Three-dimensional nanofiber scaffolds with arrayed holes for engineering skin tissue constructs


Three-dimensional (3D) scaffolds composed of poly(ε-caprolactone) and gelatin nanofibers were fabricated by a combination of electrospinning and modified gas-foaming. Arrayed holes throughout the scaffold were created using a punch under cryo conditions. The crosslinking with glutaraldehyde vapor improved the water stability of the scaffolds. Cell spheroids of green fluorescent protein-labeled human dermal fibroblasts were prepared and seeded into the holes. It was found that the fibroblasts adhered well on the surface of nanofibers and migrated into the scaffolds due to the porous structures. The 3D nanofiber scaffolds may hold great potential for engineering tissue constructs for various applications.

This is a preview of subscription content, access via your institution.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5


  1. 1.

    C.K. Sen, G.M. Gordillo, S. Roy, R. Kirsner, L. Lambert, T.K. Hunt, F. Gottrup, G.C. Gurtner, and M.T. Longaker: Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 17, 763–771 (2009).

    Article  Google Scholar 

  2. 2.

    J.J. Anderson, K.J. Wallin, and L. Spencer: Split thickness skin grafts for the treatment of non-healing foot and leg ulcers in patients with diabetes: a retrospective review. Diab. Foot Ankle 3, 10204 (2017).

    Article  Google Scholar 

  3. 3.

    R. Simman and L. Phavixay: Split-thickness skin grafts remain the gold standard for the closure of large acute and chronic wounds. J. Am. Coll. Certif. Wound Spec. 3, 55–59 (2011).

    Google Scholar 

  4. 4.

    F. Hackl, J. Bergmann, S.R. Granter, T. Koyama, E. Kiwanuka, B. Zuhaili, B. Pomahac, E.J. Caterson, J.P. Junker, and E. Eriksson: Epidermal regeneration by micrograft transplantation with immediate 100-fold expansion. Plast. Reconstr. Surg. 129, 443e–452e (2012).

    Article  Google Scholar 

  5. 5.

    T. Høgsberg, T. Bjarnsholt, J.S. Thomsen, and K. Kirketerp-Møller: Success rate of split-thickness skin grafting of chronic venous leg ulcers depends on the presence of Pseudomonas aeruginosa: a retrospective study. PLoS ONE 6, 20492e (2011).

    Article  Google Scholar 

  6. 6.

    B. McCartan and T. Dinh: The use of split-thickness skin grafts on diabetic foot ulcerations: a literature review. Plastic Surg. Int. 2012, 715273 (2012).

    Article  Google Scholar 

  7. 7.

    A. Biswas, M. Bharara, C. Hurst, D.G. Armstrong, and H. Rilo: The micrograft concept for wound healing: strategies and applications. J. Diab. Sci. Technol. 4, 808–819 (2010).

    Article  Google Scholar 

  8. 8.

    R. Langer and J.P. Vacanti: Tissue engineering. Science 260, 920–926 (1993).

    CAS  Article  Google Scholar 

  9. 9.

    B. Ma, J. Xie, J. Jiang, and J. Wu: Sandwich-type fiber scaffolds with square arrayed microwells and nanostructured cues as microskin grafts for skin regeneration. Biomaterials 35, 630–641 (2014).

    CAS  Article  Google Scholar 

  10. 10.

    J. Jiang, M.A. Carlson, M.J. Teusink, H. Wang, M.R. MacEwan, and J. Xie: Expanding two-dimensional electrospun nanofiber membranes in the third dimension by a modified gas-foaming technique. ACS Biomater. Sci. Eng. 1, 991–1001 (2015).

    CAS  Article  Google Scholar 

  11. 11.

    J. Jiang, Z. Li, H. Wang, Y. Wang, M.A. Carlson, M.J. Teusink, M.R. MacEwan, L. Gu, and J. Xie: Expanded 3D nanofiber scaffolds: cell penetration, neovascularization, and host response. Adv. Healthcare Mater. 5, 2993–3003 (2016).

    CAS  Article  Google Scholar 

  12. 12.

    J. Xie, S. Zhong, B. Ma, F.D. Shuler, and C.T. Lim: Controlled biomineralization of electrospun poly(epsilon-caprolactone) fibers to enhance their mechanical properties. Acta Biomater. 9, 5698–5707 (2013).

    CAS  Article  Google Scholar 

  13. 13.

    K. Maji, S. Dasgupta, K. Pramanik, and A. Bissoyi: Preparation and evaluation of gelatin-chitosan-nanobioglass 3D porous scaffold for bone tissue engineering. Int. J. Biomater. 2016, 9825659 (2016).

    Article  Google Scholar 

  14. 14.

    H.Y. Kweon, M.K. Yoo, I.K. Park, T.H. Kim, H.C. Lee, H.S. Lee, J.S. Oh, T. Akaike, and C.S. Cho: A novel degradable polycaprolactone networks for tissue engineering. Biomaterials 24, 801–808 (2003).

