Skip to main content
Log in

Investigating the repair of alveolar bone defects by gelatin methacrylate hydrogels-encapsulated human periodontal ligament stem cells

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

Abstract

Although various efforts have been made to develop effective treatments for alveolar bone defect, alveolar regeneration has been emerging as the one with the most potential Herein, we investigated the potential of gelatin methacrylate (GelMA) hydrogels-encapsulated human periodontal ligament stem cells (hPDLSCs) to regenerate alveolar bone. The easy, rapid, and cost-effective nature of GelMA hydrogels makes them a promising mode of stem cell-delivery for clinically relevant alveolar bone regeneration. More importantly, GelMA hydrogels provide an optimal niche for hPDLSCs proliferation, migration and osteogenic differentiation, which are critical for alveolar bone regeneration. In this study, we examined the microstructure of GelMA hydrogels, and identified a highly porous and interconnected network. Compressive test of GelMA hydrogels showed that the stress reached a maximum value of 13.67 ± 0.03 kPa when the strain reached 55%. The maximum values of swelling ratio were 700 ± 47% at the fifth hour. The proliferation rate of hPDLSCs in the GelMA hydrogels resembled that in 2D culture and gradually increased. We established a critical-sized rat model of alveolar bone defects, and applied Micro-CT to assess new bone formation. Compared to the control group, there was substantial bone regeneration in the GelMA + hPDLSCs group at both 4 and 8 weeks after the operation. Histological analysis results were consistent with Micro-CT results. Our study demonstrates that the GelMA hydrogels-encapsulated hPDLSCs have a significant alveolar regenerative potential, and may represent a new strategy for the therapy of alveolar bone defects.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Farré-Guasch E, Prins HJ, Overman JR, Ten Bruggenkate CM, Schulten EA, Helder MN, et al. Human maxillary sinus floor elevation as a model for bone regeneration enabling the application of one-step surgical procedures. Tissue Eng Part B Rev. 2013;19:69–82. https://doi.org/10.1089/ten.teb.2012.0404.

    Article  Google Scholar 

  2. Du J, Mei S, Guo L, Su Y, Wang H, Liu Y, et al. Platelet-rich fibrin/aspirin complex promotes alveolar bone regeneration in periodontal defect in rats. J Periodontal Res. 2018;53:47–56. https://doi.org/10.1111/jre.12485.

    Article  CAS  Google Scholar 

  3. Iviglia G, Cassinelli C, Torre E, Baino F, Morra M, Vitale-Brovarone C. Novel bioceramic-reinforced hydrogel for alveolar bone regeneration. Acta Biomater 2016;44:97–109. https://doi.org/10.1016/j.actbio.2016.08.012.

    Article  CAS  Google Scholar 

  4. Akita D, Kano K, Saito-Tamura Y, Mashimo T, Sato-Shionome M, Tsurumachi N, et al. Use of rat mature adipocyte-derived dedifferentiated fat cells as a cell source for periodontal tissue regeneration. Front Physiol. 2016;7. https://doi.org/10.3389/fphys.2016.00050.

  5. Han J, Menicanin D, Marino V, Ge S, Mrozik K, Gronthos S, et al. Assessment of the regenerative potential of allogeneic periodontal ligament stem cells in a rodent periodontal defect model. J Periodontal Res. 2014;49:333–45. https://doi.org/10.1111/jre.12111.

    Article  CAS  Google Scholar 

  6. Yang Y, Rossi FM, Putnins EE. Periodontal regeneration using engineered bone marrow mesenchymal stromal cells. Biomaterials 2010;31:8574–82. https://doi.org/10.1016/j.biomaterials.2010.06.026.

    Article  CAS  Google Scholar 

  7. Zhang L, Wang P, Mei S, Li C, Cai C, Ding Y. In vivo alveolar bone regeneration by bone marrow stem cells/fibrin glue composition. Arch Oral Biol. 2012;57:238–44. https://doi.org/10.1016/j.archoralbio.2011.08.025.

    Article  Google Scholar 

  8. Fawzy El-Sayed KM, Mekhemar MK, Beck-Broichsitter BE, Bahr T, Hegab M, Receveur J, et al. Periodontal regeneration employing gingival margin-derived stem/progenitor cells in conjunction with IL-1ra-hydrogel synthetic extracellular matrix. J Clin Periodontol. 2015;42:448–57. https://doi.org/10.1111/jcpe.12401.

    Article  CAS  Google Scholar 

  9. Seo B-M, Miura M, Gronthos S, Mark Bartold P, Batouli S, Brahim J, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 2004;364:149–55. https://doi.org/10.1016/s0140-6736(04)16627-0.

