Skip to main content
SpringerLink
Log in

Basic Aspects of Skin Tissue Engineering: Cells, Biomaterials, Scaffold Fabrication Techniques, and Signaling Factors

  • Review Article
  • Published:
Journal of Medical and Biological Engineering Aims and scope Submit manuscript

Abstract

Purpose

Skin injuries are a worldwide health issue that affects millions of people each year. Tissue engineering has the potential to provide an opportunity to resolve this challenge. For more than 40 decades, researchers have focused on different aspects of skin tissue engineering. The purpose of the present study was to provide a comprehensive overview of the critical factors in skin tissue engineering.

Methods

Recent studies were investigated to gather relevant studies about the basic aspects of skin tissue engineering.

Results

In the present review, the nature of the native skin and natural repair of the skin injuries is described. The knowledge of this part is a foundation for producing a tissue or organ that mimics the actual one. Then, the different essential elements in skin tissue engineering are underlined. In this regard, a variety of cells and scaffolds that create the main structure of the engineered constructs are emphasized. On the other hand, the application of critical signaling factors including biochemical, physicochemical, and physical factors in skin tissue engineering are reviewed.

Conclusion

A comprehensive review of these components clarifies critical points in the regenerative medicine of the skin and guides researchers to adopt optimized approaches to achieve a viable and functional construct.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Wong, R., Geyer, S., Weninger, W., Guimberteau, J. C., & Wong, J. K. (2016). The dynamic anatomy and patterning of skin. Experimental Dermatology, 25(2), 92–98. https://doi.org/10.1111/exd.12832

    Article  PubMed  Google Scholar 

  2. White, S. D., & Yager, J. A. (1995). Resident dendritic cells in the epidermis: Langerhans cells, Merkel cells and melanocytes. Veterinary Dermatology, 6(1), 1–8. https://doi.org/10.1111/j.1365-3164.1995.tb00034.x

    Article  PubMed  Google Scholar 

  3. Zaidi, Z., & Lanigan, S. W. (2010). Skin: Structure and function. Dermatology in clinical practice. London: Springer.

    Google Scholar 

  4. Macefield, V. G. (2005). Physiological characteristics of low-threshold mechanoreceptors in joints, muscle and skin in human subjects. Clinical and Experimental Pharmacology and Physiology, 32(1–2), 135–144. https://doi.org/10.1111/j.1440-1681.2005.04143.x

    Article  PubMed  Google Scholar 

  5. Rittié, L. (2016). Cellular mechanisms of skin repair in humans and other mammals. Journal of Cell Communication and Signaling, 10(2), 103–120. https://doi.org/10.1007/s12079-016-0330-1

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ridiandries, A., Tan, J. T. M., & Bursill, C. A. (2018). The role of chemokines in wound healing. International Journal of Molecular Sciences, 19(10), 3217. https://doi.org/10.3390/ijms19103217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Clark, R. (1994). Wound repair. In R. A. F. Clark (Ed.), The molecular and cellular biology of wound repair. Boston: Springer.

    Google Scholar 

  8. Rheinwald, J., & Green, H. (1975). Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell, 6(3), 331–343.

    Article  CAS  PubMed  Google Scholar 

  9. Farhadihosseinabadi, B., Farahani, M., Tayebi, T., Jafari, A., Biniazan, F., Modaresifar, K., Moravvej, H., Bahrami, S., Redl, H., & Tayebi, L. (2018). Amniotic membrane and its epithelial and mesenchymal stem cells as an appropriate source for skin tissue engineering and regenerative medicine. Artificial Cells, Nanomedicine, and Biotechnology, 46(sup2), 431–440. https://doi.org/10.1080/21691401.2018.1458730

    Article  CAS  PubMed  Google Scholar 

  10. Keirouz, A., Zakharova, M., Kwon, J., Robert, C., Koutsos, V., Callanan, A., Chen, X., Fortunato, G., & Radacsi, N. (2020). High-throughput production of silk fibroin-based electrospun fibers as biomaterial for skin tissue engineering applications. Materials Science and Engineering: C, 112, 110939. https://doi.org/10.1016/j.msec.2020.110939

    Article  CAS  PubMed  Google Scholar 

  11. Rad, Z. P., Mokhtari, J., & Abbasi, M. (2018). Fabrication and characterization of PCL/zein/gum Arabic electrospun nanocomposite scaffold for skin tissue engineering. Materials Science and Engineering: C, 93, 356–366. https://doi.org/10.1016/j.msec.2018.08.010

    Article  CAS  Google Scholar 

  12. Zelen, C. M., Serena, T. E., Gould, L., Le, L., Carter, M. J., Keller, J., & Li, W. W. (2016). Treatment of chronic diabetic lower extremity ulcers with advanced therapies: A prospective, randomised, controlled, multi-centre comparative study examining clinical efficacy and cost. International Wound Journal, 13(2), 272–282. https://doi.org/10.1111/iwj.12566

    Article  PubMed  Google Scholar 

  13. Nicholas, M. N., Jeschke, M. G., & Amini-Nik, S. (2016). Cellularized bilayer pullulan-gelatin hydrogel for skin regeneration. Tissue Engineering Part A, 22(9–10), 754–764. https://doi.org/10.1089/ten.TEA.2015.0536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sabolinski, M. L., & Gibbons, G. (2018). Comparative effectiveness of a bilayered living cellular construct and an acellular fetal bovine collagen dressing in the treatment of venous leg ulcers. Journal of Comparative Effectiveness Research, 7(8), 797–805. https://doi.org/10.2217/cer-2018-0031

