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Cited by 129Skin and Cellular Biology ResearchAdvancements in Transdermal Drug Delivery3D Printing in Biomedical Research

Modelling the Complexity of Human Skin In Vitro

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Hofmann, Elisabeth, Schwarz, Anna, Fink, Julia, Kamolz, Lars-Peter, Kotzbeck, Petra·2023·Biomedicines
DOI 10.3390/biomedicines11030794PMC PMC10045055
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Abstract

The skin serves as an important barrier protecting the body from physical, chemical and pathogenic hazards as well as regulating the bi-directional transport of water, ions and nutrients. In order to improve the knowledge on skin structure and function as well as on skin diseases, animal experiments are often employed, but anatomical as well as physiological interspecies differences may result in poor translatability of animal-based data to the clinical situation. In vitro models, such as human reconstructed epidermis or full skin equivalents, are valuable alternatives to animal experiments. Enormous advances have been achieved in establishing skin models of increasing complexity in the past. In this review, human skin structures are described as well as the fast evolving technologies developed to reconstruct the complexity of human skin structures in vitro.

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  • The HEE model is implemented in hazard assessments and regenerative medicine and is commercially available from numerous companies.

    “Owing to its cost-effectiveness and reproducibility, the HEE model is also implemented in hazard assessments and regenerative medicine, where it is now commercially available from numerous companies [27,28].”

    From Diversity of human skin three-dimensional organotypic cultures (2024) · cites this paper as [27]

    Section 3 (Reconstructed Human Epidermis; page not provided) says reconstructed human epidermis models are commercially available from a number of companies for hazard assessments. It does not say these models are implemented in regenerative medicine. The cited passages also do not establish cost-effectiveness as the reason for their use. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • There has been a complete absence of an endogenously differentiating vascularized, hair-bearing human skin equivalent that contains immune cell populations.

    “While many attempts to generate complex 3D skin equivalents have achieved vascularization, hair follicle generation, and immune cell co‐cultures, there has been a complete absence of endogenously differentiating a vascularized, hair‐bearing human skin equivalent that contains immune cell populations.[ 21 , 22 , 23 , 24 , 25 , 26 , 27 ]”

    From Coordinated Development of Immune Cell Populations in Vascularized Skin Organoids from Human Induced Pluripotent Stem Cells (2025) · cites this paper as [24]

    Sections 4.1, 4.2, and 4.5 describe separate advances in immune-cell incorporation, vascularization, and hair-follicle formation, while section 5 says current models still face substantial limitations. The paper does not establish the claimed complete absence of a single endogenously differentiating human skin equivalent combining vascularization, hair, and immune-cell populations. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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References 132 · Cited by 129

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  1. [2]Jung E.C. Maibach H.I. Animal models for percutaneous absorption J. Appl. Toxicol. 2015 35 1 10 10.1002/jat.3004 25345378 · DOI
  2. [3]Dellambra E. Odorisio T. D’Arcangelo D. Failla C.M. Facchiano A. Non-animal models in dermatological research ALTEX 2019 36 177 202 10.14573/altex.1808022 30456412 · DOI
  3. [4]Todo H. Transdermal Permeation of Drugs in Various Animal Species Pharmaceutics 2017 9 33 10.3390/pharmaceutics9030033 28878145 PMC5620574 · DOI
  4. [6]Middelkoop E. Van Den Bogaerdt A.J. Lamme E.N. Hoekstra M.J. Brandsma K. Ulrich M.M.W. Porcine wound models for skin substitution and burn treatment Biomaterials 2004 25 1559 1567 10.1016/S0142-9612(03)00502-7 14697858 · DOI
  5. [7]Summerfield A. Meurens F. Ricklin M.E. The immunology of the porcine skin and its value as a model for human skin Mol. Immunol. 2015 66 14 21 10.1016/j.molimm.2014.10.023 25466611 · DOI · Paper page
