293
Views
0
CrossRef citations to date
0
Altmetric
Review

Recent advances in in vitro skin-on-a-chip models for drug testing

&
Pages 249-267 | Received 13 Mar 2023, Accepted 15 Jun 2023, Published online: 10 Jul 2023

References

  • Bensouilah J, Buck P. Aromadermatology : aromatherapy in the treatment and care of common skin conditions 1st. ed. London: Routledge; 2021. English. doi: 10.4324/9781785230974-1
  • Seth D, Cheldize K, Brown D, et al. Global Burden of skin disease: inequities and innovations. Curr Dermatol Rep. 2017 Sep;6(3):204–210. PubMed PMID: 29226027; PubMed Central PMCID: PMCPMC5718374. doi: 10.1007/s13671-017-0192-7
  • Chu S, Mehrmal S, Uppal P, et al. Burden of skin disease and associated socioeconomic status in Europe: an ecologic study from the Global Burden of Disease Study 2017. JAAD Int. 2020 Dec;1(2):95–103. PubMed PMID: 34409328; PubMed Central PMCID: PMCPMC8361890. doi: 10.1016/j.jdin.2020.07.001.
  • Jeong WY, Kwon M, Choi HE, et al. Recent advances in transdermal drug delivery systems: a review. Biomater Res. 2021 Jul 28;25(1):24. PubMed PMID: 34321111; PubMed Central PMCID: PMCPMC8317283. doi: 10.1186/s40824-021-00226-6
  • Randall MJ, Jungel A, Rimann M, et al. Advances in the biofabrication of 3D skin in vitro: healthy and pathological models. Front Bioeng Biotechnol. 2018;6:154. PubMed PMID: 30430109; PubMed Central PMCID: PMCPMC6220074. doi: 10.3389/fbioe.2018.00154
  • Amelian A, Wasilewska K, Megias D, et al. Application of standard cell cultures and 3D in vitro tissue models as an effective tool in drug design and development. Pharmacol Rep. 2017 Oct;69(5):861–870. PubMed PMID: 28623710. doi: 10.1016/j.pharep.2017.03.014.
  • Jensen C, Teng Y. Is it time to start transitioning from 2D to 3D cell culture? Front Mol Biosci. 2020;7:33. PubMed PMID: 32211418; PubMed Central PMCID: PMCPMC7067892. doi: 10.3389/fmolb.2020.00033
  • Moniz T, Costa Lima SA, Reis S. Human skin models: from healthy to disease-mimetic systems; characteristics and applications. Br J Pharmacol. 2020 Oct;177(19):4314–4329. PubMed PMID: 32608012; PubMed Central PMCID: PMCPMC7484561. doi: 10.1111/bph.15184.
  • Cubo N, Garcia M, Del Canizo JF, et al. 3D bioprinting of functional human skin: production and in vivo analysis. Biofabrication. 2016 Dec 5;9(1):015006. PubMed PMID: 27917823. doi: 10.1088/1758-5090/9/1/015006
  • Monfort A, Soriano-Navarro M, Garcia-Verdugo JM, et al. Production of human tissue-engineered skin trilayer on a plasma-based hypodermis. J Tissue Eng Regen Med. 2013 Jun;7(6):479–490. PubMed PMID: 22294482. doi: 10.1002/term.548
  • Lee S, Jin SP, Kim YK, et al. Construction of 3D multicellular microfluidic chip for an in vitro skin model. Biomed Microdevices. 2017 Jun;19(2):22. PubMed PMID: 28374277. doi: 10.1007/s10544-017-0156-5
  • Sung JH, Wang YI, Narasimhan Sriram N, et al. Recent advances in body-on-a-chip systems. Anal Chem. 2019 Jan 2;91(1):330–351. PubMed PMID: 30472828; PubMed Central PMCID: PMCPMC6687466. doi: 10.1021/acs.analchem.8b05293.
  • Ingber DE. Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat Rev Genet. 2022 Aug;23(8):467–491. PubMed PMID: 35338360; PubMed Central PMCID: PMCPMC8951665. doi: 10.1038/s41576-022-00466-9
  • Lee SH, Sung JH. Organ-on-a-chip technology for reproducing multiorgan physiology. Adv Healthc Mater. 2018 Jan;7(2). PubMed PMID: 28945001. doi: 10.1002/adhm.201700419
  • Dragicevic N, Maibach HI. Percutaneous penetration enhancers chemical methods in penetration enhancement : drug manipulation strategies and vehicle effects. Berlin Heidelberg: Springer Berlin Heidelberg : Imprint: Springer; 2015. doi: 10.1007/978-3-662-45013-0
  • Betts JG, Desaix P, Johnson E, et al. Anatomy & physiology. Houston (TX): OpenStax College, Rice University;2013. English.
  • Perugini P, Grignani C, Condro G, et al. Skin microbiota: setting up a protocol to evaluate a correlation between the microbial flora and skin parameters. Biomedicines. 2023 Mar;11(3). PubMed PMID: WOS:000954775600001; English. doi: 10.3390/biomedicines11030966.
