Skip to main content
SpringerLink
Log in

Transport of Substances and Nanoparticles across the Skin and in Vitro Models to Evaluate Skin Permeation and/or Penetration

  • Chapter
Nanocosmetics and Nanomedicines

Abstract

Nanotechnology can be used to modify the drug permeation/penetration of encapsulated substances, through the manipulation of many different factors, including direct contact with the skin surface and controlled release. In general, nanoparticles cannot cross the skin barrier, which can be explained by the cell cohesion and lipids of the stratum corneum, the outermost skin layer. The device most commonly used to study the transport of substances and nanoparticles across the skin is the Franz vertical diffusion cell, followed by the substance quantification in the receptor fluid or determination of the amount retained in the skin. Microscopy techniques have also been applied in skin penetration or permeation experiments. This chapter will present the fundamental considerations regarding the transport of encapsulated substances and/or nanoparticles across the skin, the experimental models applied in these studies and a review of the main studies reported in the literature in order to allow the reader to gain insight into the current knowledge available in this area.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Hadgraft, J.: Skin, the final frontier. Int. J. Pharm. 224, 1–18 (2001)

    CAS  Google Scholar 

  2. Degim, T.I.: New tools and approaches for predicting skin permeability. Drug Discov. Today 11, 11–12 (2006)

    Google Scholar 

  3. Menon, G.K.: New insights into skin structure: scratching the surface. Adv. Drug. Deliv. Rev. 54(1), 3–17 (2002)

    Google Scholar 

  4. Gray, G.M., Yardley, H.J.: Lipid compositions of cells isolated from pig, human, and rat epidermis. J. Lipid Res. 16, 434–440 (1975)

    CAS  Google Scholar 

  5. Hadgraft, J., Lane, M.E.: Skin permeation: the years of enlightenment. Int. J. Pharm. 305, 2–12 (2005)

    CAS  Google Scholar 

  6. Fartasch, M.: The nature of the epidermal barrier: structural aspects. Adv. Drug. Deliv. Rev. 18, 273–282 (1996)

    CAS  Google Scholar 

  7. Forslind, B., Engström, S., Engblom, J., Norlkn, L.: A novel approach to the understanding of human skin barrier function. J. Dermatol. Sci. 14, 115–125 (1997)

    CAS  Google Scholar 

  8. Guterres, S.S., Alves, M.P., Pohlmann, A.R.: Polymeric nanoparticles, nanospheres and nanocapsules for cutaneous applications. Drug Target Insights 2, 147–157 (2007)

    Google Scholar 

  9. Luengo, J., Weiss, B., Schneider, M., Ehlers, A., Stracke, F., Koenig, K., Kostka, K.H., Lehr, C.M., Schaefer, U.F.: Influence of nanoencapsulation on human skin transport of flufenamic acid. Skin Pharmacol. Physiol. 19(4), 190–197 (2006)

    CAS  Google Scholar 

  10. Jenning, V., Gysler, A., Schaèfer-Korting, M., Gohlaa, S.H.: Vitamin A loaded solid lipid nanoparticles for topical use: occlusive properties and drug targeting to the upper skin. Eur. J. Pharm. Biopharm. 49, 211–218 (2000)

    CAS  Google Scholar 

  11. Lademann, J., Otberg, N., Richter, H., Meyer, L., Audring, H., Teichmann, A., Thomas, S., Knüttel, A., Sterry, W.: Nanoparticles-an efficient carrier for drug delivery into the hair follicles. Eur. J. Pharm. Biopharm. 66, 159–164 (2007)

    CAS  Google Scholar 

  12. Shim, J., Kang, H.S., Park, W.-S., Han, S.-H., Kim, J., Chang, I.-S.: Transdermal delivery of mixnoxidil with block copolymer nanoparticles. J. Control Release 97, 477–484 (2004)

    CAS  Google Scholar 

  13. Ourique, A.F., Pohlmann, A.R., Guterres, S.S., Beck, R.C.R.: Tretinoin-loaded nanocapsules: Preparation, physicochemical characterization, and photostability study. Int. J. Pharm. 352, 1–4 (2008)

    CAS  Google Scholar 

  14. Fontana, M.C., Coradini, K., Guterres, S.S., Polhmann, A.R., Beck, R.C.R.: Nanoencapsulation as a way to control the release and to increase the photostability of clobetasol propionate: influence of the nanostructured system. J. Biomed. Nanotechnol. 5, 254–263 (2009)

    CAS  Google Scholar 

  15. Külkamp, I.C., Paese, K., Pohlmann, A.R., Guterres, S.S.: Estabilização do ácido lipóico via encapsulação em nanocápsulas poliméricas planejadas para aplicação cutânea. Quím. Nova 32, 2078–2084 (2009)

    Google Scholar 

  16. Paese, K., Jäger, A., Poletto, F.S., Pinto, E.F., Rossi-Bergmann, B., Pohlmann, A.R., Guterres, S.S.: Semisolid formulation containing a nanoencapsulated sunscreen: effectiveness, in vitro photostability and immune response. J. Biomed. Nanotechnol. 5, 1–7 (2009)

    Google Scholar 

  17. Crosera, M., Bovenzi, M., Maina, G., Adami, G., Zanette, C., Florio, C., Larese, F.F.: Nanoparticle dermal absorption and toxicity: a review of the literature. Int. Arch. Occup. Environ. Health 82, 1043–1055 (2009)

    CAS  Google Scholar 

  18. Galey, W.R., Lonsdale, H.K., Nacht, S.: The in vitro permeability of skin and buccal mucosa to selected drugs and tritiated water. J. Invest. Dermatol. 67, 713–717 (1976)

    CAS  Google Scholar 

  19. Scheuplein, R.J.: Permeability of the skin: a review of major concepts and some new developments. J. Invest. Dermatol. 67, 672–676 (1976)

    CAS  Google Scholar 

  20. Harada, K., Murakami, T., Yata, N., Yamamoto, S.: Role of intercellular lipids in stratum corneum in the percutaneous permeation of drugs. J. Invest. Dermatol. 99, 278–282 (1992)

