Skip to main content
Log in

Advanced In Vitro Three-Dimensional Skin Models of Atopic Dermatitis

  • Review Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Atopic dermatitis (AD) is one of the most prevalent inflammatory skin diseases that is characterized by eczematous rashes, intense itching, dry skin, and sensitive skin. Although AD significantly impacts the quality of life and the number of patients keeps increasing, its pathological mechanism is still unknown because of its complexity. The importance of developing new in vitro three-dimensional (3D) models has been underlined in order to understand the mechanisms for the development of therapeutics since the limitations of 2D models or animal models have been repeatedly reported. Thus, the new in vitro AD models should not only be created in 3D structure, but also reflect the pathological characteristics of AD, which are known to be associated with Th2-mediated inflammatory responses, epidermal barrier disruption, increased dermal T-cell infiltration, filaggrin down-regulation, or microbial imbalance. In this review, we introduce various types of in vitro skin models including 3D culture methods, skin-on-a-chips, and skin organoids, as well as their applications to AD modeling for drug screening and mechanistic studies.

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.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Galli E, Gianni S, Auricchio G, Brunetti E, Mancino G, Rossi P. Atopic dermatitis and asthma. Allergy Asthma Proc. 2007;28:540–3.

    Article  PubMed  Google Scholar 

  2. Bantz SK, Zhu Z, Zheng T. The atopic March: progression from atopic dermatitis to allergic rhinitis and asthma. J Clin Cell Immunol. 2014;5:202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bieber T. Atopic dermatitis. N Engl J Med. 2008;358:1483–94.

    Article  CAS  PubMed  Google Scholar 

  4. Kim JE, Kim HJ, Lew B-L, Lee KH, Hong SP, Jang YH, et al. Consensus guidelines for the treatment of atopic dermatitis in Korea (part I): general management and topical treatment. Ann Dermatol. 2015;27:563–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Akhavan A, Rudikoff D. The treatment of atopic dermatitis with systemic immunosuppressive agents. Clin Dermatol. 2003;21:225–40.

    Article  PubMed  Google Scholar 

  6. Furue M, Terao H, Rikihisa W, Urabe K, Kinukawa N, Nose Y, et al. Clinical dose and adverse effects of topical steroids in daily management of atopic dermatitis. Br J Dermatol. 2003;148:128–33.

    Article  CAS  PubMed  Google Scholar 

  7. Ochsner M, Textor M, Vogel V, Smith ML. Dimensionality controls cytoskeleton assembly and metabolism of fibroblast cells in response to rigidity and shape. PLoS One. 2010;5:e9445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cukierman E, Pankov R, Stevens DR, Yamada KM. Taking cell-matrix adhesions to the third dimension. Science. 2001;294:1708–12.

    Article  CAS  PubMed  Google Scholar 

  9. Sriram G, Alberti M, Dancik Y, Wu B, Wu R, Feng Z, et al. Full-thickness human skin-on-chip with enhanced epidermal morphogenesis and barrier function. Mater Today. 2018;21:326–40.

    Article  CAS  Google Scholar 

  10. Ebner-Peking P, Krisch L, Wolf M, Hochmann S, Hoog A, Vári B, et al. Self-assembly of differentiated progenitor cells facilitates spheroid human skin organoid formation and planar skin regeneration. Theranostics. 2021;11:8430–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang G, Seok JK, Kang HC, Cho YY, Lee HS, Lee JY. Skin barrier abnormalities and immune dysfunction in atopic dermatitis. Int J Mol Sci. 2020;21:2867.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Sroka-Tomaszewska J, Trzeciak M. Molecular mechanisms of atopic dermatitis pathogenesis. Int J Mol Sci. 2021;22:4130.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wong LS, Yen YT, Lee CH. The Implications of pruritogens in the pathogenesis of atopic dermatitis. Int J Mol Sci. 2021;22:7227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chieosilapatham P, Kiatsurayanon C, Umehara Y, Trujillo-Paez JV, Peng G, Yue H, et al. Keratinocytes: innate immune cells in atopic dermatitis. Clin Exp Immunol. 2021;204:296–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lefèvre-Utile A, Braun C, Haftek M, Aubin F. Five functional aspects of the epidermal barrier. Int J Mol Sci. 2021;22:11676

