SpringerLink
Log in

Highly Porous and Rigid, Full-thickness Human Skin Model from the Slime-webbed Fiber Scaffold

  • Research Paper
  • Published:
Biotechnology and Bioprocess Engineering Aims and scope Submit manuscript

Abstract

Collagen is the most prevalent scaffold material for in vitro skin models. The major limitation of collagen scaffold is its mechanical weakness, resulting in severe contraction during differentiation. Here, we presented a slime-webbed scaffold composed of perpendicularly stacked fibers with large pores. This slime-webbed scaffold did not contract while improving molecular transport and achieving comparable cell viability. Fibroblasts were seeded into the slime-webbed scaffold to mimic the dermal layer. In the epidermal layer, which was on top of this scaffold, keratinocytes expressed the differentiation biomarkers, keratin-5 and involucrin. Our slime-webbed scaffold-based human skin models overcome the critical limitations of collagen scaffold, suggesting a promising alternative skin model for consistent testing of drugs or cosmetic products.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Thailand)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Matsusaki, M., K. Fujimoto, Y. Shirakata, S. Hirakawa, K. Hashimoto, and M. Akashi (2015) Development of full-thickness human skin equivalents with blood and lymph-like capillary networks by cell coating technology. J. Biomed. Mater. Res. A 103: 3386–3396.

    Article  CAS  PubMed  Google Scholar 

  2. Serpell, J. (1996) In the Company of Animals: A Study of Human-Animal Relationships. Cambridge University Press, Cambridge, UK.

    Google Scholar 

  3. Watson, M. E., Jr., M. N. Neely, and M. G. Caparon (2016) Animal models of Streptococcus pyogenes infection. pp. 497–521. In: J. J. Ferretti, D. L. Stevens, and V. A. Fischetti (eds.). Streptococcus pyogenes: Basic Biology to Clinical Manifestations. University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

    Google Scholar 

  4. Schmook, F. P., J. G. Meingassner, and A. Billich (2001) Comparison of human skin or epidermis models with human and animal skin in in-vitro percutaneous absorption. Int. J. Pharm. 215: 51–56.

    Article  CAS  PubMed  Google Scholar 

  5. Seok, J., H. S. Warren, A. G. Cuenca, M. N. Mindrinos, H. V. Baker, W. Xu, D. R. Richards, G. P. McDonald-Smith, H. Gao, L. Hennessy, C. C. Finnerty, C. M. López, S. Honari, E. E. Moore, J. P. Minei, J. Cuschieri, P. E. Bankey, J. L. Johnson, J. Sperry, A. B. Nathens, T. R. Billiar, M. A. West, M. G. Jeschke, M. B. Klein, R. L. Gamelli, N. S. Gibran, B. H. Brownstein, C. Miller-Graziano, S. E. Calvano, P. H. Mason, J. P. Cobb, L. G. Rahme, S. F. Lowry, R. V. Maier, L. L. Moldawer, D. N. Herndon, R. W. Davis, W. **ao, R. G. Tompkins, and Inflammation and Host Response to Injury, Large Scale Collaborative Research Program (2013) Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl. Acad. Sci. U. S. A. 110: 3507–3512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Warren, H. S., C. Fitting, E. Hoff, M. Adib-Conquy, L. Beasley-Topliffe, B. Tesini, X. Liang, C. Valentine, J. Hellman, D. Hayden, and J. M. Cavaillon (2010) Resilience to bacterial infection: difference between species could be due to proteins in serum. J. Infect. Dis. 201: 223–232.

    Article  CAS  PubMed  Google Scholar 

  7. Olson, H., G. Betton, J. Stritar, and D. Robinson (1998) The predictivity of the toxicity of pharmaceuticals in humans from animal data—an interim assessment. Toxicol. Lett. 102–103: 535–538.

    Article  PubMed  Google Scholar 

  8. Kola, I. and J. Landis (2004) Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3: 711–716.

    Article  CAS  PubMed  Google Scholar 

  9. Bell, E., H. P. Ehrlich, D. J. Buttle, and T. Nakatsuji (1981) Living tissue formed in vitro and accepted as skin-equivalent tissue of full thickness. Science 211: 1052–1054.

    Article  CAS  PubMed  Google Scholar 

  10. Adler, S., D. Basketter, S. Creton, O. Pelkonen, J. van Benthem, V. Zuang, K. E. Andersen, A. Angers-Loustau, A. Aptula, A. Bal-Price, E. Benfenati, U. Bernauer, J. Bessems, F. Y. Bois, A. Boobis, E. Brandon, S. Bremer, T. Broschard, S. Casati, S. Coecke, R. Corvi, M. Cronin, G. Daston, W. Dekant, S. Felter, E. Grignard, U. Gundert-Remy, T. Heinonen, I. Kimber, J. Kleinjans, H. Komulainen, R. Kreiling, J. Kreysa, S. B. Leite, G. Loizou, G. Maxwell, P. Mazzatorta, S. Munn, S. Pfuhler, P. Phrakonkham, A. Piersma, A. Poth, P. Prieto, G. Repetto, V. Rogiers, G. Schoeters, M. Schwarz, R. Serafimova, H. Tähti, E. Testai, J. Delft, H. Loveren, M. Vinken, A. Worth, and J. M. Zaldivar (2011) Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. Arch. Toxicol. 85: 367–485.