    CAS  Google Scholar 

  21. Moser, K., Kriwet, K., Naik, A., Kalia, Y.N., Guy, R.H.: Passive skin penetration enhancement and its quantification in vitro. Eur. J. Pharm. Biopharm. 52, 103–112 (2001)

    CAS  Google Scholar 

  22. Pugh, W.J.: Relationship between- H-bonding of penetrants to stratum corneum lipids and diffusion. In: Bronaugh, R.L. (ed.) Maibach HI Percutaneous Absorption: Drugs-Cosmetics-Mechanisms-Methodology, 3rd edn., vol. 9, p. 178. Marcel Dekker, New York (1999)

    Google Scholar 

  23. Lademann, J., Richter, H., Schaefer, U.F., Blume-Peytavi, U., Teichmann, A., Otberg, N., Sterry, W.: Hair follicles – A Long-Term Reservoir for Drug Delivery. Skin Pharmacol. Physiol. 19, 232–236 (2006)

    CAS  Google Scholar 

  24. WHO: World Health Organization. Environmental Health Criteria 235 Dermal Absorption. International Labour Organization and the World Health Organization 1-197 (2006)

    Google Scholar 

  25. Franz, J.: Percutaneous absorption on the relevance of in-vitro data. J. Invest. Dermatol. 67, 190–196 (1975)

    Google Scholar 

  26. Sartorelli, P., Andersen, H.R., Angerer, J., Corish, J., Drexler, H., Göen, T., Griffin, P., Hotchkiss, S.A.M., Larese, F., Montomoli, L., Perkins, J., Schmelz, M., Van De Sandt, J., Williams, F.: Percutaneous penetration studies for risk assessment. Environ. Toxicol. Pharmacol. 8, 133–152 (2000)

    CAS  Google Scholar 

  27. SCCP: Scientific Committee On Consumer Products. Basic criteria for the in vitro assessment of dermal absorption of cosmetic ingredients. European Commission Health & Consumer Protection 12, [S. l.] (2006)

    Google Scholar 

  28. Bhandari, K.H., Lee, D.X., Newa, M., Yoon, S.I., Kim, J.S., Kim, D.D., Kim, J.-A., Yoo, B.K., Woo, J.S., Lyoo, W.S., Lee, J.H., Choi, H.G., Yong, C.S.: Evaluation of Skin Permeation and Accumulation Profiles of a Highly Lipophilic Fatty Ester. Arch. Pharm. Res. 31(2), 242–249 (2008)

    CAS  Google Scholar 

  29. Bronaugh, R.L., Steward, R.F.: Methods for in vitro percutaneous absorption studies. IV. The flow-through diffusion cell. J. Pharm. Sci. 74, 64–67 (1985)

    CAS  Google Scholar 

  30. Chien, Y.W., Valia, K.H.: Development of a dynamic skin permeation system for long-term permeation studies. Drug Dev. Ind. Pharm. 10, 575–599 (1984)

    CAS  Google Scholar 

  31. Alvarez-Román, R., Naik, A., Kalia, Y.N., Guy, R.H., Fessi, H.: Enhancement of topical delivery from biodegradable nanoparticles. Pharm. Research 21, 1818–1825 (2004)

    Google Scholar 

  32. Jiménez, M.M., Pelletier, J., Bobin, M.F., Martini, M.C.: Influence of encapsulation on the in vitro percutaneous absorption of octyl methoxycinnamate. Int. J. Pharm. 272, 45–55 (2004)

    Google Scholar 

  33. Alves, M.P., Scarrone, A.L., Santos, M., Pohlmann, A.R., Guterres, S.S.: Human skin penetration and distribution of nimesulide from hydrophilic gels containing nanocarriers. Int. J. Pharm. 341, 215–220 (2007)

    CAS  Google Scholar 

  34. Jacobi, U., Taube, H., Schaefer, U.F., Sterry, W., Lademann, J.: Comparison of four different in vitro systems to study the reservoir capacity of the stratum corneum. J. Control Release 103, 61–71 (2005)

    CAS  Google Scholar 

  35. Wagner, H., Kostka, K.-H., Lehr, C.-M., Schaefer, U.F.: pH profiles in human skin: influence of two in vitro test systems for drug delivery testing. Eur. J. Pharm. Biopharm. 55(1), 57–65 (2003)

    CAS  Google Scholar 

  36. Wagner, H., Kostka, K.-H., Lehr, C.-M., Schaefer, U.F.: Drug Distribution in Human Skin Using Two Different In Vitro Test Systems: Comparison with In Vivo Data. Pharm. Res. 17(12), 1475–1481 (2000)

    CAS  Google Scholar 

  37. Joo, H.H., Lee, H.Y., Guan, Y.S., Kim, J.-C.: Colloidal stability and in vitro permeation study of poly(e-caprolactone) nanocapsules containing hinokitiol. J. Ind. Eng. Chem. 14, 608–613 (2008)

    CAS  Google Scholar 

  38. Roberts, M.S., Roberts, M.J., Robertson, T.A., Sanchez, W., Thörling, C., Zou, Y., Zhao, X., Becker, W., Zvyagin, A.V.: In vitro and in vivo imaging of xenobiotic transport in human skin and in the rat liver. J. Biophoton. 1(6), 478–493 (2008)

    CAS  Google Scholar 

  39. Rouse, J.G., Yang, J., Ryman-Rasmussen, J.P., Barron, A.R., Monteiro-Riviere, N.A.: Effects of Mechanical Flexion on the Penetration of Fullerene Amino Acid-Derivatized Peptide Nanoparticles through Skin. Nano. Lett. 7(1), 155–160 (2007)

    CAS  Google Scholar 

  40. Sonavane, G., Tomoda, K., Sano, A., Ohshima, H., Terada, H., Makino, K.: In vitro permeation of gold nanoparticles through rat skin and rat intestine: Effect of particle size. Colloids Surf. B 65, 1–10 (2008)

    CAS  Google Scholar 

  41. Senzui, M., Tamura, T., Miura, K., Ikarashi, Y., Watanabe, Y., Fujii, M.: Study on penetration of titanium dioxide (TiO2) nanoparticles into intact and damaged skin in vitro. J. Toxicol. Sci. 35(1), 107–113 (2010)

