity. Int J Pharm. 2002a;235(1–2):35–42.PubMedCrossRefGoogle Scholar
  16. 16.
    Herwadkar A, Sachdeva V, Taylor LF, Silver H, Banga AK. Low frequency sonophoresis mediated transdermal and intradermal delivery of ketoprofen. Int J Pharm. 2012;423(2):289–96.PubMedCrossRefGoogle Scholar
  17. 17.
    Terahara T, Mitragotri S, Langer R. Porous resins as a cavitation enhancer for low-frequency sonophoresis. J Pharm Sci. 2002b;91(3):753–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Lindeque BGPMD, Shuler FDMDP, Bates CMMD. Skin temperatures generated following plaster splint application. Orthopedics (Online). 2013;36(5):364–7.CrossRefGoogle Scholar
  19. 19.
    Hao J, Ghosh P, Li SK, Newman B, Kasting GB, Raney SG. Heat effects on drug delivery across human skin. Expert Opin Drug Deliv. 2016;13(5):755–68.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Moritz AR, Henriques FC. Studies of thermal injury: II. The relative importance of time and surface temperature in the causation of cutaneous burns. Am J Pathol. 1947;23(5):695–720.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Williamson C, Scholtz JR. Time-temperature relationships in thermal blister formation*. J Investig Dermatol. 1949;12(1):41–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Tang H, Wang CCJ, Blankschtein D, Langer R. An investigation of the role of cavitation in low-frequency ultrasound-mediated transdermal drug transport. Pharm Res. 2002a;19(8):1160–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Lavon I, Grossman N, Kost J. The nature of ultrasound–SLS synergism during enhanced transdermal transport. J Control Release. 2005;107(3):484–94.PubMedCrossRefGoogle Scholar
  24. 24.
    Paliwal S, Menon GK, Mitragotri S. Low-frequency sonophoresis: ultrastructural basis for stratum corneum permeability assessed using quantum dots. J Invest Dermatol. 2006;126(5):1095–101.PubMedCrossRefGoogle Scholar
  25. 25.
    Polat BE, Figueroa PL, Blankschtein D, Langer R. Transport pathways and enhancement mechanisms within localized and non-localized transport regions in skin treated with low-frequency sonophoresis and sodium lauryl sulfate. J Pharm Sci. 2011a;100(2):512–29.PubMedCrossRefGoogle Scholar
  26. 26.
    Tezel A, Sens A, Tuchscherer J, Mitragotri S. Frequency dependence of sonophoresis. Pharm Res. 2001;18(12):1694–700.PubMedCrossRefGoogle Scholar
  27. 27.
    Tezel A, Dokka S, Kelly S, Hardee GE, Mitragotri S. Topical delivery of anti-sense oligonucleotides using low-frequency sonophoresis. Pharm Res. 2004;21(12):2219–25.PubMedCrossRefGoogle Scholar
  28. 28.
    Sarheed O, Abdul Rasool BK. Development of an optimised application protocol for sonophoretic transdermal delivery of a model hydrophilic drug. Open Biomed Eng J. 2011;5:14–24.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Rich KT, Hoerig CL, Rao MB, Mast TD. Relations between acoustic cavitation and skin resistance during intermediate- and high-frequency sonophoresis. J Control Release. 2014;194:266–77.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Han T, Das DB. Permeability enhancement for transdermal delivery of large molecule using low-frequency sonophoresis combined with microneedles. J Pharm Sci. 2013;102(10):3614–22.PubMedCrossRefGoogle Scholar
  31. 31.
    Mitragotri S, Farrell J, Tang H, Terahara T, Kost J, Langer R. Determination of threshold energy dose for ultrasound-induced transdermal drug transport. J Control Release. 2000a;63(1–2):41–52.PubMedCrossRefGoogle Scholar
  32. 32.
    Mitragotri S, Ray D, Farrell J, Tang H, Yu B, Kost J, et al. Synergistic effect of low-frequency ultrasound and sodium lauryl sulfate on transdermal transport. J Pharm Sci. 2000b;89(7):892–900.PubMedCrossRefGoogle Scholar
  33. 33.
    Mutoh M, Ueda H, Nakamura Y, Hirayama K, Atobe M, Kobayashi D, et al. Characterization of transdermal solute transport induced by low-frequency ultrasound in the hairless rat skin. J Control Release. 2003;92(1–2):137–46.PubMedCrossRefGoogle Scholar
  34. 34.
    Robertson J, Becker S. Influence of acoustic reflection on the inertial cavitation dose in a Franz diffusion cell. Ultrasound Med Biol. 2018;44(5):1100–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Dunne A, Crampton D, Egaña M. Effect of post-exercise hydrotherapy water temperature on subsequent exhaustive running performance in normothermic conditions. J Sci Med Sport. 2013;16(5):466–71.PubMedCrossRefGoogle Scholar
  36. 36.
    Vichare V, Mujgond P, Tambe V, Dhole S. Simultaneous spectrophotometric determination of paracetamol and caffeine in tablet formulation. Int J PharmTech Res. 2010;2(4):2512–6.Google Scholar
  37. 37.
    Franeta J, Agbaba D, Eric S, Pavkov S, Aleksic M, Vladimirov S. HPLC assay of acetylsalicylic acid, paracetamol, caffeine and phenobarbital in tablets. Il Farmaco. 2002;57(9):709–13.PubMedCrossRefGoogle Scholar
  38. 38.
    Rodrigues CI, Marta L, Maia R, Miranda M, Ribeirinho M, Máguas C. Application of solid-phase extraction to brewed coffee caffeine and organic acid determination by UV/HPLC. J Food Compos Anal. 2007;20(5):440–8.CrossRefGoogle Scholar
  39. 39.
    Fernandez P, Martin M, Gonzalez A, Pablos F. HPLC determination of catechins and caffeine in tea. Differentiation of green, black and instant teas. Analyst. 2000;125(3):421–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Hubert M, Vandervieren E. An adjusted boxplot for skewed distributions. Comput Stat Data Anal. 2008;52(12):5186–201.CrossRefGoogle Scholar
  41. 41.
    Krzywinski M, Altman N. Points of significance: visualizing samples with box plots: Nature Publishing Group; 2014.Google Scholar
  42. 42.
    Spitzer M, Wildenhain J, Rappsilber J, Tyers M. BoxPlotR: a web tool for generation of box plots. Nat Methods. 2014;11(2):121–2.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153(2):307–19.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Tezel A, Sens A, Mitragotri S. Investigations of the role of cavitation in low-frequency sonophoresis using acoustic spectroscopy. J Pharm Sci. 2002;91(2):444–53.PubMedCrossRefGoogle Scholar
  45. 45.
    Bader KB, Raymond JL, Mobley J, Church CC, Felipe Gaitan D. The effect of static pressure on the inertial cavitation threshold. J Acoust Soc Am. 2012;132(2):728–37.PubMedCrossRefGoogle Scholar
  46. 46.
    Brabec K, Mornstein V. Detection of ultrasonic cavitation based on low-frequency analysis of acoustic signal. Cent Eur J Biol. 2007;2(2):213–21.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.Mechanical Engineering DepartmentUniversity of CanterburyChristchurchNew Zealand
  2. 2.ChristchurchNew Zealand
  3. 3.Department of ChemistryUniversity of CanterburyChristchurchNew Zealand

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