  • Sander MA, Sander MS, Isaac-Renton JL, et al. The cutaneous microbiome: implications for dermatology practice. J Cutan Med Surg. 2019 Jul;23(4):436–441. PubMed PMID: 30938174. doi: 10.1177/1203475419839939
  • Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Nat Rev Microbiol. 2018 Mar;16(3):143–155. PubMed PMID: 29332945. doi: 10.1038/nrmicro.2017.157
  • Russo E, Di Gloria L, Cerboneschi M, et al. Facial skin microbiome: aging-related changes and exploratory functional associations with host genetic factors, a pilot study. Biomedicines. 2023 Feb 23;11(3). PubMed PMID: 36979663; PubMed Central PMCID: PMCPMC10045008. doi: 10.3390/biomedicines11030684
  • Hussain SH, Limthongkul B, Humphreys TR. The biomechanical properties of the skin. Dermatol Surg. 2013 Feb;39(2):193–203. PubMed PMID: 23350638. doi: 10.1111/dsu.12095.
  • Abaci HE, Guo Z, Doucet Y, et al. Next generation human skin constructs as advanced tools for drug development. Exp Biol Med (Maywood). 2017 Nov;242(17):1657–1668. PubMed PMID: 28592171; PubMed Central PMCID: PMCPMC5786367. doi: 10.1177/1535370217712690
  • van der Krieken DA, Ederveen TH, van Hijum SA, et al. An in vitro model for bacterial growth on human stratum corneum. Acta Derm Venereol. 2016 Nov 2;96(7):873–879. PubMed PMID: 26976779. doi: 10.2340/00015555-2401
  • Hay RJ, Johns NE, Williams HC, et al. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Invest Dermatol. 2014 Jun;134(6):1527–1534. PubMed PMID: 24166134. doi: 10.1038/jid.2013.446.
  • Singhvi G, Manchanda P, Krishna Rapalli V, et al. MicroRNAs as biological regulators in skin disorders. Biomed Pharmacother. 2018 Dec;108:996–1004. PubMed PMID: 30372911. doi: 10.1016/j.biopha.2018.09.090
  • Soliman AM, Das S, Abd Ghafar N, et al. Role of MicroRNA in proliferation phase of wound healing. Front Genet. 2018;9:38. PubMed PMID: 29491883; PubMed Central PMCID: PMCPMC5817091. doi: 10.3389/fgene.2018.00038
  • Cheng F, Shen Y, Mohanasundaram P, et al. Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-beta-Slug signaling. Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):E4320–7. PubMed PMID: 27466403; PubMed Central PMCID: PMCPMC4968728. doi: 10.1073/pnas.1519197113.
  • Heun Y, Pogoda K, Anton M, et al. HIF-1alpha dependent wound healing angiogenesis in vivo can be controlled by site-specific lentiviral magnetic targeting of SHP-2. Mol Ther. 2017 Jul 5;25(7):1616–1627. PubMed PMID: 28434868; PubMed Central PMCID: PMCPMC5498815. doi: 10.1016/j.ymthe.2017.04.007.
  • Young A, McNaught C-E. The physiology of wound healing. Surgery. 2011;29(10):475–479. doi: 10.1016/j.mpsur.2011.06.011
  • Sahah AL, Sanaa ET, Raysa MS. Genetic association of the COL1A1 gene promoter -1997 G/T (rs1107946) andSp1 +1245 G/T (rs1800012) polymorphisms and keloid scars in a Jeddah population. Turk J Med Sci. 2016 Feb 17;46(2):414–423. PubMed PMID: 27511505. doi: 10.3906/sag-1412-41
  • Tao H, Berno AJ, Cox DR, et al. In vitro human keratinocyte migration rates are associated with SNPs in the KRT1 interval. PLoS One. 2007 Aug 1;2(8):e697. PubMed PMID: 17668073; PubMed Central PMCID: PMCPMC1933256. doi: 10.1371/journal.pone.0000697.
  • Bindschadler M, McGrath JL. Sheet migration by wounded monolayers as an emergent property of single-cell dynamics. J Cell Sci. 2007 Mar 1;120(Pt 5): 876–884. PubMed PMID: 17298977. doi: 10.1242/jcs.03395
  • Wang Z, Wang Y, Farhangfar F, et al. Enhanced keratinocyte proliferation and migration in co-culture with fibroblasts. PLoS One. 2012;7(7):e40951. PubMed PMID: 22911722; PubMed Central PMCID: PMCPMC3401236. doi: 10.1371/journal.pone.0040951
  • Iyer K, Chen Z, Ganapa T, et al. Keratinocyte migration in a three-dimensional in vitro wound healing model co-cultured with fibroblasts. Tissue Eng Regen Med. 2018 Dec;15(6):721–733. PubMed PMID: 30603591; PubMed Central PMCID: PMCPMC6250652. doi: 10.1007/s13770-018-0145-7
  • Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017 Oct 7;390(10103): 1685–1699. PubMed PMID: 28413064. doi: 10.1016/S0140-6736(17)30933-9
  • Maurer B, Stanczyk J, Jungel A, et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 2010 Jun;62(6):1733–1743. PubMed PMID: 20201077. doi: 10.1002/art.27443.
  • Clark RA, McCoy GA, Folkvord JM, et al. TGF-beta 1 stimulates cultured human fibroblasts to proliferate and produce tissue-like fibroplasia: a fibronectin matrix-dependent event. J Cell Physiol. 1997 Jan;170(1):69–80. PubMed PMID: 9012786. doi: 10.1002/(SICI)1097-4652(199701)170:1<69:AID-JCP8>3.0.CO;2-J
  • Abraham DJ, Varga J. Scleroderma: from cell and molecular mechanisms to disease models. Trends Immunol. 2005 Nov;26(11):587–595. PubMed PMID: 16168711. doi: 10.1016/j.it.2005.09.004.
  • De Pieri A, Korman BD, Jungel A, et al. Engineering advanced in vitro models of systemic sclerosis for drug discovery and development. Adv Biol (Weinh). 2021 Apr;5(4):e2000168. PubMed PMID: 33852183; PubMed Central PMCID: PMCPMC8717409. doi: 10.1002/adbi.202000168.
  • Sarama R, Matharu PK, Abduldaiem Y, et al. In Vitro disease models for understanding psoriasis and atopic dermatitis. Front Bioeng Biotechnol. 2022;10:803218. PubMed PMID: 35265594; PubMed Central PMCID: PMCPMC8899215. doi: 10.3389/fbioe.2022.803218
  • Chiricozzi A, Nograles KE, Johnson-Huang LM, et al. IL-17 induces an expanded range of downstream genes in reconstituted human epidermis model. PLoS One. 2014;9(2):e90284. PubMed PMID: 24587313; PubMed Central PMCID: PMCPMC3938679. doi: 10.1371/journal.pone.0090284
  • Tjabringa G, Bergers M, van Rens D, et al. Development and validation of human psoriatic skin equivalents. Am J Pathol. 2008 Sep;173(3):815–823. PubMed PMID: 18669614; PubMed Central PMCID: PMCPMC2527086. doi: 10.2353/ajpath.2008.080173.
  • Pendaries V, Malaisse J, Pellerin L, et al. Knockdown of filaggrin in a three-dimensional reconstructed human epidermis impairs keratinocyte differentiation. J Invest Dermatol. 2014 Dec;134(12):2938–2946. PubMed PMID: 24940654. doi: 10.1038/jid.2014.259.
  • Engelhart K, El Hindi T, Biesalski HK, et al. In vitro reproduction of clinical hallmarks of eczematous dermatitis in organotypic skin models. Arch Dermatol Res. 2005 Jul;297(1):1–9. PubMed PMID: 15952007. doi: 10.1007/s00403-005-0575-7
  • Odashiro AN, Pereira PR, Marshall J-C, et al. Skin cancer models. Drug Discov Today. 2005;2(1):71–75. doi: 10.1016/j.ddmod.2005.05.011
  • Marconi A, Quadri M, Saltari A, et al. Progress in melanoma modelling in vitro. Exp Dermatol. 2018 May;27(5):578–586. PubMed PMID: 29697862. doi: 10.1111/exd.13670
  • Mohapatra S, Coppola D, Riker AI, et al. Roscovitine inhibits differentiation and invasion in a three-dimensional skin reconstruction model of metastatic melanoma. Mol Cancer Res. 2007 Feb;5(2):145–151. PubMed PMID: 17314272. doi: 10.1158/1541-7786.MCR-06-0300.
  • Commandeur S, van Drongelen V, de Gruijl FR, et al. Epidermal growth factor receptor activation and inhibition in 3D in vitro models of normal skin and human cutaneous squamous cell carcinoma. Cancer Sci. 2012 Dec;103(12):2120–2126. PubMed PMID: 22974223; PubMed Central PMCID: PMCPMC7659285. doi: 10.1111/cas.12026
  • Lee HR, Sung JH. Multiorgan-on-a-chip for realization of gut-skin axis. Biotechnol Bioeng. 2022 Sep;119(9):2590–2601. PubMed PMID: 35750599. doi: 10.1002/bit.28164.
  • Kwak BS, Jin SP, Kim SJ, et al. Microfluidic skin chip with vasculature for recapitulating the immune response of the skin tissue. Biotechnol Bioeng. 2020 Jun;117(6):1853–1863. PubMed PMID: 32100875. doi: 10.1002/bit.27320.
  • van de Kerkhof EG, de Graaf IA, Groothuis GM. In vitro methods to study intestinal drug metabolism. Curr Drug Metab. 2007 Oct;8(7):658–675. PubMed PMID: 17979654. doi: 10.2174/138920007782109742
  • Baron JM, Merk HF. Drug metabolism in the skin. Curr Opin Allergy Clin Immunol. 2001 Aug;1(4):287–291. PubMed PMID: 11964702. doi: 10.1097/01.all.0000011028.08297.b3.
  • Fan PW, Zhang D, Halladay JS, et al. Going beyond common drug metabolizing enzymes: case studies of biotransformation involving aldehyde oxidase, gamma-glutamyl transpeptidase, cathepsin B, flavin-containing monooxygenase, and ADP-Ribosyltransferase. Drug Metab Dispos. 2016 Aug;44(8):1253–1261. PubMed PMID: 27117704. doi: 10.1124/dmd.116.070169.
  • Jancova P, Anzenbacher P, Anzenbacherova E. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010 Jun;154(2):103–116. PubMed PMID: 20668491. doi: 10.5507/bp.2010.017
  • Kazem S, Linssen EC, Gibbs S. Skin metabolism phase I and phase II enzymes in native and reconstructed human skin: a short review. Drug Discov Today. 2019 Sep;24(9):1899–1910. PubMed PMID: 31176740. doi: 10.1016/j.drudis.2019.06.002
  • Pyo SM, Maibach HI. Skin metabolism: relevance of skin enzymes for rational drug design. Skin Pharmacol Physiol. 2019;32(5):283–294. PubMed PMID: 31357203. doi: 10.1159/000501732
  • Eilstein J, Lereaux G, Budimir N, et al. Comparison of xenobiotic metabolizing enzyme activities in ex vivo human skin and reconstructed human skin models from SkinEthic. Arch Toxicol. 2014 Sep;88(9):1681–1694. PubMed PMID: 24658324. doi: 10.1007/s00204-014-1218-6
  • Manevski N, Balavenkatraman KK, Bertschi B, et al. Aldehyde oxidase activity in fresh human skin. Drug Metab Dispos. 2014 Dec;42(12):2049–2057. PubMed PMID: 25249692. doi: 10.1124/dmd.114.060368
  • van Eijl S, Zhu Z, Cupitt J, et al. Elucidation of xenobiotic metabolism pathways in human skin and human skin models by proteomic profiling. PLoS One. 2012;7(7):e41721. PubMed PMID: 22848577; PubMed Central PMCID: PMCPMC3406074. doi:10.1371/journal.pone.0041721.
  • Luu-The V, Duche D, Ferraris C, et al. Expression profiles of phases 1 and 2 metabolizing enzymes in human skin and the reconstructed skin models Episkin and full thickness model from Episkin. J Steroid Biochem Mol Biol. 2009 Sep;116(3–5):178–186. PubMed PMID: 19482084. doi: 10.1016/j.jsbmb.2009.05.011.
  • Gibbs S, van de Sandt JJ, Merk HF, et al. Xenobiotic metabolism in human skin and 3D human skin reconstructs: a review. Curr Drug Metab. 2007 Dec;8(8):758–772. PubMed PMID: 18220556. doi: 10.2174/138920007782798225.
  • Smith CK, Moore CA, Elahi EN, et al. Human skin absorption and metabolism of the contact allergens, cinnamic aldehyde, and cinnamic alcohol. Toxicol Appl Pharmacol. 2000 Nov 1;168(3):189–199. PubMed PMID: 11042091. doi: 10.1006/taap.2000.9025.
  • Wiegand C, Hewitt NJ, Merk HF, et al. Dermal xenobiotic metabolism: a comparison between native human skin, four in vitro skin test systems and a liver system. Skin Pharmacol Physiol. 2014;27(5):263–275. PubMed PMID: 24943921. doi:10.1159/000358272.
  • Buckman SY, Gresham A, Hale P, et al. COX-2 expression is induced by UVB exposure in human skin: implications for the development of skin cancer. Carcinogenesis. 1998 May;19(5):723–729. PubMed PMID: 9635856. doi: 10.1093/carcin/19.5.723.
  • Piao MS, Park JJ, Choi JY, et al. Nrf2-dependent and Nrf2-independent induction of phase 2 detoxifying and antioxidant enzymes during keratinocyte differentiation. Arch Dermatol Res. 2012 Jul;304(5):387–395. PubMed PMID: 22310733. doi: 10.1007/s00403-012-1215-7
  • Gotz C, Pfeiffer R, Tigges J, et al. Xenobiotic metabolism capacities of human skin in comparison with a 3D-epidermis model and keratinocyte-based cell culture as in vitro alternatives for chemical testing: phase II enzymes. Exp Dermatol. 2012 May;21(5):364–369. PubMed PMID: 22509834. doi: 10.1111/j.1600-0625.2012.01478.x.
  • Spriggs S, Cubberley R, Loadman P, et al. A study of inter-individual variability in the Phase II metabolism of xenobiotics in human skin. Toxicol Lett. 2018 Aug;292:63–72. PubMed PMID: 29709425. doi: 10.1016/j.toxlet.2018.04.011
  • Villalba R, Benitez J, No-Lowis ED, et al. Cryopreservation of human skin with propane-1,2-diol. Cryobiology. 1996 Oct;33(5):525–529. PubMed PMID: 8893511. doi: 10.1006/cryo.1996.0056
  • Abdayem R, Roussel L, Zaman N, et al. Deleterious effects of skin freezing contribute to variable outcomes of the predictive drug permeation studies using hydrophilic molecules. Exp Dermatol. 2015 Dec;24(12):972–974. PubMed PMID: 26268618. doi: 10.1111/exd.12825.
  • Bortolin RC, Gasparotto J, Vargas AR, et al. Effects of freeze-thaw and storage on enzymatic activities, protein oxidative damage, and immunocontent of the blood, liver, and brain of rats. Biopreserv Biobank. 2017 Jun;15(3):182–190. PubMed PMID: 27662116. doi: 10.1089/bio.2016.0023.
  • Hinz B, Gabbiani G. Cell-matrix and cell-cell contacts of myofibroblasts: role in connective tissue remodeling. Thromb Haemost. 2003 Dec;90(6):993–1002. PubMed PMID: 14652629. doi: 10.1160/TH03-05-0328.
  • Duval K, Grover H, Han LH, et al. Modeling physiological events in 2D vs. 3D cell culture. Physiology. 2017 Jul;32(4):266–277. PubMed PMID: 28615311; PubMed Central PMCID: PMCPMC5545611. doi: 10.1152/physiol.00036.2016
  • Basler K, Bergmann S, Heisig M, et al. The role of tight junctions in skin barrier function and dermal absorption. J Control Release. 2016 Nov 28:242:105–118. PubMed PMID: 27521894. doi: 10.1016/j.jconrel.2016.08.007.
  • Dellambra E, Odorisio T, D’Arcangelo D, et al. Non-animal models in dermatological research. ALTEX. 2019;36(2):177–202. PubMed PMID: 30456412. doi:10.14573/altex.1808022.
  • Bottcher-Haberzeth S, Biedermann T, Reichmann E. Tissue engineering of skin. Burns. 2010 Jun;36(4):450–460. PubMed PMID: 20022702. doi: 10.1016/j.burns.2009.08.016
  • Sutterby E, Thurgood P, Baratchi S, et al. Microfluidic skin-on-a-chip models: toward biomimetic artificial skin. Small. 2020 Oct;16(39):e2002515. PubMed PMID: 33460277. doi: 10.1002/smll.202002515
  • Esch MB, Sung JH, Yang J, et al. On chip porous polymer membranes for integration of gastrointestinal tract epithelium with microfluidic ‘body-on-a-chip’ devices. Biomed Microdevices. 2012 Oct;14(5):895–906. PubMed PMID: 22847474. doi: 10.1007/s10544-012-9669-0
  • O’Neill AT, Monteiro-Riviere NA, Walker GM. Characterization of microfluidic human epidermal keratinocyte culture. Cytotechnology. 2008 Mar;56(3):197–207. PubMed PMID: 19002858; PubMed Central PMCID: PMCPMC2553630. doi: 10.1007/s10616-008-9149-9
  • Lim HY, Kim J, Song HJ, et al. Development of wrinkled skin-on-a-chip (WSOC) by cyclic uniaxial stretching. J Ind Eng Chem. 2018 Dec 25:68:238–245. PubMed PMID: WOS:000452579600029; English. doi: 10.1016/j.jiec.2018.07.050.
  • Jusoh N, Ko J, Jeon NL. Microfluidics-based skin irritation test using in vitro 3D angiogenesis platform. APL Bioeng. 2019 Sep;3(3):036101. PubMed PMID: 31431937; PubMed Central PMCID: PMCPMC6697035. doi: 10.1063/1.5093975.
  • Jeon HM, Kim K, Choi KC, et al. Side-effect test of sorafenib using 3-D skin equivalent based on microfluidic skin-on-a-chip. J Ind Eng Chem. 2020 Feb 25:82:71–80. PubMed PMID: WOS:000509616700008; English. doi: 10.1016/j.jiec.2019.09.044.
  • Kim K, Jeon HM, Choi KC, et al. Testing the effectiveness of curcuma longa leaf extract on a skin equivalent using a pumpless skin-on-a-chip model. Int J Mol Sci. 2020 May 29;21(11):8475. PubMed PMID: 32486109; PubMed Central PMCID: PMCPMC7312991. doi: 10.3390/ijms21113898.
  • Tavares RSN, Tao TP, Maschmeyer I, et al. Toxicity of topically applied drugs beyond skin irritation: static skin model vs. Two organs-on-a-chip. Int J Pharm. 2020 Nov 15 ;589:119788. PubMed PMID: WOS:000580654300013; English. doi: 10.1016/j.ijpharm.2020.119788.
  • Kim K, Jeong S, Sung GYJBJ. Effect of periodical tensile stimulation on the human skin equivalents by Magnetic Stretching Skin-on-a-Chip (MSSC). BioChip J. 2022;16(4):501–514. doi: 10.1007/s13206-022-00092-x
  • Abaci HE, Guo Z, Coffman A, et al. Human skin constructs with spatially controlled vasculature using primary and Ipsc-derived endothelial cells. Adv Healthc Mater. 2016 Jul;5(14):1800–1807. PubMed PMID: 27333469; PubMed Central PMCID: PMCPMC5031081. doi: 10.1002/adhm.201500936.
  • Mori N, Morimoto Y, Takeuchi S. Skin integrated with perfusable vascular channels on a chip. Biomaterials. 2017 Feb;116:48–56. PubMed PMID: 27914266. doi: 10.1016/j.biomaterials.2016.11.031.
  • Mori N, Morimoto Y, Takeuchi S. Perfusable and stretchable 3D culture system for skin-equivalent. Biofabrication. 2018 Nov 15;11(1):011001. PubMed PMID: 30431022. doi: 10.1088/1758-5090/aaed12
  • Salameh S, Tissot N, Cache K, et al. A perfusable vascularized full-thickness skin model for potential topical and systemic applications. Biofabrication. 2021 May 14;13(3). PubMed PMID: 33910175. doi: 10.1088/1758-5090/abfca8
  • Rimal R, Marquardt Y, Nevolianis T, et al. Dynamic flow enables long-term maintenance of 3-D vascularized human skin models. Appl Mater Today. 2021 Dec; 25;25:101213. PubMed PMID: WOS:000711994000003; English. doi: 10.1016/j.apmt.2021.101213
  • Kim BS, Gao G, Kim JY, et al. 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 Apr;8(7):e1801019. PubMed PMID: 30358939. doi: 10.1002/adhm.201801019
  • Valencia L, Canalejas-Tejero V, Clemente M, et al. A new microfluidic method enabling the generation of multi-layered tissues-on-chips using skin cells as a proof of concept. Sci Rep-UK. 2021 Jun 23;11(1). English. doi: 10.1038/s41598-021-91875-z
  • Zoio P, Lopes-Ventura S, Oliva A. Biomimetic full-thickness skin-on-a-chip based on a fibroblast-derived matrix. Micro. 2022;2(1):191–211. editors. doi: 10.3390/micro2010013
  • Sriram G, Alberti M, Dancik Y, et al. Full-thickness human skin-on-chip with enhanced epidermal morphogenesis and barrier function. Mater Today. 2018 May;21(4):326–340. PubMed PMID: WOS:000433264200012; English. doi: 10.1016/j.mattod.2017.11.002
  • Wagner I, Materne EM, Brincker S, et al. A dynamic multi-organ-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture. Lab Chip. 2013;13(18):3538–3547. PubMed PMID: WOS:000323111300008; English. doi:10.1039/c3lc50234a.
  • Maschmeyer I, Hasenberg T, Jaenicke A, et al. Chip-based human liver-intestine and liver-skin co-cultures–A first step toward systemic repeated dose substance testing in vitro. Eur J Pharm Biopharm. 2015 Sep;95(Pt A):77–87. PubMed PMID: 25857839; PubMed Central PMCID: PMCPMC6574126. doi: 10.1016/j.ejpb.2015.03.002.
  • Maschmeyer I, Lorenz AK, Schimek K, et al. A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab Chip. 2015 Jun 21;15(12):2688–2699. PubMed PMID: 25996126. doi: 10.1039/c5lc00392j
  • Kim JJ, Ellett F, Thomas CN, et al. A microscale, full-thickness, human skin on a chip assay simulating neutrophil responses to skin infection and antibiotic treatments. Lab Chip. 2019 Sep 10;19(18):3094–3103. PubMed PMID: 31423506; PubMed Central PMCID: PMCPMC6776466. doi: 10.1039/c9lc00399a
  • Atac B, Wagner I, Horland R, et al. Skin and hair on-a-chip: in vitro skin models versus ex vivo tissue maintenance with dynamic perfusion. Lab Chip. 2013 Sep 21;13(18):3555–3561. PubMed PMID: 23674126. doi: 10.1039/c3lc50227a
  • Kuhnl J, Tao TP, Brandmair K, et al. Characterization of application scenario-dependent pharmacokinetics and pharmacodynamic properties of permethrin and hyperforin in a dynamic skin and liver multi-organ-chip model. Toxicology. 2021 Jan 30:448:152637. PubMed PMID: 33220337. doi: 10.1016/j.tox.2020.152637.
  • Abaci HE, Gledhill K, Guo Z, et al. Pumpless microfluidic platform for drug testing on human skin equivalents. Lab Chip. 2015 Feb 7;15(3):882–888. PubMed PMID: 25490891; PubMed Central PMCID: PMCPMC4305008. doi: 10.1039/c4lc00999a
  • Tarnoki-Zach J, Mehes E, Varga-Medveczky Z, et al. Development and evaluation of a human skin equivalent in a semiautomatic microfluidic diffusion chamber. Pharmaceutics. 2021 Jun 20;13(6). PubMed PMID: 34202971; PubMed Central PMCID: PMCPMC8235028. doi: 10.3390/pharmaceutics13060910
  • Pires de Mello CP, Carmona-Moran C, McAleer CW, et al. Microphysiological heart-liver body-on-a-chip system with a skin mimic for evaluating topical drug delivery. Lab Chip. 2020 Feb 21;20(4):749–759. PubMed PMID: 31970354; PubMed Central PMCID: PMCPMC7123528. doi: 10.1039/c9lc00861f
  • Ronaldson-Bouchard K, Teles D, Yeager K, et al. A multi-organ chip with matured tissue niches linked by vascular flow. Nat Biomed Eng. 2022 Apr;6(4):351–371. PubMed PMID: 35478225; PubMed Central PMCID: PMCPMC9250010. doi: 10.1038/s41551-022-00882-6
  • Struver K, Friess W, Hedtrich S. Development of a perfusion platform for dynamic cultivation of in vitro skin models. Skin Pharmacol Physiol. 2017;30(4):180–189. PubMed PMID: 28651246. doi: 10.1159/000476071
  • Wufuer M, Lee G, Hur W, et al. Skin-on-a-chip model simulating inflammation, edema and drug-based treatment. Sci Rep. 2016 Nov 21;6:37471. PubMed PMID: 27869150; PubMed Central PMCID: PMCPMC5116589. doi: 10.1038/srep37471
  • Ramadan Q, Ting FC. In vitro micro-physiological immune-competent model of the human skin. Lab Chip. 2016 May 21;16(10): 1899–1908. PubMed PMID: 27098052. doi: 10.1039/c6lc00229c
  • Varga-Medveczky Z, Kocsis D, Naszlady MB, et al. Skin-on-a-chip technology for testing transdermal drug delivery—starting points and recent developments. Pharmaceutics. 2021 Nov 3;13(11):1852. PubMed PMID: 34834264; PubMed Central PMCID: PMCPMC8619496. doi: 10.3390/pharmaceutics13111852.
  • Ponmozhi J, Dhinakaran S, Varga-Medveczky Z, et al. Development of skin-on-a-chip platforms for different utilizations: factors to be considered. Micromachines (Basel). 2021 Mar 10;12(3). PubMed PMID: 33802208; PubMed Central PMCID: PMCPMC8001759. doi: 10.3390/mi12030294
  • Risueno I, Valencia L, Jorcano JL, et al. Skin-on-a-chip models: general overview and future perspectives. APL Bioeng. 2021 Sep;5(3):030901. PubMed PMID: 34258497; PubMed Central PMCID: PMCPMC8270645. doi: 10.1063/5.0046376.
  • Lukacs B, Bajza A, Kocsis D, et al. Skin-on-a-chip device for ex vivo monitoring of transdermal delivery of drugs—design, fabrication, and testing. Pharmaceutics. 2019 Sep 2;11(9):445. PubMed PMID: 31480652; PubMed Central PMCID: PMCPMC6781558. doi: 10.3390/pharmaceutics11090445.
  • Kocsis D, Horvath S, Kemeny A, et al. Drug delivery through the psoriatic epidermal barrier—A “Skin-on-a-chip” Permeability Study and ex vivo optical imaging. Int J Mol Sci. 2022 Apr;23(8):4237. PubMed PMID: WOS:000785132800001; English. doi: 10.3390/ijms23084237.
  • Bajza A, Kocsis D, Berezvai O, et al. Verification of P-Glycoprotein function at the dermal barrier in diffusion cells and dynamic “Skin-on-a-chip” microfluidic device. Pharmaceutics. 2020 Sep;12(9):804. PubMed PMID: WOS:000580145400001; English. doi: 10.3390/pharmaceutics12090804.
  • Tam J, Wang Y, Farinelli WA, et al. Fractional skin harvesting: autologous skin grafting without donor-site morbidity. Plast Reconstr Surg Glob Open. 2013;1(6):e47. doi: 10.1097/GOX.0b013e3182a85a36
  • Low DA, Jones H, Cable NT, et al. Historical reviews of the assessment of human cardiovascular function: interrogation and understanding of the control of skin blood flow. Eur J Appl Physiol. 2020 Jan;120(1):1–16. PubMed PMID: 31776694; PubMed Central PMCID: PMCPMC6969866. doi: 10.1007/s00421-019-04246-y
  • Neagu M, Caruntu C, Constantin C, et al. Chemically induced skin carcinogenesis: updates in experimental models (Review). Oncol Rep. 2016 May;35(5):2516–2528. PubMed PMID: 26986013; PubMed Central PMCID: PMCPMC4811393. doi: 10.3892/or.2016.4683.
  • Huggenberger R, Detmar M. The cutaneous vascular system in chronic skin inflammation. J Investig Dermatol Symp Proc. 2011 Dec;15(1):24–32. PubMed PMID: 22076324; PubMed Central PMCID: PMCPMC3398151. doi: 10.1038/jidsymp.2011.5.
  • Kashani-Sabet M, Sagebiel RW, Ferreira CM, et al. Vascular involvement in the prognosis of primary cutaneous melanoma. Arch Dermatol. 2001 Sep;137(9):1169–1173. PubMed PMID: 11559212. doi: 10.1001/archderm.137.9.1169.
  • Foster DS, Jones RE, Ransom RC, et al. The evolving relationship of wound healing and tumor stroma. JCI Insight. 2018 Sep 20;3(18). PubMed PMID: 30232274; PubMed Central PMCID: PMCPMC6237224 exists. doi: 10.1172/jci.insight.99911
  • Grinnell F. Fibroblast-collagen-matrix contraction: growth-factor signalling and mechanical loading. Trends Cell Biol. 2000 Sep;10(9):362–365. PubMed PMID: 10932093. doi: 10.1016/s0962-8924(00)01802-x.
  • Han YL, Ronceray P, Xu G, et al. Cell contraction induces long-ranged stress stiffening in the extracellular matrix. Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):4075–4080. PubMed PMID: 29618614; PubMed Central PMCID: PMCPMC5910866. doi: 10.1073/pnas.1722619115.
  • Ramtani S. Mechanical modelling of cell/ECM and cell/cell interactions during the contraction of a fibroblast-populated collagen microsphere: theory and model simulation. J Biomech. 2004 Nov;37(11):1709–1718. PubMed PMID: 15388313. doi: 10.1016/j.jbiomech.2004.01.028.
  • Grinnell F, Ho CH, Lin YC, et al. Differences in the regulation of fibroblast contraction of floating versus stressed collagen matrices. J Biol Chem. 1999 Jan 8;274(2):918–923. PubMed PMID: 9873032. doi: 10.1074/jbc.274.2.918.
  • Charulatha V, Rajaram A. Influence of different crosslinking treatments on the physical properties of collagen membranes. Biomaterials. 2003 Feb;24(5):759–767. PubMed PMID: 12485794. doi: 10.1016/s0142-9612(02)00412-x.
  • Kwak BS, Choi W, Jeon J-W, et al. In vitro 3D skin model using gelatin methacrylate hydrogel. Journal Of Industrial And Engineering Chemistryquery. 2018;66:254–261. doi: 10.1016/j.jiec.2018.05.037
  • Huey DJ, Athanasiou KA, Almarza A. Tension-compression loading with chemical stimulation results in additive increases to functional properties of anatomic meniscal constructs. PLoS One. 2011;6(11):e27857. PubMed PMID: 22114714; PubMed Central PMCID: PMCPMC3218070. doi: 10.1371/journal.pone.0027857
  • Huh D, Matthews BD, Mammoto A, et al. Reconstituting organ-level lung functions on a chip. Science. 2010 Jun 25;328(5986):1662–1668. PubMed PMID: 20576885; PubMed Central PMCID: PMCPMC8335790. doi: 10.1126/science.1188302
  • Kim HJ, Ingber DE. Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation. Integr Biol (Camb). 2013 Sep;5(9):1130–1140. PubMed PMID: 23817533. doi: 10.1039/c3ib40126j.
  • Miura S, Sato K, Kato-Negishi M, et al. Fluid shear triggers microvilli formation via mechanosensitive activation of TRPV6. Nat Commun. 2015 Nov 13;6:8871. PubMed PMID: 26563429; PubMed Central PMCID: PMCPMC4660203. doi: 10.1038/ncomms9871
  • Schatti O, Grad S, Goldhahn J, et al. A combination of shear and dynamic compression leads to mechanically induced chondrogenesis of human mesenchymal stem cells. Eur Cell Mater. 2011 Oct 11;22:214–225. PubMed PMID: 22048899. doi: 10.22203/ecm.v022a17
  • Tokuyama E, Nagai Y, Takahashi K, et al. Mechanical stretch on human skin equivalents increases the epidermal thickness and develops the basement membrane. PLoS One. 2015;10(11):e0141989. doi: 10.1371/journal.pone.0141989.
  • Yano S, Komine M, Fujimoto M, et al. Mechanical stretching in vitro regulates signal transduction pathways and cellular proliferation in human epidermal keratinocytes. J Invest Dermatol. 2004 Mar;122(3):783–790. PubMed PMID: 15086566. doi: 10.1111/j.0022-202X.2004.22328.x.
  • Powell HM, McFarland KL, Butler DL, et al. Uniaxial strain regulates morphogenesis, gene expression, and tissue strength in engineered skin. Tissue Eng Part A. 2010 Mar;16(3):1083–1092. PubMed PMID: 19845460. doi: 10.1089/ten.TEA.2009.0542
  • Lafrance H, Yahia LH, Germain L, et al. Mechanical properties of human skin equivalents submitted to cyclic tensile forces. Skin Res Technol. 1998;4(4):228–236. doi: 10.1111/j.1600-0846.1998.tb00115.x
  • Jung MH, Jung SM, Shin HS. Co-stimulation of HaCaT keratinization with mechanical stress and air-exposure using a novel 3D culture device. Sci Rep. 2016 Sep 27;6:33889. PubMed PMID: 27670754; PubMed Central PMCID: PMCPMC5037429 . doi: 10.1038/srep33889
  • Tordesillas L, Goswami R, Benede S, et al. Skin exposure promotes a Th2-dependent sensitization to peanut allergens. J Clin Invest. 2014 Nov;124(11):4965–4975. PubMed PMID: 25295541; PubMed Central PMCID: PMCPMC4347216. doi: 10.1172/JCI75660.
  • Chen G, Chen ZM, Fan XY, et al. Gut-brain-skin axis in psoriasis: a review. Dermatol Ther (Heidelb). 2021 Feb;11(1):25–38. PubMed PMID: 33206326; PubMed Central PMCID: PMCPMC7859123. doi: 10.1007/s13555-020-00466-9.
  • Sin A, Chin KC, Jamil MF, et al. The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors. Biotechnol Prog. 2004 Jan;20(1):338–345. PubMed PMID: 14763861. doi: 10.1021/bp034077d.
  • Sung JH, Shuler ML. A micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugs. Lab Chip. 2009 May 21;9(10): 1385–1394. PubMed PMID: 19417905. doi: 10.1039/b901377f
  • Lee H, Kim DS, Ha SK, et al. A pumpless multi-organ-on-a-chip (MOC) combined with a pharmacokinetic-pharmacodynamic (PK-PD) model. Biotechnol Bioeng. 2017 Feb;114(2):432–443. PubMed PMID: 27570096. doi: 10.1002/bit.26087.
  • Lee DW, Ha SK, Choi I, et al. 3D gut-liver chip with a PK model for prediction of first-pass metabolism. Biomed Microdevices. 2017 Nov 7;19(4):100. PubMed PMID: 29116458. doi: 10.1007/s10544-017-0242-8
  • Sung JH, Kam C, Shuler ML. A microfluidic device for a pharmacokinetic-pharmacodynamic (PK-PD) model on a chip. Lab Chip. 2010 Feb 21;10(4): 446–455. PubMed PMID: 20126684. doi: 10.1039/b917763a
  • Lee SH, Choi N, Sung JH. Pharmacokinetic and pharmacodynamic insights from microfluidic intestine-on-a-chip models. Expert Opin Drug Metab Toxicol. 2019 Dec;15(12):1005–1019. PubMed PMID: 31794278. doi: 10.1080/17425255.2019.1700950.
  • Sung JH. Multi-organ-on-a-chip for pharmacokinetics and toxicokinetic study of drugs. Expert Opin Drug Metab Toxicol. 2021 Aug;17(8):969–986. PubMed PMID: 33764248. doi: 10.1080/17425255.2021.1908996.
  • Sung JH, Esch MB, Shuler ML. Integration of in silico and in vitro platforms for pharmacokinetic-pharmacodynamic modeling. Expert Opin Drug Metab Toxicol. 2010 Sep;6(9):1063–1081. PubMed PMID: 20540627. doi: 10.1517/17425255.2010.496251.
  • O’Neill CA, Monteleone G, McLaughlin JT, et al. The gut-skin axis in health and disease: a paradigm with therapeutic implications. BioEssays. 2016 Nov;38(11):1167–1176. PubMed PMID: 27554239. doi: 10.1002/bies.201600008
  • Williams RE. Benefit and mischief from commensal bacteria. J Clin Pathol. 1973 Nov;26(11):811–818. PubMed PMID: 4271885; PubMed Central PMCID: PMCPMC477895. doi: 10.1136/jcp.26.11.811.
  • De Pessemier B, Grine L, Debaere M, et al. Gut–skin axis: current knowledge of the interrelationship between microbial dysbiosis and skin conditions. Microorganisms. 2021 Feb 11;9(2):353. PubMed PMID: 33670115; PubMed Central PMCID: PMCPMC7916842. doi: 10.3390/microorganisms9020353.
  • Zoio P, Oliva A. Skin-on-a-chip technology: microengineering physiologically relevant in vitro skin models. Pharmaceutics. 2022 Mar 21;14(3). PubMed PMID: 35336056; PubMed Central PMCID: PMCPMC8955316. doi: 10.3390/pharmaceutics14030682.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.