Skip to main content
SpringerLink
Log in
Book cover

Aging Voice pp 95–107Cite as

Current Topics in Regenerative Medicine for the Laryngeal Tissues

  • Chapter
  • First Online:

  • 923 Accesses

Abstract

Most regenerative strategies for laryngeal tissues are based on the concept of tissue engineering, and over the past few decades, various approaches, such as cell therapy, scaffolding therapy, and growth factor therapy, have been evaluated in various tissues. Although regeneration of the whole larynx, or other complex tissues, remains difficult, and has yet to be fully achieved, some positive regenerative effects for many these approaches have been demonstrated in each tissue. Within the field of laryngeal regeneration, the most frequently studied tissue is the vocal fold mucosa, which comprises unique and delicate structures. Both nonclinical and clinical studies have had some success in the morphological and functional restoration of the vocal fold mucosa. Regeneration of the laryngeal nerve using scaffolding material or gene therapy has also been well documented; however, regeneration of the laryngeal cartilages or muscles has rarely been reported. In this chapter, the general regenerative strategies are introduced and the current progress and limitations of regenerative medicine for the laryngeal tissues are discussed.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Langer R, Vacanti JP. Tissue engineering. Science. 1993;260:920–6.

    Article  CAS  PubMed  Google Scholar 

  2. Kishimoto Y, Hirano S, Suehiro A, Tateya I, Kanemaru S, Nakamura T, Ito J. Effect of exogenous hepatocyte growth factor on vocal fold fibroblasts. Ann Otol Rhinol Laryngol. 2009;118:606–11.

    Article  PubMed  Google Scholar 

  3. Kishimoto Y, Hirano S, Kitani Y, Suehiro A, Umeda H, Tateya I, Kanemaru S, Tabata Y, Ito J. Chronic vocal fold scar restoration with hepatocyte growth factor hydrogel. Laryngoscope. 2010;120:108–13.

    Article  PubMed  Google Scholar 

  4. Hirano S, Nagai H, Tateya I, Tateya T, Ford CN, Bless DM. Regeneration of aged vocal folds with basic fibroblast growth factor in a rat model: a preliminary report. Ann Otol Rhinol Laryngol. 2005;114:304–8.

    Article  PubMed  Google Scholar 

  5. Hirano S, Bless DM, del Río AM, Connor NP, Ford CN. Therapeutic potential of growth factors for aging voice. Laryngoscope. 2004;114:2161–7.

    Article  CAS  PubMed  Google Scholar 

  6. Suehiro A, Hirano S, Kishimoto Y, Rousseau B, Nakamura T, Ito J. Treatment of acute vocal fold scar with local injection of basic fibroblast growth factor: a canine study. Acta Otolaryngol (Stockh). 2010;130:844–50.

    Article  CAS  Google Scholar 

  7. Suzuki R, Kawai Y, Tsuji T, Hiwatashi N, Kishimoto Y, Tateya I, Nakamura T, Hirano S. Prevention of vocal fold scarring by local application of basic fibroblast growth factor in a rat vocal fold injury model. Laryngoscope. 2016; doi:10.1002/lary.26138.

    Google Scholar 

  8. Hirano S, Mizuta M, Kaneko M, Tateya I, Kanemaru S-I, Ito J. Regenerative phonosurgical treatments for vocal fold scar and sulcus with basic fibroblast growth factor. Laryngoscope. 2013;123:2749–55.

    Article  PubMed  Google Scholar 

  9. Hirano S, Tateya I, Kishimoto Y, Kanemaru S, Ito J. Clinical trial of regeneration of aged vocal folds with growth factor therapy. Laryngoscope. 2012;122:327–31.

    Article  CAS  PubMed  Google Scholar 

  10. Kishimoto Y, Welham NV, Hirano S. Implantation of atelocollagen sheet for vocal fold scar. Curr Opin Otolaryngol Head Neck Surg. 2010;18:507–11.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kishimoto Y, Hirano S, Kojima T, Kanemaru S, Ito J. Implantation of an atelocollagen sheet for the treatment of vocal fold scarring and sulcus vocalis. Ann Otol Rhinol Laryngol. 2009;118:613–20.

