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Sampling of disease biomarkers from skin for theranostic applications

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Abstract

Dermatological diseases including psoriasis, eczema, infections, and cancer collectively constitute a large category of human conditions. The large area and ease of access of skin open excellent opportunities for theranostic applications, that is, diagnosis as well as therapy of the disease. Such applications can be based on evaluation of skin’s molecular composition in terms of proteins, nucleic acids, and small molecules. Currently, however, such molecular information is not used in clinical practice. To bring this molecular information to routine clinical dermatology, it is essential to develop convenient and minimally invasive methods for rapid sampling molecules from skin. Here, we demonstrate an ultrasonic sampling technique that can recover a wide variety of biomolecules from skin in a minimally invasive manner. We show that ultrasound can retrieve nearly all major tissue constituents, including structural and functional proteins (cytokines, keratins, etc.), lipids (polar and non-polar lipids), and nucleic acids (DNA and RNA). Comparative analyses of skin’s molecular constituents obtained by ultrasonic sampling and skin homogenate showed high resemblance between the two biomolecular profiles, enabling us to build a unique molecular signature of skin. Using different mouse models of dermatological conditions, the ultrasonic analysis for changes in the molecular composition of skin confirmed specific regulation of several established biomarkers.

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References

  1. Elias P, Wood L, Feingold K. Epidermal pathogenesis of inflammatory dermatoses. Am J Contact Dermat. 1999;10:119–26.

    Article  PubMed  CAS  Google Scholar 

  2. Elias P. The epidermal permeability barrier: from the early days at Harvard to emerging concepts. J Invest Dermatol. 2004;122:36–9.

    Google Scholar 

  3. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 2005;6:328–40.

    Article  PubMed  CAS  Google Scholar 

  4. Williams I, Kupper T. Immunity at the surface: homeostatic mechanisms of the skin immune system. Life Sci. 1996;58:1485–507.

    Article  PubMed  CAS  Google Scholar 

  5. Carlson J, Slominski A, Linette G, Mysliborski J, Hill J, et al. Malignant melanoma 2003: predisposition, diagnosis, prognosis, and staging. Am J Clin Pathol. 2003;120:S101.

    Article  PubMed  Google Scholar 

  6. Federman D, Hogan D, Taylor J, Caralis P, Kirsner R. A comparison of diagnosis, evaluation, and treatment of patients with dermatologic disorders. J Am Acad Dermatol. 1995;32:726.

    Article  PubMed  CAS  Google Scholar 

  7. Kidwell D, Holland J, Athanaselis S. Testing for drugs of abuse in saliva and sweat. J Chromatogr B Biomed Sci Appl. 1998;713:111–35.

    Article  PubMed  CAS  Google Scholar 

  8. Ludwig J, Weinstein J. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer. 2005;5:845–56.

    Article  PubMed  CAS  Google Scholar 

  9. Bashir SJ, Chew AL, Anigbogu A, Dreher F, Maibach HI. Physical and physiological effects of stratum corneum tape stripping. Skin Res Technol. 2001;7:40–8.

    Article  PubMed  CAS  Google Scholar 

  10. Loffler H, Dreher F, Maibach HI. Stratum corneum adhesive tape stripping: influence of anatomical site, application pressure, duration and removal. Br J Dermatol. 2004;151:746–52.

    Article  PubMed  CAS  Google Scholar 

  11. Kost J, Mitragotri S, Gabbay R, Pishko M, Langer R. Transdermal monitoring of glucose and other analytes using ultrasound. Nat Med. 2000;6:347–50.

    Article  PubMed  CAS  Google Scholar 

  12. Ogura M, Paliwal S, Mitragotri S (2008) Low-frequency sonophoresis: current status and future prospects. Adv Drug Deliv Rev 60:1218-1223

    Google Scholar 

  13. Mukerjee E, Collins S, Isseroff R, Smith R. Microneedle array for transdermal biological fluid extraction and in situ analysis. Sensors Actuators: A Phys. 2004;114:267–75.

    Article  Google Scholar 

  14. Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 37(8):911–917.

    Google Scholar 

  15. Grubauer G, Feingold K, Harris R, Elias P. Lipid content and lipid type as determinants of the epidermal permeability barrier. J Lipid Res. 1989;30:89–96.