    Article  CAS  PubMed  Google Scholar 

  11. Vinci, M., S. Gowan, F. Boxall, L. Patterson, M. Zimmermann, W. Court, C. Lomas, M. Mendiola, D. Hardisson, and S. A. Eccles (2012) Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation. BMC Biol. 10: 29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ravi, M., V. Paramesh, S. R. Kaviya, E. Anuradha, and F. D. Solomon (2015) 3D cell culture systems: advantages and applications. J. Cell. Physiol. 230: 16–26.

    Article  CAS  PubMed  Google Scholar 

  13. Rhee, S. (2009) Fibroblasts in three dimensional matrices: cell migration and matrix remodeling. Exp. Mol. Med. 41: 858–865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chau, D. Y., C. Johnson, S. MacNeil, J. W. Haycock, and A. M. Ghaemmaghami (2013) The development of a 3D immunocompetent model of human skin. Biofabrication 5: 035011.

    Article  CAS  PubMed  Google Scholar 

  15. Wenger, M. P., L. Bozec, M. A. Horton, and P. Mesquida (2007) Mechanical properties of collagen fibrils. Biophys. J. 93: 1255–1263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sutterby, E., P. Thurgood, S. Baratchi, K. Khoshmanesh, and E. Pirogova (2020) Microfluidic skin-on-a-chip models: toward biomimetic artificial skin. Small 16: e2002515.

    Article  PubMed  Google Scholar 

  17. Grinnell, F. (2000) Fibroblast-collagen-matrix contraction: growth-factor signalling and mechanical loading. Trends Cell Biol. 10: 362–365.

    Article  CAS  PubMed  Google Scholar 

  18. Han, Y. L., P. Ronceray, G. Xu, A. Malandrino, R. D. Kamm, M. Lenz, C. P. Broedersz, and M. Guo (2018) Cell contraction induces long-ranged stress stiffening in the extracellular matrix. Proc. Natl. Acad. Sci. U. S. A. 115: 4075–4080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ramtani, S. (2004) Mechanical modelling of cell/ECM and cell/cell interactions during the contraction of a fibroblast-populated collagen microsphere: theory and model simulation. J. Biomech. 37: 1709–1718.

    Article  CAS  PubMed  Google Scholar 

  20. Grinnell, F., C. H. Ho, Y. C. Lin, and G. Skuta (1999) Differences in the regulation of fibroblast contraction of floating versus stressed collagen matrices. J. Biol. Chem. 274: 918–923.

    Article  CAS  PubMed  Google Scholar 

  21. Ackermann, K., S. L. Borgia, H. C. Korting, K. R. Mewes, and M. Schäfer-Korting (2010) The Phenion full-thickness skin model for percutaneous absorption testing. Skin Pharmacol. Physiol. 23: 105–112.

    Article  CAS  PubMed  Google Scholar 

  22. Charulatha, V. and A. Rajaram (2003) Influence of different crosslinking treatments on the physical properties of collagen membranes. Biomaterials 24: 759–767.

    Article  CAS  PubMed  Google Scholar 

  23. Jeong, S., J. Kim, H. M. Jeon, K. Kim, and G. Y. Sung (2021) Development of an aged full-thickness skin model using flexible skin-on-a-chip subjected to mechanical stimulus reflecting the circadian rhythm. Int. J. Mol. Sci. 22: 12788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhao, X., Q. Lang, L. Yildirimer, Z. Y. Lin, W. Cui, N. Annabi, K. W. Ng, M. R. Dokmeci, A. M. Ghaemmaghami, and A. Khademhosseini (2016) Photocrosslinkable gelatin hydrogel for epidermal tissue engineering. Adv. Healthc. Mater. 5: 108–118.

    Article  CAS  PubMed  Google Scholar 

  25. Kwak, B. S., W. Choi, J. W. Jeon, J. I. Won, G. Y. Sung, B. Kim, and J. H. Sung (2018) In vitro 3D skin model using gelatin methacrylate hydrogel. J. Ind. Eng. Chem. 66: 254–261.