    Article  PubMed  Google Scholar 

  12. Tse JR, Long JL. Microstructure characterization of a decellularized vocal fold scaffold for laryngeal tissue engineering. Laryngoscope. 2014;124:E326–31.

    Article  CAS  PubMed  Google Scholar 

  13. Li Q, Chang Z, Oliveira G, Xiong M, Smith LM, Frey BL, Welham NV. Protein turnover during in vitro tissue engineering. Biomaterials. 2016;81:104–13.

    Article  CAS  PubMed  Google Scholar 

  14. Xu CC, Chan RW, Tirunagari N. A biodegradable, acellular xenogeneic scaffold for regeneration of the vocal fold lamina propria. Tissue Eng. 2007;13:551–66.

    Article  CAS  PubMed  Google Scholar 

  15. Xu CC, Chan RW, Weinberger DG, Efune G, Pawlowski KS. Controlled release of hepatocyte growth factor from a bovine acellular scaffold for vocal fold reconstruction. J Biomed Mater Res A. 2010;93:1335–47.

    PubMed  PubMed Central  Google Scholar 

  16. Fishman JM, Long J, Gugatschka M, De Coppi P, Hirano S, Hertegard S, Thibeault SL, Birchall MA. Stem cell approaches for vocal fold regeneration. Laryngoscope. 2016;126:1865–70.

    Article  PubMed  Google Scholar 

  17. Gugatschka M, Kojima T, Ohno S, Kanemaru S, Hirano S. Recruitment patterns of side population cells during wound healing in rat vocal folds. Laryngoscope. 2011;121:1662–7.

    Article  PubMed  Google Scholar 

  18. Yamashita M, Hirano S, Kanemaru S, Tsuji S, Suehiro A, Ito J. Side population cells in the human vocal fold. Ann Otol Rhinol Laryngol. 2007;116:847–52.

    Article  PubMed  Google Scholar 

  19. Toya Y, Riabroy N, Davis CR, Kishimoto Y, Tanumihardjo SA, Bless DM, Welham NV. Interspecies comparison of stellate cell-containing macula flavae and vitamin A storage in vocal fold mucosa. J Anat. 2014;225:298–305.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sato K, Umeno H, Nakashima T. Vocal fold stem cells and their niche in the human vocal fold. Ann Otol Rhinol Laryngol. 2012;121:798–803.

    Article  PubMed  Google Scholar 

  21. Hanson SE, Kim J, Johnson BHQ, Bradley B, Breunig MJ, Hematti P, Thibeault SL. Characterization of mesenchymal stem cells from human vocal fold fibroblasts. Laryngoscope. 2010;120:546–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kawai Y, Kishimoto Y, Suzuki R, Tsuji T, Hiwatashi N, Tateya I, Yamamoto N, Nakamura T, Kanemaru S-I, Hirano S. Distribution and characteristics of slow-cycling cells in rat vocal folds. Laryngoscope. 2016;126:E164–70.

    Article  CAS  PubMed  Google Scholar 

  23. Chhetri DK, Head C, Revazova E, Hart S, Bhuta S, Berke GS. Lamina propria replacement therapy with cultured autologous fibroblasts for vocal fold scars. Otolaryngol Head Neck Surg Off J Am Acad Otolaryngol Head Neck Surg. 2004;131:864–70.

    Article  Google Scholar 

  24. Chhetri DK, Berke GS. Injection of cultured autologous fibroblasts for human vocal fold scars. Laryngoscope. 2011;121:785–92.

    Article  PubMed  Google Scholar 

  25. Kanemaru S-I, Nakamura T, Omori K, Kojima H, Magrufov A, Hiratsuka Y, Hirano S, Ito J, Shimizu Y. Regeneration of the vocal fold using autologous mesenchymal stem cells. Ann Otol Rhinol Laryngol. 2003;112:915–20.

    Article  PubMed  Google Scholar 

  26. Johnson BQ, Fox R, Chen X, Thibeault S. Tissue regeneration of the vocal fold using bone marrow mesenchymal stem cells and synthetic extracellular matrix injections in rats. Laryngoscope. 2010;120:537–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kumai Y, Kobler JB, Herrera VLM, Zeitels SM. Perspectives on adipose-derived stem/stromal cells as potential treatment for scarred vocal folds: opportunity and challenges. Curr Stem Cell Res Ther. 2010;5:175–81.