    Article  PubMed  Google Scholar 

  15. Baltazar, T., Merola, J., Catarino, C., Xie, C. B., Kirkiles-Smith, N. C., Lee, V., Hotta, S., Dai, G., Xu, X., Ferreira, F. C., Saltzman, W. M., Pober, J. S., & Karande, P. (2020). Three dimensional bioprinting of a vascularized and perfusable skin graft using human keratinocytes, fibroblasts, pericytes, and endothelial cells. Tissue Engineering Part A, 26(5–6), 227–238. https://doi.org/10.1089/ten.TEA.2019.0201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Barros, N. R., Kim, H. J., Gouidie, M. J., Lee, K., Bandaru, P., Banton, E. A., Sarikhani, E., Sun, W., Zhang, S., Cho, H. J., Hartel, M. C., Ostrovidov, S., Ahadian, S., Hussain, S. M., Ashammakhi, N., Dokmeci, M. R., Herculano, R. D., Lee, J., & Khademhosseini, A. (2021). Biofabrication of endothelial cell, dermal fibroblast, and multilayered keratinocyte layers for skin tissue engineering. Biofabrication, 13(3), 035030. https://doi.org/10.1088/1758-5090/aba503

    Article  CAS  Google Scholar 

  17. Zhong, J., Wang, H., Yang, K., Wang, H., Duan, C., Ni, N., An, L., Luo, Y., Zhao, P., Gou, Y., Sheng, S., Shi, D., Chen, C., Wagstaff, W., Hendren-Santiago, B., Haydon, R. C., Luu, H. H., Reid, R. R., Ho, S. H., … Fan, J. (2022). Reversibly immortalized keratinocytes (iKera) facilitate re-epithelization and skin wound healing: Potential applications in cell-based skin tissue engineering. Bioactive Material, 9, 523–540. https://doi.org/10.1016/j.bioactmat.2021.07.022

    Article  CAS  Google Scholar 

  18. Hashemi, S. S., Mohammadi, A. A., Moshirabadi, K., & Zardosht, M. (2021). Effect of dermal fibroblasts and mesenchymal stem cells seeded on an amniotic membrane scaffold in skin regeneration: A case series. Journal of Cosmetic Dermatology, 20(12), 4040–4047. https://doi.org/10.1111/jocd.14043

    Article  PubMed  Google Scholar 

  19. Loh, E. Y. X., Fauzi, M. B., Ng, M. H., Ng, P. Y., Ng, S. F., & Amin, M. C. I. M. (2020). Insight into delivery of dermal fibroblast by non-biodegradable bacterial nanocellulose composite hydrogel on wound healing. International Journal of Biological Macromolecules, 159, 497–509. https://doi.org/10.1016/j.ijbiomac.2020.05.011

    Article  CAS  PubMed  Google Scholar 

  20. Shera, S. S., & Banik, R. M. (2021). Development of tunable silk fibroin/xanthan biopolymeric scaffold for skin tissue engineering using L929 fibroblast cells. Journal of Bionic Engineering, 18(1), 103–117. https://doi.org/10.1007/s42235-021-0004-4

    Article  Google Scholar 

  21. Sharif, S., Ai, J., Azami, M., Verdi, J., Atlasi, M. A., Shirian, S., & Samadikuchaksaraei, A. (2018). Collagen-coated nano-electrospun PCL seeded with human endometrial stem cells for skin tissue engineering applications. Journal of Biomedical Materials Research Part B, Applied Biomaterials, 106(4), 1578–1586. https://doi.org/10.1002/jbm.b.33966

    Article  CAS  PubMed  Google Scholar 

  22. Oryan, A., Alemzadeh, E., Mohammadi, A. A., & Moshiri, A. (2019). Healing potential of injectable Aloe vera hydrogel loaded by adipose-derived stem cell in skin tissue-engineering in a rat burn wound model. Cell and Tissue Research, 377(2), 215–227. https://doi.org/10.1007/s00441-019-03015-9

    Article  CAS  PubMed  Google Scholar 

  23. Ranjbarvan, P., Golchin, A., Azari, A., & Niknam, Z. (2021). The bilayer skin substitute based on human adipose-derived mesenchymal stem cells and neonate keratinocytes on the 3D nanofibrous PCL-platelet gel scaffold. Polymer Bulletin, 79, 4013–4030. https://doi.org/10.1007/s00289-021-03702-0

    Article  CAS  Google Scholar 

  24. Zhang, Z., Li, Z., Li, Y., Wang, Y., Yao, M., Zhang, K., Chen, Z., Yue, H., Shi, J., Guan, F., & Ma, S. (2021). Sodium alginate/collagen hydrogel loaded with human umbilical cord mesenchymal stem cells promotes wound healing and skin remodeling. Cell and Tissue Research, 383(2), 809–821. https://doi.org/10.1007/s00441-020-03321-7

    Article  CAS  PubMed  Google Scholar 

  25. Cui, B., Zhang, C., Gan, B., Liu, W., Liang, J., Fan, Z., Wen, Y., Yang, Y., Peng, X., & Zhou, Y. (2020). Collagen-tussah silk fibroin hybrid scaffolds loaded with bone mesenchymal stem cells promote skin wound repair in rats. Materials Science & Engineering, C: Materials for Biological Applications, 109, 110611. https://doi.org/10.1016/j.msec.2019.110611

    Article  CAS  Google Scholar 

  26. Kaviani, M., Geramizadeh, B., Rahsaz, M., & Marzban, S. (2015). Considerations in the improvement of human epidermal keratinocyte culture in vitro. Experimental and Clinical Transplantation, 13(Suppl 1), 366–370. https://doi.org/10.6002/ect.mesot2014.L4

    Article  PubMed  Google Scholar 

  27. Rahsaz, M., Geramizadeh, B., Kaviani, M., & Marzban, S. (2015). Gelatin for purification and proliferation of primary keratinocyte culture for use in chronic wounds and burns. Experimental and Clinical Transplantation, 13(1), 361–365. https://doi.org/10.6002/ect.mesot2014.L4

