to irritants and increased TEWL, indicating that these two CER species are essential for barrier function.63 One research group demonstrated that a twice-daily regimen of a synthetic CERcontaining cleanser and moisturizer in AD patients significantly improved skin condition, clinical outcome, and quality of life after 42-day treatment.64 Similarly, combining synthetic skinidentical CERs 1, 3 6-II with multi-lamellar vesicular emulsion (MVE) technology can effectively deliver these lipids within the skin layers over a sustained period of time.65 This unique approach to CER-containing formulation was shown to restore skin barrier integrity and improve clinical appearance of rosacea, eczema, skin dryness, and more recently in conjunction with combination therapy, for treating facial acne vulgaris.65–69 While there is clear evidence of barrier restoration following the mentioned routines of ceramide-infused skin products, continuous research is essential in identifying the correct combination of skin essential lipids in conjunction with a proper delivery system in order to improve and maximize skin health.
CONCLUSION
Lipid abnormalities, stemmed from inherited, exogenous, or pathological factors, are often associated with impaired skin barrier function and integrity. To achieve optimal results and bring the right strategy for skin care formulation, it is crucial to utilize models to not only understand skin barrier function but the role of lipids in maintaining barrier integrity. In situ, ex vivo, and RHE models are value tools in understanding the relationship of lipids with skin barrier integrity without the ethical constraints present in clinical evaluations. However, such models exist in controlled and simplified conditions that may not hold true for real-world applications. Ex vivo models are able to provide a comprehensive and clinically relevant understanding to barrier components because of its intact barrier. As the models grow in complexity, the full barrier function, especially lipid composition, can be thoroughly evaluated; however, there is an increasing limitation in study size and biological variability.
Because of their benefits in promoting health barrier function, improving appearance of lesions, minimizing skin irritation, and increasing patients’ compliance and treatment efficacy, incorporation of CERs and other barrier-enforcing lipids into formulas have become increasingly popular across the skincare field. In the future, it would be critical to determine the benefits of these lipids-containing formulations on compromised skin barrier caused by daily skin stressors, such as pollution and UVR.
Because of their benefits in promoting health barrier function, improving appearance of lesions, minimizing skin irritation, and increasing patients’ compliance and treatment efficacy, incorporation of CERs and other barrier-enforcing lipids into formulas have become increasingly popular across the skincare field. In the future, it would be critical to determine the benefits of these lipids-containing formulations on compromised skin barrier caused by daily skin stressors, such as pollution and UVR.
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28. Mieremet A, Rietveld M, Absalah S, et al. Improved epidermal barrier formation in human skin models by Chitosan modulated dermal matrices. PLoS One. 2017;12(3). doi:10.1371/journal.pone.0174478
2. De Jager MW, Gooris GS, Ponec M, Bouwstra JA. Lipid mixtures prepared with well-defined synthetic ceramides closely mimic the unique stratum corneum lipid phase behavior. J Lipid Res. 2005. doi:10.1194/jlr.M500221- JLR200
3. Groen D. Stratum corneum model membranes: molecular organization in relation to skin barrier function. 2011.
4. Groen D, Gooris GS, Barlow DJ, et al. Disposition of ceramide in model lipid membranes determined by neutron diffraction. Biophys J. 2011. doi:10.1016/j. bpj.2011.02.001
5. Bouwstra JA, Gooris GS, Dubbelaar FER, Ponec M. Phase behavior of lipid mixtures based on human ceramides: Coexistence of crystalline and liquid phases. J Lipid Res. 2001.
