Deri; tüm mekanik hasarlara, fiziksel, kimyasal ve biyolojik ajanlara karşı vücudun koruyucu kalkanı olup, insan vücudunda termoregülasyon ve sıvı elektrolit dengesinin korunması da dâhil birçok hayati işlevin sürdürülmesinde önemli rol oynamaktadır. İnsan derisinin koruyucu özelliği oldukça yüksektir. Yanıklar, diyabetik ayak ülserleri, travmalara bağlı yaralanmalar ya da doğuştan gelen deride hasar ve nekrozlara sebep olan anomaliler, sonradan oluşan patolojiler deri bütünlüğünün bozulmasına yol açarak bu önemli fonksiyonların ve vücudun ilk savunma hattının sekteye uğramasına neden olabilirler. Sağlıklı deri, bazal membranda bulunan rejenerasyon yeteneğine sahiptir ve proliferatif kök hücreler aracılığıyla epidermis hasarını yenileme yeteneğine sahiptir. Ancak daha derin yaralanmalarda bu yenilenme gerçekleşemez. Derinin, doğal işlevini ve yapısını sürdürebilmesi için derinin bütünlüğünün sağlanması gereklidir ve bu amaçla günümüzde çok çeşitli deri ikameleri geliştirilmektedir. Doku mühendisliğindeki gelişmelerle, birçok doku modellemesi yapılmakta, çeşitli ilaç ve ksenobiyotiklerin dermal toksisitelerinin belirlenmesinde bu modeller kullanmaktadır. Bu sayede in vivo testlerde kullanılacak deney hayvanları sayısının azalması da mümkün olmaktadır. Ayrıca bu doku modelleri sayesinde deride etnik özelliklerin değerlendirilmesi, deri hassasiyeti, alerjik reaksiyonlar, deri kanserleri, yaşlanma, deri mikrobiyotasının incelenmesi gibi pek çok konuda araştırmalar yapılabilmektedir. Bu derlemede, eski ve yeni doku modelleri, bu doku modellerinin avantajları, dezavantajları, deri ikameleri, kullanım alanları ve olası istenmeyen etkileri hakkında bilgi vermek amaçlanmıştır.
Anahtar Kelimeler: Deri doku modelleri; deri ikameleri; deri greftleri
The skin is the body's protective shield against mechanical injuries, physical chemical, and biological agents; plays an important role in maintenance many vital functions in the human body, including thermoregulation and fluid-electrolyte balance. Protective characteristics of human skin are very high. Different factors such as burns, diabetic foot ulcers, traumatic injuries or congenital anomalies causing skin damage/necrosis or secondary pathologies may cause disruption of skin integrity and interruption of these important functions and the body's first line of defense. Healthy skin has ability to regenerate epidermis damage through proliferative stem cells and it has regeneration ability located in basal membrane. However, this regeneration cannot occur in deeper injuries. For maintaining its natural function and structure, it is necessary to provide integrity of the skin. For this purpose, wide variety of skin substitutes are currently being developed. With advances in tissue engineering, many tissuemodeling studies are performed and these models are used to determine dermal toxicities of various drugs/xenobiotics. In this way, it is possible to reduce number of experimental animals for in vivo tests. In addition, thanks to these tissue models, several research can be carried out on many subjects such as evaluation of ethnic characteristics of skin, skin sensitivity, allergic reactions, skin cancers, aging, and examination of skin microbiota. In this review, we aim to give information about old and new tissue models, advantages and disadvantages of tissue models, skin substitutes, their utilization, and possible unwanted effects.