    Article  PubMed  PubMed Central  Google Scholar 

  16. Seneschal J, Clark Rachael A, Gehad A, Baecher-Allan Clare M, Kupper TS. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity. 2012;36:873–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Szöllősi AG, Oláh A, Lisztes E, Griger Z, Tóth BI. Pruritus: a sensory symptom generated in cutaneous immuno-neuronal crosstalk. Front Pharmacol. 2022;13:745658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Acevedo N, Benfeitas R, Katayama S, Bruhn S, Andersson A, Wikberg G, et al. Epigenetic alterations in skin homing CD4+CLA+ T cells of atopic dermatitis patients. Sci Rep. 2020;10:18020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sabat R, Wolk K, Loyal L, Döcke W-D, Ghoreschi K. T cell pathology in skin inflammation. Semin Immunopathol. 2019;41:359–77.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ni Z, Walcheck B. Cutaneous lymphocyte-associated antigen (CLA) T cells up-regulate P-selectin ligand expression upon their activation. Clin Immunol. 2009;133:257–64.

    Article  CAS  Google Scholar 

  21. Radonjic-Hoesli S, Brüggen M-C, Feldmeyer L, Simon H-U, Simon D. Eosinophils in skin diseases. Semin Immunopathol. 2021;43:393–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Böhm I, Bauer R. Th1 cells, Th2 cells and atopic dermatitis. Hautarzt. 1997;48:223–7.

    Article  PubMed  Google Scholar 

  23. Brunner PM, Guttman-Yassky E, Leung DYM. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol. 2017;139:S65–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Humeau M, Boniface K, Bodet C. Cytokine-mediated crosstalk between keratinocytes and T Cells in atopic dermatitis. Front Immunol. 2022;13:801.

    Article  CAS  Google Scholar 

  25. Imai Y. Interleukin-33 in atopic dermatitis. J Dermatol Sci. 2019;96:2–7.

    Article  CAS  PubMed  Google Scholar 

  26. Rak GD, Osborne LC, Siracusa MC, Kim BS, Wang K, Bayat A, et al. IL-33-dependent group 2 innate lymphoid cells promote cutaneous wound healing. J Invest Dermatol. 2016;136:487–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jiang M, Tao S, Zhang S, Wang J, Zhang F, Li F, et al. Type 2 innate lymphoid cells participate in IL-33-stimulated Th2-associated immune response in chronic obstructive pulmonary disease. Exp Ther Med. 2019;18:3109–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Savinko T, Matikainen S, Saarialho-Kere U, Lehto M, Wang G, Lehtimäki S, et al. IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors. J Investig Dermatol. 2012;132:1392–400.

    Article  CAS  PubMed  Google Scholar 

  29. Chiricozzi A, Maurelli M, Peris K, Girolomoni G. Targeting IL-4 for the treatment of atopic dermatitis. Immunotargets Ther. 2020;9:151–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sugaya M. The role of Th17-related cytokines in atopic dermatitis. Int J Mol Sci. 2020;21:1314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Noda S, Suárez-Fariñas M, Ungar B, Kim SJ, de Guzman SC, Xu H, et al. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol. 2015;136:1254–64.

    Article  CAS  PubMed  Google Scholar 

  32. Ebina-Shibuya R, Leonard WJ. Role of thymic stromal lymphopoietin in allergy and beyond. Nat Rev Immunol. 2023;23:24–37.

    Article  CAS  PubMed  Google Scholar 

  33. Cianferoni A, Spergel J. The importance of TSLP in allergic disease and its role as a potential therapeutic target. Expert Rev Clin Immunol. 2014;10:1463–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang Y, Zhou B. Functions of thymic stromal lymphopoietin in immunity and disease. Immunol Res. 2012;52:211–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kubo T, Kamekura R, Kumagai A, Kawata K, Yamashita K, Mitsuhashi Y, et al. ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis. PLoS One. 2014;9:e105498.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Wang SH, Zuo YG. Thymic stromal lymphopoietin in cutaneous immune-mediated diseases. Front Immunol. 2021;12:698522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jang S, Morris S, Lukacs NW. TSLP promotes induction of Th2 differentiation but is not necessary during established allergen-induced pulmonary disease. PLoS One. 2013;8:e56433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Eyerich K, Novak N. Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy. 2013;68:974–82.