    PubMed  CAS  Google Scholar 

  16. Fartasch M. Ultrastructure of the epidermal barrier after irritation. Microsc Res Tech. 1997;37:193–9.

    Article  PubMed  CAS  Google Scholar 

  17. Tsai J, Feingold K, Crumrine D, Wood L, Grunfeld C, et al. Permeability barrier disruption alters the localization and expression of TNFα/protein in the epidermis. Arch Dermatol Res. 1994;286:242–8.

    Article  PubMed  CAS  Google Scholar 

  18. Wood L, Elias P, Calhoun C, Tsai J, Grunfeld C, et al. Barrier disruption stimulates interleukin-1&agr; expression and release from a pre-formed pool in murine epidermis. J Invest Dermatol. 1996;106:397–403.

    Article  PubMed  CAS  Google Scholar 

  19. Wood L, Jackson S, Elias P, Grunfeld C, Feingold K (1992) Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice. J Clin Invest 90(2):482-487

    Google Scholar 

  20. Chan L (2004) Animal models of human inflammatory skin diseases. Florence: Informa Healthcare.

  21. Vestergaard C, Yoneyama H, Murai M, Nakamura K, Tamaki K, et al. Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions. J Clin Invest. 1999;104:1097–105.

    Article  PubMed  CAS  Google Scholar 

  22. Barker J, Alegre V, MacDonald D. Surface-bound immunoglobulin E on antigen-presenting cells in cutaneous tissue of atopic dermatitis. J Invest Dermatol. 1988;90:117–21.

    Article  PubMed  CAS  Google Scholar 

  23. Leung D, Schneeberger E, Siraganian R, Geha R, Bhan A. The presence of IgE on macrophages and dendritic cells infiltrating into the skin lesion of atopic dermatitis. Clin Immunol Immunopathol. 1987;42:328–37.

    Article  PubMed  CAS  Google Scholar 

  24. Aioi A, Tonogaito H, Suto H, Hamada K, Ra C, et al. Impairment of skin barrier function in NC/Nga Tnd mice as a possible model for atopic dermatitis. Br J Dermatol. 2001;144:12.

    Article  PubMed  CAS  Google Scholar 

  25. Gudjonsson J, Johnston A, Dyson M, Valdimarsson H, Elder J. Mouse models of psoriasis. J Invest Dermatol. 2007;127:1292–308.

    Article  PubMed  CAS  Google Scholar 

  26. Morita K, Hogan M, Nanney L, King Jr L, Manabe M, et al. Cutaneous ultrastructural features of the flaky skin (fsn) mouse mutation. J Dermatol. 1995;22:385.

    PubMed  CAS  Google Scholar 

  27. Schon MP. Animal models of psoriasis: what can we learn from them? J Invest Dermatol. 1999;112:405–10.

    Article  PubMed  CAS  Google Scholar 

  28. Schon MP, Denzer D, Kubitza R, Ruzicka T, Sch NM. Critical role of neutrophils for the generation of psoriasiform skin lesions in flaky skin mice. J Invest Dermatol. 2000;114:976–83.

    Article  PubMed  CAS  Google Scholar 

  29. Sundberg J, Beamer W, Shultz L, Dunstan R. Inherited mouse mutations as models of human adnexal, cornification, and papulosquamous dermatoses. J Invest Dermatol. 1990;95:62S–3S.

    Article  Google Scholar 

  30. Sundberg J, Boggess D, Sundberg B, Beamer W, Shultz L. Epidermal dendritic cell populations in the flaky skin mutant mouse. Immunol Invest. 1993;22:389–401.

    Article  PubMed  CAS  Google Scholar 

  31. Madison K. Barrier function of the skin:“ la raison d’etre” of the epidermis. J Invest Dermatol. 2003;121:231–41.

    Article  PubMed  CAS  Google Scholar 

  32. Ghadially R, Reed J, Elias P. Stratum corneum structure and function correlates with phenotype in psoriasis. J Invest Dermatol. 1996;107:558–64.

    Article  PubMed  CAS  Google Scholar 

  33. Robert C, Kupper T. Inflammatory skin diseases, T cells, and immune surveillance. N Engl J Med. 1999;341:1817.

    Article  PubMed  CAS  Google Scholar 

  34. Ullman S, Halberg P, Hentzer B. Deposits of immunoglobulin and complement in psoriatic lesions. J Cutan Pathol. 1980;7:271–5.