Keywords: Skin tissue models; skin substitutes; skin grafts
- The European Parliament and The Council of The European Union [İnternet]. [Erişim tarihi: 10.08.2020]. Regulation (EC) No 1223/2009 of The European Parliament and of The Council of 30 November 2009 on cosmetic products. Erişim linki: [Link]
- Netzlaff F, Lehr CM, Wertz PW, Schaefer UF. The human epidermis models EpiSkin, SkinEthic and EpiDerm: an evaluation of morphology and their suitability for testing phototoxicity, irritancy, corrosivity, and substance transport. Eur J Pharm Biopharm. 2005;60(2):167-78. [Crossref] [PubMed]
- Lee M, Hwang JH, Lim KM. Alternatives to In Vivo Draize Rabbit Eye and Skin Irritation Tests with a Focus on 3D Reconstructed Human Cornea-Like Epithelium and Epidermis Models. Toxicol Res. 2017;33(3):191-203. [Crossref] [PubMed] [PMC]
- Rheinwald JG, Green H. Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes. Nature. 1977;265(5593):421-4. [Crossref] [PubMed]
- Kandárová H, Leta?iová S. Alternative methods in toxicology: pre-validated and validated methods. Interdiscip Toxicol. 2011;4(3):107-13. [Crossref] [PubMed] [PMC]
- Kandárová H, Hayden P, Klausner M, Kubilus J, Sheasgreen J. An in vitro skin irritation test (SIT) using the EpiDerm reconstructed human epidermal (RHE) model. J Vis Exp. 2009;(29):1366. [PubMed] [PMC]
- Alrubaiy L, Al-Rubaiy KK. Skin substitutes: a brief review of types and clinical applications. Oman Med J. 2009;24(1):4-6. [PubMed] [PMC]
- Vyas KS, Vasconez HC. Wound Healing: Biologics, Skin Substitutes, Biomembranes and Scaffolds. Healthcare (Basel). 2014;2(3):356-400. [Crossref] [PubMed] [PMC]
- Monteiro IP, Shukla A, Marques AP, Reis RL, Hammond PT. Spray-assisted layer-by-layer assembly on hyaluronic acid scaffolds for skin tissue engineering. J Biomed Mater Res A. 2015;103(1):330-40. [Crossref] [PubMed]
- De Wever B, Kurdykowski S, Descargues P. Human skin models for research applications in pharmacology and toxicology: Introducing NativeSkin®, the "missing link" bridging cell culture and/or reconstructed skin models and human clinical testing. Applied In Vitro Toxicology. 2015;1(1):26-32. [Crossref]
- Poumay Y, Coquette A. Modelling the human epidermis in vitro: tools for basic and applied research. Arch Dermatol Res. 2007;298(8):361-9. [Crossref] [PubMed] [PMC]
- Neupane R, Boddu SHS, Renukuntla J, Babu RJ, Tiwari AK. Alternatives to Biological Skin in Permeation Studies: Current Trends and Possibilities. Pharmaceutics. 2020;12(2):152. [Crossref] [PubMed] [PMC]
- Liebsch M, Grune B, Seiler A, Butzke D, Oelgeschläger M, Pirow R, et al. Alternatives to animal testing: current status and future perspectives. Arch Toxicol. 2011;85(8):841-58. [Crossref] [PubMed] [PMC]
- Choksi NY, Truax J, Layton A, Matheson J, Mattie D, Varney T, et al. United States regulatory requirements for skin and eye irritation testing. Cutan Ocul Toxicol. 2019;38(2):141-55. [Crossref] [PubMed] [PMC]
- Mertsching H, Weimer M, Kersen S, Brunner H. Human skin equivalent as an alternative to animal testing. GMS Krankenhhyg Interdiszip. 2008;3(1):Doc11. [PubMed] [PMC]
- Zhang Z, Michniak-Kohn BB. Tissue engineered human skin equivalents. Pharmaceutics. 2012;4(1):26-41. [Crossref] [PubMed] [PMC]
- Ng WL, Yeong WY. The future of skin toxicology testing - Three-dimensional bioprinting meets microfluidics. Int J Bioprint. 2019;5(2.1):237. Erratum in: Int J Bioprint. 2020;6(4):309. [Crossref] [PubMed] [PMC]
- EpiCS datasheet (Erişim Tarihi: 10.08.2020) [Link]
- Ackermann K, Borgia SL, Korting HC, Mewes KR, Schäfer-Korting M. The Phenion full-thickness skin model for percutaneous absorption testing. Skin Pharmacol Physiol. 2010;23(2):105-12. [Crossref] [PubMed]
