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Regeneration of the tympanic membrane using fibroblast growth factor-2

  • Z-C Lou (a1), Z-H Lou (a2) and J Xiao (a3)



A systematic review was conducted to investigate the effectiveness of fibroblast growth factor-2 on the regeneration of tympanic membrane perforation.


The PubMed database was searched for relevant studies. Experimental studies, human randomised controlled trials, prospective single-arm studies and retrospective studies reporting acute and chronic tympanic membrane perforations in relation to two healing outcomes (success rate and closure time), were selected.


All 11 clinical studies investigating the effect of fibroblast growth factor-2 on traumatic tympanic membrane perforations in humans reported a success rate of 89.3–100 per cent, with a closure time of around 2 weeks. Three studies of fibroblast growth factor-2 combined with Gelfoam showed that the success rate of chronic tympanic membrane perforation was 83–98.1 per cent in the fibroblast growth factor-2 group, but 10 per cent in the gelatine sponge groups.


Fibroblast growth factor-2 with or without biological material patching promotes regeneration in cases of acute and chronic tympanic membrane perforation, and is safe and efficient. However, the best dosage, application time and administration pathway of fibroblast growth factor-2 are still to be elucidated.


Corresponding author

Author for correspondence: Dr Zheng-Cai Lou, Department of Otorhinolaryngology, Affiliated YiWu Hospital of Wenzhou Medical University, 699 Jiangdong Road, YiWu, Zhejiang 322000, China Fax: +86 0579 520 9678 E-mail:


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Dr Z-C Lou takes responsibility for the integrity of the content of the paper



