Hyaluronic Acid Coating on Hydrophobic Tracheal Scaffold Enhances Mesenchymal Stem Cell Adhesion and Tracheal Regeneration



Long segmental tracheal repair is challenging in regenerative medicine due to low adhesion of stem cells to tracheal scaffolds. Optimal transplantation of stem cells for tracheal defects has not been established. We evaluated the role of hyaluronic acid (HA) coating of tracheal scaffolds in mesenchymal stem cell (MSC) adhesion and tracheal regeneration in a rabbit model.


A three-dimensionally printed tubular tracheal prosthesis was incubated with dopa-HA-fluorescein isothiocyanate in phosphate-buffered saline for 2 days. MSCs were incubated with an HA-coated scaffold, and their adhesion was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. HA coated scaffolds with or without MSC seeding were transplanted at the circumferential tracheal defect in rabbits, and survival, rigid bronchoscopy, radiologic findings, and histologic findings were compared between the two groups.


HA-coated scaffolds showed better MSC adhesion than non-coated scaffolds. The HA-coated scaffolds with MSC group showed a wider airway and greater mucosal regeneration compared to the HA-coated scaffolds without MSC group.


HA coating of scaffolds can promote MSC adhesion and tracheal regeneration.

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  1. 1.

    Ahn HJ, Khalmuratova R, Park SA, Chung EJ, Shin HW, Kwon SK. Serial analysis of tracheal restenosis after 3D-printed scaffold implantation: recruited inflammatory cells and associated tissue changes. Tissue Eng Regen Med. 2017;14:631–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Du XF, Kwon SK, Song JJ, Cho CG, Park SW. Tracheal reconstruction by mesenchymal stem cells with small intestine submucosa in rabbits. Int J Pediatr Otorhinolaryngol. 2012;76:345–51.

    PubMed  Google Scholar 

  3. 3.

    Kim IG, Park SA, Lee SH, Choi JS, Cho H, Lee SJ, et al. Transplantation of a 3D-printed tracheal graft combined with iPS cell-derived MSCs and chondrocytes. Sci Rep. 2020;10:4326.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Lee DY, Lee JH, Ahn HJ, Oh SH, Kim TH, Kim HB, et al. Synergistic effect of laminin and mesenchymal stem cells on tracheal mucosal regeneration. Biomaterials. 2015;44:134–42.

    CAS  PubMed  Google Scholar 

  5. 5.

    Kim SH, Lee HR, Yu SJ, Han ME, Lee DY, Kim SY, et al. Hydrogel-laden paper scaffold system for origami-based tissue engineering. Proc Natl Acad Sci U S A. 2015;112:15426–31.

    CAS  PubMed  Google Scholar 

  6. 6.

    Kwon SK, Song JJ, Cho CG, Park SW, Kim JR, Oh SH, et al. Tracheal reconstruction with asymmetrically porous polycaprolactone/pluronic F127 membranes. Head Neck. 2014;36:643–51.

    PubMed  Google Scholar 

  7. 7.

    Lee SJ, Choi JS, Eom MR, Jo HH, Kwon IK, Kwon SK, et al. Dexamethasone loaded bilayered 3D tubular scaffold reduces restenosis at the anastomotic site of tracheal replacement: in vitro and in vivo assessments. Nanoscale. 2020;12:4846–58.

    CAS  PubMed  Google Scholar 

  8. 8.

    Choi JS, Huh BK, Lee SJ, Han MJ, Eom MR, Ahn HJ, et al. Tranilast-loaded tubular scaffold and surgical suture for suppression of stenosis after tracheal prosthesis transplantation. J Ind Eng Chem. 2020;82:81–8.

    CAS  Google Scholar 

  9. 9.

    Lee M, Choi JS, Eom MR, Jeong EJ, Kim J, Park SA, et al. Prevascularized tracheal scaffolds using the platysma flap for enhanced tracheal regeneration. Laryngoscope. 2020. https://doi.org/10.1002/lary.29178.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Lee DY, Kim HB, Shim IK, Kanai N, Okano T, Kwon SK. Treatment of chemically induced oral ulcer using adipose-derived mesenchymal stem cell sheet. J Oral Pathol Med. 2017;46:520–7.

    CAS  PubMed  Google Scholar 

  11. 11.

    Lee JS, Kim S, Choi JS, Eom MR, Shin H, Kwon SK. Adipose-derived mesenchymal stem cell spheroid sheet accelerates regeneration of ulcerated oral mucosa by enhancing inherent therapeutic properties. J Ind Eng Chem. 2020;91:296–310.

    CAS  Google Scholar 

  12. 12.