- Wiegand C, Hewitt NJ, Merk HF, Reisinger K. 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):263-75. [Crossref] [PubMed]
- Groeber F, Schober L, Schmid FF, Traube A, Kolbus-Hernandez S, Daton K, et al. Catch-up validation study of an in vitro skin irritation test method based on an open source reconstructed epidermis (phase II). Toxicol In Vitro. 2016;36:254-261. [Crossref] [PubMed]
- Phenion [İnternet]. ©2020 Henkel AG & Co. KGaA [Erişim tarihi: 10.08.2020]. The Phenion® Open Source Reconstructed Epidermis [OS-REp] goes live! Erişim linki: [Link]
- Alépée N, Bahinski A, Daneshian M, De Wever B, Fritsche E, Goldberg A, et al. State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology. ALTEX. 2014;31(4):441-77. [Crossref] [PubMed] [PMC]
- Groeber F, Engelhardt L, Lange J, Kurdyn S, Schmid FF, Rücker C, et al. A first vascularized skin equivalent as an alternative to animal experimentation. ALTEX. 2016;33(4):415-422. [Crossref] [PubMed]
- Cellink Life Sciences [İnternet]. CELLINK 2021, All rights reserved [Erişim tarihi: 10.08.2020]. The skinny on bioprinting human skin. Erişim linki: [Link]
- BioSpace [İnternet]. ©1985-2021 BioSpace.com [Erişim Tarihi: 10.08.2020]. Bioprinting advanced skin architecture complete with blood vessels using cellink technology. Erişim linki: [Link]
- News medical life sciences [İnternet]. An AZoNetwork Site Owned and operated by AZoNetwork, © 2000-2021 [Erişim tarihi: 10.08.2020]. Labskin-3D human skin model for ethical testing. Erişim linki: [Link]
- Harvey A, Cole LM, Day R, Bartlett M, Warwick J, Bojar R, et al. MALDI-MSI for the analysis of a 3D tissue-engineered psoriatic skin model. Proteomics. 2016;16(11-2):1718-25. [Crossref] [PubMed] [PMC]
- El Ghalbzouri A, Siamari R, Willemze R, Ponec M. Leiden reconstructed human epidermal model as a tool for the evaluation of the skin corrosion and irritation potential according to the ECVAM guidelines. Toxicol In Vitro. 2008;22(5):1311-20. [Crossref] [PubMed]
- Mathes SH, Ruffner H, Graf-Hausner U. The use of skin models in drug development. Adv Drug Deliv Rev. 2014;69-70:81-102. [Crossref] [PubMed]
- Straticell [İnternet]. ©2020 - Straticell | designed with passion by weeb [Erişim tarihi: 10.08.2020]. In Vitro Skin Models.
- Suhail S, Sardashti N, Jaiswal D, Rudraiah S, Misra M, Kumbar SG. Engineered Skin Tissue Equivalents for Product Evaluation and Therapeutic Applications. Biotechnol J. 2019;14(7):e1900022. [Crossref] [PubMed] [PMC]
- Nam KH, Smith AS, Lone S, Kwon S, Kim DH. Biomimetic 3D Tissue Models for Advanced High-Throughput Drug Screening. J Lab Autom. 2015;20(3):201-15. [Crossref] [PubMed] [PMC]
- Pedrosa TDN, Catarino CM, Pennacchi PC, Assis SR, Gimenes F, Consolaro MEL, et al. A new reconstructed human epidermis for in vitro skin irritation testing. Toxicol In Vitro. 2017;42:31-37. [Crossref] [PubMed]
- Lee JY, Lee J, Min D, Kim J, Kim HJ, No KT. Tyrosinase-Targeting Gallacetophenone Inhibits Melanogenesis in Melanocytes and Human Skin-Equivalents. Int J Mol Sci. 2020;21(9):3144. [Crossref] [PubMed] [PMC]
- Pillaiyar T, Manickam M, Namasivayam V. Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors. J Enzyme Inhib Med Chem. 2017;32(1):403-425. [Crossref] [PubMed] [PMC]
- Mattek [İnternet]. ©2021 mattek all rights reserved [Erişim tarihi: 10.08.2020]. MelanoDerm?. Erişim linki: [Link]
- epiCS (Erişim Tarihi: 10.08.2020) [Link]
- Cell Systems [İnternet]. ©2020 Imprint - Privacy Policy [Erişim tarihi: 10.08.2020]. epiCS-M/Human Epidermis Equivalent with Melanocytes.