    Article  PubMed  Google Scholar 

  28. Luckett, L. R., & Gallucci, R. M. (2007). Interleukin-6 (IL-6) modulates migration and matrix metalloproteinase function in dermal fibroblasts from IL-6KO mice. British Journal of Dermatology, 156(6), 1163–1171. https://doi.org/10.1111/j.1365-2133.2007.07867.x

    Article  CAS  PubMed  Google Scholar 

  29. Nolte, S. V., Xu, W., Rennekampff, H.-O., & Rodemann, H. P. (2008). Diversity of fibroblasts–a review on implications for skin tissue engineering. Cells Tissues Organs, 187(3), 165–176. https://doi.org/10.1159/000111805

    Article  PubMed  Google Scholar 

  30. Zhao, X., Psarianos, P., Ghoraie, L. S., Yip, K., Goldstein, D., Gilbert, R., Witterick, I., Pang, H., Hussain, A., Lee, J. H., Williams, J., Bratman, S. V., Ailles, L., Haibe-Kains, B., & Liu, F. F. (2019). Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis. Nature Metabolism, 1(1), 147–157. https://doi.org/10.1038/s42255-018-0008-5

    Article  CAS  PubMed  Google Scholar 

  31. Chopra, A., Murray, M. E., Byfield, F. J., Mendez, M. G., Halleluyan, R., Restle, D. J., Raz-Ben Aroush, D., Galie, P. A., Pogoda, K., Bucki, R., Marcinkiewicz, C., Prestwich, G. D., Zarembinski, T. I., Chen, C. S., Pure, E., Kresh, J. Y., & Janmey, P. A. (2014). Augmentation of integrin-mediated mechanotransduction by hyaluronic acid. Biomaterials, 35(1), 71–82. https://doi.org/10.1016/j.biomaterials.2013.09.066

    Article  CAS  PubMed  Google Scholar 

  32. Sasaki, M., Abe, R., Fujita, Y., Ando, S., Inokuma, D., & Shimizu, H. (2008). Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. The Journal of Immunology, 180(4), 2581–2587. https://doi.org/10.4049/jimmunol.180.4.2581

    Article  CAS  PubMed  Google Scholar 

  33. Jin, G., Prabhakaran, M. P., & Ramakrishna, S. (2011). Stem cell differentiation to epidermal lineages on electrospun nanofibrous substrates for skin tissue engineering. Acta Biomaterialia, 7(8), 3113–3122. https://doi.org/10.1016/j.actbio.2011.04.017

    Article  CAS  PubMed  Google Scholar 

  34. Han, C. M., Zhang, L. P., Sun, J. Z., Shi, H. F., Zhou, J., & Gao, C. Y. (2010). Application of collagen-chitosan/fibrin glue asymmetric scaffolds in skin tissue engineering. Journal of Zhejiang University Science B, 11(7), 524–530. https://doi.org/10.1631/jzus.B0900400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee, J. J., Lee, S.-G., Park, J. C., Yang, Y. I., & Kim, J. K. (2007). Investigation on biodegradable PLGA scaffold with various pore size structure for skin tissue engineering. Current Applied Physics, 7, e37–e40. https://doi.org/10.1016/j.cap.2006.11.011

    Article  Google Scholar 

  36. Liu, Y., Ma, L., & Gao, C. (2012). Facile fabrication of the glutaraldehyde cross-linked collagen/chitosan porous scaffold for skin tissue engineering. Materials Science and Engineering C, 32(8), 2361–2366. https://doi.org/10.1016/j.msec.2012.07.008

    Article  CAS  Google Scholar 

  37. Ma, L., Gao, C., Mao, Z., Zhou, J., Shen, J., Hu, X., & Han, C. (2003). Collagen/chitosan porous scaffolds with improved biostability for skin tissue engineering. Biomaterials, 24(26), 4833–4841. https://doi.org/10.1016/s0142-9612(03)00374-0

    Article  CAS  PubMed  Google Scholar 

  38. Vázquez, J. J., & Martínez, E. S. M. (2019). Collagen and elastin scaffold by electrospinning for skin tissue engineering applications. Journal of Materials Research, 34(16), 2819–2827. https://doi.org/10.1557/jmr.2019.233

    Article  CAS  Google Scholar 

  39. Zulkifli, F. H., Hussain, F. S. J., Rasad, M. S. B. A., & Yusoff, M. M. (2014). In vitro degradation study of novel HEC/PVA/collagen nanofibrous scaffold for skin tissue engineering applications. Polymer Degradation and Stability, 110, 473–481. https://doi.org/10.1016/j.polymdegradstab.2014.10.017

    Article  CAS  Google Scholar 

  40. Gautam, S., Chou, C. F., Dinda, A. K., Potdar, P. D., & Mishra, N. C. (2014). Surface modification of nanofibrous polycaprolactone/gelatin composite scaffold by collagen type I grafting for skin tissue engineering. Materials Science & Engineering, C: Materials for Biological Applications, 34, 402–409. https://doi.org/10.1016/j.msec.2013.09.043

    Article  CAS  Google Scholar 

  41. Gomes, S., Rodrigues, G., Martins, G., Henriques, C., & Silva, J. C. (2017). Evaluation of nanofibrous scaffolds obtained from blends of chitosan, gelatin and polycaprolactone for skin tissue engineering. International Journal of Biological Macromolecules, 102, 1174–1185. https://doi.org/10.1016/j.ijbiomac.2017.05.004

    Article  CAS  PubMed  Google Scholar 

  42. Han, F., Dong, Y., Su, Z., Yin, R., Song, A., & Li, S. (2014). Preparation, characteristics and assessment of a novel gelatin–chitosan sponge scaffold as skin tissue engineering material. International Journal of Pharmaceutics, 476(1–2), 124–133. https://doi.org/10.1016/j.ijpharm.2014.09.036

