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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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T. Hyaluronic acid in inflammation and tissue regeneration. Wounds. 2016;28:78–88.
Prestwich GD. Hyaluronic acid-based clinical biomaterials derived for cell and molecule delivery in regenerative medicine. J Control Release. 2011;155:193–9.
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.
Toole BP, Wight TN, Tammi MI. Hyaluronan-cell interactions in cancer and vascular disease. J Biol Chem. 2002;277:4593–6.
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.
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.
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.
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.
Lee H, Lee BP, Messersmith PB. A reversible wet/dry adhesive inspired by mussels and geckos. Nature. 2007;448:338–41.
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.
Lee H, Dellatore SM, Miller WM, Messersmith PB. Mussel-inspired surface chemistry for multifunctional coatings. Science. 2007;318:426–30.
Abatangelo G, Vindigni V, Avruscio G, Pandis L, Brun P. Hyaluronic acid: redefining its role. Cells. 2020;9:1743.
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.
Maytin EV. Hyaluronan: more than just a wrinkle filler. Glycobiology. 2016;26:553–9.
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.
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.
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.
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.
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.
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.
Grillo HC. Tracheal replacement: a critical review. Ann Thorac Surg. 2002;73:1995–2004.
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).
Conflict of interest
The authors declare no conflict of interest.
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
- Trachea regeneration
- Mesenchymal stem cell
- Hyaluronic acid