  6. [8]Leist M. Hasiwa N. Rovida C. Daneshian M. Basketter D. Kimber I. Clewell H. Gocht T. Goldberg A. Busquet F. Consensus report on the future of animal-free systemic toxicity testing Altern. Anim. Exp. ALTEX 2014 31 341 356 10.14573/altex.1406091 25061899 · DOI
  7. [10]Proksch E. Brandner J.M. Jensen J.-M. The skin: An indispensable barrier Exp. Dermatol. 2008 17 1063 1072 10.1111/j.1600-0625.2008.00786.x 19043850 · DOI · Paper page
  8. [11]Wertz P.W. Current Understanding of Skin Biology Pertinent to Skin Penetration: Skin Biochemistry Skin Pharmacol. Physiol. 2013 26 217 226 10.1159/000351949 23921108 · DOI
  9. [12]Lee Y. Hwang K. Skin thickness of Korean adults Surg. Radiol. Anat. 2002 24 183 189 10.1007/s00276-002-0034-5 12375070 · DOI
  10. [13]Honari G. Maibach H. Chapter 1—Skin Structure and Function Applied Dermatotoxicology Maibach H. Honari G.B.T.-A.D. Academic Press Cambridge, MA, USA 2014 1 10 978-0-12-420130-9
  11. [14]Nafisi S. Maibach H.I. Chapter 3—Skin penetration of nanoparticles Micro and Nano Technologies Shegokar R. Souto E.B.B.T.-E.N. Elsevier Boston, MA, USA 2018 47 88 978-0-323-40016-9
  12. [15]Rousselle P. Braye F. Dayan G. Re-epithelialization of adult skin wounds: Cellular mechanisms and therapeutic strategies Adv. Drug Deliv. Rev. 2019 146 344 365 10.1016/j.addr.2018.06.019 29981800 · DOI
  13. [16]Houben E. De Paepe K. Rogiers V. A Keratinocyte’s Course of Life Skin Pharmacol. Physiol. 2007 20 122 132 10.1159/000098163 17191035 · DOI
  14. [17]Srivastava S.S. Alam H. Patil J.S. Shrinivasan R. Raikundalia S. Chaudhari Rajeev P. Vaidya M.M. Keratin 5/14-mediated cell differentiation and transformation are regulated by TAp63 and Notch-1 in oral squamous cell carcinoma-derived cells Oncol. Rep. 2018 39 2393 2401 10.3892/or.2018.6298 29512781 · DOI
  15. [18]Barbieri J.S. Wanat K. Seykora J. Skin: Basic Structure and Function Pathobiology of Human Disease McManus L.M. Mitchell R.N.B.T.-P. Academic Press Cambridge, MA, USA 2014 1134 1144 978-0-12-386457-4
  16. [19]Yousef H. Alhajj M. Sharma S. Anatomy, Skin (Integument), Epidermis StatPearls [Internet] StatPearls Treasure Island, FL, USA 2022 29262154
  17. [20]Tong L. Corrales R.M. Chen Z. Villarreal A.L. De Paiva C.S. Beuerman R. Li D.-Q. Pflugfelder S.C. Expression and regulation of cornified envelope proteins in human corneal epithelium Invest. Ophthalmol. Vis. Sci. 2006 47 1938 1946 10.1167/iovs.05-1129 16639001 PMC2906387 · DOI
  18. [21]Jackson B. Tilli C.M.L.J. Hardman M.J. Avilion A.A. MacLeod M.C. Ashcroft G.S. Byrne C. Late Cornified Envelope Family in Differentiating Epithelia—Response to Calcium and Ultraviolet Irradiation J. Investig. Dermatol. 2005 124 1062 1070 10.1111/j.0022-202X.2005.23699.x 15854049 · DOI
  19. [23]Nemes Z. Steinert P.M. Bricks and mortar of the epidermal barrier Exp. Mol. Med. 1999 31 5 19 10.1038/emm.1999.2 10231017 · DOI · Paper page
  20. [24]Cichorek M. Wachulska M. Stasiewicz A. Tymińska A. Skin melanocytes: Biology and development Postep. Dermatol. Alergol. 2013 30 30 41 10.5114/pdia.2013.33376 PMC3834696 24278043 · DOI
  21. [26]Mathes S.H. Ruffner H. Graf-Hausner U. The use of skin models in drug development Adv. Drug Deliv. Rev. 2014 69–70 81 102 10.1016/j.addr.2013.12.006 24378581 · DOI
  22. [27]Stoitzner P. Stössel H. Romani N. Pfaller K. A Close-Up View of Migrating Langerhans Cells in the Skin J. Investig. Dermatol. 2002 118 117 125 10.1046/j.0022-202x.2001.01631.x 11851884 · DOI
  23. [28]Otsuka M. Egawa G. Kabashima K. Uncovering the Mysteries of Langerhans Cells, Inflammatory Dendritic Epidermal Cells, and Monocyte-Derived Langerhans Cell-Like Cells in the Epidermis Front. Immunol. 2018 9 1768 10.3389/fimmu.2018.01768 30105033 PMC6077183 · DOI
  24. [29]Doebel T. Voisin B. Nagao K. Langerhans Cells—The Macrophage in Dendritic Cell Clothing Trends Immunol. 2017 38 817 828 10.1016/j.it.2017.06.008 28720426 · DOI · Paper page
  25. [30]Fukunaga A. Khaskhely N.M. Sreevidya C.S. Byrne S.N. Ullrich S.E. Dermal dendritic cells, and not Langerhans cells, play an essential role in inducing an immune response J. Immunol. 2008 180 3057 3064 10.4049/jimmunol.180.5.3057 18292528 PMC2408377 · DOI
  26. [31]Shpichka A. Butnaru D. Bezrukov E.A. Sukhanov R.B. Atala A. Burdukovskii V. Zhang Y. Timashev P. Skin tissue regeneration for burn injury Stem Cell Res. Ther. 2019 10 94 10.1186/s13287-019-1203-3 30876456 PMC6419807 · DOI