    Article  CAS  PubMed  Google Scholar 

  43. Pezeshki-Modaress, M., Mirzadeh, H., & Zandi, M. (2015). Gelatin–GAG electrospun nanofibrous scaffold for skin tissue engineering: fabrication and modeling of process parameters. Materials Science and Engineering: C, 48, 704–712. https://doi.org/10.1016/j.msec.2014.12.023

    Article  CAS  PubMed  Google Scholar 

  44. Pezeshki-Modaress, M., Zandi, M., & Rajabi, S. (2018). Tailoring the gelatin/chitosan electrospun scaffold for application in skin tissue engineering: An in vitro study. Progress in Biomaterials, 7(3), 207–218. https://doi.org/10.1007/s40204-018-0094-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bhardwaj, N., Sow, W. T., Devi, D., Ng, K. W., Mandal, B. B., & Cho, N.-J. (2015). Silk fibroin–keratin based 3D scaffolds as a dermal substitute for skin tissue engineering. Integrative Biology, 7(1), 53–63. https://doi.org/10.1039/C4IB00208C

    Article  CAS  PubMed  Google Scholar 

  46. Adekogbe, I., & Ghanem, A. (2005). Fabrication and characterization of DTBP-crosslinked chitosan scaffolds for skin tissue engineering. Biomaterials, 26(35), 7241–7250. https://doi.org/10.1016/j.biomaterials.2005.05.043

    Article  CAS  PubMed  Google Scholar 

  47. Shalumon, K. T., Anulekha, K. H., Chennazhi, K. P., Tamura, H., Nair, S. V., & Jayakumar, R. (2011). Fabrication of chitosan/poly(caprolactone) nanofibrous scaffold for bone and skin tissue engineering. International Journal of Biological Macromolecules, 48(4), 571–576. https://doi.org/10.1016/j.ijbiomac.2011.01.020

    Article  CAS  PubMed  Google Scholar 

  48. Zhu, T., Jiang, J., Zhao, J., Chen, S., & Yan, X. (2019). Regulating preparation of functional alginate-chitosan three-dimensional scaffold for skin tissue engineering. International Journal of Nanomedicine, 14, 8891–8903. https://doi.org/10.2147/IJN.S210329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Keskin, Z., Sendemir Urkmez, A., & Hames, E. E. (2017). Novel keratin modified bacterial cellulose nanocomposite production and characterization for skin tissue engineering. Materials Science & Engineering, C: Materials for Biological Applications, 75, 1144–1153. https://doi.org/10.1016/j.msec.2017.03.035

    Article  CAS  Google Scholar 

  50. Monteiro, I. P., Shukla, A., Marques, A. P., Reis, R. L., & Hammond, P. T. (2015). Spray-assisted layer-by-layer assembly on hyaluronic acid scaffolds for skin tissue engineering. Journal of Biomedical Materials Research. Part A, 103(1), 330–340. https://doi.org/10.1002/jbm.a.35178

    Article  CAS  PubMed  Google Scholar 

  51. Solovieva, E. V., Fedotov, A. Y., Mamonov, V. E., Komlev, V. S., & Panteleyev, A. A. (2018). Fibrinogen-modified sodium alginate as a scaffold material for skin tissue engineering. Biomedical Materials, 13(2), 025007. https://doi.org/10.1088/1748-605X/aa9089

    Article  PubMed  Google Scholar 

  52. El Ghalbzouri, A., Lamme, E. N., van Blitterswijk, C., Koopman, J., & Ponec, M. (2004). The use of PEGT/PBT as a dermal scaffold for skin tissue engineering. Biomaterials, 25(15), 2987–2996. https://doi.org/10.1016/j.biomaterials.2003.09.098

    Article  CAS  PubMed  Google Scholar 

  53. Kumbar, S. G., Nukavarapu, S. P., James, R., Nair, L. S., & Laurencin, C. T. (2008). Electrospun poly(lactic acid-co-glycolic acid) scaffolds for skin tissue engineering. Biomaterials, 29(30), 4100–4107. https://doi.org/10.1016/j.biomaterials.2008.06.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ru, C., Wang, F., Pang, M., Sun, L., Chen, R., & Sun, Y. (2015). Suspended, shrinkage-free, electrospun PLGA nanofibrous scaffold for skin tissue engineering. ACS Applied Materials & Interfaces, 7(20), 10872–10877. https://doi.org/10.1021/acsami.5b01953

    Article  CAS  Google Scholar 

  55. Zulkifli, F. H., Hussain, F. S. J., Zeyohannes, S. S., Rasad, M., & Yusuff, M. M. (2017). A facile synthesis method of hydroxyethyl cellulose-silver nanoparticle scaffolds for skin tissue engineering applications. Materials Science & Engineering, C: Materials for Biological Applications, 79, 151–160. https://doi.org/10.1016/j.msec.2017.05.028

    Article  CAS  Google Scholar 

  56. Cui, W., Zhu, X., Yang, Y., Li, X., & Jin, Y. (2009). Evaluation of electrospun fibrous scaffolds of poly (dl-lactide) and poly (ethylene glycol) for skin tissue engineering. Materials Science and Engineering: C, 29(6), 1869–1876. https://doi.org/10.1016/j.msec.2009.02.013

    Article  CAS  Google Scholar 

  57. Wolfe, P. S., Sell, S. A., & Bowlin, G. L. (2011). Natural and synthetic scaffolds. In N. Pallua & C. Suscheck (Eds.), Tissue engineering (pp. 41–67). Berlin: Springer.