    CAS  Article  Google Scholar 

  15. 15.

    J.L. Ungerleider and K.L. Christman: Concise review: injectable biomaterials for the treatment of myocardial infarction and peripheral artery disease: translational challenges and progress. Stem Cells Transl. Med. 3, 1090–1099 (2014).

    CAS  Article  Google Scholar 

  16. 16.

    R. Foty: A simple hanging drop cell culture protocol for generation of 3D spheroids. J. Vis. Exp. 51 (2011). doi: 10.3791/2720.

  17. 17.

    E. Fennema, N. Rivron, J. Rouwkema, C. van Blitterswijk, and J. de Boer: Spheroid culture as a tool for creating 3D complex tissues. Trends Biotechnol. 31, 108–115 (2013).

    CAS  Article  Google Scholar 

  18. 18.

    M.S. Kim, I. Jun, Y.M. Shin, W. Jang, S.I. Kim, and H. Shin: The development of genipin-crosslinked poly(caprolactone) (PCL)/gelatin nanofibers for tissue engineering applications. Macromol. Biosci. 10, 91–100 (2010).

    CAS  Article  Google Scholar 

  19. 19.

    T. Mazaki, Y. Shiozaki, K. Yamane, A. Yoshida, M. Nakamura, Y. Yoshida, D. Zhou, T. Kitajima, M. Tanaka, Y. Ito, T. Ozaki, and A. Matsukawa: A novel, visible light-induced, rapidly cross-linkable gelatin scaffold for osteochondral tissue engineering. Sci. Rep. 4, 4457 (2014).

    Article  Google Scholar 

  20. 20.

    A. Bigi, G. Cojazzi, S. Panzavolta, N. Roveri, and K. Rubini: Stabilization of gelatin films by crosslinking with genipin. Biomaterials 23, 4827–4832 (2002).

    CAS  Article  Google Scholar 

  21. 21.

    X. Zhang, M.D. Do, P. Casey, A. Sulistio, G.G. Qiao, L. Lundin, P. Lillford, and S. Kosaraju: Chemical cross-linking gelatin with natural phenolic compounds as studied by high-resolution NMR spectroscopy. Biomacromolecules 11, 1125–1132 (2010).

    CAS  Article  Google Scholar 

  22. 22.

    A. Almodumeegh, P.I. Heidekrueger, M. Ninkovic, J. Rubenbauer, E. Hadjipanayi, and P.N. Broer: The MEEK technique: 10-year experience at a tertiary burn centre. Int. Wound J. (2016). doi: 10.1111/iwj.12650.

    Google Scholar 

  23. 23.

    D.B. Doughty: Strategies for minimizing chronic wound pain. Adv. Skin Wound Care 19, 82–85 (2006).

    Article  Google Scholar 

  24. 24.

    P. Chaisri, A. Chingsungnoen, and S. Siri: Repetitive Arg-Gly-Asp peptide as a cell-stimulating agent on electrospun poly(-caprolactone) scaffold for tissue engineering. Biotechnol. J. 8, 1323–1331 (2013).

    CAS  Article  Google Scholar 

  25. 25.

    Z. Cesarz and K. Tamama: Spheroid culture of mesenchymal stem cells. Stem Cells Int. 2016, 9176357 (2016).

    Article  Google Scholar 

  26. 26.

    M. Zanoni, F. Piccinini, C. Arienti, A. Zamagni, S. Santi, R. Polico, A. Bevilacqua, and A. Tesei: 3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained. Sci. Rep. 6, 19103 (2016).

    CAS  Article  Google Scholar 

  27. 27.

    R.A. Franco, T.H. Nguyen, and B.T. Lee: Preparation and characterization of electrospun PCL/PLGA membranes and chitosan/gelatin hydrogels for skin bioengineering applications. J. Mater. Sci. Mater. Med. 22, 2207 (2011).

    CAS  Article  Google Scholar 

  28. 28.

    C.N. Manning, A.G. Schwartz, W. Liu, J. Xie, N. Havlioglu, S.E. Sakiyama-Elbert, M.J. Silva, Y. Xia, R.H. Gelberman, and S. Thomopoulos: Controlled delivery of mesenchymal stem cells and growth factors using a nanofiber scaffold for tendon repair. Acta Biomater. 9, 6905–6914 (2013).

    CAS  Article  Google Scholar 

Download references


This work was supported partially from startup funds from University of Nebraska Medical Center (UNMC) and National Institute of General Medical Science (NIGMS) grant 2P20 GM1034 0-06. The authors thank the McGoogan Library of Medicine at University of Nebraska Medical Center for use of the LulzBot TAZ 5 3D printer.

Author information



Corresponding author

Correspondence to Jingwei Xie.

Supplementary material

Supplementary material

The supplementary material for this article can be found at

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fu, L., Xie, J., Carlson, M.A. et al. Three-dimensional nanofiber scaffolds with arrayed holes for engineering skin tissue constructs. MRS Communications 7, 361–366 (2017).

Download citation