Skip to main content
SpringerLink
Log in

Chitosan/LiCl composite scaffolds promote skin regeneration in full-thickness loss

  • Research Paper
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

Small molecules loaded into biological materials present a promising strategy for stimulating endogenous repair mechanisms for in situ skin regeneration. Lithium can modulate various biologic processes, promoting proliferation, angiogenesis, and decreasing inflammation. However, its role in skin repair is rarely reported. In this study, we loaded lithium chloride (LiCl) into the chitosan (CHI) hydrogel and develop a sterile and biocompatible sponge scaffold through freeze-drying. In-vitro assessment demonstrated that the CHI-LiCl composite scaffolds (CLiS) possessed favorable cytocompatibility, swelling and biodegradation. We created full-thickness skin wounds in male C57BL/c mice to evaluate the healing capacity of CLiS. Compared with the wounds of control and CHI scaffold (CS) groups, the wounds in the CLiS-treated group showed reduced inflammation, improved angiogenesis, accelerated re-epithelialization, sustained high expression of β-catenin with a small amount of regenerated hair follicles. Therefore, CLiS may be a promising therapeutic dressing for skin wound repair and regeneration.

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.

Similar content being viewed by others

References

  • Amini-Nik, S., Cambridge, E., Yu, W., Guo, A., Whetstone, H., Nadesan, P., Poon, R., Hinz, B., and Alman, B.A. (2014). β-Catenin-regulated myeloid cell adhesion and migration determine wound healing. J Clin Invest 124, 2599–2610.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bonani, W., Motta, A., Migliaresi, C., and Tan, W. (2012). Biomolecule gradient in micropatterned nanofibrous scaffold for spatiotemporal release. Langmuir 28, 13675–13687.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cao, Q., Karthikeyan, A., Dheen, S.T., Kaur, C., and Ling, E.A. (2017). Production of proinflammatory mediators in activated microglia is synergistically regulated by Notch-1, glycogen synthase kinase (GSK-3β) and NF-κB/p65 signalling. PLoS ONE 12, e0186764.

    PubMed  PubMed Central  Google Scholar 

  • Chen, D., Jarrell, A., Guo, C., Lang, R., and Atit, R. (2012). Dermal b-catenin activity in response to epidermal Wnt ligands is required for fibroblast proliferation and hair follicle initiation. Development 139, 1522–1533.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen, X., Zhang, M., Wang, X., Chen, Y., Yan, Y., Zhang, L., and Zhang, L. (2017). Peptide-modified chitosan hydrogels promote skin wound healing by enhancing wound angiogenesis and inhibiting inflammation. Am J Transl Res 9, 2352–2362.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chiu, C.T., Wang, Z., Hunsberger, J.G., and Chuang, D.M. (2013). Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol Rev 65, 105–142.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chow, A., Stuckey, D.J., Kidher, E., Rocco, M., Jabbour, R.J., Mansfield, C.A., Darzi, A., Harding, S.E., Stevens, M.M., and Athanasiou, T. (2017). Human induced pluripotent stem cell-derived cardiomyocyte encapsulating bioactive hydrogels improve rat heart function post myocardial infarction. Stem Cell Rep 9, 1415–1422.

    CAS  Google Scholar 

  • Comblain, F., Rocasalbas, G., Gauthier, S., and Henrotin, Y. (2017). Chitosan: a promising polymer for cartilage repair and viscosupplementation. Bio-Med Mater Eng 28, S209–S215.

    CAS  Google Scholar 

  • Dell’Osso, L., Del Grande, C., Gesi, C., Carmassi, C., and Musetti, L. (2016). A new look at an old drug: neuroprotective effects and therapeutic potentials of lithium salts. Neuropsychiat Disease Treatment 12, 1687–1703.

    Google Scholar 

  • Dong, L., Hao, H., Liu, J., Ti, D., Tong, C., Hou, Q., Li, M., Zheng, J., Liu, G., Fu, X., et al. (2017a). A conditioned medium of umbilical cord mesenchymal stem cells overexpressing Wnt7a promotes wound repair and regeneration of hair follicles in mice. Stem Cells Int 2017, 1–13.

    Google Scholar 

  • Dong, L., Hao, H., Liu, J., Tong, C., Ti, D., Chen, D., Chen, L., Li, M., Liu, H., Fu, X., et al. (2017b). Wnt1a maintains characteristics of dermal papilla cells that induce mouse hair regeneration in a 3D preculture system. J Tissue Eng Regen Med 11, 1479–1489.