    CAS  Google Scholar 

  42. Bronaugh, R.L., Collier, S.W.: Preparation of Human And Animal Skin. In: Bronaugh, R.L., Maibach, H.I. (eds.) In vitro Percutaneous Absorption: Principles, Fundamentals, and Applications, vol. 1, pp. 2–5. CRC Press, Boca Raton (1991)

    Google Scholar 

  43. Huong, S.P., Bun, H., Fourneron, J.-D., Reynier, J.-P., Andrieu, V.: Use of various models for in vitro percutaneous absorption studies of ultraviolet filters. Skin Res. Tech. 15, 253–261 (2009)

    Google Scholar 

  44. Golden, G.M., Guzek, D.B., Kennedy, A.H., Mckie, J.E., Potts, R.O.: Stratum corneum lipid phase transitions and water barrier properties. Biochemistry 26, 2382–2388 (1987)

    CAS  Google Scholar 

  45. Wagner, H., Kostka, K.-H., Lehr, C.-M., Schaefer, U.F.: Interrelation of permeation and penetration parameters obtained from in vitro experiments with human skin and skin equivalents. J. Control. Release 75, 283–295 (2001)

    CAS  Google Scholar 

  46. Swarbrick, J., Lee, G., Brom, J.: Drug permeation through human skin: I. Effects of storage conditions of skin. J. Invest Dermatol. 78, 63–68 (1982)

    CAS  Google Scholar 

  47. Netzlaff, F., Kaca, M., Bock, U., Haltner-Ukomadu, E., Meiers, P., Lehr, C.-M., Schaefer, U.F.: Permeability of the reconstructed human epidermis model Episkin_in comparison to various human skin preparations. Eur. J. Pharm Biopharm. 66, 127–134 (2007)

    CAS  Google Scholar 

  48. Wester, R.C., Christoffel, J., Hartway, T., Poblete, N., Maibach, H.I., Forsell, J.: Human cadaver skin viability for in vitro percutaneous absorption: storage and detrimental effects of heat-separation and freezing. Pharm. Res. 15(1), 82–84 (1998)

    CAS  Google Scholar 

  49. Akomeah, F., Nazir, T., Martin, G.P., Brown, M.B.: Effect of heat on the percutaneous absorption and skin retention of three model penetrants. Eur. J. Pharm. Sci. 21, 337–345 (2004)

    CAS  Google Scholar 

  50. Wang, T., Kasichayanula, S., Gu, X.: In vitro permeation of repellent DEET and sunscreen oxybenzone across three artificial membranes. Int. J. Pharm. 310, 110–117 (2006)

    CAS  Google Scholar 

  51. Loftsson, T., Konrádsdóttir, F., Másson, M.: Development and evaluation of an artificial membrane for determination of drug availability. Int. J. Pharm, 326, 60–68 (2006)

    CAS  Google Scholar 

  52. Ansari, M., Kazemipour, M., Aklamli, M.: The study of drug permeation through natural membranes. Int. J. Pharm. 327, 6–11 (2006)

    CAS  Google Scholar 

  53. Larese, F., Gianpietro, A., Venier, M., Maina, G., Renzi, N.: In vitro percutaneous absorption of metal compounds. Toxicol. Lett. 170, 49–56 (2007)

    CAS  Google Scholar 

  54. Weiss-Angeli, V., Bourgeois, S., Pelletier, J., Guterres, S.S., Fessi, H., Bolzinger, M.A.: Development of an original method to study drug release from polymeric nanocapsules in the skin. J. Pharm. Pharmacol. 62(1), 35–45 (2010)

    CAS  Google Scholar 

  55. USFDA: United States Department of Health and Human Services, Food and Drug Administration: Guidance for industry: topical dermatological drug product NDAs and ANDAs — in vivo bioavailability, bioequivalence, in vitro release, and associated studies. United States Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, [S. l.] (1998)

    Google Scholar 

  56. Marchiori, M.L., Lubini, G., Dalla Nora, G., Friedrich, R.B., Fontana, M.C., Ourique, A.F., Bastos, M.O., Rigo, L.A., Silva, C.B., Tedesco, S.B., Beck, R.C.R.: Hydrogel containing dexamethasone-loaded nanocapsules for cutaneous administration: preparation, characterization, and in vitro drug release study. Drug Dev. Ind. Pharm. 36(8), 962–971 (2010)

    CAS  Google Scholar 

  57. Gabbanini, S., Matera, R., Beltramini, C., Minghetti, A., Luca Valgimigli, L.: Analysis of in vitro release through reconstructed human epidermis and synthetic membranes of multi-vitamins from cosmetic formulations. J. Pharmaceut. Biomed. Anal. 52, 461–467 (2010)

    CAS  Google Scholar 

  58. Paolino, D., Lucania, G., Mardente, D., Alhaique, F., Fresta, M.: Ethosomes for skin delivery of ammonium glycyrrhizinate: In vitro percutaneous permeation through human skin and in vivo anti-inflammatory activity on human volunteers. J. Control. Release 106, 99–110 (2006)

    Google Scholar 

  59. Ricci, M., Puglia, C., Bonina, F., Di Giovanni, C., Giovagnoli, S., Rossi, C.: Evaluation of indomethacin percutaneous absorption from nanostructured lipid carriers (NLC): in vitro and in vivo studies. J. Pharm. Sci. 94(5), 1149–1159 (2005)

    CAS  Google Scholar 

  60. Puglia, C., Ostacolo, C., Sacchi, A., Laneri, S., Bonina, F.: In vitro and in vivo evaluation of oligoethylene esters as dermal prodrugs of 18β-glycyrrhetic acid. J. Pharm. Pharmacol. 58(3), 311–319 (2006)

    CAS  Google Scholar 

  61. Van De Sandt, J.J.M., Van Burgsteden, J.A., Cage, S., Carmichael, P.L., Dick, I., Kenyon, F.S., Korinth, G., Larese, F., Limasset, J.C., Maas, W.J.M., Montomoli, L., Nielsen, J.B., Payan, J.P., Robinson, E., Sartorelli, P., Schaller, K.H., Wilkinson, S.C., Williams, F.M.: In vitro predictions of skin absorption of caffeine, testosterone, and benzoic acid: a multi-centre comparison study. Regul. Toxicol. Pharm. 39, 271–281 (2004)

