Skip to main content

Advertisement

SpringerLink
Log in

Hyaluronic acid (HA)-based hydrogels for full-thickness wound repairing and skin regeneration

  • Tissue Engineering Constructs and Cell Substrates
  • Original Research
  • Published:
Journal of Materials Science: Materials in Medicine Aims and scope Submit manuscript

Abstract

In this work, two kinds of hyaluronic acid (HA)-based hydrogels were fabricated: one is made from physical freezing-thawing of HA solution (HA1), and the other is from chemical cross-linking of HA and polysaccharide (HA2). They were applied to repair full-thickness skin defects with New Zealand rabbits as the test animals, using powder HA and cotton dress as the references. The wound starts to heal after wounds were disinfected with iodine followed by coating with HA2, HA1, HA and cotton dress (the control), respectively. They were recorded as 4 treatments (groups), HA2, HA1, HA and the control. The healing progress was followed and tested in the duration of 56 days, and the biological repairing mechanism was explored. From the wound area alteration, white blood cell (WBC) measurements and H&E staining, HA2 was the most promising treatment in promoting the wound healing with least serious scar formation. Immunochemistry analyses and real-time PCR tests of the bio-factors involved in the wound healing, vascular endothelial growth factor (VEGF), alpha-smooth muscle actin (α-SMA) and transforming growth factor beta-1 (TGF-β1), exhibited that HA2 enhanced VEGF and α-SMA secretion but reduced TGF-β1 expression at early stage, which alleviated the wound inflammation, improved the skin regeneration and relieved the scar formation.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Macneil S. Progress and opportunities for tissue-engineered skin. Nature. 2007;445:874.

    Article  CAS  Google Scholar 

  2. Shevchenko RV, James SL, James SE. A review of tissue-engineered skin bioconstructs available for skin reconstruction. J R Soc Interface. 2010;7:229.

    Article  CAS  Google Scholar 

  3. Mihail C, Erika M, Farkash EA, Qiao J, Rousseau CF, Dong S, et al. Bioengineered self-assembled skin as an alternative to skin grafts. Plast Reconstr Surg Glob Open. 2016;4:e731.

    Article  Google Scholar 

  4. Yu SC, Xu YY, Li Y, Xu B, Sun Q, Li F, et al. Construction of tissue engineered skin with human amniotic mesenchymal stem cells and human amniotic epithelial cells. Eur Rev Med Pharmacol Sci. 2015;19:4627.

    Google Scholar 

  5. Selvaraj D, Vijaya PV, Elango S. Wound dressings–a review. Biomedicine. 2015;5:22.

    Article  Google Scholar 

  6. Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453:314–21.

    Article  CAS  Google Scholar 

  7. Gambichler T, Pljakic A, Schmitz L. Recent advances in clinical application of optical coherence tomography of human skin. Clin Cosmet Investig. 2015;8:345–54.

    Article  Google Scholar 

  8. Pereira RF, Barrias CC, Granja PL, Bartolo PJ. Advanced biofabrication strategies for skin regeneration and repair. Nanomedicine. 2013;8:603–21.

    Article  CAS  Google Scholar 

  9. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomiccanic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16:585–601.

    Article  Google Scholar 

  10. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003;83:835.

    Article  CAS  Google Scholar 

  11. Peng LH, Chen X, Chen L, Li N, Liang WQ, Gao JQ. Topical astragaloside IV-releasing hydrogel improves healing of skin wounds in vivo. Biol Pharm Bull. 2012;35:881.

    Article  CAS  Google Scholar 

  12. Abramov Y, Hirsch E, Ilievski V, Goldberg RP, Botros SM, Sand PK. Transforming growth factor beta 1 gene expression during vaginal vs cutaneous surgical wound healing in the rabbit. Int Urogynecology J. 2013;24:671–5.

    Article  Google Scholar 

  13. Rockey DC, Weymouth N, Shi Z. Smooth muscle α actin (Acta2) and myofibroblast function during hepatic wound healing. PLoS ONE. 2013;8:e77166.

    Article  CAS  Google Scholar 

  14. Gates RE, King LE Jr, Hanks SK, Nanney LB. Potential role for focal adhesion kinase in migrating and proliferating keratinocytes near epidermal wounds and in culture. Cell Growth Differ. 1994;5:891.

    CAS  Google Scholar 

  15. Santos MF, Mccormack SA, Guo Z, Okolicany J, Zheng Y, Johnson LR, et al. Rho proteins play a critical role in cell migration during the early phase of mucosal restitution. J Clin Investig. 1997;100:216.

    Article  CAS  Google Scholar 

  16. Soyer T, Ayva S, Aliefendioğlu D, Aktuna Z, Aslan MK, Senyücel MF, et al. Effect of phototherapy on growth factor levels in neonatal rat skin. J Pediatr Surg. 2011;46:2128.

    Article  Google Scholar 

  17. Yiu-Hei C, Sutton TL, Pierpont YN, Robson MC, Payne WG. The use of growth factors and other humoral agents to accelerate and enhance burn wound healing. Eplasty. 2011;11:e41.

    Google Scholar 

  18. Kajdaniuk D, Marek B, Borgielmarek H, Koskudła B. Vascular endothelial growth factor (VEGF) -part 1: in physiology and pathophysiology. Endokrynol Pol. 2011;62:444–55.

    CAS  Google Scholar 

  19. Nissen NN, Polverini PJ, Koch AE, Volin MV, Gamelli RL, Dipietro LA. Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am J Pathol. 1998;152:1445.