  27. [32]Kruegel J. Miosge N. Basement membrane components are key players in specialized extracellular matrices Cell. Mol. Life Sci. 2010 67 2879 2895 10.1007/s00018-010-0367-x 20428923 PMC2921489 · DOI
  28. [33]Borradori L. Sonnenberg A. Structure and Function of Hemidesmosomes: More Than Simple Adhesion Complexes J. Investig. Dermatol. 1999 112 411 418 10.1046/j.1523-1747.1999.00546.x 10201522 · DOI
  29. [34]Dos Santos M. Michopoulou A. André-Frei V. Boulesteix S. Guicher C. Dayan G. Whitelock J. Damour O. Rousselle P. Perlecan expression influences the keratin 15-positive cell population fate in the epidermis of aging skin Aging 2016 8 751 768 10.18632/aging.100928 26996820 PMC4925826 · DOI
  30. [35]Sugawara K. Tsuruta D. Ishii M. Jones J.C.R. Kobayashi H. Laminin-332 and -511 in skin Exp. Dermatol. 2008 17 473 480 10.1111/j.1600-0625.2008.00721.x 18474082 · DOI
  31. [36]Abreu-Velez A.M. Howard M.S. Collagen IV in Normal Skin and in Pathological Processes N. Am. J. Med. Sci. 2012 4 1 8 10.4103/1947-2714.92892 22393540 PMC3289483 · DOI
  32. [37]Breitkreutz D. Koxholt I. Thiemann K. Nischt R. Skin basement membrane: The foundation of epidermal integrity—BM functions and diverse roles of bridging molecules nidogen and perlecan Biomed Res. Int. 2013 2013 179784 10.1155/2013/179784 23586018 PMC3618921 · DOI
  33. [38]Mortensen J.H. Karsdal M.A. Chapter 7—Type VII Collagen Biochemistry of Collagens, Laminins and Elastin Karsdal M.A. Academic Press Cambridge, MA, USA 2016 57 60 978-0-12-809847-9
  34. [39]Villone D. Fritsch A. Koch M. Bruckner-Tuderman L. Hansen U. Bruckner P. Supramolecular interactions in the dermo-epidermal junction zone: Anchoring fibril-collagen VII tightly binds to banded collagen fibrils J. Biol. Chem. 2008 283 24506 24513 10.1074/jbc.M802415200 18599485 PMC3259843 · DOI
  35. [41]Marinkovich M.P. Keene D.R. Rimberg C.S. Burgeson R.E. Cellular origin of the dermal-epidermal basement membrane Dev. Dyn. Off. Publ. Am. Assoc. Anat. 1993 197 255 267 10.1002/aja.1001970404 8292823 · DOI
  36. [42]Fleischmajer R. Schechter A. Bruns M. Perlish J.S. Macdonald E.D. Pan T.C. Timpl R. Chu M.L. Skin fibroblasts are the only source of nidogen during early basal lamina formation in vitro J. Investig. Dermatol. 1995 105 597 601 10.1111/1523-1747.ep12323604 7561165 · DOI
  37. [43]Oltulu P. Ince B. Kökbudak N. Fındık S. Kiliç F. Measurement of epidermis, dermis, and total skin thicknesses from six different body regions with a new ethical histometric technique Turk Plast. Rekonstr. Ve Estet. Cerrahi Derg. 2018 26 56 61 10.4103/tjps.TJPS_2_17 · DOI
  38. [44]Wong R. Geyer S. Weninger W. Guimberteau J.-C. Wong J.K. The dynamic anatomy and patterning of skin Exp. Dermatol. 2016 25 92 98 10.1111/exd.12832 26284579 · DOI
  39. [45]Zeng Q. Macri L.K. Prasad A. Clark R.A.F. Zeugolis D.I. Hanley C. Garcia Y. Pandit A. Leavesley D.I. Stupar D. 6.20 Skin Tissue Engineering Comprehensive Biomaterials II Ducheyne P. Elsevier Oxford, UK 2017 334 382 978-0-08-100692-4
  40. [46]Reihsner R. Balogh B. Menzel E.J. Two-dimensional elastic properties of human skin in terms of an incremental model at the in vivo configuration Med. Eng. Phys. 1995 17 304 313 10.1016/1350-4533(95)90856-7 7633759 · DOI
  41. [47]Chermnykh E. Kalabusheva E. Vorotelyak E. Extracellular Matrix as a Regulator of Epidermal Stem Cell Fate Int. J. Mol. Sci. 2018 19 1003 10.3390/ijms19041003 29584689 PMC5979429 · DOI · Paper page
  42. [48]Nguyen A.V. Soulika A.M. The dynamics of the skin’s immune system Int. J. Mol. Sci. 2019 20 1811 10.3390/ijms20081811 31013709 PMC6515324 · DOI
  43. [49]Haniffa M. Gunawan M. Jardine L. Human skin dendritic cells in health and disease J. Dermatol. Sci. 2015 77 85 92 10.1016/j.jdermsci.2014.08.012 25301671 PMC4728191 · DOI · Paper page
  44. [50]Krystel-Whittemore M. Dileepan K.N. Wood J.G. Mast cell: A multi-functional master cell Front. Immunol. 2016 6 620 10.3389/fimmu.2015.00620 26779180 PMC4701915 · DOI
  45. [51]Benyon R.C. The human skin mast cell Clin. Exp. Allergy 1989 19 375 387 10.1111/j.1365-2222.1989.tb02402.x 2667702 · DOI
  46. [52]Cruz M.S. Diamond A. Russell A. Jameson J.M. Human αβ and γδ T cells in skin immunity and disease Front. Immunol. 2018 9 1304 10.3389/fimmu.2018.01304 29928283 PMC5997830 · DOI
  47. [54]Klar A.S. Zimoch J. Biedermann T. Skin Tissue Engineering: Application of Adipose-Derived Stem Cells Biomed Res. Int. 2017 2017 9747010 10.1155/2017/9747010 28337463 PMC5350314 · DOI