    Chapter  Google Scholar 

  58. Sundar, G., Joseph, J., John, A., & Abraham, A. (2021). Natural collagen bioscaffolds for skin tissue engineering strategies in burns: A critical review. International Journal of Polymeric Materials and Polymeric Biomaterials, 70(9), 593–604. https://doi.org/10.1080/00914037.2020.1740991

    Article  CAS  Google Scholar 

  59. Willard, J. J., Drexler, J. W., Das, A., Roy, S., Shilo, S., Shoseyov, O., & Powell, H. M. (2013). Plant-derived human collagen scaffolds for skin tissue engineering. Tissue Engineering Part A, 19(13–14), 1507–1518. https://doi.org/10.1089/ten.TEA.2012.0338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sarkar, S. D., Farrugia, B. L., Dargaville, T. R., & Dhara, S. (2013). Chitosan–collagen scaffolds with nano/microfibrous architecture for skin tissue engineering. Journal of Biomedical Materials Research Part A, 101(12), 3482–3492. https://doi.org/10.1002/jbm.a.34660

    Article  CAS  PubMed  Google Scholar 

  61. Ramanathan, G., Singaravelu, S., Muthukumar, T., Thyagarajan, S., Perumal, P. T., & Sivagnanam, U. T. (2017). Design and characterization of 3D hybrid collagen matrixes as a dermal substitute in skin tissue engineering. Materials Science and Engineering: C, 72, 359–370. https://doi.org/10.1016/j.msec.2016.11.095

    Article  CAS  PubMed  Google Scholar 

  62. Rnjak-Kovacina, J., Wise, S. G., Li, Z., Maitz, P. K., Young, C. J., Wang, Y., & Weiss, A. S. (2012). Electrospun synthetic human elastin: Collagen composite scaffolds for dermal tissue engineering. Acta Biomaterialia, 8(10), 3714–3722. https://doi.org/10.1016/j.actbio.2012.06.032

    Article  CAS  PubMed  Google Scholar 

  63. Buttafoco, L., Kolkman, N. G., Engbers-Buijtenhuijs, P., Poot, A. A., Dijkstra, P. J., Vermes, I., & Feijen, J. (2006). Electrospinning of collagen and elastin for tissue engineering applications. Biomaterials, 27(5), 724–734. https://doi.org/10.1016/j.biomaterials.2005.06.024

    Article  CAS  PubMed  Google Scholar 

  64. Gu, L. H., & Coulombe, P. A. (2007). Keratin function in skin epithelia: A broadening palette with surprising shades. Current Opinion in Cell Biology, 19(1), 13–23. https://doi.org/10.1016/j.ceb.2006.12.007

    Article  CAS  PubMed  Google Scholar 

  65. Madub, K., Goonoo, N., Gimie, F., Ait Arsa, I., Schonherr, H., & Bhaw-Luximon, A. (2021). Green seaweeds ulvan-cellulose scaffolds enhance in vitro cell growth and in vivo angiogenesis for skin tissue engineering. Carbohydrate Polymers, 251, 117025. https://doi.org/10.1016/j.carbpol.2020.117025

    Article  CAS  PubMed  Google Scholar 

  66. Shefa, A. A., Amirian, J., Kang, H. J., Bae, S. H., Jung, H. I., Choi, H. J., Lee, S. Y., & Lee, B. T. (2017). In vitro and in vivo evaluation of effectiveness of a novel TEMPO-oxidized cellulose nanofiber-silk fibroin scaffold in wound healing. Carbohydrate Polymers, 177, 284–296. https://doi.org/10.1016/j.carbpol.2017.08.130

    Article  CAS  PubMed  Google Scholar 

  67. Koh, L.-D., Cheng, Y., Teng, C.-P., Khin, Y.-W., Loh, X.-J., Tee, S.-Y., Low, M., Ye, E., Yu, H.-D., & Zhang, Y.-W. (2015). Structures, mechanical properties and applications of silk fibroin materials. Progress in Polymer Science, 46, 86–110. https://doi.org/10.1016/j.progpolymsci.2015.02.001

    Article  CAS  Google Scholar 

  68. Hodgkinson, T., Yuan, X. F., & Bayat, A. (2014). Electrospun silk fibroin fiber diameter influences in vitro dermal fibroblast behavior and promotes healing of ex vivo wound models. Journal of Tissue Engineering, 5, 2041731414551661. https://doi.org/10.1177/2041731414551661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chlapanidas, T., Tosca, M., Farago, S., Perteghella, S., Galuzzi, M., Lucconi, G., Antonioli, B., Ciancio, F., Rapisarda, V., & Vigo, D. (2013). Formulation and characterization of silk fibroin films as a scaffold for adipose-derived stem cells in skin tissue engineering. International Journal of Immunopathology and Pharmacology, 26(1_suppl), 43–49. https://doi.org/10.1177/03946320130260S106

    Article  CAS  PubMed  Google Scholar 

  70. Bacakova, M., Musilkova, J., Riedel, T., Stranska, D., Brynda, E., Zaloudkova, M., & Bacakova, L. (2016). The potential applications of fibrin-coated electrospun polylactide nanofibers in skin tissue engineering. International Journal of Nanomedicine, 11, 771–789. https://doi.org/10.2147/IJN.S99317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bacakova, M., Pajorova, J., Stranska, D., Hadraba, D., Lopot, F., Riedel, T., Brynda, E., Zaloudkova, M., & Bacakova, L. (2017). Protein nanocoatings on synthetic polymeric nanofibrous membranes designed as carriers for skin cells. International Journal of Nanomedicine, 12, 1143. https://doi.org/10.2147/IJN.S121299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bacakova, M., Pajorova, J., Sopuch, T., & Bacakova, L. (2018). Fibrin-modified cellulose as a promising dressing for accelerated wound healing. Materials, 11(11), 2314. https://doi.org/10.3390/ma11112314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kenawy, E.-R., Abdel-Hay, F. I., El-Magd, A. A., & Mahmoud, Y. (2005). Biologically active polymers: Modification and anti-microbial activity of chitosan derivatives. Journal of Bioactive and Compatible Polymers, 20(1), 95–111. https://doi.org/10.1177/0883911505049655

