Hostname: page-component-848d4c4894-xfwgj Total loading time: 0 Render date: 2024-06-15T23:09:31.790Z Has data issue: false hasContentIssue false

Regenerative medicine in otorhinolaryngology

Published online by Cambridge University Press:  24 June 2015

J C R Wormald*
Department of ENT, St Mary's Hospital, Imperial College Healthcare Trust, London, UK
J M Fishman
Department of Surgery, UCL Institute of Child Health, London, UK UCL Ear Institute, Royal National Throat, Nose and Ear Hospital, London, UK
S Juniat
UCL Ear Institute, Royal National Throat, Nose and Ear Hospital, London, UK
N Tolley
Department of ENT, St Mary's Hospital, Imperial College Healthcare Trust, London, UK
M A Birchall
UCL Ear Institute, Royal National Throat, Nose and Ear Hospital, London, UK
Address for correspondence: Dr Justin C R Wormald, Department of ENT, St Mary's Hospital, Imperial College Healthcare Trust, Praed Street, Paddington, London W2 1NY, UK E-mail:



Tissue engineering using biocompatible scaffolds, with or without cells, can permit surgeons to restore structure and function following tissue resection or in cases of congenital abnormality. Tracheal regeneration has emerged as a spearhead application of these technologies, whilst regenerative therapies are now being developed to treat most other diseases within otolaryngology.

Methods and results:

A systematic review of the literature was performed using Ovid Medline and Ovid Embase, from database inception to 15 November 2014. A total of 561 papers matched the search criteria, with 76 fulfilling inclusion criteria. Articles were predominantly pre-clinical animal studies, reflecting the current status of research in this field. Several key human research articles were identified and discussed.


The main issues facing research in regenerative surgery are translation of animal model work into human models, increasing stem cell availability so it can be used to further research, and development of better facilities to enable implementation of these advances.

Review Articles
Copyright © JLO (1984) Limited 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


1Orlando, G, Baptista, P, Birchall, M, De Coppi, P, Farney, A, Guimaraes-Souza, NK et al. Regenerative medicine as applied to solid organ transplantation: current status and future challenges. Transpl Int 2011;24:223–32CrossRefGoogle ScholarPubMed
2Orlando, G, Wood, KJ, De Coppi, P, Baptista, PM, Binder, KW, Bitar, KN et al. Regenerative medicine as applied to general surgery. Ann Surg 2012;255:867–80CrossRefGoogle ScholarPubMed
3Grikscheit, TC, Siddique, A, Ochoa, ER, Srinivasan, A, Alsberg, E, Hodin, RA et al. Tissue-engineered small intestine improves recovery after massive small bowel resection. Ann Surg 2004;240:748–54CrossRefGoogle ScholarPubMed
4Lange, P, Fishman, JM, Elliott, MJ, De Coppi, P, Birchall, MA. What can regenerative medicine offer for infants with laryngotracheal agenesis? Otolaryngol Head Neck Surg 2011;145:544–50CrossRefGoogle ScholarPubMed
5Maher, B. Tissue engineering: how to build a heart. Nature 2013;499:20–2CrossRefGoogle ScholarPubMed
6Shaker, A, Rubin, DC. Stem cells: one step closer to gut repair. Nature 2012;485:181–2CrossRefGoogle ScholarPubMed
7Totonelli, G. Esophageal tissue engineering: a new approach for esophageal replacement. World J Gastroenterol 2012;18:6900–7CrossRefGoogle ScholarPubMed
8Totonelli, G, Maghsoudlou, P, Garriboli, M, Riegler, J, Orlando, G, Burns, AJ et al. A rat decellularized small bowel scaffold that preserves villus-crypt architecture for intestinal regeneration. Biomaterials 2012;33:3401–10CrossRefGoogle ScholarPubMed
9Vandewoude, S, Rollin, BE. Practical considerations in regenerative medicine research: IACUCs, ethics, and the use of animals in stem cell studies. ILAR J 2010;51:82–4CrossRefGoogle Scholar
10Elliott, MJ, De Coppi, P, Speggiorin, S, Roebuck, D, Butler, CR, Samuel, E et al. Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet 2012;380:9941000CrossRefGoogle Scholar
11Hu, Z, Ulfendahl, M. The potential of stem cells for the restoration of auditory function in humans. Regen Med 2013;8:309–18CrossRefGoogle ScholarPubMed
12Roth, TN, Hanebuth, D, Probst, R. Prevalence of age-related hearing loss in Europe: a review. Eur Arch Otorhinolaryngol 2011;268:1101–7CrossRefGoogle ScholarPubMed
13Lin, FR. Hearing loss and cognition among older adults in the United States. J Gerontol A Biol Sci Med Sci 2011;66:1131–6CrossRefGoogle ScholarPubMed
14Monzani, D, Galeazzi, GM, Genovese, E, Marrara, A, Martini, A. Psychological profile and social behaviour of working adults with mild or moderate hearing loss. Acta Otorhinolaryngol Ital 2008;28:61–6Google ScholarPubMed
15Lin, FR, Metter, EJ, O'Brien, RJ, Resnick, SM, Zonderman, AB, Ferrucci, L. Hearing loss and incident dementia. Arch Neurol 2011;68:214–20CrossRefGoogle ScholarPubMed
16Daniel, E. Noise and hearing loss: a review. J Sch Health 2007;77:225–31CrossRefGoogle ScholarPubMed
17Ibekwe, TS, Ramma, L, Chindo, BA. Potential roles of stem cells in the management of sensorineural hearing loss. J Laryngol Otol 2012;126:653–7CrossRefGoogle ScholarPubMed
18Rubel, EW, Furrer, SA, Stone, JS. A brief history of hair cell regeneration research and speculations on the future. Hear Res 2013;297:4251CrossRefGoogle ScholarPubMed
19Okano, T, Kelley, MW. Stem cell therapy for the inner ear: recent advances and future directions. Trends Amplif 2012;16:418CrossRefGoogle ScholarPubMed
20Rask-Andersen, H, Boström, M, Gerdin, B, Kinnefors, A, Nyberg, G, Engstrand, T et al. Regeneration of human auditory nerve. In vitro/in video demonstration of neural progenitor cells in adult human and guinea pig spiral ganglion. Hear Res 2005;203:180–91CrossRefGoogle ScholarPubMed