    Chung EJ, Choi JS, Shin J, Cho HN, Kim S, Park JY, et al. Prevention of irradiation-induced damage to salivary glands by local delivery of adipose-derived stem cells via hyaluronic acid-based hydrogels. J Ind Eng Chem. 2020;90:47–57.

    CAS  Google Scholar 

  13. 13.

    Kwon SK, Lee BJ. The combined effect of autologous mesenchymal stem cells and hepatocyte growth factor on vocal fold regeneration and fibrosis in vocal fold wound. Tissue Eng Regen Med. 2008;5:735–42.

    Google Scholar 

  14. 14.

    Kusuma GD, Carthew J, Lim R, Frith JE. Effect of the microenvironment on mesenchymal stem cell paracrine signaling: opportunities to engineer the therapeutic effect. Stem Cells Dev. 2017;26:617–31.

    CAS  Google Scholar 

  15. 15.

    Yang Y, Lin H, Shen H, Wang B, Lei G, Tuan RS. Mesenchymal stem cell-derived extracellular matrix enhances chondrogenic phenotype of and cartilage formation by encapsulated chondrocytes in vitro and in vivo. Acta Biomater. 2018;69:71–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Witt R, Weigand A, Boos AM, Cai A, Dippold D, Boccaccini AR, et al. Mesenchymal stem cells and myoblast differentiation under HGF and IGF-1 stimulation for 3D skeletal muscle tissue engineering. BMC Cell Biol. 2017;18:15.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Chan DS, Gabra N, Baig A, Manoukian JJ, Daniel SJ. Bridging the gap: using 3D printed polycaprolactone implants to reconstruct circumferential tracheal defects in rabbits. Laryngoscope. 2020;130:E767–72.

    CAS  PubMed  Google Scholar 

  18. 18.

    Lee HS, Jeong MS, Ko SC, Heo SY, Kang HW, Kim SW, et al. Fabrication and biological activity of polycaprolactone/phlorotannin endotracheal tube to prevent tracheal stenosis: an in vitro and in vivo study. J Biomed Mater Res B Appl Biomater. 2020;108:1046–56.

    CAS  PubMed  Google Scholar 

  19. 19.

    Chan DS, Fnais N, Ibrahim I, Daniel SJ, Manoukian J. Exploring polycaprolactone in tracheal surgery: a scoping review of in-vivo studies. Int J Pediatr Otorhinolaryngol. 2019;123:38–42.

    PubMed  Google Scholar 

  20. 20.

    Townsend JM, Ott LM, Salash JR, Fung KM, Easley JT, Seim HB 3rd, et al. Reinforced electrospun polycaprolactone nanofibers for tracheal repair in an in vivo ovine model. Tissue Eng Part A. 2018;24:1301–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Jang YS, Jang CH, Cho YB, Kim M, Kim GH. Tracheal regeneration using polycaprolactone/collagen-nanofiber coated with umbilical cord serum after partial resection. Int J Pediatr Otorhinolaryngol. 2014;78:2237–43.

    PubMed  Google Scholar 

  22. 22.

    Chen X, Lin Z, Feng Y, Tan H, Xu X, Luo J, et al. Zwitterionic PMCP-modified polycaprolactone surface for tissue engineering: antifouling, cell adhesion promotion, and osteogenic differentiation properties. Small. 2019;15:e1903784.

    PubMed  Google Scholar 

  23. 23.

    Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T. Hyaluronic acid in inflammation and tissue regeneration. Wounds. 2016;28:78–88.

    PubMed  Google Scholar 

  24. 24.

    Prestwich GD. Hyaluronic acid-based clinical biomaterials derived for cell and molecule delivery in regenerative medicine. J Control Release. 2011;155:193–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Bhattacharya D, Svechkarev D, Souchek JJ, Hill TK, Taylor MA, Natarajan A, et al. Impact of structurally modifying hyaluronic acid on CD44 interaction. J Mater Chem B. 2017;5:8183–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Toole BP, Wight TN, Tammi MI. Hyaluronan-cell interactions in cancer and vascular disease. J Biol Chem. 2002;277:4593–6.

    CAS  PubMed  Google Scholar 

  27. 27.

    Lee MS, Lee JE, Byun E, Kim NW, Lee K, Lee H, et al. Target-specific delivery of siRNA by stabilized calcium phosphate nanoparticles using dopa-hyaluronic acid conjugate. J Control Release. 2014;192:122–30.

    CAS  PubMed  Google Scholar 

  28. 28.

    Wu SC, Chen CH, Chang JK, Fu YC, Wang CK, Eswaramoorthy R, et al. Hyaluronan initiates chondrogenesis mainly via CD44 in human adipose-derived stem cells. J Appl Physiol (1985). 2013;114:1610–8.

    CAS  Google Scholar 

  29. 29.

    Camilleri ET, Gustafson MP, Dudakovic A, Riester SM, Garces CG, Paradise CR, et al. Identification and validation of multiple cell surface markers of clinical-grade adipose-derived mesenchymal stromal cells as novel release criteria for good manufacturing practice-compliant production. Stem Cell Res Ther. 2016;7:107.

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Wu SC, Chang JK, Wang CK, Wang GJ, Ho ML. Enhancement of chondrogenesis of human adipose derived stem cells in a hyaluronan-enriched microenvironment. Biomaterials. 2010;31:631–40.

    PubMed  Google Scholar 

  31. 31.

    Lee H, Lee BP, Messersmith PB. A reversible wet/dry adhesive inspired by mussels and geckos. Nature. 2007;448:338–41.

    CAS  PubMed  Google Scholar 

  32. 32.

    Guo Q, Chen J, Wang J, Zeng H, Yu J. Recent progress in synthesis and application of mussel-inspired adhesives. Nanoscale. 2020;12:1307–24.

    CAS  PubMed  Google Scholar 

  33. 33.

    Lee H, Dellatore SM, Miller WM, Messersmith PB. Mussel-inspired surface chemistry for multifunctional coatings. Science. 2007;318:426–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Abatangelo G, Vindigni V, Avruscio G, Pandis L, Brun P. Hyaluronic acid: redefining its role. Cells. 2020;9:1743.

    CAS  PubMed Central  Google Scholar 

  35. 35.

    Wu PT, Su WR, Li CL, Hsieh JL, Ma CH, Wu CL, et al. Inhibition of CD44 induces apoptosis, inflammation, and matrix metalloproteinase expression in tendinopathy. J Biol Chem. 2019;294:20177–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Maytin EV. Hyaluronan: more than just a wrinkle filler. Glycobiology. 2016;26:553–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Kim CH, Lim CY, Lee JH, Kim KC, Ahn JY, Lee EJ. Human embryonic stem cells-derived mesenchymal stem cells reduce the symptom of psoriasis in imiquimod-induced skin model. Tissue Eng Regen Med. 2019;16:93–102.

    CAS  PubMed  Google Scholar 

  38. 38.

    Oh SY, Choi DH, Jin YM, Yu Y, Kim HY, Kim G, et al. Optimization of microenvironments inducing differentiation of tonsil-derived mesenchymal stem cells into endothelial cell-like cells. Tissue Eng Regen Med. 2019;16:631–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Kim KJ, Choi MS, Shim JH, Rhie JW. Bone morphogenetic protein 2-conjugated silica particles enhanced early osteogenic differentiation of adipose stem cells on the polycaprolactone scaffold. Tissue Eng Regen Med. 2019;16:395–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Shrestha KR, Jeon SH, Jung AR, Kim IG, Kim GE, Park YH, et al. Stem cells seeded on multilayered scaffolds implanted into an injured bladder rat model improves bladder function. Tissue Eng Regen Med. 2019;16:201–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Drela K, Siedlecka P, Sarnowska A, Domanska-Janik K. Human mesenchymal stem cells in the treatment of neurological diseases. Acta Neurobiol Exp (Wars). 2013;73:38–56.

    Google Scholar 

  42. 42.

    Kobayashi K, Suzuki T, Nomoto Y, Tada Y, Miyake M, Hazama A, et al. A tissue-engineered trachea derived from a framed collagen scaffold, gingival fibroblasts and adipose-derived stem cells. Biomaterials. 2010;31:4855–63.

    CAS  PubMed  Google Scholar 

  43. 43.

    Grillo HC. Tracheal replacement: a critical review. Ann Thorac Surg. 2002;73:1995–2004.

    PubMed  Google Scholar 

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This research was supported by a Grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HI18C1174).

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Correspondence to Ji Hoon Jeong or Seong Keun Kwon.

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All protocols and experimental parameters were reviewed and approved by the Institutional Animal Care and Use Committee of Seoul National University Hospital (SNUH-IACUC No. 19–0147), and animals were maintained in an AAALAC International-accredited facility (#001169) in accordance with the Guide for the Care and Use of Laboratory Animals Eighth Edition, NRC (2010).

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Choi, J.S., Lee, M.S., Kim, J. et al. Hyaluronic Acid Coating on Hydrophobic Tracheal Scaffold Enhances Mesenchymal Stem Cell Adhesion and Tracheal Regeneration. Tissue Eng Regen Med 18, 225–233 (2021). https://doi.org/10.1007/s13770-021-00335-2

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  • Trachea regeneration
  • Mesenchymal stem cell
  • Hyaluronic acid