    Article  CAS  PubMed  Google Scholar 

  39. Kumar S, Jeong Y, Ashraf MU, Bae YS. Dendritic cell-mediated Th2 immunity and immune disorders. Int J Mol Sci. 2019;20:2159.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383:787–93.

    Article  CAS  PubMed  Google Scholar 

  41. Trautmann A, Akdis M, Kleemann D, Altznauer F, Simon H-U, Graeve T, et al. T cell–mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest. 2000;106:25–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Summey BT, Bowen SE, Allen HB. Lichen planus-like atopic dermatitis: expanding the differential diagnosis of spongiotic dermatitis. J Cutan Pathol. 2008;35:311–4.

    Article  PubMed  Google Scholar 

  43. van Smeden J, Janssens M, Kaye ECJ, Caspers PJ, Lavrijsen AP, Vreeken RJ, et al. The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients. Exp Dermatol. 2014;23:45–52.

    Article  CAS  PubMed  Google Scholar 

  44. Ito S, Ishikawa J, Naoe A, Yoshida H, Hachiya A, Fujimura T, et al. Ceramide synthase 4 is highly expressed in involved skin of patients with atopic dermatitis. J Eur Acad Dermatol Venereol. 2017;31:135–41.

    Article  CAS  PubMed  Google Scholar 

  45. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, et al. Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol. 2011;127:773-86.e7.

    Article  CAS  PubMed  Google Scholar 

  46. Kanda N, Hoashi T, Saeki H. Nutrition and atopic dermatitis. J Nippon Med Sch. 2021;88:171–7.

    Article  CAS  PubMed  Google Scholar 

  47. Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet. 2020;396:345–60.

    Article  CAS  PubMed  Google Scholar 

  48. Bieber T, de la Salle H, Wollenberg A, Hakimi J, Chizzonite R, Ring J, et al. Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc epsilon RI). J Exp Med. 1992;175:1285–90.

    Article  CAS  PubMed  Google Scholar 

  49. Clayton K, Vallejo AF, Davies J, Sirvent S, Polak ME. Langerhans cells—programmed by the epidermis. Front Immunol. 2017;8:1676.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Deckers J, Hammad H, Hoste E. Langerhans Cells: sensing the environment in health and disease. Front Immunol. 2018;9:93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Stoitzner P, Tripp CH, Eberhart A, Price KM, Jung JY, Bursch L, et al. Langerhans cells cross-present antigen derived from skin. Proc Natl Acad Sci U S A. 2006;103:7783–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Leung DY. Role of IgE in atopic dermatitis. Curr Opin Immunol. 1993;5:956–62.

    Article  CAS  PubMed  Google Scholar 

  53. Matsui T, Amagai M. Dissecting the formation, structure and barrier function of the stratum corneum. Int Immunol. 2015;27:269–80.

    Article  CAS  PubMed  Google Scholar 

  54. Pellerin L, Henry J, Hsu CY, Balica S, Jean-Decoster C, Méchin MC, et al. Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. J Allergy Clin Immunol. 2013;131:1094–102.

    Article  CAS  PubMed  Google Scholar 

  55. Agrawal R, Woodfolk JA. Skin barrier defects in atopic dermatitis. Curr Allergy Asthma Rep. 2014;14:433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Suárez-Fariñas M, Tintle SJ, Shemer A, Chiricozzi A, Nograles K, Cardinale I, et al. Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol. 2011;127:954-64.e1-4.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Theerawatanasirikul S, Sailasuta A, Thanawongnuwech R, Nakbed T, Charngkaew K, Suriyaphol G. Differential expression patterns of proteins involved in epidermal proliferation and differentiation in canine atopic dermatitis. Thai J Vet Med. 2012;42:287–96.

    Article  Google Scholar 

  58. Catarino CM, do Nascimento Pedrosa T, Pennacchi PC, de Assis SR, Gimenes F, Consolaro MEL et al. Skin corrosion test: a comparison between reconstructed human epidermis and full thickness skin models. Eur J Pharm Biopharm. 2018;125:51–7.