21Chai, R, Xia, A, Wang, T, Jan, TA, Hayashi, T, Bermingham-McDonogh, O et al. Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea. J Assoc Res Otolaryngol 2011;12:455–69CrossRefGoogle ScholarPubMed
22Jopling, C, Boue, S, Izpisua Belmonte, JC. Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nat Rev Mol Cell Biol 2011;12:7989CrossRefGoogle ScholarPubMed
23Pau, H, Fagan, P, Oleskevich, S. Locating the scala media in the fixed human temporal bone for therapeutic access: a preliminary study. J Laryngol Otol 2006;120:914–15CrossRefGoogle ScholarPubMed
24Chen, W, Jongkamonwiwat, N, Abbas, L, Eshtan, SJ, Johnson, SL, Kuhn, S et al. Restoration of auditory evoked responses by human ES-cell-derived otic progenitors. Nature 2012;490:278–82CrossRefGoogle ScholarPubMed
25Koehler, KR, Mikosz, AM, Molosh, AI, Patel, D, Hashino, E. Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 2013;500:217–21CrossRefGoogle Scholar
26Oshima, K, Shin, K, Diensthuber, M, Peng, AW, Ricci, AJ, Heller, S. Mechanosensitive hair cell-like cells from embryonic and induced pluripotent stem cells. Cell 2010;141:704–16CrossRefGoogle ScholarPubMed
27Geleoc, GS, Holt, JR. Sound strategies for hearing restoration. Science 2014;344:1241062CrossRefGoogle ScholarPubMed
28Chen, W, Johnson, SL, Marcotti, W, Andrews, PW, Moore, HD, Rivolta, MN. Human fetal auditory stem cells can be expanded in vitro and differentiate into functional auditory neurons and hair cell-like cells. Stem Cells 2009;27:1196–204CrossRefGoogle ScholarPubMed
29Yaguchi, Y, Wada, K, Uchimizu, H, Tanaka, Y, Kojima, H, Moriyama, H. Middle ear mucosa regeneration by grafting of artificial mucosa. Acta Otolaryngol 2007;127:1038–44CrossRefGoogle ScholarPubMed
30Wada, K, Tanaka, Y, Kojima, H, Inamatsu, M, Yoshizato, K, Moriyama, H. In vitro reconstruction of a three-dimensional middle ear mucosal organ and its in vivo transplantation. Acta Otolaryngol 2006;126:801–10CrossRefGoogle ScholarPubMed
31Danti, S, D'Alessandro, D, Pietrabissa, A, Petrini, M, Berrettini, S. Development of tissue-engineered substitutes of the ear ossicles: PORP-shaped poly(propylene fumarate)-based scaffolds cultured with human mesenchymal stromal cells. J Biomed Mater Res A 2010;92:1343–56CrossRefGoogle ScholarPubMed
32Luers, JC, Beutner, D, Huttenbrink, KB. Reconstruction of the ossicular chain – current strategies [in German]. Laryngorhinootologie 2010;89:172–8Google ScholarPubMed
33Hong, P, Bance, M, Gratzer, PF. Repair of tympanic membrane perforation using novel adjuvant therapies: a contemporary review of experimental and tissue engineering studies. Int J Pediatr Otorhinolaryngol 2013;77:312CrossRefGoogle ScholarPubMed
34Kanemaru, S, Umeda, H, Kitani, Y, Nakamura, T, Hirano, S, Ito, J. Regenerative treatment for tympanic membrane perforation. Otol Neurotol 2011;32:1218–23CrossRefGoogle ScholarPubMed
35Raj, A, Sayal, A, Rathore, PK, Meher, R. Sutureless tympanoplasty using acellular dermis. Am J Otolaryngol 2011;32:96–9CrossRefGoogle ScholarPubMed
36Rahman, A, Olivius, P, Dirckx, J, Von Unge, M, Hultcrantz, M. Stem cells and enhanced healing of chronic tympanic membrane perforation. Acta Otolaryngol 2008;128:352–9CrossRefGoogle ScholarPubMed
37Nayyer, L, Patel, KH, Esmaeili, A, Rippel, RA, Birchall, M, O'Toole, G et al. Tissue engineering: revolution and challenge in auricular cartilage reconstruction. Plast Reconstr Surg 2012;129:1123–37CrossRefGoogle ScholarPubMed
38Guasti, L, Vagaska, B, Bulstrode, NW, Seifalian, AM, Ferretti, P. Chondrogenic differentiation of adipose tissue-derived stem cells within nanocaged POSS-PCU scaffolds: a new tool for nanomedicine. Nanomedicine 2014;10:279–89CrossRefGoogle ScholarPubMed
39Au, E, Roskams, AJ. Olfactory ensheathing cells of the lamina propria in vivo and in vitro. Glia 2003;41:224–36CrossRefGoogle ScholarPubMed