    Article  CAS  Google Scholar 

  10. Cantu DA, Hematti P, Kao WJ. Cell encapsulating biomaterial regulates mesenchymal stromal/stem cell differentiation and macrophage immunophenotype. Stem Cells Transl Med. 2012;1:740–9. https://doi.org/10.5966/sctm.2012-0061.

    Article  CAS  Google Scholar 

  11. Moshaverinia A, Chen C, Xu X, Ansari S, Zadeh HH, Schricker SR, et al. Regulation of the stem cell-host immune system interplay using hydrogel coencapsulation system with an anti-inflammatory drug. Adv Funct Mater. 2015;25:2296–307. https://doi.org/10.1002/adfm.201500055.

    Article  CAS  Google Scholar 

  12. Khayat A, Monteiro N, Smith EE, Pagni S, Zhang W, Khademhosseini A, et al. GelMA-Encapsulated hDPSCs and HUVECs for Dental Pulp Regeneration. J Dent Res. 2017;96:192–9. https://doi.org/10.1177/0022034516682005.

    Article  CAS  Google Scholar 

  13. Nikkhah M, Eshak N, Zorlutuna P, Annabi N, Castello M, Kim K, et al. Directed endothelial cell morphogenesis in micropatterned gelatin methacrylate hydrogels. Biomaterials 2012;33:9009–18. https://doi.org/10.1016/j.biomaterials.2012.08.068.

    Article  CAS  Google Scholar 

  14. Zhao X, Sun X, Yildirimer L, Lang Q, Lin ZYW, Zheng R, et al. Cell infiltrative hydrogel fibrous scaffolds for accelerated wound healing. Acta Biomater 2017;49:66–77. https://doi.org/10.1016/j.actbio.2016.11.017.

    Article  CAS  Google Scholar 

  15. Annabi N, Tamayol A, Uquillas JA, Akbari M, Bertassoni LE, Cha C, et al. 25th anniversary article: Rational design and applications of hydrogels in regenerative medicine. Adv Mater 2014;26:85–123. https://doi.org/10.1002/adma.201303233.

    Article  CAS  Google Scholar 

  16. Nichol JW, Koshy ST, Bae H, Hwang CM, Yamanlar S, Khademhosseini A. Cell-laden microengineered gelatin methacrylate hydrogels. Biomaterials 2010;31:5536–44. https://doi.org/10.1016/j.biomaterials.2010.03.064.

    Article  CAS  Google Scholar 

  17. Chen YC, Lin RZ, Qi H, Yang Y, Bae H, Melero-Martin JM, et al. Functional human vascular network generated in photocrosslinkable gelatin methacrylate hydrogels. Adv Funct Mater. 2012;22:2027–39. https://doi.org/10.1002/adfm.201101662.

    Article  CAS  Google Scholar 

  18. Yue K, Trujillo-de Santiago G, Alvarez MM, Tamayol A, Annabi N, Khademhosseini A. Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. Biomaterials. 2015;73:254–71. https://doi.org/10.1016/j.biomaterials.2015.08.045.

    Article  CAS  Google Scholar 

  19. Fairbanks BD, Schwartz MP, Bowman CN, Anseth KS. Photoinitiated polymerization of PEG-diacrylate with lithium phenyl-2,4,6-trimethylbenzoylphosphinate: polymerization rate and cytocompatibility. Biomaterials 2009;30:6702–7. https://doi.org/10.1016/j.biomaterials.2009.08.055.

    Article  CAS  Google Scholar 

  20. Zhao BJ, Liu YH. Simvastatin induces the osteogenic differentiation of human periodontal ligament stem cells. Fundam Clin Pharm. 2014;28:583–92. https://doi.org/10.1111/fcp.12050.

    Article  CAS  Google Scholar 

  21. Koh KS, Choi JW, Park EJ, Oh TS. Bone regeneration using silk hydroxyapatite hybrid composite in a rat alveolar defect model. Int J Med Sci. 2018;15:59–68. https://doi.org/10.7150/ijms.21787.

    Article  CAS  Google Scholar 

  22. Nguyen PD, Lin CD, Allori AC, Ricci JL, Saadeh PB, Warren SM. Establishment of a critical-sized alveolar defect in the rat: a model for human gingivoperiosteoplasty. Plast Reconstructive Surg. 2009;123:817–25. https://doi.org/10.1097/PRS.0b013e31819ba2f4.

    Article  CAS  Google Scholar 

  23. Nguyen PD, Lin CD, Allori AC, Schachar JS, Ricci JL, Saadeh PB, et al. Scaffold-based rhBMP-2 therapy in a rat alveolar defect model: implications for human gingivoperiosteoplasty. Plast Reconstr Surg. 2009;124:1829–39. https://doi.org/10.1097/PRS.0b013e3181bf8024.