    CAS  Google Scholar 

  20. Bao P, Kodra A, Tomiccanic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res. 2009;153:347–58.

    Article  CAS  Google Scholar 

  21. Lee EY, Xia Y, Kim WS, Kim MH, Kim TH, Kim KJ, et al. Hypoxia-enhanced wound-healing function of adipose-derived stem cells: increase in stem cell proliferation and up-regulation of VEGF and bFGF. Wound Repair Regen. 2009;17:540.

    Article  Google Scholar 

  22. Nauta A, Seidel C, Deveza L, Montoro D, Grova M, Ko SH, et al. Adipose-derived stromal cells overexpressing vascular endothelial growth factor accelerate mouse excisional wound healing. Mol Ther J Am Soc Gene Ther. 2013;21:445–55.

    Article  CAS  Google Scholar 

  23. Andrei A, Bogdan MV, Lorand S, Catalin M, Edward S, Raluca I, et al. Clinical improvement after treatment with VEGF165in patients with severe chronic lower limb ischaemia. Genomic Med. 2007;1:47.

    Article  Google Scholar 

  24. Miyoshi T, Okamoto A. Biocompatible gel of hyaluronan-medical applications. Hyaluronan. 2002; p. 21–6.

    Book  Google Scholar 

  25. Gong C, Hou L, Zhu Y, Lv J, Liu Y, Luo L. In vitro constitution of esophageal muscle tissue with endocyclic and exolongitudinal patterns. ACS Appl Mater Interfaces. 2013;5:6549–55.

    Article  CAS  Google Scholar 

  26. Tadeu AMB, Horsley V. Epithelial stem cells in adult skin. Curr Top Dev Biol. 2014;107:109.

    Article  CAS  Google Scholar 

  27. Fernandes R, Smyth NR, Muskens OL, Nitti S, Heuerjungemann A, Ardernjones MR, et al. Interactions of skin with gold nanoparticles of different surface charge, shape, and functionality. Small. 2015;11:713–21.

    Article  CAS  Google Scholar 

  28. Sun BK, Siprashvili Z, Khavari PA. Advances in skin grafting and treatment of cutaneous wounds. Science. 2014;346:941.

    Article  CAS  Google Scholar 

  29. AJ S, RA C. Cutaneous wound healing. N Engl J Med. 1999;341:738.

    Article  Google Scholar 

  30. Yoshiba N, Yoshiba K, Ohkura N, Shigetani Y, Takei E, Hosoya A, et al. Immunohistochemical analysis of two stem cell markers of α-smooth muscle actin and STRO-1 during wound healing of human dental pulp. Histochem Cell Biol. 2012;138:583.

    Article  CAS  Google Scholar 

  31. Yoshiba N, Yoshiba K, Ohkura N, Takei E, Edanami N, Oda Y, et al. Correlation between Fibrillin-1 degradation and mRNA downregulation and myofibroblasts differentiation in cultured human dental pulp tissue. J Histochem Cytochem. 2015;63:438–48.

    Article  CAS  Google Scholar 

  32. Micallef L, Vedrenne N, Billet F, Coulomb B, Darby IA, Desmoulière A. The myofibroblast, multiple origins for major roles in normal and pathological tissue repair. Fibrogenes Tissue Repair. 2012;5(S1):1–5.

    Google Scholar 

  33. Gilbert RWD, Vickaryous MK, Viloria-Petit AM. Signalling by transforming growth factor beta isoforms in wound healing and tissue. Regeneration. 2016;4:21.

    Google Scholar 

  34. Lu SW, Zhang XM, Luo HM, Fu YC, Xu MY, Tang SJ. Clodronate liposomes reduce excessive scar formation in a mouse model of burn injury by reducing collagen deposition and TGF-β1 expression. Mol Biol Rep. 2014;41:2143–9.

    Article  CAS  Google Scholar 

  35. Tang QL, Han SS, Feng J, Di JQ, Qin WX, Fu J, et al. Moist exposed burn ointment promotes cutaneous excisional wound healing in rats involving VEGF and bFGF. Mol Med Rep. 2014;9:1277.

    Article  CAS  Google Scholar 

  36. Liu X, Shen R, Bian M, Ling LI, Xia Y, Yang Y. Expressions of vegf,pdgf and bfgf in wound cutaneous tissue and their significance in rats. Acta Academiae Medicinae Qingdao Universitatis. 2016;2016:209–211.

    Google Scholar 

  37. Johnson KE, Wilgus TA. Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care. 2014;3:647.

    Article  Google Scholar 

  38. Aya K, Stern R. Hyaluronan in wound healing: rediscovering a major player. Wound Repair Regen. 2014;22:579–93.

    Article  Google Scholar 

  39. Naseri-Nosara M, Ziorab ZM. Wound dressings from naturally-occurring polymers: a review on homopolysaccharide-based composites. Carbohydr Polym. 2018;189:379–98.

    Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the financial support from the National Science Foundation (81471797) and Project of Scientific Innovation Team of Ningbo (2015B11050 and 2014B82002), China. This work was also sponsored by K.C. Wang Magna/Education Fund of Ningbo University.

Author information

Authors and Affiliations

  1. The Medical School of Ningbo University, Ningbo, 315211, China

    Lei Hong, Meiting Shen, Jiaxi Fang, Yezhao Wang, Zhiyuan Bao, Shizhong Bu & Yabin Zhu

Authors
  1. Lei Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meiting Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiaxi Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yezhao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhiyuan Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shizhong Bu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yabin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yabin Zhu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hong, L., Shen, M., Fang, J. et al. Hyaluronic acid (HA)-based hydrogels for full-thickness wound repairing and skin regeneration. J Mater Sci: Mater Med 29, 150 (2018). https://doi.org/10.1007/s10856-018-6158-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10856-018-6158-x

Search

Navigation