40Lindsay, SL, Riddell, JS, Barnett, SC. Olfactory mucosa for transplant-mediated repair: a complex tissue for a complex injury? Glia 2010;58:125–34CrossRefGoogle ScholarPubMed
41Lipson, AC, Widenfalk, J, Lindqvist, E, Ebendal, T, Olson, L. Neurotrophic properties of olfactory ensheathing glia. Exp Neurol 2003;180:167–71CrossRefGoogle ScholarPubMed
42Vats, A, Birchall, M. Stem cells and regenerative medicine: potentials and realities for rhinology. Rhinology 2010;48:259–64Google ScholarPubMed
43de Corgnol, AC, Guerout, N, Duclos, C, Verin, E, Marie, JP. Olfactory ensheathing cells in a rat model of laryngeal reinnervation. Ann Otol Rhinol Laryngol 2011;120:273–80CrossRefGoogle Scholar
44Choi, D, Li, D, Law, S, Powell, M, Raisman, G. A prospective observational study of the yield of olfactory ensheathing cells cultured from biopsies of septal nasal mucosa. Neurosurgery 2008;62:1140–4; discussion 1144–5CrossRefGoogle ScholarPubMed
45Murrell, W, Féron, F, Wetzig, A, Cameron, N, Splatt, K, Bellette, B et al. Multipotent stem cells from adult olfactory mucosa. Dev Dyn 2005;233:496515CrossRefGoogle ScholarPubMed
46Nivet, E, Vignes, M, Girard, SD, Pierrisnard, C, Baril, N, Devèze, A et al. Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions. J Clin Invest 2011;121:2808–20CrossRefGoogle ScholarPubMed
47Jakob, M, Hemeda, H, Janeschik, S, Bootz, F, Rotter, N, Lang, S et al. Human nasal mucosa contains tissue-resident immunologically responsive mesenchymal stromal cells. Stem Cells Dev 2010;19:635–44CrossRefGoogle ScholarPubMed
48Gómez-Barrena, E, Rosset, P, Müller, I, Giordano, R, Bunu, C, Layrolle, P et al. Bone regeneration: stem cell therapies and clinical studies in orthopaedics and traumatology. J Cell Mol Med 2011;15:1266–86CrossRefGoogle ScholarPubMed
49Wu, L, Cai, X, Zhang, S, Karperien, M, Lin, Y. Regeneration of articular cartilage by adipose tissue derived mesenchymal stem cells: perspectives from stem cell biology and molecular medicine. J Cell Physiol 2013;228:938–44CrossRefGoogle ScholarPubMed
50Birchall, MA, Seifalian, AM. Tissue engineering's green shoots of disruptive innovation. Lancet 2014;384:288–90CrossRefGoogle ScholarPubMed
51Fulco, I, Miot, S, Haug, MD, Barbero, A, Wixmerten, A, Feliciano, S et al. Engineered autologous cartilage tissue for nasal reconstruction after tumour resection: an observational first-in-human trial. Lancet 2014;384:337–46CrossRefGoogle ScholarPubMed
52Fishman, JM, De Coppi, P, Elliott, MJ, Atala, A, Birchall, MA, Macchiarini, P. Airway tissue engineering. Expert Opin Biol Ther 2011;11:1623–35CrossRefGoogle ScholarPubMed
53Tojo, T, Niwaya, K, Sawabata, N. Tracheal replacement with cryopreserved tracheal allograft: experiment in dogs. Ann Thorac Surg 1998;66:209–13CrossRefGoogle ScholarPubMed
54Macchiarini, P, Jungebluth, P, Go, T, Asnaghi, MA, Rees, LE, Cogan, TA et al. Clinical transplantation of a tissue-engineered airway. Lancet 2008;372:2023–30CrossRefGoogle ScholarPubMed
55Gonfiotti, A, Jaus, MO, Barale, D, Baiguera, S, Comin, C, Lavorini, F et al. The first tissue-engineered airway transplantation: 5-year follow-up results. Lancet 2014;383:238–44CrossRefGoogle ScholarPubMed
56Fishman, JM, Wiles, K, Lowdell, MW, De Coppi, P, Elliott, MJ, Atala, A et al. Airway tissue engineering: an update. Expert Opin Biol Ther 2014;14:1477–91CrossRefGoogle ScholarPubMed
57Fishman, J, Lowdell, M, Ansari, T, Sibbons, P, De Coppi, P, Birchall, M. Characterisation and immunogenicity of a decellularised skeletal muscle scaffold for laryngeal tissue engineering. Lancet 2013;381:S42CrossRefGoogle Scholar