    Google Scholar 

  62. Sartorelli, P., Cenni, A., Matteucci, G., Montomoli, L., Novelli, M.T., Palmi, S.: Dermal exposure assessment of polycyclic aromatic hydrocarbons: In vitro percutaneous penetration from lubricating oil. International Arch. Environ. Occup. Health 72, 528–532 (1999)

    CAS  Google Scholar 

  63. Bronaugh, R.L., Maibach, H.I.: Percutaneous absorption of nitroaromatic compounds: in vivo and in vitro studies in the human and monkey. J. Invest. Dermatol. 84, 180–183 (1985)

    CAS  Google Scholar 

  64. Ross, J.H., Dong, M.H., Krieger, R.I.: Conservatism in pesticide exposure assessment. Regul. Toxicol. Pharmacol. 31, 53–58 (2000)

    CAS  Google Scholar 

  65. Van De Sandt, J.J.M., Meuling, W.J.A., Elliott, G.R., Cnubben, N.H.P., Hakkert, B.C.: Comparative in vivo-in vitro percutaneous absorption of the pesticide propoxur. Toxicol. Sci. 58, 15–22 (2000)

    Google Scholar 

  66. Kikwai, L., Babu, R.J., Prado, R., Kolot, A., Armstrong, C.A., Ansel, J.C., Singh, M.: In vitro and in vivo evaluation of topical formulations of Spantide II. AAPS Pharmscitech. 6(4), E565–E572 (2005)

    Google Scholar 

  67. Melero, A., Garrigues, T.M., Alós, M., Kostka, K.H., Lehr, C.M., Schaefer, U.F.: Nortriptyline for smoking cessation: Release and human skin diffusion from patches. Int. J. Pharm. 378(1-2), 101–107 (2009)

    CAS  Google Scholar 

  68. Nunes, R.S., Azevedo, J.R., Vasconcelos, A.P., Pereira, N.L.: Estudo de padronização da pele de cobra espécie – Boa constrictor - como modelo de estrato córneo para permeação de fármacos. Scientia Plena 1(7), 171–175 (2005)

    Google Scholar 

  69. Baby, A.R., Haroutiounian-Filho, C.A., Sarruf, F.D., Tavante-Júnior, C.R., Pinto, C.A.S.O., Zague, V., Arêas, E.P.G., Kaneko, T.M., Velasco, M.V.R.: Estabilidade e estudo de penetração cutânea in vitro da rutina veiculada em uma emulsão cosmética através de um modelo de biomembrana alternativo. Braz. J. Pharm. Sci. 44(2), 233–248 (2008)

    CAS  Google Scholar 

  70. Fang, J.-Y., Wu, P.-C., Huang, Y.-B., Tsai, Y.-H.: In vitro permeation study of capsaicin and its synthetic derivatives from ointment bases using various skin types. Int. J. Pharm. 126, 119–128 (1995)

    CAS  Google Scholar 

  71. Netzlaff, F., Lehr, C.-M., Wertz, P.W., Schaefer, U.F.: The human epidermis models EpiSkin®, SkinEthic® and EpiDerm®: An evaluation of morphology and their suitability for testing phototoxicity, irritancy, corrosivity, and substance transport. Eur. J. Pharmaceut. Biopharmaceut. 60, 167–178 (2005)

    CAS  Google Scholar 

  72. OECD: OECD Guidelines for Testing of Chemicals – Guideline 428: Skin Absorption: In vitro Method (adopted April 13, 2004)

    Google Scholar 

  73. Schreiber, S., Mahmoud, A., Vuia, A., Rübbelke, M.K., Schmidt, E., Schaller, M., Kandárová, H., Haberland, A., Schäfer, U.F., Bock, U., Korting, H.C., Liebsch, M., Schäfer-Korting, M.: Reconstructed epidermis versus human and animal skin in skin absorption studies. Toxicol. in Vitro 19, 813–822 (2005)

    CAS  Google Scholar 

  74. Wilkins, L.M., Watson, S.R., Prosky, S.J., Meunier, S.F., Parenteau, N.L.: Development of a bilayered living skin construct for clinical applications. Biotechnol. Bioeng. 43(8), 747–756 (1993)

    Google Scholar 

  75. Strange, C.J.: Second Skins: A Serious Burn Is One of the Most Horrendous Traumas the Body Can Suffer FDA Consumer Magazine 31 (1997)

    Google Scholar 

  76. Doucet, O., Garcia, N., Zastrow, L.: Skin Culture Model: a Possible Alternative to the Use of Excised Human Skin for Assessing In Vitro Percutaneous Absorption. Toxicol. In Vitro 12(4), 423–430 (1998)

    CAS  Google Scholar 

  77. Schmook, F.P., Meingassner, J.G., Billich, A.: Comparison of human skin or epidermis models with human and animal skin in vitro percutaneous absorption. Int. J. Pharm. 215, 51–56 (2001)

    CAS  Google Scholar 

  78. Baroli, B.: Penetration of nanoparticles and nanomaterials in the skin: fiction or reality? J. Pharm. Sci. 99(1), 21–50 (2010)

    CAS  Google Scholar 

  79. Cevc, G., Vierl, U.: Nanotechnology and the transdermal route: A state of the art review and critical appraisal. J. Control Release 141, 277–299 (2010)

    CAS  Google Scholar 

  80. Rastogi, R., Anand, S., Koul, V.: Flexible polymerosomes-An alternative vehicle for topical delivery. Colloids Surf. B 72, 161–166 (2009)

    CAS  Google Scholar 

  81. Küchler, S., Abdel-Mottaleb, M., Lamprecht, A., Radowski, M.R., Haag, R., Schäfer-Korting, M.: Influence of nanocarrier type and size on skin delivery of hydrophilic agents. Int. J. Pharm. 377, 169–172 (2009)

    Google Scholar 

  82. Lboutounne, H., Faivre, V., Falson, F., Pirot, F.: Characterization of Transport of Chlorhexidine-Loaded Nanocapsules through Hairless and Wistar Rat Skin. Skin Pharmacol. Physiol. B 17, 176–182 (2004)

    CAS  Google Scholar 

  83. Yow, H.N., Wu, X., Routh, A.F., Guy, R.H.: Dye diffusion from microcapsules with different shell thickness into mammalian skin. Eur. J. Pharm. Biopharm. 72, 62–68 (2009)

    CAS  Google Scholar 

  84. Lboutounne H, Guillaume YC, Michel L, Makki S, Humbert P, Millet J (2004) Study and development of encapsulated forms of 4, 5′, 8-Trimethylpsoralen for topical drug delivery. Drug Develop. Res. 61:86–94 A.