    Article  CAS  Google Scholar 

  24. Lee JS, Kim E, Han S, Kang KL, Heo JS. Evaluating the oxysterol combination of 22(S)-hydroxycholesterol and 20(S)-hydroxycholesterol in periodontal regeneration using periodontal ligament stem cells and alveolar bone healing models. Stem Cell Res Ther. 2017;8:276. https://doi.org/10.1186/s13287-017-0725-9.

    Article  CAS  Google Scholar 

  25. Su F, Liu SS, Ma JL, Wang DS, E LL, Liu HC. Enhancement of periodontal tissue regeneration by transplantation of osteoprotegerin-engineered periodontal ligament stem cells. Stem Cell Res Ther. 2015;6:22. https://doi.org/10.1186/s13287-015-0023-3.

    Article  CAS  Google Scholar 

  26. Wada N, Menicanin D, Shi S, Bartold PM, Gronthos S. Immunomodulatory properties of human periodontal ligament stem cells. J Cell Physiol. 2009;219:667–76. https://doi.org/10.1002/jcp.21710.

    Article  CAS  Google Scholar 

  27. Alge DL, Anseth KS. Bioactive hydrogels: Lighting the way. Nat Mater 2013;12:950–2. https://doi.org/10.1038/nmat3794.

    Article  CAS  Google Scholar 

  28. West JL. Protein-patterned hydrogels: customized cell microenvironments. Nat Mater 2011;10:727–9. https://doi.org/10.1038/nmat3132.

    Article  CAS  Google Scholar 

  29. Monteiro N, Thrivikraman G, Athirasala A, Tahayeri A, Franca CM, Ferracane JL, et al. Photopolymerization of cell-laden gelatin methacryloyl hydrogels using a dental curing light for regenerative dentistry. Dent Mater 2018;34:389–99. https://doi.org/10.1016/j.dental.2017.11.020.

    Article  CAS  Google Scholar 

  30. Liu Y, Chan-Park MB. A biomimetic hydrogel based on methacrylated dextran-graft-lysine and gelatin for 3D smooth muscle cell culture. Biomaterials 2010;31:1158–70. https://doi.org/10.1016/j.biomaterials.2009.10.040.

    Article  CAS  Google Scholar 

  31. Hu J, Hou Y, Park H, Choi B, Hou S, Chung A, et al. Visible light crosslinkable chitosan hydrogels for tissue engineering. Acta Biomater 2012;8:1730–8. https://doi.org/10.1016/j.actbio.2012.01.029.

    Article  CAS  Google Scholar 

  32. Shin SR, Aghaei-Ghareh-Bolagh B, Dang TT, Topkaya SN, Gao X, Yang SY, et al. Cell-laden microengineered and mechanically tunable hybrid hydrogels of gelatin and graphene oxide. Adv Mater 2013;25:6385–91. https://doi.org/10.1002/adma.201301082.

    Article  CAS  Google Scholar 

  33. Celikkin N, Mastrogiacomo S, Jaroszewicz J, Walboomers XF, Swieszkowski W. Gelatin methacrylate scaffold for bone tissue engineering: the influence of polymer concentration. J Biomed Mater Res A 2018;106:201–9. https://doi.org/10.1002/jbm.a.36226.

    Article  CAS  Google Scholar 

  34. Miri AK, Hosseinabadi HG, Cecen B, Hassan S, Zhang YS. Permeability mapping of gelatin methacryloyl hydrogels. Acta Biomater 2018;77:38–47. https://doi.org/10.1016/j.actbio.2018.07.006.

    Article  CAS  Google Scholar 

  35. Pan J, Wang J, Hao L, Zhu G, Nguyen DN, Li Q, et al. The triple functions of D2 silencing in treatment of periapical disease. J Endod 2017;43:272–8. https://doi.org/10.1016/j.joen.2016.07.014.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81470768, 21703031), Shanghai Science and Technology Innovation Fund (19ZR1445500), Project of Shanghai Municipal Health Commission (201840148) and Shanghai Talent Development Funding. JW thanks the funds from Donghua University for Distinguished Research Fellow.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jiale Wang or Yuehua Liu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pan, J., Deng, J., Yu, L. et al. Investigating the repair of alveolar bone defects by gelatin methacrylate hydrogels-encapsulated human periodontal ligament stem cells. J Mater Sci: Mater Med 31, 3 (2020). https://doi.org/10.1007/s10856-019-6333-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10856-019-6333-8

Navigation