  59. Poumay Y, Dupont F, Marcoux S, Leclercq-Smekens M, Hérin M, Coquette A. A simple reconstructed human epidermis: preparation of the culture model and utilization in in vitro studies. Arch Dermatol Res. 2004;296:203–11.

    Article  CAS  PubMed  Google Scholar 

  60. Dijkhoff IM, Petracca B, Prieux R, Valacchi G, Rothen-Rutishauser B, Eeman M. Cultivating a three-dimensional reconstructed human epidermis at a large scale. J Vis Exp. 2021.

    Article  PubMed  Google Scholar 

  61. Pruniéras M, Régnier M, Woodley D. Methods for cultivation of keratinocytes with an air-liquid interface. J Invest Dermatol. 1983;81:28s–33s.

    Article  PubMed  Google Scholar 

  62. Rossi A, Appelt-Menzel A, Kurdyn S, Walles H, Groeber F. Generation of a three-dimensional full thickness skin equivalent and automated wounding. J Vis Exp. 2015.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zhang Z, Michniak-Kohn BB. Tissue engineered human skin equivalents. Pharmaceutics. 2012;4:26–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Herson MR, Mathor MB, Altran S, Capelozzi VL, Ferreira MC. In vitro construction of a potential skin substitute through direct human keratinocyte plating onto decellularized glycerol-preserved allodermis. Artif Organs. 2001;25:901–6.

    Article  CAS  PubMed  Google Scholar 

  65. Ghosh MM, Boyce S, Layton C, Freedlander E, Neil SM. A comparison of methodologies for the preparation of human epidermal-dermal composites. Ann Plast Surg. 1997;39:390–404.

    Article  CAS  PubMed  Google Scholar 

  66. Lee DY, Ahn HT, Cho KH. A new skin equivalent model: dermal substrate that combines de-epidermized dermis with fibroblast-populated collagen matrix. J Dermatol Sci. 2000;23:132–7. https://doi.org/10.1016/S0923-1811(00)00068-2.

    Article  CAS  PubMed  Google Scholar 

  67. Chakrabarty KH, Dawson RA, Harris P, Layton C, Babu M, Gould L, et al. Development of autologous human dermal–epidermal composites based on sterilized human allodermis for clinical use. Br J Dermatol. 1999;141:811–23.

    Article  CAS  PubMed  Google Scholar 

  68. Rehder J, Souto LR, Issa CM, Puzzi MB. Model of human epidermis reconstructed in vitro with keratinocytes and melanocytes on dead de-epidermized human dermis. Sao Paulo Med J. 2004;122:22–5.

    Article  PubMed  Google Scholar 

  69. Ralston DR, Layton C, Dalley AJ, Boyce SG, Freedlander E, Mac NS. The requirement for basement membrane antigens in the production of human epidermal/dermal composites in vitro. Br J Dermatol. 1999;140:605–15.

    Article  CAS  PubMed  Google Scholar 

  70. Nashchekina Y, Nikonov P, Prasolov N, Sulatsky M, Chabina A, Nashchekin A. The structural interactions of molecular and fibrillar collagen type i with fibronectin and its role in the regulation of mesenchymal stem cell morphology and functional activity. Int J Mol Sci. 2022;23:12577.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Monteiro GA, Fernandes AV, Sundararaghavan HG, Shreiber DI. Positively and negatively modulating cell adhesion to type I collagen via peptide grafting. Tissue Eng Part A. 2011;17:1663–73.

    Article  CAS  PubMed  Google Scholar 

  72. El Ghalbzouri A, Commandeur S, Rietveld MH, Mulder AA, Willemze R. Replacement of animal-derived collagen matrix by human fibroblast-derived dermal matrix for human skin equivalent products. Biomaterials. 2009;30:71–8.

    Article  CAS  PubMed  Google Scholar 

  73. Auxenfans C, Fradette J, Lequeux C, Germain L, Kinikoglu B, Bechetoille N, et al. Evolution of three dimensional skin equivalent models reconstructed in vitro by tissue engineering. Eur J Dermatol. 2009;19:107–13.

    Article  PubMed  Google Scholar 

  74. Dubé N, Rochon MH, Ospina CE, Soucy J, Germain L, Auger FA. 119 Clinical experience with the self-assembled skin substitue as a biological dressing for chronic venous leg ulcers treatment. Wound Repair Regen. 2004;12:A31.

    Article  Google Scholar 

  75. Jean J, Lapointe M, Soucy J, Pouliot R. Development of an in vitro psoriatic skin model by tissue engineering. J Dermatol Sci. 2009;53:19–25.

    Article  CAS  PubMed  Google Scholar 

  76. Cui M, Wiraja C, Zheng M, Singh G, Yong K-T, Xu C. Recent progress in skin-on-a-chip platforms. Adv Ther. 2022;5:2100138.

    Article  Google Scholar 

  77. Risueño I, Valencia L, Holgado M, Jorcano J, Velasco D. Generation of a simplified three-dimensional skin-on-a-chip model in a micromachined microfluidic platform. J Vis Exp. 2021.

    Article  PubMed  Google Scholar 

  78. Sutterby E, Thurgood P, Baratchi S, Khoshmanesh K, Pirogova E. Microfluidic skin-on-a-chip models: toward biomimetic artificial skin. Small. 2020;16:2002515.

    Article  CAS  Google Scholar 

  79. Risueño I, Valencia L, Jorcano JL, Velasco D. Skin-on-a-chip models: general overview and future perspectives. APL Bioeng. 2021;5:030901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ponmozhi J, Dhinakaran S, Varga-Medveczky Z, Fónagy K, Bors LA, Iván K, et al. Development of skin-on-a-chip platforms for different utilizations: factors to be considered. Micromachines (Basel). 2021;12:294.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Agarwal T, Narayana GH, Banerjee I. Keratinocytes are mechanoresponsive to the microflow-induced shear stress. Cytoskeleton. 2019;76:209–18.

    Article  CAS  PubMed  Google Scholar 

  82. Aazmi A, Zhou H, Li Y, Yu M, Xu X, Wu Y, et al. Engineered vasculature for organ-on-a-chip systems. Engineering. 2022;9:131–47.

    Article  Google Scholar 

  83. Unagolla JM, Jayasuriya AC. Recent advances in organoid engineering: a comprehensive review. Appl Mater Today. 2022;29:101582.

    Article  Google Scholar 

  84. Heo JH, Kang D, Seo SJ, Jin Y. Engineering the extracellular matrix for organoid culture. Int J Stem Cells. 2022;15:60–9.

    Article  CAS  Google Scholar 

  85. Zhao Z, Chen X, Dowbaj AM, Sljukic A, Bratlie K, Lin L, et al. Organoids. Nat Rev Methods Prim. 2022;2:94.

    Article  CAS  Google Scholar 

  86. Lee J, van der Valk WH, Serdy SA, Deakin C, Kim J, Le AP, et al. Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells. Nat Protoc. 2022;17:1266–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ho BX, Pek NMQ, Soh BS. Disease modeling using 3D organoids derived from human induced pluripotent stem cells. Int J Mol Sci. 2018;19:936.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Lee J, Koehler KR. Skin organoids: a new human model for developmental and translational research. Exp Dermatol. 2021;30:613–20.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Heydari Z, Moeinvaziri F, Agarwal T, Pooyan P, Shpichka A, Maiti TK, et al. Organoids: a novel modality in disease modeling. Bio Des Manuf. 2021;4:689–716.

    Article  Google Scholar 

  90. Blutt SE, Estes MK. Organoid models for infectious disease. Annu Rev Med. 2022;73:167–82.

    Article  CAS  PubMed  Google Scholar 

  91. Jung SY, You HJ, Kim MJ, Ko G, Lee S, Kang KS. Wnt-activating human skin organoid model of atopic dermatitis induced by Staphylococcus aureus and its protective effects by Cutibacterium acnes. iScience. 2022;25:105150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Engelhart K, El Hindi T, Biesalski H-K, Pfitzner I. In vitro reproduction of clinical hallmarks of eczematous dermatitis in organotypic skin models. Arch Dermatol Res. 2005;297:1–9.