    CAS  PubMed  Google Scholar 

  • Fathi, M., Sahandi Zangabad, P., Majidi, S., Barar, J., Erfan-Niya, H., and Omidi, Y. (2017). Stimuli-responsive chitosan-based nanocarriers for cancer therapy. Bioimpacts 7, 269–277.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fernandes-Silva, S., Moreira-Silva, J., Silva, T.H., Perez-Martin, R.I., Sotelo, C.G., Mano, J.F., Duarte, A.R.C., and Reis, R.L. (2013). Porous hydrogels from shark skin collagen crosslinked under dense carbon dioxide atmosphere. Macromol Biosci 13, 1621–1631.

    CAS  PubMed  Google Scholar 

  • Freeman, M.P., and Freeman, S.A. (2006). Lithium: clinical considerations in internal medicine. Am J Med 119, 478–481.

    CAS  PubMed  Google Scholar 

  • Fuchs, E. (1990). Epidermal differentiation: the bare essentials. J Cell Biol 111, 2807–2814.

    CAS  PubMed  Google Scholar 

  • Grellner, W., Georg, T., and Wilske, J. (2000). Quantitative analysis of proinflammatory cytokines (IL-1β, IL-6, TNF-α) in human skin wounds. Forensic Sci Int 113, 251–264.

    CAS  PubMed  Google Scholar 

  • Guo, R., Xu, S., Ma, L., Huang, A., and Gao, C. (2010). Enhanced angiogenesis of gene-activated dermal equivalent for treatment of full thickness incisional wounds in a porcine model. Biomaterials 31, 7308–7320.

    CAS  PubMed  Google Scholar 

  • Haj, J., Haj Khalil, T., Falah, M., Zussman, E., and Srouji, S. (2017). An ECM-mimicking, mesenchymal stem cell-embedded hybrid scaffold for bone regeneration. Biomed Res Int 2017, 1–12.

    Google Scholar 

  • Hao, H., Wen, L., Li, J., Wang, Y., Ni, B., Wang, R., Wang, X., Sun, M., Fan, H., and Mao, X. (2015). LiCl inhibits PRRSV infection by enhancing Wnt/β-catenin pathway and suppressing inflammatory responses. Antiviral Res 117, 99–109.

    CAS  PubMed  Google Scholar 

  • Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G., and Birchmeier, W. (2001). β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533–545.

    CAS  PubMed  Google Scholar 

  • Jayakumar, R., Prabaharan, M., Sudheesh Kumar, P.T., Nair, S.V., and Tamura, H. (2011). Biomaterials based on chitin and chitosan in wound dressing applications. Biotech Adv 29, 322–337.

    CAS  Google Scholar 

  • Kathju, S., Gallo, P.H., and Satish, L. (2012). Scarless integumentary wound healing in the mammalian fetus: molecular basis and therapeutic implications. Birth Defects Res C 96, 223–236.

    CAS  Google Scholar 

  • Kathuria, N., Tripathi, A., Kar, K.K., and Kumar, A. (2009). Synthesis and characterization of elastic and macroporous chitosan-gelatin cryogels for tissue engineering. Acta Biomater 5, 406–418.

    CAS  PubMed  Google Scholar 

  • Kumar, P.T.S., Lakshmanan, V.K., Anilkumar, T.V., Ramya, C., Reshmi, P., Unnikrishnan, A.G., Nair, S.V., and Jayakumar, R. (2012). Flexible and microporous chitosan hydrogel/nano ZnO composite bandages for wound dressing: in vitro and in vivo evaluation. ACS Appl Mater Interfaces 4, 2618–2629.

    PubMed  Google Scholar 

  • Lee, S.H., Kim, M.Y., Kim, H.Y., Lee, Y.M., Kim, H., Nam, K.A., Roh, M. R., Min, D.S., Chung, K.Y., and Choi, K.Y. (2015). The dishevelledbinding protein CXXC5 negatively regulates cutaneous wound healing. J Exp Med 212, 1061–1080.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Leeds, P.R., Yu, F., Wang, Z., Chiu, C.T., Zhang, Y., Leng, Y., Linares, G. R., and Chuang, D.M. (2014). A new avenue for lithium: intervention in traumatic brain injury. ACS Chem Neurosci 5, 422–433.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lei, H., Wang, Y., Zhang, T., Chang, L., Wu, Y., and Lai, Y. (2017). TLR3 activation induces S100A7 to regulate keratinocyte differentiation after skin injury. Sci China Life Sci 60, 158–167.

    CAS  PubMed  Google Scholar 

  • Li, M., Zhao, Y., Hao, H., Han, W., and Fu, X. (2017a). Theoretical and practical aspects of using fetal fibroblasts for skin regeneration. Ageing Res Rev 36, 32–41.