- EU Science Hub [İnternet]. [Erişim tarihi: 10.08.2020]. SAC Opinion on the validation study of the epiCS® Skin Irritation Test (SIT) based on the EURL ECVAM/ OECD Performance Standards for in vitro skin irritation testing using Reconstructed human Epidermis (RhE). Erişim linki: [Link]
- Rasmussen C, Gratz K, Liebel F, Southall M, Garay M, Bhattacharyya S, et al. The StrataTest® human skin model, a consistent in vitro alternative for toxicological testing. Toxicol In Vitro. 2010;24(7):2021-9. [Crossref] [PubMed]
- Gratz K, Rasmussen C, Corner A, Pirnstill S, Nataraj P, Simon S, Allen-Hoffman L. Utility of StrataTest (R), an in vitro human skin model, for skin irritancy and corrosivity assessments. Toxicology Letters. 2009;189:S85. [Crossref]
- Bernard FX, Barrault C, Deguercy A, De Wever B, Rosdy M. Development of a highly sensitive in vitro phototoxicity assay using the SkinEthic reconstructed human epidermis. Cell Biol Toxicol. 2000;16(6):391-400. [Crossref] [PubMed]
- Brohem CA, Cardeal LB, Tiago M, Soengas MS, Barros SB, Maria-Engler SS. Artificial skin in perspective: concepts and applications. Pigment Cell Melanoma Res. 2011;24(1):35-50. [Crossref] [PubMed] [PMC]
- Jones PA, King AV, Earl LK, Lawrence RS. An assessment of the phototoxic hazard of a personal product ingredient using in vitro assays. Toxicol In Vitro. 2003;17(4):471-80. [Crossref] [PubMed]
- Bayer M, Doucet O, Garcia NL, Marty JP, Zastrow L. Use of reconstituted human epidermis cultures to assess the disrupting effect of organic solvents on the barrier function of excised human skin. In Vitro and Molecular Toxicology. 2000;13(3):159-71. [Link]
- Lago MEL, Cerqueira MT, Pirraco RP, Reis RL, Marques AP. Skin in vitro models to study dermal white adipose tissue role in skin healing. In: Marques AP, Pirraco RP, Cerqueira MT, Reis RL, eds. Skin Tissue Models. 1st ed. USA: Academic Press, Elsevier, Cambridge, MA; 2018. p. 327-52. [Crossref]
- Cavo M, Fato M, Pe-uela L, Beltrame F, Raiteri R, Scaglione S. Microenvironment complexity and matrix stiffness regulate breast cancer cell activity in a 3D in vitro model. Sci Rep. 2016;6:35367. [Crossref] [PubMed] [PMC]
- Randall MJ, 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. [Crossref] [PubMed] [PMC]
- Sakolish CM, Esch MB, Hickman JJ, Shuler ML, Mahler GJ. Modeling Barrier Tissues In Vitro: Methods, Achievements, and Challenges. EBioMedicine. 2016;5:30-9. [Crossref] [PubMed] [PMC]
- Abaci HE, Guo Z, Doucet Y, Jacków J, Christiano A. Next generation human skin constructs as advanced tools for drug development. Exp Biol Med (Maywood). 2017;242(17):1657-68. [Crossref] [PubMed] [PMC]
- Arnette C, Koetsier JL, Hoover P, Getsios S, Green KJ. In Vitro Model of the Epidermis: Connecting Protein Function to 3D Structure. Methods Enzymol. 2016;569:287-308. [Crossref] [PubMed] [PMC]
- Nathoo R, Howe N, Cohen G. Skin substitutes: an overview of the key players in wound management. J Clin Aesthet Dermatol. 2014;7(10):44-8. [PubMed] [PMC]
- Jeschke MG, van Baar ME, Choudhry MA, Chung KK, Gibran NS, Logsetty S. Burn injury. Nat Rev Dis Primers. 2020;6(1):11. [Crossref] [PubMed] [PMC]
- Perez-Favila A, Martinez-Fierro ML, Rodriguez-Lazalde JG, Cid-Baez MA, Zamudio-Osuna MJ, Martinez-Blanco MDR, et al. Current Therapeutic Strategies in Diabetic Foot Ulcers. Medicina (Kaunas). 2019;55(11):714. [Crossref] [PubMed] [PMC]