    Article  CAS  PubMed  Google Scholar 

  93. Wallmeyer L, Dietert K, Sochorová M, Gruber AD, Kleuser B, Vávrová K, et al. TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents. Sci Rep. 2017;7:774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Furue M. Regulation of skin barrier function via competition between AHR axis versus IL-13/IL-4-JAK-STAT6/STAT3 axis: pathogenic and therapeutic implications in atopic dermatitis. J Clin Med. 2020;9:3741.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Kim K, Kim H, Sung GY. An interleukin-4 and interleukin-13 induced atopic dermatitis human skin equivalent model by a skin-on-a-chip. Int J Mol Sci. 2022;23:2116.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Furue K, Ito T, Tsuji G, Ulzii D, Vu YH, Kido-Nakahara M, et al. The IL-13–OVOL1–FLG axis in atopic dermatitis. Immunology. 2019;158:281–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Novak N, Simon D. Atopic dermatitis—from new pathophysiologic insights to individualized therapy. Allergy. 2011;66:830–9.

    Article  PubMed  Google Scholar 

  98. Hvid M, Vestergaard C, Kemp K, Christensen GB, Deleuran B, Deleuran M. IL-25 in atopic dermatitis: a possible link between inflammation and skin barrier dysfunction? J Investig Dermatol. 2011;131:150–7.

    Article  CAS  PubMed  Google Scholar 

  99. De Vuyst É, Giltaire S, de Lambert Rouvroit C, Malaisse J, Mound A, Bourtembourg M, et al. Methyl-β-cyclodextrin concurs with interleukin (IL)-4, IL-13 and IL-25 to induce alterations reminiscent of atopic dermatitis in reconstructed human epidermis. Exp Dermatol. 2018;27:435–7.

    Article  CAS  PubMed  Google Scholar 

  100. Danso MO, van Drongelen V, Mulder A, van Esch J, Scott H, van Smeden J, et al. TNF-α and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents. J Invest Dermatol. 2014;134:1941–50.

    Article  CAS  PubMed  Google Scholar 

  101. Zwara A, Wertheim-Tysarowska K, Mika A. Alterations of ultra long-chain fatty acids in hereditary skin diseases—review article. Front Med (Lausanne). 2021;8:730855.

    Article  Google Scholar 

  102. Cameron DJ, Tong Z, Yang Z, Kaminoh J, Kamiyah S, Chen H, et al. Essential role of Elovl4 in very long chain fatty acid synthesis, skin permeability barrier function, and neonatal survival. Int J Biol Sci. 2007;3:111–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rouaud-Tinguely P, Boudier D, Marchand L, Barruche V, Bordes S, Coppin H, et al. From the morphological to the transcriptomic characterization of a compromised three-dimensional in vitro model mimicking atopic dermatitis. Br J Dermatol. 2015;173:1006–14.

    Article  CAS  PubMed  Google Scholar 

  104. Yuki T, Tobiishi M, Kusaka-Kikushima A, Ota Y, Tokura Y. Impaired tight junctions in atopic dermatitis skin and in a skin-equivalent model treated with interleukin-17. PLoS One. 2016;11:e0161759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kamsteeg M, Bergers M, de Boer R, Zeeuwen PL, Hato SV, Schalkwijk J, et al. Type 2 helper T-cell cytokines induce morphologic and molecular characteristics of atopic dermatitis in human skin equivalent. Am J Pathol. 2011;178:2091–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lee SH, Bae IH, Choi H, Choi HW, Oh S, Marinho PA, et al. Ameliorating effect of dipotassium glycyrrhizinate on an IL-4- and IL-13-induced atopic dermatitis-like skin-equivalent model. Arch Dermatol Res. 2019;311:131–40.

    Article  CAS  PubMed  Google Scholar 

  107. Vidal SEL, Tamamoto KA, Nguyen H, Abbott RD, Cairns DM, Kaplan DL. 3D biomaterial matrix to support long term, full thickness, immuno-competent human skin equivalents with nervous system components. Biomaterials. 2019;198:194–203.

    Article  CAS  PubMed  Google Scholar 

  108. Guo Z, Tong CK, Jacków J, Doucet YS, Abaci HE, Zeng W, et al. Engineering human skin model innervated with itch sensory neuron-like cells differentiated from induced pluripotent stem cells. Bioeng Transl Med. 2022;7:e10247.