    Article  PubMed  CAS  Google Scholar 

  35. Mitragotri S, Blankschtein D, Langer R. Transdermal drug delivery using low-frequency sonophoresis. Pharm Res. 1996;13:411–20.

    Article  PubMed  CAS  Google Scholar 

  36. Mitragotri S, Kost J. Low-frequency sonophoresis: a review. Adv Drug Deliv Rev. 2004;56:589–601.

    Article  PubMed  CAS  Google Scholar 

  37. Paliwal S, Menon G, Mitragotri S. Low-frequency sonophoresis: ultrastructural basis for stratum corneum permeability assessed using quantum dots. J Invest Dermatol. 2006;126:1095–101.

    Article  PubMed  CAS  Google Scholar 

  38. Becker B, Helfrich S, Baker E, Lovgren K, Minugh P, et al. Ultrasound with topical anesthetic rapidly decreases pain of intravenous cannulation. Acad Emerg Med. 2005;12:289–95.

    Article  PubMed  Google Scholar 

  39. Chuang H, Taylor E, Davison T. Clinical evaluation of a continuous minimally invasive glucose flux sensor placed over ultrasonically permeated skin. Diabetes Technol Ther. 2004;6:21–30.

    Article  PubMed  CAS  Google Scholar 

  40. Katz N, Shapiro D, Herrmann T, Kost J, Custer L (2004) Rapid onset of cutaneous anesthesia with EMLA cream after pretreatment with a new ultrasound-emitting device. IARS 98:371–376.

    Google Scholar 

  41. SantoiannI P, Nino M, Calabro G. Intradermal drug delivery by low-frequency sonophoresis (25 kHz). Dermatol Online J. 2004;10:24.

    PubMed  Google Scholar 

  42. Tang H, Wang C, Blankschtein D, Langer R. An investigation of the role of cavitation in low-frequency ultrasound-mediated transdermal drug transport. Pharm Res. 2002;19:1160–9.

    Article  PubMed  CAS  Google Scholar 

  43. Tezel A, Mitragotri S. Interactions of inertial cavitation bubbles with stratum corneum lipid bilayers during low-frequency sonophoresis. Biophys J. 2003;85:3502–12.

    Article  PubMed  CAS  Google Scholar 

  44. Tezel A, Sens A, Mitragotri S. Investigations of the role of cavitation in low-frequency sonophoresis using acoustic spectroscopy. J Pharm Sci. 2002;91:444–53.

    Article  PubMed  CAS  Google Scholar 

  45. Alvarez-Rom NR, Merino G, Kalia Y, Naik A, Guy R. Skin permeability enhancement by low frequency sonophoresis: lipid extraction and transport pathways. J Pharm Sci. 2003;92:1138–46.

    Article  Google Scholar 

  46. Paliwal S, Ogura M, Mitragotri S (2010) One-step acquisition of functional biomolecules from tissues. Proc Natl Acad Sci U S A 107:14627-14632

    Google Scholar 

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Acknowledgments

We want to acknowledge Dr. Anubhav Arora and the staff at Animal Resource Center, UCSB, for help with in vivo protocols and experiments. We thank Dr. Raphael Simon for help in establishing with biochemical techniques used in this study. MO was partially supported by the JSPS (Japan Society for the Promotion of Science) Postdoctoral Fellowship for Research Abroad. This work was supported by TATRC.

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Authors and Affiliations

  1. Department of Chemical Engineering, University of California, Santa Barbara, CA, 93106, USA

    Makoto Ogura, Sumit Paliwal & Samir Mitragotri

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  1. Makoto Ogura
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  2. Sumit Paliwal
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  3. Samir Mitragotri
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Correspondence to Samir Mitragotri.

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The authors Makoto Ogura and Sumit Paliwal made equal contributions to this study.

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Ogura, M., Paliwal, S. & Mitragotri, S. Sampling of disease biomarkers from skin for theranostic applications. Drug Deliv. and Transl. Res. 2, 87–94 (2012). https://doi.org/10.1007/s13346-012-0061-7

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