    Article  CAS  Google Scholar 

  74. Madni, A., Kousar, R., Naeem, N., & Wahid, F. (2021). Recent advancements in applications of chitosan-based biomaterials for skin tissue engineering. Journal of Bioresources and Bioproducts, 6(1), 11–25. https://doi.org/10.1016/j.jobab.2021.01.002

    Article  CAS  Google Scholar 

  75. Asghari, F., Rabiei Faradonbeh, D., Malekshahi, Z. V., Nekounam, H., Ghaemi, B., Yousefpoor, Y., Ghanbari, H., & Faridi-Majidi, R. (2022). Hybrid PCL/chitosan-PEO nanofibrous scaffolds incorporated with A. euchroma extract for skin tissue engineering application. Carbohydrate Polymers, 278, 118926. https://doi.org/10.1016/j.carbpol.2021.118926

    Article  CAS  PubMed  Google Scholar 

  76. Liu, H., Mao, J., Yao, K., Yang, G., Cui, L., & Cao, Y. (2004). A study on a chitosan-gelatin-hyaluronic acid scaffold as artificial skin in vitro and its tissue engineering applications. Journal of Biomaterials Science, Polymer Edition, 15(1), 25–40. https://doi.org/10.1163/156856204322752219

    Article  CAS  PubMed  Google Scholar 

  77. Abatangelo, G., Vindigni, V., Avruscio, G., Pandis, L., & Brun, P. (2020). Hyaluronic acid: Redefining its role. Cells, 9(7), 1743. https://doi.org/10.3390/cells9071743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wolf, K. J., & Kumar, S. (2019). Hyaluronic acid: incorporating the bio into the material. ACS Biomaterials Science & Engineering, 5(8), 3753–3765. https://doi.org/10.1021/acsbiomaterials.8b01268

    Article  CAS  Google Scholar 

  79. Ehterami, A., Salehi, M., Farzamfar, S., Samadian, H., Vaez, A., Ghorbani, S., Ai, J., & Sahrapeyma, H. (2019). Chitosan/alginate hydrogels containing Alpha-tocopherol for wound healing in rat model. Journal of Drug Delivery Science and Technology, 51, 204–213. https://doi.org/10.1016/j.jddst.2019.02.032

    Article  CAS  Google Scholar 

  80. Shi, L., Xiong, L., Hu, Y., Li, W., Chen, Z., Liu, K., & Zhang, X. (2018). Three-dimensional printing alginate/gelatin scaffolds as dermal substitutes for skin tissue engineering. Polymer Engineering & Science, 58(10), 1782–1790. https://doi.org/10.1002/pen.24779

    Article  CAS  Google Scholar 

  81. Aderibigbe, B. A., & Buyana, B. (2018). Alginate in wound dressings. Pharmaceutics, 10(2), 42. https://doi.org/10.3390/pharmaceutics10020042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yang, D., & Jones, K. S. (2009). Effect of alginate on innate immune activation of macrophages. Journal of Biomedical Materials Research. Part A, 90(2), 411–418. https://doi.org/10.1002/jbm.a.32096

    Article  CAS  PubMed  Google Scholar 

  83. Sadeghi, A., Nokhasteh, S., Molavi, A., Khorsand-Ghayeni, M., Naderi-Meshkin, H., & Mahdizadeh, A. (2016). Surface modification of electrospun PLGA scaffold with collagen for bioengineered skin substitutes. Materials Science and Engineering: C, 66, 130–137. https://doi.org/10.1016/j.msec.2016.04.073

    Article  CAS  PubMed  Google Scholar 

  84. Cipitria, A., Skelton, A., Dargaville, T., Dalton, P., & Hutmacher, D. (2011). Design, fabrication and characterization of PCL electrospun scaffolds—a review. Journal of Materials Chemistry, 21(26), 9419–9453. https://doi.org/10.1039/C0JM04502K

    Article  CAS  Google Scholar 

  85. Wang, H. J., Bertrand-De Haas, M., Riesle, J., Lamme, E., & Van Blitterswijk, C. A. (2003). Tissue engineering of dermal substitutes based on porous PEGT/PBT copolymer scaffolds: Comparison of culture conditions. Journal of Materials Science. Materials in Medicine, 14(3), 235–240. https://doi.org/10.1023/a:1022880623151

    Article  CAS  PubMed  Google Scholar 

  86. Law, J. X., Liau, L. L., Saim, A., Yang, Y., & Idrus, R. (2017). Electrospun collagen nanofibers and their applications in skin tissue engineering. Tissue Engineering and Regenerative Medicine, 14(6), 699–718. https://doi.org/10.1007/s13770-017-0075-9

    Article  PubMed  PubMed Central  Google Scholar 

  87. Ghafari, R., Jonoobi, M., Amirabad, L. M., Oksman, K., & Taheri, A. R. (2019). Fabrication and characterization of novel bilayer scaffold from nanocellulose based aerogel for skin tissue engineering applications. International Journal of Biological Macromolecules, 136, 796–803. https://doi.org/10.1016/j.ijbiomac.2019.06.104

    Article  CAS  PubMed  Google Scholar 

  88. Pereira, R. F., Barrias, C. C., Bartolo, P. J., & Granja, P. L. (2018). Cell-instructive pectin hydrogels crosslinked via thiol-norbornene photo-click chemistry for skin tissue engineering. Acta Biomaterialia, 66, 282–293. https://doi.org/10.1016/j.actbio.2017.11.016

    Article  CAS  PubMed  Google Scholar 

  89. Su, T., Zhang, M., Zeng, Q., Pan, W., Huang, Y., Qian, Y., Dong, W., Qi, X., & Shen, J. (2021). Mussel-inspired agarose hydrogel scaffolds for skin tissue engineering. Bioactive Materials, 6(3), 579–588. https://doi.org/10.1016/j.bioactmat.2020.09.004