    CAS  Google Scholar 

  85. Luppi, B., Cerchiara, T., Bigucci, F., Basile, R., Zecchi, V.: Polymeric nanoparticles composed of fatty acids and polyvinylalcohol for topical application of sunscreens. J. Pharm. Pharmacol. 56, 407–411 (2004)

    CAS  Google Scholar 

  86. Vettor, M., Bourgeois, S., Fessi, H., Pelletier, J., Perugini, P., Pavanetto, F., Bolzinger, M.A.: Skin absorption studies of octyl-methoxycinnamate loaded poly(D,L-lactide) nanoparticles: Estimation of the UV filter distribution and release behaviour in skin layers. J. Microencapsul. 27(3), 253–262 (2010)

    CAS  Google Scholar 

  87. Miyazaki, S., Takahashi, A., Kubo, W., Bachynsky, J., Lobenberg, R.: Poly n-butylcyanoacrylate (PNBCA) nanocapsules as a carrier for NSAIDs: in vitro release and in vivo skin penetration. J. Pharm. and Pharm. Sci. 6, 238–245 (2003)

    Google Scholar 

  88. Şenyiğit, T., Sonvico, F., Barbieri, S., Özer, Ö., Santi, P., Colombo, P.: Lecithin/chitosan nanoparticles of clobetasol-17-propionate capable of accumulation in pig skin. J. Control. Release 142, 368–373 (2010)

    Google Scholar 

  89. Lboutounne, H., Chaule, J.-F., Ploton, C., Falson, F., Pirot, F.: Sustained ex vivo skin antiseptic activity of chlorhexidine in poly(e-caprolactone) nanocapsule encapsulated form and as a digluconate. J. Control Release 82, 319–334 (2002)

    CAS  Google Scholar 

  90. Alvarez-Roman, R., Naik, A., Kalia, Y.N., Guya, R.H., Fessi, H.: Skin penetration and distribution of polymeric nanoparticles. J. Control. Release A 99, 53–62 (2004)

    CAS  Google Scholar 

  91. Lademann, J., Richter, H., Schanzer, S., Knorr, F., Meinke, M., Sterry, W., Patzelt, A.: Penetration and storage of particles in human skin: Perspectives and safety aspects. Eur. J. Pharm. Biopharm. (2010), doi:10.1016/j.ejpb.2010.10.015

    Google Scholar 

  92. Wu, X., Griffin, P., Price, G.J., Guy, R.H.: Preparation and in Vitro Evaluation of Topical Formulations Based on Polystyrene-poly-2-hydroxyl Methacrylate Nanoparticles. Mol. Pharmaceutics 6(5), 1449–1456 (2009)

    CAS  Google Scholar 

  93. Wu, X., Price, G.J., Guy, R.H.: Disposition of Nanoparticles and an Associated Lipophilic Permeant following Topical Application to the Skin. Mol. Pharmaceutics 6(5), 1441–1448 (2009)

    CAS  Google Scholar 

  94. Stracke, F., Weiss, B., Lehr, C.-M., Konig, K., Schaefer, U.F., Schneider, M.J.: Multiphoton microscopy for the investigation of dermal penetration of nanoparticle-borne drugs. J. Invest. Dermatol. 126, 2224–2233 (2006)

    CAS  Google Scholar 

  95. Zhang, L.W., Yu, W.W., Colvin, V.L., Monteiro-Riviere, N.A.: Biological interactions of quantum dot nanoparticles in skin and in human epidermal keratinocytes. Toxicol. Appl. Pharmacol. 228, 200–211 (2008)

    CAS  Google Scholar 

  96. Vogt, A., Combadiere, B., Hadam, S., Stieler, K.M., Lademann, J., Schaefer, H., Autran, B., Sterry, W., Blume-Peytavi, U.: 40 nm, but not 750 or 1,500 nm, nanoparticles enter epidermal CD1a+ cells after transcutaneous application on human skin. J. Invest. Dermatol. 126, 1316–1322 (2006)

    CAS  Google Scholar 

  97. Gu, H., Roy, K.: Topical permeation enhancers significantly increase delivery of polymer micro and nanoparticles to epidermal Langerhans’ cells. J. Drug Deliv. Sci. Tech. 14, 265–273 (2004)

    CAS  Google Scholar 

  98. Küchler, S., Radowski, M.R., Blaschke, T., Dathe, M., Plendl, J., Haag, R., Schäfer-Korting, M., Kramer, K.D.: Nanoparticles for skin penetration enhancement - A comparison of a dendritic core-multishell-nanotransporter and solid lipid nanoparticles. Eur. J. Pharm. Biopharm. 71, 243–250 (2009)

    Google Scholar 

  99. Paolino, D., Muzzalupo, R., Ricciardi, A., Celia, C., Picci, N., Fresta, M.: In vitro and in vivo evaluation of Bola-surfactant containing niosomes for transdermal delivery. Biomed. Microdevices 9, 421–433 (2007)

    CAS  Google Scholar 

  100. Espósito, E., Cortesi, R., Drechsler, M., Paccamiccio, L., Mariani, P., Contado, C., Stellin, E., Menegatti, E., Bonina, F., Puglia, C.: Cubosome dispersions as delivery systems for percutaneous administration of indomethacin. Pharm. Res. 22, 2163–2173 (2005)