6. Gooris GS, Bouwstra JA. Infrared spectroscopic study of stratum corneum model membranes prepared from human ceramides, cholesterol, and fatty acids. Biophys J. 2007. doi:10.1529/biophysj.106.094292
7. de Jager M, Groenink W, van der Spek J, et al. Preparation and characterization of a stratum corneum substitute for in vitro percutaneous penetration studies. Biochim Biophys Acta - Biomembr. 2006. doi:10.1016/j. bbamem.2006.04.001
8. Školová B, Januìššová B, Zbytovská J, et al. Ceramides in the skin lipid membranes: Length matters. Langmuir. 2013. doi:10.1021/la4037474
9. Groen D, Poole DS, Gooris GS, Bouwstra JA. Is an orthorhombic lateral packing and a proper lamellar organization important for the skin barrier function? Biochim Biophys Acta - Biomembr. 2011. doi:10.1016/j. bbamem.2010.10.015
10. Groen D, Poole DS, Gooris GS, Bouwstra JA. Investigating the barrier function of skin lipid models with varying compositions. Eur J Pharm Biopharm. 2011. doi:10.1016/j.ejpb.2011.05.007
11. Sun T, McMinn P, Coakley S, et al. An integrated systems biology approach to understanding the rules of keratinocyte colony formation. J R Soc Interface. 2007. doi:10.1098/rsif.2007.0227
12. Das C, Olmsted PD. The physics of stratum corneum lipid membranes. Philos Trans R Soc A Math Phys Eng Sci. 2016. doi:10.1098/rsta.2015.0126
13. Gupta R, Dwadasi BS, Rai B. Molecular dynamics simulation of skin lipids: effect of ceramide chain lengths on bilayer properties. J Phys Chem B. 2016. doi:10.1021/acs.jpcb.6b08059
14. Moore TC, Iacovella CR, Leonhard AC, Bunge AL, McCabe C. Molecular dynamics simulations of stratum corneum lipid mixtures: A multiscale perspective. Biochem Biophys Res Commun. 2018. doi:10.1016/j. bbrc.2017.09.040
15. Kmiecik S, Gront D, Kolinski M, et al. Coarse-grained protein models and their applications. Chem Rev. 2016. doi:10.1021/acs.chemrev.6b00163
16. Marques AP, Reis RL, Pirraco RP, Cerqueira M. Skin Tissue Models.
17. Niehues H, Bouwstra JA, El Ghalbzouri A, et al. 3D skin models for 3R research: The potential of 3D reconstructed skin models to study skin barrier function. Exp Dermatol. 2018;27(5):501-511. doi:10.1111/exd.13531
18. Desprez B, Barroso J, Griesinger C, et al. Two novel prediction models improve predictions of skin corrosive sub-categories by test methods of OECD Test Guideline No. 431. Toxicol Vitr. 2015;29(8):2055-2080. doi:10.1016/j.tiv.2015.08.015
19. Smits JPH, Niehues H, Rikken G, et al. Immortalized N/TERT keratinocytes as an alternative cell source in 3D human epidermal models.
20. Wei Z, Liu X, Ooka M, et al. Two-dimensional cellular and threedimensional bio-printed skin models to screen topical-use compounds for irritation potential. Front Bioeng Biotechnol. 2020;8:109. doi:10.3389/ FBIOE.2020.00109
21. Ramadan Q, Ting FCW, Thyssen JP, et al. In vitro micro-physiological immune-competent model of the human skin. Lab Chip. 2016;16(10):1899- 1908. doi:10.1039/C6LC00229C
22. Sriram G, Bigliardi PL, Bigliardi-Qi M. Full-thickness human skin equivalent models of atopic dermatitis. Methods Mol Biol. 2019;1879:367-383. doi:10.1007/7651_2018_163
23. Boehnke K, Mirancea N, Pavesio A, Fusenig NE, Boukamp P, Stark HJ. Effects of fibroblasts and microenvironment on epidermal regeneration and tissue function in long-term skin equivalents. Eur J Cell Biol. 2007;86(11- 12):731-746. doi:10.1016/j.ejcb.2006.12.005
24. Smits JPH, Niehues H, Rikken G, et al. Immortalized N/TERT keratinocytes as an alternative cell source in 3D human epidermal models. Sci Rep. 2017;7(1):11838. doi:10.1038/s41598-017-12041-y
25. Hawkes JE, Chan TC, Krueger JG, York N. Psoriasis pathogenesis and the development of novel targeted immune therapies. 2017. doi:10.1016/j. jaci.2017.07.004
26. Bernard F-X, Morel F, Camus M, et al. Keratinocytes under fire of proinflammatory cytokines: bona fide innate immune cells involved in the physiopathology of chronic atopic dermatitis and psoriasis. J Allergy. 2012;2012:1-10. doi:10.1155/2012/718725
27. Harvey A, Cole LM, Day R, et al. MALDI-MSI for the analysis of a 3D tissueengineered psoriatic skin model. Proteomics. 2016;16(11-12):1718-1725. doi:10.1002/pmic.201600036
28. Mieremet A, Rietveld M, Absalah S, et al. Improved epidermal barrier formation in human skin models by Chitosan modulated dermal matrices. PLoS One. 2017;12(3). doi:10.1371/journal.pone.0174478