    Article  CAS  PubMed  Google Scholar 

  109. Ramadan Q, Ting FC. In vitro micro-physiological immune-competent model of the human skin. Lab Chip. 2016;16:1899–908.

    Article  CAS  PubMed  Google Scholar 

  110. Wufuer M, Lee G, Hur W, Jeon B, Kim BJ, Choi TH, et al. Skin-on-a-chip model simulating inflammation, edema and drug-based treatment. Sci Rep. 2016;6:37471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ren X, Getschman AE, Hwang S, Volkman BF, Klonisch T, Levin D, et al. Investigations on T cell transmigration in a human skin-on-chip (SoC) model. Lab Chip. 2021;21:1527–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Akiyama M. FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics. Br J Dermatol. 2010;162:472–7.

    Article  CAS  PubMed  Google Scholar 

  113. Thyssen JP, Godoy-Gijon E, Elias PM. Ichthyosis vulgaris: the filaggrin mutation disease. Br J Dermatol. 2013;168:1155–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Muhandes L, Chapsa M, Pippel M, Behrendt R, Ge Y, Dahl A, et al. Low threshold for cutaneous allergen sensitization but no spontaneous dermatitis or atopy in FLG-deficient mice. J Investig Dermatol. 2021;141:2611-9.e2.

    Article  CAS  PubMed  Google Scholar 

  115. Elias MS, Long HA, Newman CF, Wilson PA, West A, McGill PJ, et al. Proteomic analysis of filaggrin deficiency identifies molecular signatures characteristic of atopic eczema. J Allergy Clin Immunol. 2017;140:1299–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Pendaries V, Le Lamer M, Cau L, Hansmann B, Malaisse J, Kezic S, et al. In a three-dimensional reconstructed human epidermis filaggrin-2 is essential for proper cornification. Cell Death Dis. 2015;6:e1656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Pendaries V, Malaisse J, Pellerin L, Le Lamer M, Nachat R, Kezic S, et al. Knockdown of filaggrin in a three-dimensional reconstructed human epidermis impairs keratinocyte differentiation. J Invest Dermatol. 2014;134:2938–46.

    Article  CAS  PubMed  Google Scholar 

  118. Küchler S, Henkes D, Eckl KM, Ackermann K, Plendl J, Korting HC, et al. Hallmarks of atopic skin mimicked in vitro by means of a skin disease model based on FLG knock-down. Altern Lab Anim. 2011;39:471–80.

    Article  PubMed  Google Scholar 

  119. van Drongelen V, Alloul-Ramdhani M, Danso MO, Mieremet A, Mulder A, van Smeden J, et al. Knock-down of filaggrin does not affect lipid organization and composition in stratum corneum of reconstructed human skin equivalents. Exp Dermatol. 2013;22:807–12.

    Article  CAS  PubMed  Google Scholar 

  120. Kim J, Kim BE, Ahn K, Leung DYM. Interactions between atopic dermatitis and staphylococcus aureus infection: clinical implications. Allergy Asthma Immunol Res. 2019;11:593–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Abeck D, Mempel M. Staphylococcus aureus colonization in atopic dermatitis and its therapeutic implications. Br J Dermatol. 1998;139:13–6.

    Article  PubMed  Google Scholar 

  122. Choi SY, Lee YJ, Kim JM, Kang HJ, Cho SH, Chang SE. Epidermal growth factor relieves inflammatory signals in Staphylococcus aureus-treated human epidermal keratinocytes and atopic dermatitis-like skin lesions in Nc/Nga mice. Biomed Res Int. 2018;2018:9439182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Liu X, Michael S, Bharti K, Ferrer M, Song MJ. A biofabricated vascularized skin model of atopic dermatitis for preclinical studies. Biofabrication. 2020;12:035002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Park JH, Jang J, Lee J-S, Cho D-W. Current advances in three-dimensional tissue/organ printing. Tissue Eng Regen Med. 2016;13:612–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kim K. Influences of environmental chemicals on atopic dermatitis. Toxicol Res. 2015;31:89–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Reithofer M, Jahn-Schmid B. Allergens with protease activity from house dust mites. Int J Mol Sci. 2017;18:1368.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Catherine Mack Correa M, Nebus J. Management of patients with atopic dermatitis: the role of emollient therapy. Dermatol Res Pract. 2012;2012:836931.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Baker BS. The role of microorganisms in atopic dermatitis. Clin Exp Immunol. 2006;144:1–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Buske-Kirschbaum A, Geiben A, Hellhammer D. Psychobiological aspects of atopic dermatitis: An overview. Psychother Psychosom. 2001;70:6–16.