  48. [55]Ramakrishnan V.M. Boyd N.L. The Adipose Stromal Vascular Fraction as a Complex Cellular Source for Tissue Engineering Applications Tissue Eng. Part B Rev. 2018 24 289 299 10.1089/ten.teb.2017.0061 28316259 PMC6080106 · DOI
  49. [56]Diegel K.L. Danilenko D.M. Wojcinski Z.W. Chapter 24—The Integumentary System Fundamentals of Toxicologic Pathology 3rd ed. Wallig M.A. Haschek W.M. Rousseaux C.G. Bolon B. Academic Press Cambridge, MA, USA 2018 791 822 978-0-12-809841-7
  50. [57]Kershaw E.E. Flier J.S. Adipose tissue as an endocrine organ J. Clin. Endocrinol. Metab. 2004 89 2548 2556 10.1210/jc.2004-0395 15181022 · DOI · Paper page
  51. [58]Prunieras M. Regnier M. Woodley D. Methods for Cultivation of Keratinocytes with an Air-Liquid Interface J. Investig. Dermatol. 1983 81 S28 S33 10.1111/1523-1747.ep12540324 6190962 · DOI · Paper page
  52. [60]Rosdy M. Pisani A. Ortonne J.P. Production of basement membrane components by a reconstructed epidermis cultured in the absence of serum and dermal factors Br. J. Dermatol. 1993 129 227 234 10.1111/j.1365-2133.1993.tb11839.x 8286218 · DOI
  53. [61]Rosdy M. Clauss L.C. Terminal epidermal differentiation of human keratinocytes grown in chemically defined medium on inert filter substrates at the air-liquid interface J. Investig. Dermatol. 1990 95 409 414 10.1111/1523-1747.ep12555510 1698886 · DOI · Paper page
  54. [62]Ponec M. Boelsma E. Weerheim A. Mulder A. Bouwstra J. Mommaas M. Lipid and Ultrastructural Characterization of Reconstructed Skin Models Elsevier Amsterdam, The Netherlands 2000 Volume 203 211 225 10967443
  55. [63]Gazel A. Ramphal P. Rosdy M. De Wever B. Tornier C. Hosein N. Lee B. Tomic-Canic M. Blumenberg M. Transcriptional Profiling of Epidermal Keratinocytes: Comparison of Genes Expressed in Skin, Cultured Keratinocytes, and Reconstituted Epidermis, Using Large DNA Microarrays J. Investig. Dermatol. 2003 121 1459 1468 10.1111/j.1523-1747.2003.12611.x 14675197 · DOI
  56. [64]Sriram G. Lorenz Bigliardi P. Bigliardi-Qi M. Fibroblast heterogeneity and its implications for engineering organotypic skin models in vitro Eur. J. Cell Biol. 2015 94 483 512 10.1016/j.ejcb.2015.08.001 26344860 · DOI
  57. [65]Boehnke K. Mirancea N. Pavesio A. Fusenig N.E. Boukamp P. Stark H.-J.J. Effects of fibroblasts and microenvironment on epidermal regeneration and tissue function in long-term skin equivalents Eur. J. Cell Biol. 2007 86 731 746 10.1016/j.ejcb.2006.12.005 17292509 · DOI
  58. [66]El Ghalbzouri A. Lamme E. Ponec M. Crucial role of fibroblasts in regulating epidermal morphogenesis Cell Tissue Res. 2002 310 189 199 10.1007/s00441-002-0621-0 12397374 · DOI
  59. [67]Michel M. Uheureux N. Pouliot R. Xu W. Auger F.A. Germain L. Characterization of a new tissue-engineered human skin equivalent with hair Vitro Cell. Dev. Biol. Anim. 1999 35 318 326 10.1007/s11626-999-0081-x 10476918 · DOI
  60. [68]Alépée N. Bahinski A. Daneshian M. De Wever B. Fritsche E. Goldberg A. Hansmann J. Hartung T. Haycock J. Hogberg H.T. State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology ALTEX 2014 31 441 477 10.14573/altex1406111 25027500 PMC4783151 · DOI
  61. [69]Mewes K.R. Fischer A. Zöller N.N. Laubach V. Bernd A. Jacobs A. van Rompay A. Liebsch M. Pirow R. Petersohn D. Catch-up validation study of an in vitro skin irritation test method based on an open source reconstructed epidermis (phase I) Toxicol. Vitr. 2016 36 238 253 10.1016/j.tiv.2016.07.007 27432483 · DOI
  62. [70]Groeber F. Schober L. Schmid F.F. Traube A. Kolbus-Hernandez S. Daton K. Hoffmann S. Petersohn D. Schäfer-Korting M. Walles H. Catch-up validation study of an in vitro skin irritation test method based on an open source reconstructed epidermis (phase II) Toxicol. Vitr. 2016 36 254 261 10.1016/j.tiv.2016.07.008 27435616 · DOI
  63. [71]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 296 203 211 10.1007/s00403-004-0507-y 15349789 · DOI
  64. [72]Liu Y. Suwa F. Wang X. Takemura A. Fang Y.R. Li Y. Zhao Y. Jin Y. Reconstruction of a tissue-engineered skin containing melanocytes Cell Biol. Int. 2007 31 985 990 10.1016/j.cellbi.2007.03.009 17467308 · DOI
  65. [73]Schmid F. Groeber-Becker F. Schwab S. Thude S. Goebeler M. Walles H. Hansmann J. A standardized method based on pigmented epidermal models evaluates sensitivity against UV-irradiation ALTEX 2018 35 390 396 10.14573/altex.1712211 29697852 · DOI
  66. [74]Lee J.H. Kim J.E. Kim B.J. Cho K.H. In vitro phototoxicity test using artificial skin with melanocytes Photodermatol. Photoimmunol. Photomed. 2007 23 73 80 10.1111/j.1600-0781.2007.00279.x 17523928 · DOI
  67. [75]Contard P. Bartel R.L. Jacobs L. Perlish J.S. MacDonald E.D. Handler L. Cone D. Fleischmajer R. Culturing Keratinocytes and Fibroblasts in a Three-Dimensional Mesh Results in Epidermal Differentiation and Formation of a Basal Lamina-Anchoring Zone J. Investig. Dermatol. 1993 100 35 39 10.1111/1523-1747.ep12349952 8423391 · DOI
  68. [76]El Ghalbzouri A. Jonkman M.F. Dijkman R. Ponec M. Basement Membrane Reconstruction in Human Skin Equivalents Is Regulated by Fibroblasts and/or Exogenously Activated Keratinocytes J. Investig. Dermatol. 2005 124 79 86 10.1111/j.0022-202X.2004.23549.x 15654956 · DOI
  69. [77]Parenteau-Bareil R. Gauvin R. Berthod F. Collagen-based biomaterials for tissue engineering applications Materials 2010 3 1863 1887 10.3390/ma3031863 · DOI
  70. [78]Sarrigiannidis S.O. Rey J.M. Dobre O. González-García C. Dalby M.J. Salmeron-Sanchez M. A tough act to follow: Collagen hydrogel modifications to improve mechanical and growth factor loading capabilities Mater. Today Bio 2021 10 100098 10.1016/j.mtbio.2021.100098 PMC7973388 33763641 · DOI
  71. [79]Randall M.J. Jüngel A. Rimann M. Wuertz-Kozak K. Advances in the Biofabrication of 3D Skin in vitro: Healthy and Pathological Models Front. Bioeng. Biotechnol. 2018 6 154 10.3389/fbioe.2018.00154 30430109 PMC6220074 · DOI
  72. [80]Vidal S.E.L. Tamamoto K.A. Nguyen H. Abbott R.D. Cairns D.M. Kaplan D.L. 3D biomaterial matrix to support long term, full thickness, immuno-competent human skin equivalents with nervous system components Biomaterials 2019 198 194 203 10.1016/j.biomaterials.2018.04.044 29709325 PMC6200656 · DOI
  73. [81]Bellas E. Seiberg M. Garlick J. Kaplan D.L. In Vitro 3D Full-Thickness Skin-Equivalent Tissue Model Using Silk and Collagen Biomaterials Macromol. Biosci. 2012 12 1627 1636 10.1002/mabi.201200262 23161763 PMC3724336 · DOI
  74. [82]Gil E.S. Panilaitis B. Bellas E. Kaplan D.L. Functionalized Silk Biomaterials for Wound Healing Adv. Healthc. Mater. 2013 2 206 217 10.1002/adhm.201200192 23184644 PMC3735446 · DOI
  75. [83]Rosa E. Diaferia C. Gianolio E. Sibillano T. Gallo E. Smaldone G. Stornaiuolo M. Giannini C. Morelli G. Accardo A. Multicomponent Hydrogel Matrices of Fmoc-FF and Cationic Peptides for Application in Tissue Engineering Macromol. Biosci. 2022 22 2200128 10.1002/mabi.202200128 35524744 · DOI
  76. [84]Arab W.T. Susapto H.H. Alhattab D. Hauser C.A.E. Peptide nanogels as a scaffold for fabricating dermal grafts and 3D vascularized skin models J. Tissue Eng. 2022 13 20417314221111868 10.1177/20417314221111868 35923174 PMC9340315 · DOI
  77. [85]Bergers L.I.J.C. Reijnders C.M.A. Van Den Broek L.J. Spiekstra S.W. De Gruijl T.D. Weijers E.M. Gibbs S. Immune-competent human skin disease models Drug Discov. Today 2016 21 1479 1488 10.1016/j.drudis.2016.05.008 27265772 · DOI
  78. [86]Pupovac A. Senturk B. Griffoni C. Maniura-Weber K. Rottmar M. McArthur S.L. Toward Immunocompetent 3D Skin Models Adv. Healthc. Mater. 2018 7 1701405 10.1002/adhm.201701405 29542274 · DOI
  79. [87]Ouwehand K. Spiekstra S.W. Waaijman T. Scheper R.J. de Gruijl T.D. Gibbs S. Technical Advance: Langerhans cells derived from a human cell line in a full-thickness skin equivalent undergo allergen-induced maturation and migration J. Leukoc. Biol. 2011 90 1027 1033 10.1189/jlb.0610374 21697260 · DOI
  80. [88]Kühbacher A. Henkel H. Stevens P. Grumaz C. Finkelmeier D. Burger-Kentischer A. Sohn K. Rupp S. Central Role for Dermal Fibroblasts in Skin Model Protection against Candida albicans J. Infect. Dis. 2017 215 1742 1752 10.1093/infdis/jix153 28368492 · DOI
  81. [89]Chau D.Y.S. Johnson C. Macneil S. Haycock J.W. Ghaemmaghami A.M. The development of a 3D immunocompetent model of human skin Biofabrication 2013 5 035011 10.1088/1758-5082/5/3/035011 23880658 · DOI
  82. [90]Bechetoille N. Dezutter-Dambuyant C. Damour O. André V. Orly I. Perrier E. Effects of Solar Ultraviolet Radiation on Engineered Human Skin Equivalent Containing Both Langerhans Cells and Dermal Dendritic Cells Tissue Eng. 2007 13 2667 2679 10.1089/ten.2006.0405 17883323 · DOI
  83. [91]Schellenberger M.T. Bock U. Hennen J. Groeber-Becker F. Walles H. Blömeke B. A coculture system composed of THP-1 cells and 3D reconstructed human epidermis to assess activation of dendritic cells by sensitizing chemicals after topical exposure Toxicol. Vitr. 2019 57 62 66 10.1016/j.tiv.2019.02.002 30771472 · DOI
  84. [92]Griffoni C. Neidhart B. Yang K. Groeber-Becker F. Maniura-Weber K. Dandekar T. Walles H. Rottmar M. In vitro skin culture media influence the viability and inflammatory response of primary macrophages Sci. Rep. 2021 11 7070 10.1038/s41598-021-86486-7 33782484 PMC8007571 · DOI
  85. [93]Black A.F. Berthod F. L’Heureux N. Germain L. Auger F.A. In vitro reconstruction of a human capillary-like network in a tissue-engineered skin equivalent FASEB J. 1998 12 1331 1340 10.1096/fasebj.12.13.1331 9761776 · DOI
  86. [94]Ponec M. El Ghalbzouri A. Dijkman R. Kempenaar J. Van Der Pluijm G. Koolwijk P. Endothelial network formed with human dermal microvascular endothelial cells in autologous multicellular skin substitutes Angiogenesis 2004 7 295 305 10.1007/s10456-004-6315-3 15886873 · DOI
  87. [95]Frueh F.S. Später T. Lindenblatt N. Calcagni M. Giovanoli P. Scheuer C. Menger M.D. Laschke M.W. Adipose Tissue-Derived Microvascular Fragments Improve Vascularization, Lymphangiogenesis, and Integration of Dermal Skin Substitutes J. Investig. Dermatol. 2017 137 217 227 10.1016/j.jid.2016.08.010 27574793 · DOI
  88. [96]Frueh F.S. Später T. Körbel C. Scheuer C. Simson A.C. Lindenblatt N. Giovanoli P. Menger M.D. Laschke M.W. Prevascularization of dermal substitutes with adipose tissue-derived microvascular fragments enhances early skin grafting Sci. Rep. 2018 8 10977 10.1038/s41598-018-29252-6 30030486 PMC6054621 · DOI
  89. [97]Matei A.E. Chen C.W. Kiesewetter L. Györfi A.H. Li Y.N. Trinh-Minh T. Xu X. Tran Manh C. Van Kuppevelt T. Hansmann J. Vascularised human skin equivalents as a novel in vitro model of skin fibrosis and platform for testing of antifibrotic drugs Ann. Rheum. Dis. 2019 78 1686 1692 10.1136/annrheumdis-2019-216108 31540936 · DOI
  90. [98]Abaci H.E. Guo Z. Coffman A. Gillette B. Lee W.H. Sia S.K. Christiano A.M. Human Skin Constructs with Spatially Controlled Vasculature Using Primary and iPSC-Derived Endothelial Cells Adv. Healthc. Mater. 2016 5 1800 1807 10.1002/adhm.201500936 27333469 PMC5031081 · DOI
  91. [99]Ng W.L. Wang S. Yeong W.Y. Naing M.W. Skin Bioprinting: Impending Reality or Fantasy? Trends Biotechnol. 2016 34 689 699 10.1016/j.tibtech.2016.04.006 27167724 · DOI
  92. [100]Roggenkamp D. Köpnick S. Stäb F. Wenck H. Schmelz M. Neufang G. Epidermal Nerve Fibers Modulate Keratinocyte Growth via Neuropeptide Signaling in an Innervated Skin Model J. Investig. Dermatol. 2013 133 1620 1628 10.1038/jid.2012.464 23283070 · DOI
  93. [101]Blais M. Mottier L. Germain M.-A. Bellenfant S. Cadau S. Berthod F. Sensory Neurons Accelerate Skin Reepithelialization via Substance P in an Innervated Tissue-Engineered Wound Healing Model Tissue Eng. Part A 2014 20 2180 2188 10.1089/ten.tea.2013.0535 24716723 PMC4137331 · DOI
  94. [102]Cairns D.M. Chwalek K. Moore Y.E. Kelley M.R. Abbott R.D. Moss S. Kaplan D.L. Expandable and Rapidly Differentiating Human Induced Neural Stem Cell Lines for Multiple Tissue Engineering Applications Stem. Cell Rep. 2016 7 557 570 10.1016/j.stemcr.2016.07.017 27569063 PMC5032182 · DOI
  95. [103]Choi J.H. Gimble J.M. Lee K. Marra K.G. Rubin J.P. Yoo J.J. Vunjak-Novakovic G. Kaplan D.L. Adipose tissue engineering for soft tissue regeneration Tissue Eng. Part B Rev. 2010 16 413 426 10.1089/ten.teb.2009.0544 20166810 PMC2946881 · DOI
  96. [104]Asuku M. Yu T.-C. Yan Q. Böing E. Hahn H. Hovland S. Donelan M.B. Split-thickness skin graft donor-site morbidity: A systematic literature review Burns 2021 47 1525 1546 10.1016/j.burns.2021.02.014 33781633 · DOI
  97. [105]Pereira R.F. Sousa A. Barrias C.C. Bayat A. Granja P.L. Bártolo P.J. Advances in bioprinted cell-laden hydrogels for skin tissue engineering Biomanuf. Rev. 2017 2 1 26 10.1007/s40898-017-0003-8 · DOI
  98. [106]Trottier V. Marceau-Fortier G. Germain L. Vincent C. Fradette J. IFATS Collection: Using Human Adipose-Derived Stem/Stromal Cells for the Production of New Skin Substitutes Stem Cells 2008 26 2713 2723 10.1634/stemcells.2008-0031 18617689 · DOI
  99. [107]Monfort A. Soriano-Navarro M. García-Verdugo J.M. Izeta A. Production of human tissue-engineered skin trilayer on a plasma-based hypodermis J. Tissue Eng. Regen. Med. 2013 7 479 490 10.1002/term.548 22294482 · DOI
  100. [108]von Heimburg D. Hemmrich K. Zachariah S. Staiger H. Pallua N. Oxygen consumption in undifferentiated versus differentiated adipogenic mesenchymal precursor cells Respir. Physiol. Neurobiol. 2005 146 107 116 10.1016/j.resp.2004.12.013 15766899 · DOI
  101. [109]Gimble J.M. Katz A.J. Bunnell B.A. Adipose-derived stem cells for regenerative medicine Circ. Res. 2007 100 1249 1260 10.1161/01.RES.0000265074.83288.09 17495232 PMC5679280 · DOI · Paper page
  102. [110]Satija N.K. Gurudutta G.U. Sharma S. Afrin F. Gupta P. Verma Y.K. Singh V.K. Tripathi R.P. Mesenchymal stem cells: Molecular targets for tissue engineering Stem Cells Dev. 2007 16 7 23 10.1089/scd.2006.9998 17348802 · DOI
  103. [111]Huber B. Link A. Linke K. Gehrke S.A. Winnefeld M. Kluger P.J. Integration of Mature Adipocytes to Build-Up a Functional Three-Layered Full-Skin Equivalent Tissue Eng.—Part C Methods 2016 22 756 764 10.1089/ten.tec.2016.0141 27334067 PMC4991605 · DOI
  104. [112]Huber B. Kluger P.J. Decelerating Mature Adipocyte Dedifferentiation by Media Composition Tissue Eng. Part C Methods 2015 21 1237 1245 10.1089/ten.tec.2015.0166 26228997 · DOI
  105. [113]Huber B. Borchers K. Tovar G.E.M. Kluger P.J. Methacrylated gelatin and mature adipocytes are promising components for adipose tissue engineering J. Biomater. Appl. 2015 30 699 710 10.1177/0885328215587450 26017717 · DOI
  106. [114]Kober J. Gugerell A. Schmid M. Kamolz L.P. Keck M. Generation of a Fibrin Based Three-Layered Skin Substitute Biomed Res. Int. 2015 2015 170427 10.1155/2015/170427 26236715 PMC4508374 · DOI
  107. [115]Ataç B. Wagner I. Horland R. Lauster R. Marx U. Tonevitsky A.G. Azar R.P. Lindner G. Skin and hair on-a-chip: In vitro skin models versus ex vivo tissue maintenance with dynamic perfusion Lab. Chip 2013 13 3555 3561 10.1039/c3lc50227a 23674126 · DOI
  108. [116]Ojeh N. Pastar I. Tomic-Canic M. Stojadinovic O. Stem cells in skin regeneration, wound healing, and their clinical applications Int. J. Mol. Sci. 2015 16 25476 25501 10.3390/ijms161025476 26512657 PMC4632811 · DOI
  109. [117]Langan E.A. Philpott M.P. Kloepper J.E. Paus R. Human hair follicle organ culture: Theory, application and perspectiDes Exp. Dermatol. 2015 24 200 215 10.1111/exd.12836 26284830 · DOI
  110. [118]Ghetti M. Topouzi H. Theocharidis G. Papa V. Williams G. Bondioli E. Cenacchi G. Connelly J.T. Higgins C.A. Subpopulations of dermal skin fibroblasts secrete distinct extracellular matrix: Implications for using skin substitutes in the clinic Br. J. Dermatol. 2018 179 381 393 10.1111/bjd.16255 29266210 PMC6175479 · DOI
  111. [119]Higgins C.A. Chen J.C. Cerise J.E. Jahoda C.A.B. Christiano A.M. Microenvironmental reprogramming by threedimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth Proc. Natl. Acad. Sci. USA 2013 110 19679 19688 10.1073/pnas.1309970110 24145441 PMC3856847 · DOI
  112. [120]Topouzi H. Logan N.J. Williams G. Higgins C.A. Claire Higgins C.A. Methods for the isolation and 3D culture of dermal papilla cells from human hair follicles Exp. Dermatol. 2017 26 491 496 10.1111/exd.13368 28418608 PMC5519926 · DOI
  113. [121]Abaci H.E. Guo Z. Doucet Y. Jacków J. Christiano A. Next generation human skin constructs as advanced tools for drug development Exp. Biol. Med. 2017 242 1657 1668 10.1177/1535370217712690 PMC5786367 28592171 · DOI · Paper page
  114. [122]Abaci H.E. Coffman A. Doucet Y. Chen J. Jacków J. Wang E. Guo Z. Shin J.U. Jahoda C.A. Christiano A.M. Tissue engineering of human hair follicles using a biomimetic developmental approach Nat. Commun. 2018 9 5301 10.1038/s41467-018-07579-y 30546011 PMC6294003 · DOI · Paper page
  115. [123]Matai I. Kaur G. Seyedsalehi A. McClinton A. Laurencin C.T. Progress in 3D bioprinting technology for tissue/organ regenerative engineering Biomaterials 2020 226 10.1016/j.biomaterials.2019.119536 31648135 · DOI · Paper page
  116. [124]Murphy S.V. Atala A. 3D bioprinting of tissues and organs Nat. Biotechnol. 2014 32 773 785 10.1038/nbt.2958 25093879 · DOI · Paper page
  117. [125]Lee W. Debasitis J.C. Lee V.K. Lee J.H. Fischer K. Edminster K. Park J.K. Yoo S.S. Multi-layered culture of human skin fibroblasts and keratinocytes through three-dimensional freeform fabrication Biomaterials 2009 30 1587 1595 10.1016/j.biomaterials.2008.12.009 19108884 · DOI
  118. [126]Koch L. Kuhn S. Sorg H. Gruene M. Schlie S. Gaebel R. Polchow B. Reimers K. Stoelting S. Ma N. Laser Printing of Skin Cells and Human Stem Cells Tissue Eng. Part C Methods 2009 16 847 854 10.1089/ten.tec.2009.0397 19883209 · DOI
  119. [127]Olejnik A. Semba J.A. Kulpa A. Dańczak-Pazdrowska A. Rybka J.D. Gornowicz-Porowska J. 3D Bioprinting in Skin Related Research: Recent Achievements and Application Perspectives ACS Synth. Biol. 2022 11 26 38 10.1021/acssynbio.1c00547 34967598 PMC8787816 · DOI
  120. [128]Manita P.G. Garcia-orue I. Santos-vizcaino E. Hernandez R.M. Igartua M. 3D Bioprinting of Functional Skin Substitutes: From Current Achievements to Future Goals Pharmaceuticals 2021 14 362 10.3390/ph14040362 33919848 PMC8070826 · DOI
  121. [130]Lee V. Singh G. Trasatti J.P. Bjornsson C. Xu X. Tran T.N. Yoo S.S. Dai G. Karande P. Design and Fabrication of Human Skin by Three-Dimensional Bioprinting Tissue Eng. Part C Methods 2014 20 473 10.1089/ten.tec.2013.0335 24188635 PMC4024844 · DOI
  122. [131]Ashammakhi N. Ahadian S. Xu C. Montazerian H. Ko H. Nasiri R. Barros N. Khademhosseini A. Bioinks and bioprinting technologies to make heterogeneous and biomimetic tissue constructs Mater. Today Bio. 2019 1 100008 10.1016/j.mtbio.2019.100008 PMC7061634 32159140 · DOI · Paper page
  123. [132]Velasco D. Quílez C. Garcia M. del Cañizo J.F. Jorcano J.L. 3D human skin bioprinting: A view from the bio side J. 3D Print. Med. 2018 2 141 162 10.2217/3dp-2018-0008 · DOI
  124. [133]Parak A. Pradeep P. du Toit L.C. Kumar P. Choonara Y.E. Pillay V. Functionalizing bioinks for 3D bioprinting applications Drug Discov. Today 2019 24 198 205 10.1016/j.drudis.2018.09.012 30244080 · DOI
  125. [134]Williams D. Thayer P. Martinez H. Gatenholm E. Khademhosseini A. A perspective on the physical, mechanical and biological specifications of bioinks and the development of functional tissues in 3D bioprinting Bioprinting 2018 9 19 36 10.1016/j.bprint.2018.02.003 · DOI
  126. [135]Gopinathan J. Noh I. Recent trends in bioinks for 3D printing Biomater. Res. 2018 22 11 10.1186/s40824-018-0122-1 29636985 PMC5889544 · DOI
  127. [136]Perez-Valle A. Del Amo C. Andia I. Overview of Current Advances in Extrusion Bioprinting for Skin Applications Int. J. Mol. Sci. 2020 21 6679 10.3390/ijms21186679 32932676 PMC7555324 · DOI
  128. [137]Kim B.S. Gao G. Kim J.Y. Cho D. 3D Cell Printing of Perfusable Vascularized Human Skin Equivalent Composed of Epidermis, Dermis, and Hypodermis for Better Structural Recapitulation of Native Skin Adv. Healthc. Mater. 2019 8 1801019 10.1002/adhm.201801019 30358939 · DOI
  129. [138]Baltazar T. Merola J. Catarino C. Xie C.B. Kirkiles-Smith N.C. Lee V. Hotta S. Dai G. Xu X. Ferreira F.C. Three Dimensional Bioprinting of a Vascularized and Perfusable Skin Graft Using Human Keratinocytes, Fibroblasts, Pericytes, and Endothelial Cells Tissue Eng. Part A 2020 26 227 10.1089/ten.tea.2019.0201 31672103 PMC7476394 · DOI
  130. [139]Liu X. Michael S. Bharti K. Ferrer M. Song M.J. A biofabricated vascularized skin model of atopic dermatitis for preclinical studies Biofabrication 2020 12 035002 10.1088/1758-5090/ab76a1 32059197 PMC7457159 · DOI
  131. [140]Groeber F. Engelhardt L. Lange J. Kurdyn S. Schmid F.F. Rücker C. Mielke S. Walles H. Hansmann J. A first vascularized skin equivalent for as an alternative to animal experimentation ALTEX 2016 33 415 422 10.14573/altex.1604041 27180196 · DOI

Authors
Hofmann, E., Schwarz, A., Fink, J., Kamolz, L.-P., & Kotzbeck, P.
Affiliations
Joanneum Research (AT)
Corresponding author
Kotzbeck, Petra
ORCID
Venue
Biomedicines
Publisher
MDPI AG
Published
2023-03-06
Volume
11
Issue
3
Pages
794
ISSN
2227-9059 (ISSN-L)
DOI
10.3390/biomedicines11030794
PMC
PMC10045055
OpenAlex
W4323311400
Cited by
129
References
132
Citations by year
2026: 38 · 2025: 50 · 2024: 34 · 2023: 7
FWCI
4.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomedicines (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Austrian Federal Ministry of Climate Action, Environment, Energy, Mobility, Innovation and Technology (BMVIT-612.018/0016-lll/I1/2018-Tec.Reg, 888162, 880618)
  • Austrian Research Promotion Agency (BMVIT-612.018/0016-lll/I1/2018-Tec.Reg, 888162, 880618)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
Keywords
human skin, in vitro skin model, reconstructed epidermis, skin barrier function, skin anatomy, skin diseases, alternatives to animal testing

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