    CAS  PubMed  Google Scholar 

  • Li, X., He, X.T., Yin, Y., Wu, R.X., Tian, B.M., and Chen, F.M. (2017b). Administration of signalling molecules dictates stem cell homing for in situ regeneration. J Cell Mol Med 21, 3162–3177.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lian, X., Selekman, J., Bao, X., Hsiao, C., Zhu, K., and Palecek, S.P. (2013). A small molecule inhibitor of SRC family kinases promotes simple epithelial differentiation of human pluripotent stem cells. PLoS ONE 8, e60016.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lin, T., and Wu, S. (2015). Reprogramming with small molecules instead of exogenous transcription factors. Stem Cells Int 2015, 1–11.

    Google Scholar 

  • Lin, Y.H., Fu, K.Y., Hong, P.D., Ma, H., Liou, N.H., Ma, K.H., Liu, J.C., Huang, K.L., Dai, L.G., Chang, S.C., et al. (2013). The effects of microenvironment on wound healing by keratinocytes derived from mesenchymal stem cells. Ann Plastic Surgery 71, 1.

    Google Scholar 

  • Makoukji, J., Belle, M., Meffre, D., Stassart, R., Grenier, J., Shackleford, G.G., Fledrich, R., Fonte, C., Branchu, J., Goulard, M., et al. (2012). Lithium enhances remyelination of peripheral nerves. Proc Natl Acad Sci USA 109, 3973–3978.

    CAS  PubMed  Google Scholar 

  • Nasser, W., Amitai-Lange, A., Soteriou, D., Hanna, R., Tiosano, B., Fuchs, Y., and Shalom-Feuerstein, R. (2018). Corneal-committed cells restore the stem cell pool and tissue boundary following injury. Cell Rep 22, 323–331.

    CAS  PubMed  Google Scholar 

  • Oryan, A., and Sahvieh, S. (2017). Effectiveness of chitosan scaffold in skin, bone and cartilage healing. Int J Biol Macromol 104, 1003–1011.

    CAS  PubMed  Google Scholar 

  • Ouyang, Q.Q., Zhao, S., Li, S.D., and Song, C. (2017). Application of chitosan, chitooligosaccharide, and their derivatives in the treatment of Alzheimer’s Disease. Mar Drugs 15, 322.

    PubMed Central  Google Scholar 

  • Panich, U., Sittithumcharee, G., Rathviboon, N., and Jirawatnotai, S. (2016). Ultraviolet radiation-induced skin aging: the role of DNA damage and oxidative stress in epidermal stem cell damage mediated skin aging. Stem Cells Int 2016, 1–14.

    Google Scholar 

  • Park, G., Yoon, B.S., Kim, Y.S., Choi, S.C., Moon, J.H., Kwon, S., Hwang, J., Yun, W., Kim, J.H., Park, C.Y., et al. (2015). Conversion of mouse fibroblasts into cardiomyocyte-like cells using small molecule treatments. Biomaterials 54, 201–212.

    CAS  PubMed  Google Scholar 

  • Park, S.N., Park, J.C., Kim, H.O., Song, M.J., and Suh, H. (2002). Characterization of porous collagen/hyaluronic acid scaffold modified by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide cross-linking. Biomaterials 23, 1205–1212.

    CAS  PubMed  Google Scholar 

  • Patrulea, V., Ostafe, V., Borchard, G., and Jordan, O. (2015). Chitosan as a starting material for wound healing applications. Eur J Pharm Biopharm 97, 417–426.

    CAS  PubMed  Google Scholar 

  • Price, R.D., Berry, M.G., and Navsaria, H.A. (2007). Hyaluronic acid: the scientific and clinical evidence. J Plastic Reconstruct Aesthetic Surgery 60, 1110–1119.

    Google Scholar 

  • Qi, W., Yang, C., Dai, Z., Che, D., Feng, J., Mao, Y., Cheng, R., Wang, Z., He, X., Zhou, T., et al. (2015). High levels of pigment epitheliumderived factor in diabetes impair wound healing through suppression of Wnt signaling. Diabetes 64, 1407–1419.

    CAS  PubMed  Google Scholar 

  • Rodríguez-Vázquez, M., Vega-Ruiz, B., Ramos-Zúñiga, R., Saldaña-Koppel, D.A., and Quiñones-Olvera, L.F. (2015). Chitosan and its potential use as a scaffold for tissue engineering in regenerative medicine. Biomed Res Int 2015, 1–15.

    Google Scholar 

  • Rognoni, E., Gomez, C., Pisco, A.O., Rawlins, E.L., Simons, B.D., Watt, F. M., and Driskell, R.R. (2016). Inhibition of β-catenin signalling in dermal fibroblasts enhances hair follicle regeneration during wound healing. Development 143, 2522–2535.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schoellhammer, C.M., Blankschtein, D., and Langer, R. (2014). Skin permeabilization for transdermal drug delivery: recent advances and future prospects. Expert Opin Drug Deliv 11, 393–407.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Selekman, J.A., Lian, X., and Palecek, S.P. (2016). Generation of epithelial cell populations from human pluripotent stem cells using a small-Molecule inhibitor of Src family kinases. Methods Mol Biol 1307, 319–327.