    Article  CAS  PubMed  Google Scholar 

  28. Hiwatashi N, Hirano S, Mizuta M, Tateya I, Kanemaru S, Nakamura T, Ito J. Adipose-derived stem cells versus bone marrow-derived stem cells for vocal fold regeneration. Laryngoscope. 2014;124:E461–9.

    Article  CAS  PubMed  Google Scholar 

  29. Cedervall J, Ahrlund-Richter L, Svensson B, Forsgren K, Maurer FHJ, Vidovska D, Hertegård S. Injection of embryonic stem cells into scarred rabbit vocal folds enhances healing and improves viscoelasticity: short-term results. Laryngoscope. 2007;117:2075–81.

    Article  PubMed  Google Scholar 

  30. Svensson B, Nagubothu SR, Nord C, Cedervall J, Hultman I, Ährlund-Richter L, Tolf A, Hertegård S. Stem cell therapy in injured vocal folds: a three-month xenograft analysis of human embryonic stem cells. Biomed Res Int. 2015;2015:754876.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Imaizumi M, Sato Y, Yang DT, Thibeault SL. In vitro epithelial differentiation of human induced pluripotent stem cells for vocal fold tissue engineering. Ann Otol Rhinol Laryngol. 2013;122:737–47.

    Article  PubMed  Google Scholar 

  32. Kanemaru S, Nakamura T, Yamashita M, et al. Destiny of autologous bone marrow-derived stromal cells implanted in the vocal fold. Ann Otol Rhinol Laryngol. 2005;114:907–12.

    Article  PubMed  Google Scholar 

  33. Ling C, Li Q, Brown ME, et al. Bioengineered vocal fold mucosa for voice restoration. Sci Transl Med. 2015;7:314ra187.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ehrhardt J, Morgan J. Regenerative capacity of skeletal muscle. Curr Opin Neurol. 2005;18:548–53.

    Article  CAS  PubMed  Google Scholar 

  35. Montarras D, L’honoré A, Buckingham M. Lying low but ready for action: the quiescent muscle satellite cell. FEBS J. 2013;280:4036–50.

    Article  CAS  PubMed  Google Scholar 

  36. Halum SL, Naidu M, Delo DM, Atala A, Hingtgen CM. Injection of autologous muscle stem cells (myoblasts) for the treatment of vocal fold paralysis: a pilot study. Laryngoscope. 2007;117:917–22.

    Article  PubMed  Google Scholar 

  37. Halum SL, Hiatt KK, Naidu M, Sufyan AS, Clapp DW. Optimization of autologous muscle stem cell survival in the denervated hemilarynx. Laryngoscope. 2008;118:1308–12.

    Article  PubMed  Google Scholar 

  38. Kanemaru S, Kitani Y, Ohno S, Shigemoto T, Kojima T, Ishikawa S, Mizuta M, Hirano S, Nakamura T, Dezawa M. Functional regeneration of laryngeal muscle using bone marrow-derived stromal cells. Laryngoscope. 2013;123:2728–34.

    Article  PubMed  Google Scholar 

  39. Dirja BT, Yoshie S, Ikeda M, Imaizumi M, Nakamura R, Otsuki K, Nomoto Y, Wada I, Hazama A, Omori K. Potential of laryngeal muscle regeneration using induced pluripotent stem cell-derived skeletal muscle cells. Acta Otolaryngol (Stockh). 2016;136:391–6.

    Article  CAS  Google Scholar 

  40. Grasman JM, Zayas MJ, Page RL, Pins GD. Biomimetic scaffolds for regeneration of volumetric muscle loss in skeletal muscle injuries. Acta Biomater. 2015;25:2–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gu X, Ding F, Williams DF. Neural tissue engineering options for peripheral nerve regeneration. Biomaterials. 2014;35:6143–56.

    Article  CAS  PubMed  Google Scholar 

  42. Faroni A, Mobasseri SA, Kingham PJ, Reid AJ. Peripheral nerve regeneration: experimental strategies and future perspectives. Adv Drug Deliv Rev. 2015;82–83:160–7.