    Article  CAS  PubMed  Google Scholar 

  90. Afghah, F., Ullah, M., Seyyed Monfared Zanjani, J., Akkus Sut, P., Sen, O., Emanet, M., Saner Okan, B., Culha, M., Menceloglu, Y., Yildiz, M., & Koc, B. (2020). 3D printing of silver-doped polycaprolactone-poly(propylene succinate) composite scaffolds for skin tissue engineering. Biomedical Materials, 15(3), 035015. https://doi.org/10.1088/1748-605X/ab7417

    Article  CAS  PubMed  Google Scholar 

  91. Daikuara, L. Y., Yue, Z., Skropeta, D., & Wallace, G. G. (2021). In vitro characterisation of 3D printed platelet lysate-based bioink for potential application in skin tissue engineering. Acta Biomaterialia, 123, 286–297. https://doi.org/10.1016/j.actbio.2021.01.021

    Article  CAS  PubMed  Google Scholar 

  92. Xue, J., Wu, T., Dai, Y., & Xia, Y. (2019). Electrospinning and electrospun nanofibers: Methods, materials, and applications. Chemical Reviews, 119(8), 5298–5415. https://doi.org/10.1021/acs.chemrev.8b00593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Keirouz, A., Chung, M., Kwon, J., Fortunato, G., & Radacsi, N. (2020). 2D and 3D electrospinning technologies for the fabrication of nanofibrous scaffolds for skin tissue engineering: A review. Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology, 12(4), e1626. https://doi.org/10.1002/wnan.1626

    Article  PubMed  Google Scholar 

  94. Park, Y. R., Ju, H. W., Lee, J. M., Kim, D. K., Lee, O. J., Moon, B. M., Park, H. J., Jeong, J. Y., Yeon, Y. K., & Park, C. H. (2016). Three-dimensional electrospun silk-fibroin nanofiber for skin tissue engineering. International Journal of Biological Macromolecules, 93(Pt B), 1567–1574. https://doi.org/10.1016/j.ijbiomac.2016.07.047

    Article  CAS  PubMed  Google Scholar 

  95. Iswariya, S., Bhanukeerthi, A., Velswamy, P., Uma, T., & Perumal, P. T. (2016). Design and development of a piscine collagen blended pullulan hydrogel for skin tissue engineering. RSC Advances, 6(63), 57863–57871. https://doi.org/10.1039/C6RA03578G

    Article  CAS  Google Scholar 

  96. Derr, K., Zou, J., Luo, K., Song, M. J., Sittampalam, G. S., Zhou, C., Michael, S., Ferrer, M., & Derr, P. (2019). Fully three-dimensional bioprinted skin equivalent constructs with validated morphology and barrier function. Tissue Engineering. Part C, Methods, 25(6), 334–343. https://doi.org/10.1089/ten.TEC.2018.0318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Choi, K. Y., Ajiteru, O., Hong, H., Suh, Y. J., Sultan, M. T., Lee, H., Lee, J. S., Lee, Y. J., Lee, O. J., Kim, S. H., & Park, C. H. (2023). A digital light processing 3D-printed artificial skin model and full-thickness wound models using silk fibroin bioink. Acta Biomaterialia, 164, 159–174. https://doi.org/10.1016/j.actbio.2023.04.034

    Article  CAS  PubMed  Google Scholar 

  98. Park, U., & Kim, K. (2017). Multiple growth factor delivery for skin tissue engineering applications. Biotechnology and Bioprocess Engineering, 22(6), 659–670. https://doi.org/10.1007/s12257-017-0436-1

    Article  CAS  Google Scholar 

  99. Colige, A., Nusgens, B., & Lapiere, C. (1988). Effect of EGF on human skin fibroblasts is modulated by the extracellular matrix. Archives of Dermatological Research, 280, S42–S46.

    CAS  PubMed  Google Scholar 

  100. Yun, Y. R., Won, J. E., Jeon, E., Lee, S., Kang, W., Jo, H., Jang, J. H., Shin, U. S., & Kim, H. W. (2010). Fibroblast growth factors: Biology, function, and application for tissue regeneration. Journal of Tissue Engineering, 2010(1), 218142. https://doi.org/10.4061/2010/218142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Grazul-Bilska, A. T., Luthra, G., Reynolds, L. P., Bilski, J. J., Johnson, M. L., Adbullah, S. A., Redmer, D. A., & Abdullah, K. M. (2002). Effects of basic fibroblast growth factor (FGF-2) on proliferation of human skin fibroblasts in type II diabetes mellitus. Experimental and Clinical Endocrinology & Diabetes, 110(4), 176–181. https://doi.org/10.1055/s-2002-32149

    Article  CAS  Google Scholar 

  102. Rinsch, C., Quinodoz, P., Pittet, B., Alizadeh, N., Baetens, D., Montandon, D., Aebischer, P., & Pepper, M. S. (2001). Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia. Gene Therapy, 8(7), 523–533. https://doi.org/10.1038/sj.gt.3301436

    Article  CAS  PubMed  Google Scholar 

  103. Qu, Y., Cao, C., Wu, Q., Huang, A., Song, Y., Li, H., Zuo, Y., Chu, C., Li, J., & Man, Y. (2018). The dual delivery of KGF and b FGF by collagen membrane to promote skin wound healing. Journal of Tissue Engineering and Regenerative Medicine, 12(6), 1508–1518. https://doi.org/10.1002/term.2691

    Article  CAS  PubMed  Google Scholar 

  104. Tan, J., Li, L., Wang, H., Wei, L., Gao, X., Zeng, Z., Liu, S., Fan, Y., Liu, T., & Chen, J. (2021). Biofunctionalized fibrin gel co-embedded with BMSCs and VEGF for accelerating skin injury repair. Materials Science & Engineering, C: Materials for Biological Applications, 121, 111749. https://doi.org/10.1016/j.msec.2020.111749