58Fishman, JM, Lowdell, MW, Urbani, L, Ansari, T, Burns, AJ, Turmaine, M et al. Immunomodulatory effect of a decellularized skeletal muscle scaffold in a discordant xenotransplantation model. Proc Natl Acad Sci USA 2013;110:14360–5CrossRefGoogle Scholar
59Johnson, 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;120:537–45CrossRefGoogle ScholarPubMed
60Svensson, B, Nagubothu, SR, Cedervall, J, Chan, RW, Le Blanc, K, Kimura, M et al. Injection of human mesenchymal stem cells improves healing of vocal folds after scar excision--a xenograft analysis. Laryngoscope 2011;121:2185–90CrossRefGoogle ScholarPubMed
61Zopf, DA, Hollister, SJ, Nelson, ME, Ohye, RG, Green, GE. Bioresorbable airway splint created with a three-dimensional printer. N Engl J Med 2013;368:2043–5CrossRefGoogle ScholarPubMed
62Aframian, DJ, Palmon, A. Current status of the development of an artificial salivary gland. Tissue Eng Part B Rev 2008;14:187–98CrossRefGoogle ScholarPubMed
63Ogawa, M, Oshima, M, Imamura, A, Sekine, Y, Ishida, K, Yamashita, K et al. Functional salivary gland regeneration by transplantation of a bioengineered organ germ. Nature Commun 2013;4:2498CrossRefGoogle ScholarPubMed
64Joraku, A, Sullivan, CA, Yoo, J, Atala, A. In-vitro reconstitution of three-dimensional human salivary gland tissue structures. Differentiation 2007;75:318–24CrossRefGoogle ScholarPubMed
65Xiong, X, Shi, X, Chen, F. Human adipose tissue-derived stem cells alleviate radiation-induced xerostomia. Int J Mol Med 2014;34:749–55CrossRefGoogle ScholarPubMed
66Jeong, J, Baek, H, Kim, YJ, Choi, Y, Lee, H, Lee, E et al. Human salivary gland stem cells ameliorate hyposalivation of radiation-damaged rat salivary glands. Exp Mol Med 2013;45:e58CrossRefGoogle ScholarPubMed
67Lim, JY, Ra, JC, Shin, IS, Jang, YH, An, HY, Choi, JS et al. Systemic transplantation of human adipose tissue-derived mesenchymal stem cells for the regeneration of irradiation-induced salivary gland damage. PloS one 2013;8:e71167CrossRefGoogle ScholarPubMed
68Watanabe, Y, Sasaki, R, Matsumine, H, Yamato, M, Okano, T. Undifferentiated and differentiated adipose-derived stem cells improve nerve regeneration in a rat model of facial nerve defect. J Tissue Eng Regen Med 2014. Epub 2014 Jun 1Google Scholar
69Matsumine, H, Sasaki, R, Tabata, Y, Matsui, M, Yamato, M, Okano, T et al. Facial nerve regeneration using basic fibroblast growth factor-impregnated gelatin microspheres in a rat model. J Tissue Eng Regen Med. 2014. Epub 2014 Apr 16CrossRefGoogle Scholar
70Cui, Y, Lu, C, Meng, D, Xiao, Z, Hou, X, Ding, W et al. Collagen scaffolds modified with CNTF and bFGF promote facial nerve regeneration in minipigs. Biomaterials 2014;35:7819–27CrossRefGoogle ScholarPubMed
71Chen, D, Chen, S, Wang, W, Zhang, C, Zheng, H. Spontaneous regeneration of recurrent laryngeal nerve following long-term vocal fold paralysis in humans: histologic evidence. Laryngoscope 2011;121:1035–9CrossRefGoogle ScholarPubMed
72Halum, 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;122:2482–96CrossRefGoogle ScholarPubMed
73Lerner, 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;124:2555–60CrossRefGoogle ScholarPubMed
74Herford, AS, Boyne, PJ. Reconstruction of mandibular continuity defects with bone morphogenetic protein-2 (rhBMP-2). J Oral Maxillofac Surg 2008;66:616–24CrossRefGoogle Scholar
75Lee, MK, DeConde, A, Aghaloo, T, Lee, M, Tetradis, S, St John, M. Biomimetic scaffolds loaded with adipose-derived stem cells and BMP-2 induce healing of mandibular defects. Otolaryngol Head Neck Surg 2013;1:35–6Google Scholar
76Kelly, MP, Savage, JW, Bentzen, SM, Hsu, WK, Ellison, SA, Anderson, PA. Cancer risk from bone morphogenetic protein exposure in spinal arthrodesis. J Bone Joint Surg Am 2014;96:1417–22CrossRefGoogle ScholarPubMed