    Article  PubMed  Google Scholar 

  43. Lerner MZ, Matsushita T, Lankford KL, Radtke C, Kocsis JD, Young NO. Intravenous mesenchymal stem cell therapy after recurrent laryngeal nerve injury: a preliminary study. Laryngoscope. 2014;124:2555–60.

    Article  PubMed  Google Scholar 

  44. Halum SL, McRae B, Bijangi-Vishehsaraei K, Hiatt K. Neurotrophic factor-secreting autologous muscle stem cell therapy for the treatment of laryngeal denervation injury. Laryngoscope. 2012;122:2482–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Xie J, Jin B, Li D-W, Shen B, Gong N, Zhang T-Z, Dong P. Effect of laminin-binding BDNF on induction of recurrent laryngeal nerve regeneration by miR-222 activation of mTOR signal pathway. Am J Transl Res. 2015;7:1071–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kanemaru S-I, Nakamura T, Omori K, Kojima H, Magrufov A, Hiratsuka Y, Ito J, Shimizu Y. Recurrent laryngeal nerve regeneration by tissue engineering. Ann Otol Rhinol Laryngol. 2003;112:492–8.

    Article  PubMed  Google Scholar 

  47. Suzuki H, Araki K, Matsui T, Tomifuji M, Yamashita T, Kobayashi Y, Shiotani A. Value of a novel PGA-collagen tube on recurrent laryngeal nerve regeneration in a rat model. Laryngoscope. 2016;126:E233–9.

    Article  CAS  PubMed  Google Scholar 

  48. Shiotani A, O’Malley BW, Coleman ME, Alila HW, Flint PW. Reinnervation of motor endplates and increased muscle fiber size after human insulin-like growth factor I gene transfer into the paralyzed larynx. Hum Gene Ther. 1998;9:2039–47.

    Article  CAS  PubMed  Google Scholar 

  49. Rubin AD, Hogikyan ND, Oh A, Feldman EL. Potential for promoting recurrent laryngeal nerve regeneration by remote delivery of viral gene therapy. Laryngoscope. 2012;122:349–55.

    Article  CAS  PubMed  Google Scholar 

  50. Flint PW, Shiotani A, O’Malley BW. IGF-1 gene transfer into denervated rat laryngeal muscle. Arch Otolaryngol Head Neck Surg. 1999;125:274–9.

    Article  CAS  PubMed  Google Scholar 

  51. Rotter N, Haisch A, Bücheler M. Cartilage and bone tissue engineering for reconstructive head and neck surgery. Eur Arch Otorhinolaryngol Head Neck. 2004;262:539–45.

    Google Scholar 

  52. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331:889–95.

    Article  CAS  PubMed  Google Scholar 

  53. Tsumaki N, Okada M, Yamashita A. iPS cell technologies and cartilage regeneration. Bone. 2015;70:48–54.

    Article  CAS  PubMed  Google Scholar 

  54. Bernhard JC, Vunjak-Novakovic G. Should we use cells, biomaterials, or tissue engineering for cartilage regeneration? Stem Cell Res Ther. 2016;7:56.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Mariani E, Pulsatelli L, Facchini A. Signaling pathways in cartilage repair. Int J Mol Sci. 2014;15:8667–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kanzaki M, Yamato M, Hatakeyama H, Kohno C, Yang J, Umemoto T, Kikuchi A, Okano T, Onuki T. Tissue engineered epithelial cell sheets for the creation of a bioartificial trachea. Tissue Eng. 2006;12:1275–83.

    Article  PubMed  Google Scholar 

  57. Chia HN, Wu BM. Recent advances in 3D printing of biomaterials. J Biol Eng. 2015;9:4.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Ochi M, Uchio Y, Kawasaki K, Wakitani S, Iwasa J. Transplantation of cartilage-like tissue made by tissue engineering in the treatment of cartilage defects of the knee. J Bone Joint Surg Br. 2002;84:571–8.

    Article  CAS  PubMed  Google Scholar 

  59. Wambach BA, Cheung H, Josephson GD. Cartilage tissue engineering using thyroid chondrocytes on a type I collagen matrix. Laryngoscope. 2000;110:2008–11.