    Google Scholar 

  101. Kwon, T.K., Lee, H.Y., Kim, J.D., Shin, W.C., Park, S.K., Kim, J.C.: In Vitro Skin Permeation of Cubosomes Containing Water Soluble Extracts of Korean Barberry. Colloid. Journal 72(2), 205–210 (2010)

    CAS  Google Scholar 

  102. Rubio, L., Alonso, C., Rodríguez, G., Barbosa-Barros, L., Coderch, L., De la Maza, A., Parra, J.L., López, O.: Bicellar systems for in vitro percutaneous absorption of diclofenac. Int. J. Pharm. 386, 108–113 (2010)

    CAS  Google Scholar 

  103. Honeywell-Nguyen, P.L., Gooris, G.S., Bouwstra, J.A.: Quantitative Assessment of the Transport of Elastic and Rigid Vesicle Components and a Model Drug from these Vesicle Formulations into Human Skin In Vivo. J. Invest. Dermatol. 123, 902–910 (2004)

    CAS  Google Scholar 

  104. Kim, J.C.: In vivo hair re-growth efficacies of minoxidil preparations: distearyldimethylammonium chloride vesicles, cellulose acetate phthalate microparticles, and poloxamer solution. J. Drug Deliv. Sci. Tec. 19(5), 343–346 (2009)

    CAS  Google Scholar 

  105. Lopes, L.B., Ferreira, D.A., de Paula, D., Garcia, M.T.J., Thomazini, J.A., Fantini, M.C.A.: MVLB Reverse hexagonal phase nanodispersion of monoolein and oleic acid for topical delivery of peptides: in vitro and in vivo skin penetration of cyclosporin A. Pharm. Research. 23, 1332–1342 (2006)

    CAS  Google Scholar 

  106. Junyaprasert, V.B., Teeranachaideekul, V., Souto, E.B., Boonmed, P., Müller, R.H.: Q10-loaded NLC versus nanoemulsions: Stability, rheology and in vitro skin permeation. Int. J. Pharm. 377, 207–214 (2009)

    CAS  Google Scholar 

  107. Teeranachaideeku, V., Boonme, P., Souto, E.B., Müller, R.H., Junyaprasert, V.B.: Influence of oil content on physicochemical properties and skin distribution of Nile red-loaded NLC. J. Control. Release 128, 134–141 (2008)

    Google Scholar 

  108. Mei, Z., Wu, Q., Hu, S., Li, X.: Triptolide loaded solid lipid nanoparticle hydrogel for topical application. Drug Dev. Ind. Pharm. 31, 161–168 (2005)

    CAS  Google Scholar 

  109. Madhusudhan, B., Rambhau, D., Apte, S.S., Gopinath, D.: Improved in Vitro Permeation of Nabumetone across Rat Skin from 1-O-Alkylglycerol/Lecithin Stabilized o/w Nanoemulsions. J. Dispersion Sci. Tech. 27, 921–926 (2006)

    CAS  Google Scholar 

  110. Dubey, V., Mishra, D., Jain, N.: Melatonin loaded ethanolic liposomes: physicochemical characterization and enhanced transdermal delivery. Eur. J. Pharm. Biopharm. 67, 398–405 (2007)

    CAS  Google Scholar 

  111. Dubey, V., Mishra, D., Dutta, T., Nahar, M., Saraf, D.K., Jain, N.K.: Dermal and transdermal delivery of an anti-psoriatic agent via ethanolic liposomes. J. Control. Release 123, 148–154 (2007)

    CAS  Google Scholar 

  112. Mei, Z., Chen, H., Weng, T., Yang, Y., Yang, X.: Solid lipid nanoparticle and microemulsion for topical delivery of triptolide. Eur. J. Pharm. Biopharm. 56, 189–196 (2003)

    CAS  Google Scholar 

  113. Cho, S.M., Lee, H.Y., Kim, J.-C.: Characterization and In-vitro Permeation Study of Stearic Acid Nanoparticles containing Hinokitiol. J. Am. Oil Chem. Soc. 84, 859–863 (2007)

    CAS  Google Scholar 

  114. Kang, M.J., Eum, J.Y., Jeong, M.S., Choi, S.E., Park, S.H., Cho, H.I., Cho, C.S., Seo, S.J., Lee, M.W., Choi, Y.W.: Facilitated Skin Permeation of Oregonin by Elastic Liposomal Formulations and Suppression of Atopic Dermatitis in NC/Nga Mice. Biol. Pharm. Bull. 33(1), 100–106 (2010)

    CAS  Google Scholar 

  115. Pople, P.V., Singh, K.K.: Development and evaluation of topical formulation containing solid lipid nanoparticles of vitamin. A AAPS Pharm. Sci. Tech. 7(4), 91 (2006)

    Google Scholar 

  116. Chen, H., Chang, X., Du, D., Liu, W., Liu, J., Weng, T., Yang, Y., Xu, H., Yang, X.: Podophyllotoxin-loaded solid lipid nanoparticles for epidermal targeting. J. Contr. Release 110, 296–310 (2006)

    CAS  Google Scholar 

  117. Borgia, S.L., Regehly, M., Sivaramakrishnan, R., Mehnert, W., Korting, H.C., Danker, K., Röder, B., Kramer, K.D., Schäfer-Korting, M.: J. Contr. Release 110, 151–163 (2005)

    Google Scholar 

  118. Bhalekar, M.R., Pokharkar, V., Madgulkar, A., Patil, N., Patil, N.: Preparation and Evaluation of Miconazole Nitrate-Loaded Solid Lipid Nanoparticles for Topical Delivery. AAPS Pharm. Sci. Tech. 10(1), 289–296 (2009)

    CAS  Google Scholar 

  119. Liu, J., Hu, W., Chen, H., Ni, Q., Xu, H., Yang, X.: Isotretinoin-loaded solid lipid nanoparticles with skin targeting for topical delivery. Int. J. Pharm. 328, 191–195 (2007)

    CAS  Google Scholar 

  120. Kuntsche, J., Bunjes, H., Fahr, A., Pappinen, S., Rönkkö, S., Suhonen, M., Urtti, A.: Interaction of lipid nanoparticles with human epidermis and an organotypic cell culture model. Int. J. Pharm. 354, 180–195 (2008)