    Article  CAS  Google Scholar 

  26. Sriram, G., M. Alberti, Y. Dancik, B. Wu, R. Wu, Z. Feng, S. Ramasamy, P. L. Bigliardi, M. Bigliardi-Qi, and Z. Wang (2018) Full-thickness human skin-on-chip with enhanced epidermal morphogenesis and barrier function. Mater. Today (Kidlington) 21: 326–340.

    Article  CAS  Google Scholar 

  27. Jusoh, N., J. Ko, and N. L. Jeon (2019) Microfluidics-based skin irritation test using in vitro 3D angiogenesis platform. APL Bioeng. 3: 036101.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Rhee, J. K. (2019) Fiber manufacturing apparatus. US Patent 11,091,853.

  29. Avendano, A., J. J. Chang, M. G. Cortes-Medina, A. J. Seibel, B. R. Admasu, C. M. Boutelle, A. R. Bushman, A. A. Garg, C. M. DeShetler, S. L. Cole, and J. W. Song (2020) Integrated biophysical characterization of fibrillar collagen-based hydrogels. ACS Biomater. Sci. Eng. 6: 1408–1417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lee, S., S. P. **, Y. K. Kim, G. Y. Sung, J. H. Chung, and J. H. Sung (2017) Construction of 3D multicellular microfluidic chip for an in vitro skin model. Biomed. Microdevices 19: 22.

    Article  PubMed  Google Scholar 

  31. Lee, W., V. Lee, S. Polio, P. Keegan, J. H. Lee, K. Fischer, J. K. Park, and S. S. Yoo (2010) On-demand three-dimensional freeform fabrication of multi-layered hydrogel scaffold with fluidic channels. Biotechnol. Bioeng. 105: 1178–1186.

    CAS  PubMed  Google Scholar 

  32. Song, H. J., H. Y. Lim, W. Chun, K. C. Choi, J. H. Sung, and G. Y. Sung (2017) Fabrication of a pumpless, microfluidic skin chip from different collagen sources. J. Ind. Eng. Chem. 56: 375–381.

    Article  CAS  Google Scholar 

  33. Carlson, M. W., A. Alt-Holland, C. Egles, and J. A. Garlick (2008) Three-dimensional tissue models of normal and diseased skin. Curr. Protoc. Cell Biol. Chapter 19: Unit 19.9.

  34. D’Orazio, J., S. Jarrett, A. Amaro-Ortiz, and T. Scott (2013) UV radiation and the skin. Int. J. Mol. Sci. 14: 12222–12248.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Reijnders, C. M., A. van Lier, S. Roffel, D. Kramer, R. J. Scheper, and S. Gibbs (2015) Development of a full-thickness human skin equivalent in vitro model derived from TERT-immortalized keratinocytes and fibroblasts. Tissue Eng. Part A 21: 2448–2459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the Technology development Program of MSS (S3251721, S3316767) by Korea Technology and Information Promotion Agency, Basic Research Lab (2022R1A4A2000748) and Bio & Medical Technology Development Program (2022M3A9B6018217) by National Research Foundation of Korea, Technology Innovation Program (20008414) and the Alchemist Project of the Korea Evaluation Institute of Industrial Technology (KEIT 20018560, NTIS 1415180625) by the Ministry of Trade, Industry & Energy (MOTIE), Hongik University Research Fund. It was also supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) by the Ministry of Education, Science and Technology (NRF-2021R1F1A1056188), the High Value-added Food Technology Development Program, the Ministry of Agriculture, Food and Rural Affairs (MAFRA) (321021031HD030), RP-Grant 2020 and Research Grant 2020–2021 of Ewha Womans University.

Author information

Author notes

  1. Jae Jung Kim and Nam Keun Lee contributed equally to this work.

Authors and Affiliations

  1. Department of Chemical Engineering, Hongik University, Seoul, 04066, Korea

    Jae Jung Kim, Da Eun Ryu, Byoung Ho Ko, Ju Hyeon Kim & Jong Hwan Sung

  2. Department of Food Science and Biotechnology, Ewha Womans University, Seoul, 03760, Korea

    Nam Keun Lee & **-Kyu Rhee

  3. SuFAB Inc., Cheongju, 28116, Korea

    **-Kyu Rhee

Authors
  1. Jae Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nam Keun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Da Eun Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Byoung Ho Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ju Hyeon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. **-Kyu Rhee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jong Hwan Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to **-Kyu Rhee or Jong Hwan Sung.

Ethics declarations

The authors declare no conflict of interest.

Neither ethical approval nor informed consent was required for this study.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material (ESM)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, J.J., Lee, N.K., Ryu, D.E. et al. Highly Porous and Rigid, Full-thickness Human Skin Model from the Slime-webbed Fiber Scaffold. Biotechnol Bioproc E 28, 246–254 (2023). https://doi.org/10.1007/s12257-022-0341-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12257-022-0341-0

Keywords

Search

Navigation