    PubMed  PubMed Central  Google Scholar 

  • Stepniewski, M., Martynkiewicz, J., and Gosk, J. (2017). Chitosan and its composites: properties for use in bone substitution. Polim Med 47, 49–53.

    PubMed  Google Scholar 

  • Trébol, J., Georgiev-Hristov, T., Vega-Clemente, L., García-Gómez, I., Carabias-Orgaz, A., García-Arranz, M., and García-Olmo, D. (2018). Rat model of anal sphincter injury and two approaches for stem cell administration. World J Stem Cells 10, 1–14.

    PubMed  PubMed Central  Google Scholar 

  • Wada, A. (2009). Lithium and neuropsychiatric therapeutics: neuroplasticity via glycogen synthase kinase-3β, β-catenin, and neurotrophin cascades. J Pharmacol Sci 110, 14–28.

    CAS  PubMed  Google Scholar 

  • Wang, T., Zhao, J., Zhang, J., Mei, J., Shao, M., Pan, Y., Yang, W., Jiang, Y., Liu, F., and Jia, W. (2018). Heparan sulfate inhibits inflammation and improves wound healing by downregulating the NLR family pyrin domain containing 3 (NLRP3) inflammasome in diabetic rats. J Diabetes 10, 556–563.

    CAS  PubMed  Google Scholar 

  • Wang, W., Li, P., Li, W., Jiang, J., Cui, Y., Li, S., and Wang, Z. (2017). Osteopontin activates mesenchymal stem cells to repair skin wound. PLoS ONE 12, e0185346.

    PubMed  PubMed Central  Google Scholar 

  • Watt, F.M. (2014). Mammalian skin cell biology: at the interface between laboratory and clinic. Science 346, 937–940.

    CAS  PubMed  Google Scholar 

  • Xu, J., Wu, W., Zhang, L., Dorset-Martin, W., Morris, M.W., Mitchell, M. E., and Liechty, K.W. (2012). The role of microRNA-146a in the pathogenesis of the diabetic wound-healing impairment: correction with mesenchymal stem cell treatment. Diabetes 61, 2906–2912.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yucel Falco, C., Falkman, P., Risbo, J., Cárdenas, M., and Medronho, B. (2017). Chitosan-dextran sulfate hydrogels as a potential carrier for probiotics. Carbohydr Polym 172, 175–183.

    CAS  PubMed  Google Scholar 

  • Zhang, D.L., Gu, L.J., Liu, L., Wang, C.Y., Sun, B.S., Li, Z., and Sung, C. K. (2009). Effect of Wnt signaling pathway on wound healing. Biochem Biophys Res Commun 378, 149–151.

    CAS  PubMed  Google Scholar 

  • Zhang, M., Lin, Y.H., Sun, Y.J., Zhu, S., Zheng, J., Liu, K., Cao, N., Li, K., Huang, Y., and Ding, S. (2016). Pharmacological reprogramming of fibroblasts into neural stem cells by signaling-directed transcriptional activation. Cell Stem Cell 18, 653–667.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key Research & Development Program of China (2017YFC1104701 and 2017YFC1103300), the National Natural Science Foundation of China (81721092 and 81501669), and the Key Research and Development Project of Hainan (ZDYF2016135 and ZDYF2017095).

Author information

Author notes

  1. Contributed equally to this work

Authors and Affiliations

  1. Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, 100853, China

    Jifang Yuan, Qian Hou, Deyun Chen, Lingzhi Zhong, Ziying Zhu, Meirong Li & Xiaobing Fu

  2. Laboratory Animal Center, Chinese PLA General Hospital, Beijing, 100853, China

    Jifang Yuan & Xin Dai

  3. Trauma Treatment Center, Central Laboratory, Chinese PLA General Hospital Hainan Branch, Sanya, 572014, China

    Meirong Li

Authors
  1. Jifang Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qian Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Deyun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lingzhi Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xin Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ziying Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Meirong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaobing Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Meirong Li or Xiaobing Fu.

Additional information

Compliance and ethics

The author(s) 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

Yuan, J., Hou, Q., Chen, D. et al. Chitosan/LiCl composite scaffolds promote skin regeneration in full-thickness loss. Sci. China Life Sci. 63, 552–562 (2020). https://doi.org/10.1007/s11427-018-9389-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-018-9389-6

Keywords

Search

Navigation