    Article  CAS  PubMed  Google Scholar 

  130. Archer NK, Adappa ND, Palmer JN, Cohen NA, Harro JM, Lee SK, et al. Interleukin-17A (IL-17A) and IL-17F are critical for antimicrobial peptide production and clearance of Staphylococcus aureus nasal colonization. Infect Immun. 2016;84:3575–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Gaffen SL. Recent advances in the IL-17 cytokine family. Curr Opin Immunol. 2011;23:613–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Malhotra N, Yoon J, Leyva-Castillo JM, Galand C, Archer N, Miller LS, et al. IL-22 derived from γδ T cells restricts Staphylococcus aureus infection of mechanically injured skin. J Allergy Clin Immunol. 2016;138:1098-107.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mulcahy ME, Leech JM, Renauld JC, Mills KH, McLoughlin RM. Interleukin-22 regulates antimicrobial peptide expression and keratinocyte differentiation to control Staphylococcus aureus colonization of the nasal mucosa. Mucosal Immunol. 2016;9:1429–41.

    Article  CAS  PubMed  Google Scholar 

  134. Toda M, Leung DYM, Molet S, Boguniewicz M, Taha R, Christodoulopoulos P, et al. Polarized in vivo expression of IL-11 and IL-17 between acute and chronic skin lesions. J Allergy Clin Immunol. 2003;111:875–81.

    Article  CAS  PubMed  Google Scholar 

  135. Gupta RK, Gupta K, Dwivedi PD. Pathophysiology of IL-33 and IL-17 in allergic disorders. Cytokine Growth Factor Rev. 2017;38:22–36.

    Article  CAS  PubMed  Google Scholar 

  136. Mu Z, Zhao Y, Liu X, Chang C, Zhang J. Molecular biology of atopic dermatitis. Clin Rev Allergy Immunol. 2014;47:193–218.

    Article  CAS  PubMed  Google Scholar 

  137. Olivry T, Mayhew D, Paps JS, Linder KE, Peredo C, Rajpal D, et al. Early activation of Th2/Th22 inflammatory and pruritogenic pathways in acute canine atopic dermatitis skin lesions. J Investig Dermatol. 2016;136:1961–9.

    Article  CAS  PubMed  Google Scholar 

  138. Gittler JK, Shemer A, Suárez-Fariñas M, Fuentes-Duculan J, Gulewicz KJ, Wang CQF, et al. Progressive activation of TH2/TH22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012;130:1344–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Tan Q, Yang H, Liu E, Wang H. P38/ERK MAPK signaling pathways are involved in the regulation of filaggrin and involucrin by IL-17. Mol Med Rep. 2017;16:8863–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Gutowska-Owsiak D, Schaupp AL, Salimi M, Selvakumar TA, McPherson T, Taylor S, et al. IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion. Exp Dermatol. 2012;21:104–10.

    Article  CAS  PubMed  Google Scholar 

  141. Leung DYM, Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol. 2014;134:769–79.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M, et al. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. Exp Dermatol. 2001;10:11–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2022R1F1A1074813). Also, this research was supported by the Chung-Ang University Research Grants in 2021.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jung Bok Lee or Jeong-Kee Yoon.

Ethics declarations

Ethical statement

There are no animal experiments carried out for this article.

Conflict of interest

The authors declare that there is no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jang, HJ., Lee, J.B. & Yoon, JK. Advanced In Vitro Three-Dimensional Skin Models of Atopic Dermatitis. Tissue Eng Regen Med 20, 539–552 (2023). https://doi.org/10.1007/s13770-023-00532-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13770-023-00532-1

Keywords

Navigation