    Article  CAS  PubMed  Google Scholar 

  60. Tcacencu I, Carlsöö B, Stierna P, Hultenby K. Local treatment of cricoid cartilage defects with rhBMP-2 induces growth plate-like morphology of chondrogenesis. Otolaryngol Head Neck Surg Off J Am Acad Otolaryngol Head Neck Surg. 2006;135:427–33.

    Article  Google Scholar 

  61. Katic V, Majstorovic L, Maticic D, Pirkic B, Yin S, Kos J, Martinovic S, McCartney JE, Vukicevic S. Biological repair of thyroid cartilage defects by osteogenic protein-1 (bone morphogenetic protein-7) in dog. Growth Factors. 2000;17:221–32.

    Article  CAS  PubMed  Google Scholar 

  62. Yamashita M, Omori K, Kanemaru S-I, Magrufov A, Tamura Y, Umeda H, Kishimoto M, Nakamura T, Ito J. Experimental regeneration of canine larynx: a trial with tissue engineering techniques. Acta Otolaryngol (Stockh). 2007;127:66–72.

    Article  Google Scholar 

  63. Yamashita M, Kanemaru S, Hirano S, Umeda H, Kitani Y, Omori K, Nakamura T, Ito J. Glottal reconstruction with a tissue engineering technique using polypropylene mesh: a canine experiment. Ann Otol Rhinol Laryngol. 2010;119:110–7.

    Article  PubMed  Google Scholar 

  64. Kitani Y, Kanemaru S-I, Umeda H, Suehiro A, Kishimoto Y, Hirano S, Nakamura T, Ito J. Laryngeal regeneration using tissue engineering techniques in a canine model. Ann Otol Rhinol Laryngol. 2011;120:49–56.

    Article  PubMed  Google Scholar 

  65. Omori K, Nakamura T, Kanemaru S, Kojima H, Magrufov A, Hiratsuka Y, Shimizu Y. Cricoid regeneration using in situ tissue engineering in canine larynx for the treatment of subglottic stenosis. Ann Otol Rhinol Laryngol. 2004;113:623–7.

    Article  PubMed  Google Scholar 

  66. Omori K, Nakamura T, Kanemaru S, Magrufov A, Yamashita M, Shimizu Y. In situ tissue engineering of the cricoid and trachea in a canine model. Ann Otol Rhinol Laryngol. 2008;117:609–13.

    Article  PubMed  Google Scholar 

  67. Kitamura M, Hirano S, Kanemaru S-I, Kitani Y, Ohno S, Kojima T, Nakamura T, Ito J, Rosen CA, Gilbert TW. Glottic regeneration with a tissue-engineering technique, using acellular extracellular matrix scaffold in a canine model. J Tissue Eng Regen Med. 2014; doi:10.1002/term.1855.

    PubMed  PubMed Central  Google Scholar 

  68. Sun A, Meng Q, Li W, Liu S, Chen W. Construction of tissue-engineered laryngeal cartilage with a hollow, semi-flared shape using poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) as a scaffold. Exp Ther Med. 2015;9:1482–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nomoto Y, Okano W, Imaizumi M, Tani A, Nomoto M, Omori K. Bioengineered prosthesis with allogenic heterotopic fibroblasts for cricoid regeneration. Laryngoscope. 2012;122:805–9.

    Article  PubMed  Google Scholar 

  70. Wu G, Cui Y, Wang YT, Yao M, Hu J, Li JX, Wang Y, Zhang B. Repair of cartilage defects in BMSCs via CDMP1 gene transfection. Genet Mol Res. 2014;13:291–301.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Otolaryngology Head and Neck Surgery, Kyoto University, Kyoto, Japan

    Yo Kishimoto MD, PhD

Authors
  1. Yo Kishimoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yo Kishimoto MD, PhD .

Editor information

Editors and Affiliations

  1. Department of Otorhinolaryngology-Head Neck Surgery, Nihon University, School of Medicine, Tokyo, Japan

    Kiyoshi Makiyama

  2. Department of Otolaryngology-Head Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Shigeru Hirano

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Kishimoto, Y. (2017). Current Topics in Regenerative Medicine for the Laryngeal Tissues. In: Makiyama, K., Hirano, S. (eds) Aging Voice. Springer, Singapore. https://doi.org/10.1007/978-981-10-3698-9_10

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-3698-9_10

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-3697-2

  • Online ISBN: 978-981-10-3698-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation