Outlook for Tissue Engineering of the Tympanic Membrane

Maria A Villar-Fernandez, Jose A Lopez-Escamez, Maria A Villar-Fernandez, Jose A Lopez-Escamez

Abstract

Tympanic membrane perforation is a common problem leading to hearing loss. Despite the autoregenerative activity of the eardrum, chronic perforations require surgery using different materials, from autologous tissue - fascia, cartilage, fat or perichondrium - to paper patch. However, both, surgical procedures (myringoplasty or tympanoplasty) and the materials employed, have a number of limitations. Therefore, the advances in this field are incorporating the principles of tissue engineering, which includes the use of scaffolds, biomolecules and cells. This discipline allows the development of new biocompatible materials that reproduce the structure and mechanical properties of the native tympanic membrane, while it seeks to implement new therapeutic approaches that can be performed in an outpatient setting. Moreover, the creation of an artificial tympanic membrane commercially available would reduce the duration of the surgery and costs. The present review analyzes the current treatment of tympanic perforations and examines the techniques of tissue engineering, either to develop bioartificial constructs, or for tympanic regeneration by using different scaffold materials, bioactive molecules and cells. Finally, it considers the aspects regarding the design of scaffolds, release of biomolecules and use of cells that must be taken into account in the tissue engineering of the eardrum. The possibility of developing new biomaterials, as well as constructs commercially available, makes tissue engineering a discipline with great potential, capable of overcoming the drawbacks of current surgical procedures.

Keywords: cells; growth factors; myringoplasty; regenerative medicine; scaffold material; tympanic membrane perforation.

Figures

Figure 1.
Figure 1.
Schematic structure of the tympanic membrane. The tympanic membrane is trilaminar, consisting of an outer epithelial layer formed by keratinocytes; a fibrous middle layer consisting of fibroblasts and collagen - mainly type II and III - (lamina propria); and an inner mucosal non-keratinized epithelium layer. The thickness of the eardrum is heterogeneous in different locations, ranging from 30 to 150 µm. Most authors adopt a mean value of 74 µm. Modified from Teh et al., 2013.

References

    1. Mallo M. Formation of the middle ear: recent progress on the developmental and molecular mechanisms. Dev Biol 2001;231:410-9.
    1. Teh BM, Marano RJ, Shen Y, Friedland PL. Tissue engineering of the tympanic membrane. Tissue Eng B 2013;19:116-32.
    1. Stevens A LJ. Histology. Hong Kong: Gower Medical Publishing; 1992.
    1. De Juan J, et al. Tympanic membrane prosthesis with mechanical fixation. US Patent 6309419; 2001.
    1. Volandri G, Di Puccio F, Forte P, Carmignani C. Biomechanics of the tympanic membrane. J Biomech 2011;44:1219-36.
    1. Aernouts J, Soons J a M, Dirckx JJJ. Quantification of tympanic membrane elasticity parameters from in situ point indentation measurements: validation and preliminary study. Hear. Res. 2010;263:177-82.
    1. Hong 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;77:3-12.
    1. Tringali S, Dubreuil C, Bordure P. Tympanic membrane perforation and tympanoplasty. Ann Otolaryngol Chir Cervicofac 2008;125:261-72.
    1. Cheng T, Dai C, Gan RZ. Viscoelastic properties of human tympanic membrane. Ann Biomed Eng 2007;35:305-14.
    1. Gil-Carcedo L, Vallejo L, Gil-Carcedo E. Otología. Madrid: Editorial Médica Panamericana; 2011. pp 23, 229.
    1. Knutsson J, Bagger-Sjöbäck D, Von Unge M. Collagen type distribution in the healthy human tympanic membrane. Otol Neurotol 2009;30:1225-29.
    1. Knutsson J, Bagger-Sjöbäck D, Von Unge M. Different kinds of collagens in tympanic membranes. Hear Res 2010;263:233-52.
    1. Stenfeldt K, Johansson C, Hellström S. The collagen structure of the tympanic membrane. Arch Otolaryngol Head Neck Surg 2006;132:293-8.
    1. Young B, Lowe J, Stevens A, Heath J. Wheater’s functional histology: a text and colour atlas. (Young B., Ed.). Shanghai: Churchill Livingstone-Elsevier; 2006. pp 417.
    1. Zhang Q, Lou Z. Impact of basic fibroblast growth factor on healing of tympanic membrane perforations due to direct penetrating trauma: a prospective non-blinded/controlled study. Clin Otolaryngol 2012;37:446-51.
    1. Kwong KM, Smith MM, Coticchia JM. Fat graft myringoplasty using umbilical fat. Int J Pediatr Otorhinolaryngol 2012;76:1098-101.
    1. Acar M, Yazıcı D, San T, Muluk NB, Muluk NB, Cingi C. Fat-plug myringoplasty of ear lobule vs abdominal donor sites. Eur Arch Otorhinolaryngol;2014.
    1. Kim JH, Bae J-H, Lim KT, Choung PH, Park JS, Choi SJ, et al. Development of water-insoluble chitosan patch scaffold to repair traumatic tympanic membrane perforations. J Biomed Mater Res A 2009;90:446-55.
    1. Güneri EA, Tekin S, Yilmaz O, Ozkara E, Erda TK, Ikiz AO, et al. The effects of hyaluronic acid, epidermal growth factor, and mitomycin in an experimental model of acute traumatic tympanic membrane perforation. Otol Neurotol 2003;24:371-6.
    1. Kang W, Kr H, Kr S, et al. Artificial eardrum using silk. US Patent 8500808; 2013.
    1. Kakehata S, Hirose Y, Kitani R, Futai K, Maruya S, Ishii K, et al. Autologous serum eardrops therapy with a chitin membrane for closing tympanic membrane perforations. Otol Neurotol 2008;29:791-5.
    1. Nardone M, Sommerville R, Bowman J, Danesi G. Myringoplasty in simple chronic otitis media: critical analysis of long-term results in a 1,000-adult patient series. Otol Neurotol 2012;33:48-53.
    1. Hakuba N, Taniguchi M, Shimizu Y, Futai K, Maruya S, Ishii K, et al. A new method for closing tympanic membrane perforations using basic fibroblast growth factor. Laryngoscope 2003;113:1352-5.
    1. Zhang Z, Huang Q, Zheng Y, Sun W, Chen YB, Si Y, et al. Three autologous substitutes for myringoplasty: a comparative study. Otol Neurotol 2011;32:1234-8.
    1. Ozgursoy OB, Yorulmaz I. Fat graft myringoplasty: a cost-effective but underused procedure. J Laryngol Otol 2005;119:277-9.
    1. Harrison R, St-Pierre J, Stevens M. Tissue Engineering and regenerative medicine : a year in review. Tissue Eng B 2014;20:1-16.
    1. Kaftan H. Trommelfellrekonstruktion mit nicht-autogenen Transplantaten und alloplastischen Materialien Autogenous Transplants and Alloplastic Materials. Laryngorhinootologie 2010;89:562-8; quiz 569-70.
    1. Parekh A, Mantle B, Banks J, Swarts JD, Badylak SF, Dohar JE, et al. Repair of the tympanic membrane with urinary bladder matrix. Laryngoscope 2009;119:1206-13.
    1. Perkins. Synthetic tympanic membrane US Patent 4077069; 1978.
    1. Shen Y, Redmond SL, Teh BM, Yan S, Wang Y, Atlas MD, et al. Tympanic membrane repair using silk fibroin and acellular collagen scaffolds. Laryngoscope 2013;123:1976-82.
    1. Albera R, Dagna F, Lacilla M, Canale A. Equine versus bovine pericardium in transmeatal underlay myringoplasty. Ann Otol Rhinol Laryngol 2009;118:287-91.
    1. Lou Z-C, He J-G. A randomised controlled trial comparing spontaneous healing, gelfoam patching and edge-approximation plus gelfoam patching in traumatic tympanic membrane perforation with inverted or everted edges. Clin Otolaryngol 2011;36:221-6.
    1. Miranda Araujo M, Tanaka Massuda E, Hyppolito M. Anatomical and functional evaluation of tympanoplasty using a transitory natural latex biomembrane implant from the rubber tree Hevea brasiliensis. Acta Cirúrgica Bras 2012;27:566-71.
    1. Kim J, Kim CH, Park CH, Seo JN, Kweon H, Kang SW, et al. Comparison of methods for the repair of acute tympanic membrane perforations: Silk patch vs. paper patch. Wound Repair Regen 2010;18:132-8.
    1. Levin B, Redmond SL, Rajkhowa R, Eikelboom RH, Atlas MD, Marano RJ. Utilising silk fibroin membranes as scaffolds for the growth of tympanic membrane keratinocytes and application to myringoplasty surgery. J Laryngol Otol 2013;127:S13-20.
    1. Ghassemifar R, Redmond S, Zainuddin S, Chirila T. Advancing towards a tissue-engineered tympanic membrane: silk fibroin as substratum for growing human eardrum keratinocytes. Appl J Biomater 2010;24:591-606.
    1. Kim J, Choi S, Park J, Lim KT, Choung PH, Kim SW, et al. Tympanic membrane regeneration using a water-soluble chitosan patch. Tissue Eng A 2010;16:225-32.
    1. Kim J, Kim S, Choi S, Lim KT, Lee JB, Seonwoo H, et al. A healing method of tympanic membrane perforations using three-dimensional porous chitosan scaffolds. Tissue Eng A 2011;17:2763-72.
    1. Weber DE, Semaan MT, Wasman JK, Beane R, Bonassar LJ, Megerian CA. Tissue-engineered calcium alginate patches in the repair of chronic chinchilla tympanic membrane perforations. Laryngoscope. 2006;116:700-4.
    1. Konakçi E, Koyuncu M, Ünal R, Tekat A, Uyar M. Repair of subtotal tympanic membrane perforations with Seprafilm. J Laryngol Otol 2004;118:862-5.
    1. Prior M, Gibbins N, John G, Rhys-Williams S, Scott P. Hyaluronic acid ester in myringoplasty. J Laryngol Otol 2007;122:e3.
    1. Saliba I, Woods O. Hyaluronic acid fat graft myringoplasty: a minimally invasive technique. Laryngoscope 2011;121:375-80.
    1. Saliba I, Froehlich P. Hyaluronic acid fat graft myringoplasty: an office-based technique adapted to children. Arch Otolaryngol Head Neck Surg 2011;137:1203-9.
    1. Wieland A, Sundback C, Hart A, Kulig K, Masiakos PT, Hartnick CJ. Poly (glicerol sebacate)-engineered plugs to repair chronic tympanic membrane perforations in a chinchilla model. Otolaryngol Neck Surg 2010;143:127-33.
    1. Fina M, Baird A, Ryan A. Direct application of basic fibroblast growth factor improves tympanic membrane perforation healing. Laryngoscope 1993;103:804-9.
    1. Hakuba N, Iwanaga M, Tanaka S, Hiratsuka Y, Kumabe Y, Konishi M, et al. Basic fibroblast growth factor combined with atelocollagen for closing chronic tympanic membrane perforations in 87 patients. Otol Neurotol 2010;31:118-21.
    1. Park A. Crosslinked hydrogels for tympanic membrane repair. Otolaryngol Neck Surg 2006;135:877-83.
    1. Lou Z, Xu L, Yang J, Wu X. Outcome of children with edge-everted traumatic tympanic membrane perforations following spontaneous healing versus fibroblast growth factor-containing gelfoam patching with or without edge repair. Int J Pediatr Otorhinolaryngol 2011;75:1285-8.
    1. O’Daniel T, Petitjean M, Jones SC, Zogg J, Martinez SA, Nolph MB, et al. Epidermal growth factor binding and action on tympanic membranes. Ann Otol Rhinol Laryngol 1990;99:80-4.
    1. Amoils C, Jackler R, Lustig L. Repair of chronic tympanic membrane perforations using epidermal growth factor. Arch Otolaryngol Head Neck Surg 1992;107:669-83.
    1. Lee A, Jackler R, Kato B, Scott N. Repair of chronic tympanic membrane perforations using epidermal growth factor: progress towards clinical application. Otol Neurotol 1994;15:10-8.
    1. Dvorak D, Abbas G, Ali T, Stevenson S, Welling DB. Repair of chronic tympanic membrane perforations with long-term epidermal growth factor. Laryngoscope 1995;105:1300-4.
    1. Ramsay H, Heikkonen E, Laurila P. Effect of epidermal growth factor on tympanic membranes with chronic perforations: a clinical trial. Otolaryngol. Neck Surg 1995;113:375-9.
    1. Cha D, O’Brien P, O’Toole E, Woodley DT, Hudson LG. Enhanced modulation of keratinocyte motility by transforming growth factor alpha (TGF-a) relative to epidermal growth factor (EGF). J Invest Dermatol 1996;106:590-7.
    1. Koba R, Kawabata I. Immunohistochemical study of transforming growth factor-expression in normal and perforated tympanic membrane. Ann Otol Rhinol Laryngol 1995;104:793-7.
    1. Kakigi A, Uchida A, Nishimura M, Takeda T, Takeda S, Nakatani H. Expression of fibroblast growth factor receptors 1-4 in human chronic tympanic membrane perforation. J Otorhinolaryngol Relat Spec 2010;71:67-70.
    1. Kato M, Jackler R. Repair of chronic tympanic membrane perforations with fibroblast growth factor. Otolaryngol Neck Surg 1996;115:538-47.
    1. Fina M, Bresnick S, Baird A, Ryan A. Improved healing of tympanic membrane perforations with basic fibroblast growth factor. Growth Factors 1991;5:265-72.
    1. Hakuba N, Hato N, Omotehara Y, Okada M, Gyo K. Epithelial pearl formation following tympanic membrane regeneration therapy using an atelocollagen/silicone membrane and basic fibroblast growth factor: our experience from a retrospective study of one hundred sixteen patients. Clin Otolaryngol 2013;38:394-7.
    1. Kanemaru S-I, Umeda H, Kitani Y, Nakamura T, Hirano S, Ito J. Regenerative treatment for tympanic membrane perforation. Otol Neurotol 2011;32:1218-23.
    1. Ishibashi T, Shinogami M, Ishimoto S, Yoshida K, Kaga K. Induction of KGF, basic FGF, and TGF alpha mRNA expression during healing of experimental TM perforations. Acta Otolaryngol 1998;118:701-4.
    1. Clymer M, Schwaber M, Davidson J. The effects of keratinocyte growth factor on healing of tympanic membrane perforations. Laryngoscope 1996;106:280-5.
    1. Yeo S, Kim S, Suh B, Cho S. Effects of platelet-derived growth factor-AA on the healing process of tympanic membrane perforation. Am J Otolaryngol 2000;21:153-60.
    1. Röösli C, Von Büren T, Gassmann N, Huber A. The impact of platelet-derived growth factor on closure of chronic tympanic membrane perforations: a randomized, double-blind, placebo-controlled study. Otol Neurotol 2011;32:1224-9.
    1. Cho K, Lee D, Shin D, Park YD, Chon KM. The importance of vascular endothelial growth factor in the healing of acute tympanic membrane perforation. Am J Otolaryngol 2009;31:309-14.
    1. Kaftan H, Herzog M, Miehe B, Hosemann W. Topical application of transforming growth factor beta-1 in acute traumatic tympanic membrane perforations: an experimental study in rats. Wound Repair Regen 2006;14:453-6.
    1. Eken M, Ates G, Sanli A, Evren C, Bozkurt S. The effect of topical insulin on the healing of acute tympanic membrane perforations: a histopathologic study. Eur Arch Otorhinolaryngol 2007;264:999-1002.
    1. Erkilet E, Koyuncu M, Atmaca S, Yarim M. Platelet-rich plasma improves healing of tympanic membrane perforations: experimental study. J Laryngol Otol 2009;123:482-7.
    1. Ho C, Beom Y, Yeo M, Lee H, Min EJ, Lee BH, et al. Regeneration of chronic tympanic membrane perforation using 3D collagen with topical umbilical cord serum. Int J Biol Macromol 2013;62:232-40.
    1. Ozturk K, Yaman H, Avunduk M, Arbag H, Keles B, Uyar Y. Effectiveness of MeroGel hyaluronic acid on tympanic membrane perforations. Acta Otolaryngol 2006;126:1158-63.
    1. Pujary P, Pujary K, Ramawamy B, Kanth S. Topical insulin for treatment of small central perforations - a pilot study. Int Adv Otol 2011;7:317-22.
    1. Wang AY, Shen Y, Wang JT, Eikelboom RH, Dilley RJ. Animal models of chronic tympanic membrane perforation: in response to plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice. Clin Transl Med 2014;3:5.
    1. Shen Y, Guo Y, Wilczynska M, Li J, Hellström S, Ny T. Plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice. J Transl Med 2014;12:5.
    1. Stenfors L. Treatment of tympanic membrane perforations with hyaluronan in an open pilot study of unselected patients. Acta Otolaryngol 1987;104:81-7.
    1. Deng Z, Wu J, Qiu J, Wang J, Tian Y, Li Y, et al. Comparison of porcine acellular dermis and dura mater as natural scaffolds for bioengineering tympanic membrane. Tissue Eng A 2009;15:3729-39.
    1. Von Unge M, Dirckx JJJ, Olivius NP. Embryonic stem cells enhance the healing of tympanic membrane perforations. Int J Pediatr Otorhinolaryngol 2003;67:215-9.
    1. Rahman A, Von Unge M, Olivius P, Dirckx J, Hultcrantz M. Healing time, long-term result and effects of stem cell treatment in acute tympanic membrane perforation. Int J Pediatr Otorhinolaryngol 2007;71:1129-37.
    1. Rocca A, D’Alessandro D, Chiellini F, Dinucci D, Puppi D, Trombi L, et al. In vitro study on the generation of tympanic membrane substitutes via tissue engineering. Ital J Anat Embriol 2012;117:2012.
    1. Rahman A, Olivius P, Dirckx J, Von Unge M, Hultcrantz M, et al. Stem cells and enhanced healing of chronic tympanic membrane perforation. Stem Cells 2008;128:352-9.
    1. Knutsson J, Von Unge M, Rask-Andersen H. Localization of progenitor/stem cells in the human tympanic membrane. Audiol Neurootol 2011;16:263-9.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa