Journal of Investigative Dermatology, Journal Year: 2024, Volume and Issue: 144(12), P. 2650 - 2670

Published: Aug. 10, 2024

Skin in vitro models offer much promise for research, testing drugs, cosmetics, and medical devices, reducing animal extensive clinical trials. There are several approaches to mimicking human skin behavior, ranging from simple cell monolayer complex organotypic bioengineered 3-dimensional models. Some have been approved preclinical studies pharmaceuticals, chemicals. However, development of physiologically reliable remains its infancy. This review reports on advances study homeostasis, aging, disease. The generation that accurately reproduce all layers (epidermis, dermis, subcutis), including appendages such as sweat glands (SGs), hair follicles, or arrector pili muscle, represents a significant hurdle the field tissue engineering. we still far full cellular structural complexity living (Antoni et al., 2015Antoni D. Burckel H. Josset E. Noel G. Three-dimensional culture: breakthrough vivo.Int J Mol Sci. 2015; 16: 5517-5527Crossref PubMed Scopus (699) Google Scholar; Sanabria-de la Torre 2020Sanabria-de R. Fernández-González A. Quiñones-Vico M.I. Montero-Vilchez T. Arias-Santiago S. Bioengineered intended model Pharmacosmetics, disease environmental impact analysis.Biomedicines. 2020; 8: 464Crossref (17) Sutterby 2022Sutterby Thurgood P. Baratchi Khoshmanesh K. Pirogova Evaluation studying effects external stressors stimuli developing treatment modalities.View. 2022; 320210012Crossref (18) Scholar). demand innovative effective (3D) engineered equivalents has increased not only improving purposes grafts but also essential (patho)physiological investigations, unravel underlying mechanisms disorders well assessing effectiveness potential toxicity active substances cosmetic pharmaceutical research (Olejnik 2022Olejnik Semba J.A. Kulpa Dańczak-Pazdrowska Rybka J.D. Gornowicz-Porowska J. 3D bioprinting related research: recent achievements application perspectives.ACS Synth Biol. 11: 26-38Crossref (40) Salameh 2021Salameh Tissot N. Cache Lima Suzuki I. Marinho P.A. al.A perfusable vascularized full-thickness topical systemic applications.Biofabrication. 2021; 13035042Crossref (30) Current aim replicate critical characteristics, barrier function, elasticity, immune response, blood flow, technical biological issues limit true functional (Klicks 2017Klicks von Molitor Ertongur-Fauth Rudolf Hafner M. In three-dimensional their applications.J Cell Biotechnol. 2017; 3: 21-39Crossref evolution substitutes paralleled technological resulted with varying degrees complexity. Although is linear, main drive innovation lies physiologic relevance (Figure 1). simplest approach 2-dimensional (2D) culture primary keratinocytes fibroblasts. do cell–cell cell–matrix communication organization skin, they very useful drug screening; cytotoxicity assays; molecular diseases cancer (Duval 2017Duval Grover Han L.H. Mou Y. Pegoraro A.F. Fredberg al.Modeling physiological events 2D vs. culture.Physiology (Bethesda). 32: 266-277Crossref (1158) Hofmann 2023Hofmann Fink Pignet A.L. Schwarz Schellnegger Nischwitz S.P. al.Human wound healing disorders.Biomedicines. 2023; 1056Crossref Moon 2021Moon Kim D.H. Shin J.U. response skin.Yonsei Med 62: 969-980Crossref (0) Stanton 2022Stanton D.N. Ganguli-Indra Indra A.K. Karande efficacy disease: last 10 years.Pharmaceutics. 14: 319Crossref (5) Incorporation extracellular matrix (ECM) components into provided cells important cues native environment, promoting more representative growth, proliferation, function resembling some conditions vivo Langhans, 2018Langhans S.A. discovery repositioning.Front Pharmacol. 2018; 9: 6Crossref (1000) Sarkiri 2019Sarkiri Fox S.C. Fratila-Apachitei L.E. Zadpoor A.A. modeling.Int 2019; 20: 1407Crossref (24) Valdoz 2021Valdoz J.C. Johnson B.C. Jacobs D.J. Franks N.A. Dodson E.L. Sanders C. al.The ECM: scaffold, question.Int 2212690Crossref (60) systems includes organoids 1), simplified system which grow 3D-well chemically defined microenvironment—composed ECM media—to form self-organized clusters differentiate distinct types mimic structure organ (Corrò 2020Corrò Novellasdemunt L. Li V.S.W. A brief history organoids.Am Physiol Physiol. 319: C151-C165Crossref Hofer Lutolf, 2021Hofer Lutolf M.P. Engineering organoids.Nat Rev Mater. 6: 402-420Crossref (524) 2020bKim Koo B.K. Knoblich Human organoids: biology medicine.Nat 21: 571-584Crossref Whereas recapitulate different internal organs gut (Taelman 2022Taelman Diaz Guiu intestinal challenge.Front Dev 10854740Crossref (31) Scholar), lung (Matkovic Leko 2023Matkovic Schneider R.T. Thimraj T.A. Schrode Beitler Liu H.Y. distal organoid interstitial disease, viral infection development.Nat Protoc. 18: 2283-2312Crossref brain (Eichmüller Knoblich, 2022Eichmüller O.L. cerebral - new tool neurology research.Nat Neurol. 661-680Crossref (21) bladder (Minoli 2023Minoli Cantore Hanhart Kiener Fedrizzi La Manna F. al.Bladder stages therapy response.Nat Commun. 2214Crossref tumors (Xu 2022Xu Jiao Wu Tumor applications modeling potentials precision medicine.J Hematol Oncol. 15: 58Crossref (69) traditional consist 2 dermo–epidermal formed by fibroblasts embedded an gel cultured top gel, generated insert's porous membrane allow epidermal keratinization (Gangatirkar 2007Gangatirkar Paquet-Fifield Rossi Kaur Establishment cultures using neonatal cells.Nat 2007; 2: 178-186Crossref (124) These (HSEs) well-established available market (Hayden 2003Hayden P.J. Ayehunie Jackson G.R. Kupfer-Lamore Last T.J. al.In equivalent testing.in: Alternative toxicological methods. CRC Press, Boca Raton2003: 229-248Google Suhail 2019Suhail Sardashti Jaiswal Rudraiah Misra Kumbar S.G. Engineered product evaluation therapeutic applications.Biotechnol 14e1900022Crossref (46) Presently, there range commercially HSEs offering source screening, tests, sensitivity tests (Table Several patients, animal-based, ex assays used identify potentially irritant chemicals compatible high-throughput screening required industry. This, along legislative move toward nonanimal (European Regulation 1223/2009 United States Federal Food, Drug, Cosmetic Act, 2022), prompted commercial regulatory toxicology, validated epithelial-only methods corrosion irritation adopted Organisation Economic Co-operation Development (Test Guidelines 431 439, respectively) (Kandárová 2006Kandárová Liebsch Schmidt Genschow Traue Spielmann al.Assessment SkinEthic reconstructed common protocol evaluated ECVAM validation study.Altern Lab Anim. 2006; 34: 393-406Crossref (52) 2007Spielmann Hoffmann Botham Fentem J.H. Eskes international acute irritation: report validity Episkin EpiDerm Integrity Function Test.Altern 35: 559-601Crossref (184) based metabolic activity, provide indirect measure viability, 50% threshold set acceptable chemical safety levels. More sophisticated (KeratinoSens [Andreas 2011Andreas Caroline B. Leslie Frank Kimberly Allison intra- inter-laboratory reproducibility predictivity KeratinoSens assay predict sensitizers vitro: results ring-study five laboratories.Toxicol Vitro. 2011; 25: 733-744Crossref (98) Emter 2010Emter Ellis Natsch Performance novel keratinocyte-based reporter line screen vitro.Toxicol Appl 2010; 245: 281-290Crossref (269) Scholar] LuSens [Ramirez 2014Ramirez Mehling Kolle S.N. Wruck C.J. Teubner W. Eltze al.LuSens: keratinocyte ARE gene use integrated strategies sensitization hazard identification.Toxicol 2014; 28: 1482-1497Crossref (104) Scholar]) utilize luciferase basis induced activation transcription factor, nuclear factor erythroid 2. these architecture permeability yet be translated systems. number altered expression profiles known irritants, SENS-IS being currently most developed (Cottrez 2015Cottrez Boitel Auriault Aeby Groux Genes specifically modulated sensitized skins detection model. assay.Toxicol 29: 787-802Crossref (80) Harding 2021Harding Murdoch Danby Hasan M.Z. Nakanishi Furuno al.Determination signature tissue-engineered equivalents.JID Innov. 1100011Abstract Full Text PDF (3) 2019Hasan Kitamura Kawai Ohira Mori Shoju al.Transcriptional profiling lactic acid treated epidermis reveals pathways stinging itch.Toxicol 57: 164-173Crossref (13) Saito 2017Saito Takenouchi O. Nukada Miyazawa Sakaguchi An termed EpiSensA broad sets lipophilic pre/pro-haptens.Toxicol 40: 11-25Crossref (33) recently, 2023Harding Colley H.E. Vazquez I.B. al.c-Src marker chemical-induced equivalents.Exp Dermatol. 220-225Crossref (1) Scholar analyzed immediate up-stream signaling cascades upon irritants specific kinases could tested rapid formats. Despite evident progress HSEs, constraint lack neural compartment, isolating stimulus rather than providing orchestrated feedback whole (Basso 2019Basso Serhan Tauber Gaudenzio Peripheral neurons: master regulators mucosal response.Eur Immunol. 49: 1984-1997Crossref Cohen 2020Cohen Kaplan Neuronal regulation cutaneous immunity.J 204: 264-270Crossref (27) Trier 2019Trier A.M. Mack M.R. B.S. neuroimmune axis sensation, inflammation, 202: 2829-2835Crossref (36) Scholar).Table 1Commercially Available Full-Thickness HSECompanySystemRegional AvailabilityReferenceEpiSkin, Lyon, FranceT-SkinGlobalBataillon 2019Bataillon Lelièvre Chapuis Thillou Autourde J.B. Durand al.Characterization thickness model, T-SkinTM, investigations anti-aging compounds.Int 2240Crossref Luu-The 2009Luu-The V. Duche Ferraris Meunier J.R. Leclaire Labrie Expression phases 1 metabolizing enzymes Episkin.J Steroid Biochem 2009; 116: (75) ScholarMatTek, Ashland, MAEpiDermFTGlobalMallampati 2010Mallampati Patlolla R.R. Agarwal Babu R.J. Hayden Klausner al.Evaluation thickness-300 (EFT-300) aliphatic hydrocarbons.Toxicol 24: 669-676Crossref ScholarPhenion, Henkel AG KGaA, Düsseldorf, GermanyPhenion FTEurope (and wider1More specifically, supply places reachable courier service within 72 hours.)Pinto 2022Pinto Trink Giuliani Rinaldi Protective sunscreen (50+) octatrienoic 0.1% actinic keratosis UV damages.J Investig Med. 70: 92-98Crossref ScholarSterlab, Vallauris, FranceFull-thickness skin——Abbreviation: HSE, equivalent.1 hours. Open table tab Abbreviation: equivalent. academia, persisting efforts made sophisticate increase experimental throughput complexity, while methodological aspects faithfully diseases. Here, large collaborative networks formed, similar European Network Modeling (NETSKINMODELS) EU COST Action (CA21108, 2022-2026) over 330 participants 40 countries both academia industry united. With this review, members NETSKINMODELS now stage current developments knowledge technology gaps guidelines resources later fuel implementation academic industrial research. earlier-mentioned properly resemble physiopathology presence circulatory flow imitating vessels distributes nutrients other molecules. addition, natural growth occurs simultaneously body exposed multiple stresses conditions. Therefore, diverse dynamic microfluidic devices stimulate facilitate key tissues vitro, example, bioreactors chip (SoC) 2a). projected induce vivo–like biophysiological at bench scale stimulate, mature, monitor, prolong healthy duration. stretch-based bioreactors—either unidirectional, bidirectional, radial force—to mature basement (Tokuyama 2015Tokuyama Nagai Takahashi Kimata Naruse Mechanical stretch increases develops membrane.PLoS One. 10e0141989Crossref (44) stratum corneum (Jung 2016Jung M.H. Jung S.M. H.S. Co-stimulation HaCaT mechanical stress air-exposure device.Sci Rep. 2016; 633889Crossref (23) stiffer dermis (Wahlsten 2021Wahlsten Rütsche Nanni Giampietro Biedermann Reichmann al.Mechanical stimulation induces fibroblast proliferation accelerates early maturation substitutes.Biomaterials. 273120779Crossref wrinkled (Lim 2018Lim Song H.J. Choi K.C. Park al.Development skin-on-a-chip (WSOC) cyclic uniaxial stretching.J Ind Eng Chem. 68: 238-245Crossref (37) Because maintenance process involving biophysiological, chemical, stimuli, tend simplify focus introduction few design development. Nowadays, can find bioreactor techniques cultivation models: perfusion 2b–h). Perfusion fresh media same time removal waste metabolites. enable shear cells, produced endothelium, responsible various protein synthesis division. channel placed just below (Lee 2017Lee Jin Y.K. Sung G.Y. Chung Construction multicellular model.Biomed Microdevices. 19: 22Crossref (97) Rimal 2021Rimal Marquardt Nevolianis Djeljadini Marquez A.B. Huth al.Dynamic enables long-term 3-D models.Appl Mater Today. 25101213Google 2018Song Lim Chun Lee skin-equivalent pump-less chip.J 60: 355-359Crossref (38) Scholar) around (Sriram 2018Sriram Alberti Dancik Feng Z. al.Full-thickness skin-on-chip enhanced morphogenesis function.Mater 326-340Crossref (185) passively gravity-based platform peristaltic pump (Rimal Sriram across dermal compartment vascular network (Mori 2017Mori Morimoto Takeuchi channels chip.Biomaterials. 48-56Crossref Owing variable demands needed desired dedicated HSEs. Nevertheless, ample evidence benefits cultures, soon expect shift cultures. will lead cheaper, For this, upcoming simplification, ease use, less manual input modular integration sensors, apparatus single platform. trends require realistic environment analysis. succeed first, macroscale limited scalability. regard, SoCs miniaturized microflows, forces, gradients obtain accurate treatments drugs (Abaci 2016Abaci Guo Coffman Gillette W.-H. Sia S.K. constructs spatially controlled vasculature iPSC-derived endothelial cells.Adv Healthc 5: 1800-1807Crossref 2018Mori Perfusable stretchable skin-equivalent.Biofabrication. 11011001Crossref (51) Scholar, SoC platforms divided groups, depending inside 2). First, microfluidics biopsies transferred SoCs. original definition organ-on-a-chip given Ingber (Bhatia Ingber, 2014Bhatia D.E. Microfluidic organs-on-chips.Nat 760-772Crossref (2406) shown good when transdermal transport bacterial infections 2015Abaci Gledhill Christiano Shuler M.L. Pumpless equivalents.Lab Chip. 882-888Crossref 2019aKim J.J. Ellett Thomas C.N. Jalali Anderson Irimia microscale, full-thickness, simulating neutrophil responses antibiotic treatments.Lab 3094-3103Crossref commonly multiorgan-on-a-chip (Maschmeyer 2015Maschmeyer Lorenz Schimek Hasenberg Ramme A.P. Hübner four-organ-chip interconnected co-culture intestine, liver, kidney 2688-2699Crossref Wagner 2013Wagner Materne E.M. Brincker Süssbier U. Frädrich Busek multi-organ-chip substance proven liver co-culture.Lab 2013; 13: 3538-3547Crossref second group refers those directly device. monolayers, either (Ramadan Ting, 2016Ramadan Q. Ting F.C. micro-physiological immune-competent skin.Lab 1899-1908Crossref monolayers (Wufuer 2016Wufuer Hur Jeon B.J. T.H. al.Skin-on-a-chip edema drug-based treatment.Sci 637471Crossref (234) groups gone step further, generating structures device, single-differentiated (Zhang 2021Zhang Chen Zhang Wang X. Ouyang Zhu al.Construction high fidelity epidermis-on-a-chip scalable evaluation.Lab 3804-3818Crossref 2Summary Dynamic Models Found LiteratureType PlatformDermal MatrixCellsApplicationReferenceMicrofluidic platformNoneNormal keratinocytesNHKs cultureO'Neill 2008O'Neill A.T. Monteiro-Riviere Walker G.M. Characterization culture.Cytotechnology. 2008; 56: 197-207Crossref ScholarVascularized HSECollagenNormal + HUVECsPercutaneous absorption, permeabilityMori HSECollagenPrimary

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