- Shpichka A, Butnaru D, Bezrukov EA, Sukhanov RB, Atala A, Burdukovskii V, et al. Skin tissue regeneration for burn injury. Stem Cell Res Ther. 2019;10(1):94. [Crossref] [PubMed] [PMC]
- Genoskin ex vivo clinical testing [İnternet]. Genoskin ©2020 [Erişim tarihi: 10.08.2020]. Incospharm publishes results using NativeSkin®. Erişim linki: [Link]
- Organogenesis [İnternet]. ©2020 Organogenesis Inc. [Erişim tarihi: 10.08.2020]. Apligraf. Erişim linki: [Link]
- Zaulyanov L, Kirsner RS. A review of a bi-layered living cell treatment (Apligraf) in the treatment of venous leg ulcers and diabetic foot ulcers. Clin Interv Aging. 2007;2(1):93-8. [Crossref] [PubMed] [PMC]
- Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound Healing: A Cellular Perspective. Physiol Rev. 2019;99(1):665-706. [Crossref] [PubMed] [PMC]
- Hart CE, Loewen-Rodriguez A, Lessem J. Dermagraft: Use in the Treatment of Chronic Wounds. Adv Wound Care (New Rochelle). 2012;1(3):138-141. [Crossref] [PubMed] [PMC]
- Li X, Xu G, Chen J. Tissue engineered skin for diabetic foot ulcers: a meta-analysis. Int J Clin Exp Med. 2015;8(10):18191-6. [PubMed] [PMC]
- Santema TB, Poyck PP, Ubbink DT. Skin grafting and tissue replacement for treating foot ulcers in people with diabetes. Cochrane Database Syst Rev. 2016;2(2):CD011255. [Crossref] [PubMed] [PMC]
- Food and Drug Administration [İnternet]. [Erişim tarihi: 10.08.2020]. Summary of safety and effectiveness data. Erişim linki: [Link]
- Savoji H, Godau B, Hassani MS, Akbari M. Skin Tissue Substitutes and Biomaterial Risk Assessment and Testing. Front Bioeng Biotechnol. 2018;6:86. [Crossref] [PubMed] [PMC]
- Varkey M, Ding J, Tredget EE. Advances in Skin Substitutes-Potential of Tissue Engineered Skin for Facilitating Anti-Fibrotic Healing. J Funct Biomater. 2015;6(3):547-63. [Crossref] [PubMed] [PMC]
- JAWSpodiatry [İnternet]. Copyright © 2020 JAWS Podiatry [Erişim tarihi: 10.08.2020]. TheraSkin Skin Graft Surgery. Erişim linki: [Link]
- Wound Source. [İnternet]. © 2008-2021 Kestrel Health Information, Inc. [Erişim tarihi: 10.08.2020]. TheraSkin®. Erişim linki: [Link]
- Horch RE, Jeschke MG, Spilker G, Herndon DN, Kopp J. Treatment of second degree facial burns with allografts--preliminary results. Burns. 2005;31(5):597-602. [Crossref] [PubMed]
- Supp DM, Boyce ST. Engineered skin substitutes: practices and potentials. Clin Dermatol. 2005;23(4):403-12. [Crossref] [PubMed]
- Shakespeare P, Shakespeare V. Survey: use of skin substitute materials in UK burn treatment centres. Burns. 2002;28(4):295-7. [Crossref] [PubMed]
- Shakespeare PG. The role of skin substitutes in the treatment of burn injuries. Clin Dermatol. 2005;23(4):413-8. [Crossref] [PubMed]
- Bello YM, Falabella AF, Eaglstein WH. Tissue-engineered skin. Current status in wound healing. Am J Clin Dermatol. 2001;2(5):305-13. [Crossref] [PubMed]
- Leigh IM, Watt FM. The culture of human epidermal keratinocytes. In: Leigh I, Lane B, Watt F, eds. The keratinocyte handbook. 1st ed. UK/Cambridge: Cambridge University Press; 1994. p. 43-51.
- Rheinwald JG, Green H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell. 1975;6(3):331-43. [Crossref] [PubMed]
.: Process List