    CAS  Google Scholar 

  121. Kim, S.Y., Lee, Y.M.: Lipid nanospheres containing vitamin A or vitamin E: Evaluation of their stabilities and in vitro skin permeability. J. Ind. Eng. Chem. 5, 306–313 (1999)

    Google Scholar 

  122. He, R., Cui, D.-X., Gao, F.: Preparation of fluorescence ethosomes based on quantum dots and their skin scar penetration properties. Mater. Lett. 63, 1662–1664 (2009)

    CAS  Google Scholar 

  123. Primo, F.L., Rodrigues, M.M.A., Simioni, A.R., Bentley, M.V.L.B., Morais, P.C., Tedesco, A.C.: In vitro studies of cutaneous retention of magnetic nanoemulsion loaded with zinc phthalocyanine for synergic use in skin cancer treatment. J. Magn. Magn. Mater. 320, e211–e214 (2008)

    Google Scholar 

  124. Mandawgade, S.D., Patravale, V.B.: Development of SLNs from natural lipids: Application to topical delivery of tretinoin. Int. J. Pharm. 363, 132–138 (2008)

    CAS  Google Scholar 

  125. Üner, M., Wissing, S.A., Yener, G., Muller, R.H.: Skin moisturizing effect and skin penetration of ascorbyl palmitate entrapped in Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) incorporated into hydrogel. Pharmazie 60, 751–755 (2005)

    Google Scholar 

  126. Puglia, C., Filosa, R., Peduto, A., Caprariis, P., Rizza, L., Bonina, F., Blasi, P.: Evaluation of Alternative Strategies to Optimize Ketorolac Transdermal Delivery. AAPS Pharm. Sci. Tech. 7, E1–E9 (2006)

    Google Scholar 

  127. Wissing, S.A., Muller, R.H.: Solid lipid nanoparticles as carrier for susncreens: in vitro release and in vivo skin penetration. J. Cont. Release 81, 225–233 (2002)

    CAS  Google Scholar 

  128. Puglia, C., Blasi, P., Rizza, L., Schoubben, A., Bonina, F., Rossi, C., Ricci, M.: Lipid nanoparticles for prolonged topical delivery: An in vitro and in vivo investigation. Int. J. Pharm. 357, 295–304 (2008)

    CAS  Google Scholar 

  129. Lai, F., Sinico, C., De Logu, A., Zaru, M., Müller, R.H., Fadda, A.M.: SLN as a topical delivery system for Artemisia arborescens essential oil: In vitro antiviral activity and skin permeation study. Int. J. Nanomed. 2(3), 419–425 (2007)

    CAS  Google Scholar 

  130. Piao, H., Kamiya, N., Hirata, A., Fujii, T., Goto, M.: A Novel Solid-in-oil Nanosuspension for Transdermal Delivery of Diclofenac Sodium. Pharm. Res. 25(4), 896–901 (2008)

    CAS  Google Scholar 

  131. Passerini, N., Gavini, E., Albertini, B., Rassu, G., Di Sabatino, M., Sanna, V., Giunchedi, P., Rodriguez, L.: Evaluation of solid lipid microparticles produced by spray congealing for topical application of econazole nitrate. J. Pharm. Pharmacol. 61(5), 559–567 (2009)

    CAS  Google Scholar 

  132. Olvera-Martínez, B.I., Zares-Delgadillo, J.C., Calderilla-Fajardo, S.B., Villalobos-García, R., Ganem-Quintanar, A., Quintanar-Guerrero, D.: Preparation of polymeric nanocapsules containing octyl methoxycinnamate by the emulsification–diffusion technique: Penetration across the stratum corneum. J. Pharm. Sci. 94, 1552–1559 (2005)

    Google Scholar 

  133. Izquierdo, P., Wiechers, J.W., Escribano, E., Garcia-Celma, M.J., Tadros, T.F., Esquena, J., Dederen, J.C., Solans, C.: A study on the influence of emulsion droplet size on the skin penetration of tetracaine. Skin Pharm. Phys. 20(5), 263–270 (2007)

    CAS  Google Scholar 

  134. Munster, U., Nakamura, C., Haberland, A., Jores, K., Mehnert, W., Rummel, S., Schaller, M., Korting, H.C., Zouboulis, C.C., Blume-Peytavi, U., Schäfer-Korting, M.: Ru 58841-Myristate - Prodrug development for topical treatment of acne and androgenetic alopecia. Pharmazie 60(1), 8–12 (2005)

    CAS  Google Scholar 

  135. Babu, S., Fan, C., Stepanskiy, L., Uitto, J., Papazoglou, E.: Effect of size at the nanoscale and bilayer rigidity on skin diffusion of liposomes. J. Biomed. Mater. Res. 91(1), 140–148 (2009)

    Google Scholar 

  136. Schilling, K., Bradford, B., Castelli, D., Dufour, E., Nash, J.F., Pape, W., Schulte, S., Tooley, I., van den Boschi, J., Schellauf, F.: Human safety review of “nano” titanium dioxide and zinc oxide. Photochem. Photobiol. Sci. 9, 495–509 (2010)

    CAS  Google Scholar 

  137. Menzel, F., Reinert, T., Vogt, J., Butz, T.: Investigations of percutaneous uptake of ultrafine TiO2 particles at the high energy ion nanoprobe LIPSION. Nucl. Instrum. Methods Phys. Res. B 219-220, 82–86 (2004)

    CAS  Google Scholar 

  138. Cross, S.E., Innes, B., Roberts, M.S., Tsuzuki, T., Robertson, T.A., McCormick, P.: Human Skin Penetration of Sunscreen Nanoparticles: In-vitro Assessment of a Novel Micronized Zinc Oxide Formulation. Skin Pharmacol. Physiol. 20, 148–154 (2007)

    CAS  Google Scholar 

  139. Lekki, J., Stachura, Z., Dabros, W., Stachura, J., Menzel, F., Reinert, T., Butz, T., Pallon, J., Gontier, E., Ynsa, M.D., Moretto, P., Kertesz, Z., Szikszai, Z., Kiss, A.Z.: On the follicular pathway of percutaneous uptake of nanoparticles: Ion microscopy and autoradiography studies. Nucl. Instrum. Methods Phys. Res. B 260, 174–177 (2007)

    CAS  Google Scholar 

  140. Pinheiro, T., Pallon, J., Alves, L.C., Verıssimo, A., Filipe, P., Silva, J.N., Silva, R.: the influence of corneocyte structure on the interpretation of permeation profiles of nanoparticles across skin. Nucl. Instrum. Methods Phys. Res. B 260, 119–123 (2007)

    CAS  Google Scholar 

  141. Gontier, E., Ynsa, M.D., Biro, T., Hunyadi, J., Kiss, B., Gaspar, K., Pinheiro, T., Silva, J.N., Filipe, P., Stachura, J., Dabros, W., Reinert, T., Butz, T., Moretto, P., Surleve-Bazeille, J.E.: Is there penetration of titania nanoparticles in sunscreens through skin? A comparative electron and ion microscopy study. Nanotoxicology 2(4), 218–231 (2008)

    Google Scholar 

  142. Wu, J., Liu, W., Xue, C., Zhou, S., Lan, F., Bi, L., Xub, H., Yang, X., Zeng, F.-D.: Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure. Toxicol. Lett. 191, 1–8 (2009)

    CAS  Google Scholar 

  143. Baroli, B., Ennas, M.G., Loffredo, F., Isola, M., Pinna, R., López-Quintela, M.A.: Penetration of metallic nanoparticles in human full-thickness skin. J. Invest. Dermatol. 127, 1701–1712 (2007)

    CAS  Google Scholar 

  144. Larese, F.F., D’Agostin, F., Crosera, M., Adami, G., Renzi, N., Bovenzi, M., Maina, G.: Human skin penetration of silver nanoparticles through intact and damaged skin. Toxicology 255, 33–37 (2009)

    CAS  Google Scholar 

  145. Xia, X.R., Monteiro-Riviere, N.A., Riviere, J.E.: Skin penetration and kinetics of pristine fullerenes (C60) topically exposed in industrial organic solvents. Toxicol. Appl. Pharmacol. 242, 29–37 (2010)

    CAS  Google Scholar 

  146. El-Sayed, I.H., Huang, X., El-Sayed, M.A.: Surface Plasmon Resonance Scattering and Absorption of anti-EGFR Antibody Conjugated Gold Nanoparticles in Cancer Diagnostics: Applications in Oral Cancer. Nano. Lett. 5(5), 829–834 (2005)

    CAS  Google Scholar 

  147. Huff, T.B., Tong, L., Zhao, Y., Hansen, M.N., Cheng, J.-X., Wei, A.: Hyperthermic effects of gold nanorods on tumor cells. Nanomedicine 2(1), 125–132 (2007)

    CAS  Google Scholar 

  148. Baker, I., Zeng, Q., Li, W., Sullivan, C.R.: Heat deposition in iron oxide and iron nanoparticles for localized hyperthermia. J. Appl. Phys. 99, 08H106-08H106-3 (2006)

    Google Scholar 

  149. Hadjipanayis, C.G., Bonder, M.J., Balakrishnan, S., Wang, X., Mao, H., Hadjipanayis, G.C.: Metallic iron nanoparticles for MRI contrast enhancement and local hyperthermia. Small 4(11), 1925–1929 (2008)

    CAS  Google Scholar 

  150. Sonvico, F., Mornet, S., Vasseur, S., Dubernet, C., Jaillard, D., Degrouard, J., Hoebeke, J., Duguet, E., Colombo, P., Couvreur, P.: Folate-Conjugated Iron Oxide Nanoparticles for Solid Tumor Targeting as Potential Specific Magnetic Hyperthermia Mediators: Synthesis, Physicochemical Characterization, and in Vitro Experiments. Bioconjugate Chem. 16, 1181–1188 (2005)

    CAS  Google Scholar 

  151. Chen, X., Schluesener, H.J.: Nanosilver: A nanoproduct in medical application. Toxicol. Lett. 176, 1–12 (2008)

    CAS  Google Scholar 

  152. Xiao, L., Takada, H., Maeda, K., Haramoto, M., Miwa, N.: Antioxidant effects of water-soluble fullerene derivatives against ultraviolet ray or peroxylipid through their action of scavenging the reactive oxygen species in human skin keratinocytes. Biomed. Pharmacother. 59, 351–358 (2005)

    CAS  Google Scholar 

  153. Kaur, I.P., Kapila, M., Agrawal, R.: Role of novel delivery systems in developing topical antioxidants as therapeutics to combat photoageing. Ageing Res. Rev. 6, 271–288 (2007)

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2752, 90610-000, Porto Alegre, RS, Brazil

    Renata V. Contri, Luana A. Fiel, Sílvia S. Guterres & Ruy C. R. Beck

  2. Departamento de Química Orgânica, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, CP 15003, 91501-970, Porto Alegre, RS, Brazil

    Adriana R. Pohlmann

Authors
  1. Renata V. Contri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luana A. Fiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adriana R. Pohlmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sílvia S. Guterres
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ruy C. R. Beck
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Dept. de Produção e Controle de Medicame, Faculdade de Farmácia, Federal University of Rio Grande do Sul, Av. Ipiranga 2752, 90610-000, Porto Alegre, Brazil

    Ruy Beck

  2. Faculty of Pharmacy, Dept. de Produção e Controle de Medicame, Federal University of Rio Grande do Sul, Av. Ipiranga 2752, 90610-000, Porto Alegre, Brazil

    Silvia Guterres

  3. Institut of Chemistry, Departamento de Química Orgânica, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, 91501-970, Porto Alegre, Brazil

    Adriana Pohlmann

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Contri, R.V., Fiel, L.A., Pohlmann, A.R., Guterres, S.S., Beck, R.C.R. (2011). Transport of Substances and Nanoparticles across the Skin and in Vitro Models to Evaluate Skin Permeation and/or Penetration. In: Beck, R., Guterres, S., Pohlmann, A. (eds) Nanocosmetics and Nanomedicines. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-19792-5_1

Download citation

Publish with us

Policies and ethics

Search

Navigation