    Article  CAS  Google Scholar 

  105. Li, P., Ruan, L., Wang, R., Liu, T., Song, G., Gao, X., Jiang, G., & Liu, X. (2021). Electrospun scaffold of collagen and polycaprolactone containing ZnO quantum dots for skin wound regeneration. Journal of Bionic Engineering, 18(6), 1378–1390. https://doi.org/10.1007/s42235-021-00115-7

    Article  PubMed  PubMed Central  Google Scholar 

  106. Saik, J. E., Gould, D. J., Watkins, E. M., Dickinson, M. E., & West, J. L. (2011). Covalently immobilized platelet-derived growth factor-BB promotes angiogenesis in biomimetic poly(ethylene glycol) hydrogels. Acta Biomaterialia, 7(1), 133–143. https://doi.org/10.1016/j.actbio.2010.08.018

    Article  CAS  PubMed  Google Scholar 

  107. Judith, R., Nithya, M., Rose, C., & Mandal, A. B. (2010). Application of a PDGF-containing novel gel for cutaneous wound healing. Life Sciences, 87(1–2), 1–8. https://doi.org/10.1016/j.lfs.2010.05.003

    Article  CAS  PubMed  Google Scholar 

  108. Dearman, B. L., & Greenwood, J. E. (2021). Scale-up of a composite cultured skin using a novel bioreactor device in a porcine wound model. Journal of Burn Care & Research, 42(6), 1199–1209. https://doi.org/10.1093/jbcr/irab034

    Article  Google Scholar 

  109. Sun, T., Norton, D., Haycock, J. W., Ryan, A. J., & MacNeil, S. (2005). Development of a closed bioreactor system for culture of tissue-engineered skin at an air–liquid interface. Tissue Engineering, 11(11–12), 1824–1831. https://doi.org/10.1089/ten.2005.11.1824

    Article  CAS  PubMed  Google Scholar 

  110. Wahlsten, A., Rutsche, D., Nanni, M., Giampietro, C., Biedermann, T., Reichmann, E., & Mazza, E. (2021). Mechanical stimulation induces rapid fibroblast proliferation and accelerates the early maturation of human skin substitutes. Biomaterials, 273, 120779. https://doi.org/10.1016/j.biomaterials.2021.120779

    Article  CAS  PubMed  Google Scholar 

  111. Kalyanaraman, B., & Boyce, S. T. (2009). Wound healing on athymic mice with engineered skin substitutes fabricated with keratinocytes harvested from an automated bioreactor. Journal of Surgical Research, 152(2), 296–302. https://doi.org/10.1016/j.jss.2008.04.001

    Article  CAS  PubMed  Google Scholar 

  112. Liu, J. Y., Hafner, J., Dragieva, G., & Burg, G. (2006). A novel bioreactor microcarrier cell culture system for high yields of proliferating autologous human keratinocytes. Cell Transplantation, 15(5), 435–443. https://doi.org/10.3727/000000006783981828

    Article  PubMed  Google Scholar 

  113. Kalyanaraman, B., & Boyce, S. (2007). Assessment of an automated bioreactor to propagate and harvest keratinocytes for fabrication of engineered skin substitutes. Tissue Engineering, 13(5), 983–993. https://doi.org/10.1089/ten.2006.0338

    Article  CAS  PubMed  Google Scholar 

  114. Norouzi, M., Shabani, I., Atyabi, F., & Soleimani, M. (2015). EGF-loaded nanofibrous scaffold for skin tissue engineering applications. Fibers and Polymers, 16(4), 782–787. https://doi.org/10.1007/s12221-015-0782-6

    Article  CAS  Google Scholar 

  115. Golchin, A., & Nourani, M. R. (2020). Effects of bilayer nanofibrillar scaffolds containing epidermal growth factor on full-thickness wound healing. Polymers for Advanced Technologies, 31(11), 2443–2452. https://doi.org/10.1002/pat.4960

    Article  CAS  Google Scholar 

  116. Mirdailami, O., Soleimani, M., Dinarvand, R., Khoshayand, M. R., Norouzi, M., Hajarizadeh, A., Dodel, M., & Atyabi, F. (2015). Controlled release of rh EGF and rhb FGF from electrospun scaffolds for skin regeneration. Journal of Biomedical Materials Research Part A, 103(10), 3374–3385. https://doi.org/10.1002/jbm.a.35479

    Article  CAS  PubMed  Google Scholar 

  117. Zhang, Z., Li, Z., Wang, Y., Wang, Q., Yao, M., Zhao, L., Shi, J., Guan, F., & Ma, S. (2021). PDGF-BB/SA/Dex injectable hydrogels accelerate BMSC-mediated functional full thickness skin wound repair by promoting angiogenesis. Journal of Materials Chemistry B, 9(31), 6176–6189. https://doi.org/10.1039/d1tb00952d

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Maryam Kaviani & Bita Geramizadeh

  2. Department of Pathology, Medical School of Shiraz University, Shiraz University of Medical Sciences, Shiraz, Iran

    Bita Geramizadeh

Authors
  1. Maryam Kaviani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bita Geramizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MK and BG were major contributors in the writing and critical edition of the manuscript. All authors contributed to the study conception and design. The first draft of the manuscript was written by [Maryam Kaviani] and Dr. Bita Geramizadeh commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bita Geramizadeh.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent to publish

Not applicable.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaviani, M., Geramizadeh, B. Basic Aspects of Skin Tissue Engineering: Cells, Biomaterials, Scaffold Fabrication Techniques, and Signaling Factors. J. Med. Biol. Eng. 43, 508–521 (2023). https://doi.org/10.1007/s40846-023-00822-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40846-023-00822-y

Keywords

Search

Navigation