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1Buntrock, P, Buntrock, M, Marx, I, Kranz, D, Jentzsch, KD, Heder, G. Stimulation of wound healing, using brain extract with fibroblast growth factor (FGF) activity. III. Electron microscopy, autoradiography, and ultrastructural autoradiography of granulation tissue. Exp Pathol 1984;26:247–54
2Davidson, JM, Klagsbrun, M, Hill, KE, Buckley, A, Sullivan, R, Brewer, PS et al. Accelerated wound repair, cell proliferation, and collagen accumulation are produced by a cartilage-derived growth factor. J Cell Biol 1985;100:1219–27
3Baird, A, Walicke, PA. Fibroblast growth factors. Br Med Bull 1989;45:438–52
4Mondain, M, Saffiedine, S, Uziel, A. Fibroblast growth factor improves the healing of experimental tympanic membrane perforations. Acta Otolaryngol 1991;111:337–41
5Fina, M, Bresnick, S, Baird, A, Ryan, A. Improved healing of tympanic membrane perforations with basic fibroblast growth factor. Growth Factors 1991;5:265–72
6Fina, M, Baird, A, Ryan, A. Direct application of basic fibroblast growth factor improves tympanic membrane perforation healing. Laryngoscope 1993;103:804–9
7Vrabec, JT, Schwaber, MK, Davidson, JM, Clymer, MA. Evaluation of basic fibroblast growth factor in tympanic membrane repair. Laryngoscope 1994;104:1059–64
8Chauvin, K, Bratton, C, Parkins, C. Healing large tympanic membrane perforations using hyaluronic acid, basic fibroblast growth factor, and epidermal growth factor. Otolaryngol Head Neck Surg 1999;121:43–7
9Hakuba, N, Tabata, Y, Hato, N, Fujiwara, T, Gyo, K. Gelatin hydrogel with basic fibroblast growth factor for tympanic membrane regeneration. Otol Neurotol 2014;35:540–4
10Zhang, D, Huang, Z, Sun, P, Huang, H, Zhang, Y, Dai, J et al. Acceleration of healing of traumatic tympanic membrane perforation in rats by implanted collagen membrane integrated with collagen-binding basic fibroblast growth factor. Tissue Eng Part A 2017;23:20–9
11Kato, M, Jackler, RK. Repair of chronic tympanic membrane perforations with fibroblast growth factor. Otolaryngol Head Neck Surg 1996;115:538–47
12Ozkaptan, Y, Gerek, M, Simşek, S, Deveci, S. Effects of fibroblast growth factor on the healing process of tympanic membrane perforations in an animal model. Eur Arch Otorhinolaryngol 1997;254:S25
13Santa Maria, PL, Weierich, K, Kim, S, Yang, YP. Heparin binding epidermal growth factor-like growth factor heals chronic tympanic membrane perforations with advantage over fibroblast growth factor 2 and epidermal growth factor in an animal model. Otol Neurotol 2015;36:1279–83
14Lou, Z. Healing large traumatic eardrum perforations in humans using fibroblast growth factor applied directly or via gelfoam. Otol Neurotol 2012;33:1553–7
15Lou, Z, Tang, Y, Wu, X. Analysis of the effectiveness of basic fibroblast growth factor treatment on traumatic perforation of the tympanic membrane at different time points. Am J Otolaryngol 2012;33:244–9
16Zhang, 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
17Lou, ZC, Wang, YB. Healing outcomes of large (>50%) traumatic membrane perforations with inverted edges following no intervention, edge approximation and fibroblast growth factor application; a sequential allocation, three-armed trial. Clin Otolaryngol 2013;38:289–96
18Lou, Z, Wang, Y, Yu, G. Effects of basic fibroblast growth factor dose on traumatic tympanic membrane perforation. Growth Factors 2014;32:150–4
19Lou, Z, Wang, Y. Evaluation of the optimum time for direct application of fibroblast growth factor to human traumatic tympanic membrane perforations. Growth Factors 2015;33:6570
20Lou, Z, Lou, Z, Tang, Y, Xiao, J. Utility of basic fibroblast growth factor in the repair of blast-induced total or near-total tympanic membrane perforations: a pilot study. Am J Otolaryngol 2015;36:794–7
21Lou, Z, Yang, J, Tang, Y, Xiao, J. Risk factors affecting human traumatic tympanic membrane perforation regeneration therapy using fibroblast growth factor-2. Growth Factors 2015;33:410–18
22Lou, Z, Huang, P, Yang, J, Xiao, J, Chang, J. Direct application of bFGF without edge trimming on human subacute tympanic membrane perforation. Am J Otolaryngol 2016;37:156–61
23Zhengcai-Lou, , Zihan-Lou, , Yongmei-Tang, . Comparative study on the effects of EGF and bFGF on the healing of human large traumatic perforations of the tympanic membrane. Laryngoscope 2016;126:E238
24Lou, ZC, Lou, ZH, Liu, YC, Chang, J. Healing human moderate and large traumatic tympanic membrane perforations using basic fibroblast growth factor, 0.3% ofloxacin eardrops, and Gelfoam patching. Otol Neurotol 2016;37:735–41
25Kanemaru, S, Umeda, H, Kitani, Y, Nakamura, T, Hirano, S, Ito, J. Regenerative treatment for tympanic membrane perforation. Otol Neurotol 2011;32:1218–23
26Acharya, AN, Coates, H, Tavora-Vièira, D, Rajan, GP. A pilot study investigating basic fibroblast growth factor for the repair of chronic tympanic membrane perforations in pediatric patients. Int J Pediatr Otorhinolaryngol 2015;79:332–5
27Omae, K, Kanemaru, SI, Nakatani, E, Kaneda, H, Nishimura, T, Tona, R et al. Regenerative treatment for tympanic membrane perforation using gelatin sponge with basic fibroblast growth factor. Auris Nasus Larynx 2017;44:664–71
28Hakuba, N, Taniguchi, M, Shimizu, Y, Sugimoto, A, Shinomori, Y, Gyo, K. A new method for closing tympanic membrane perforations using basic fibroblast growth factor. Laryngoscope 2003;113:1352–5
29Hakuba, 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
30Hakuba, 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
31Hakuba, N, Ikemune, K, Okada, M, Hato, N. Use of ambulatory anesthesia with manually assisted ventilation for tympanic membrane regeneration therapy in children. Am J Otolaryngol 2015;36:153–7
32Hakuba, N, Hato, N, Okada, M, Mise, K, Gyo, K. Preoperative factors affecting tympanic membrane regeneration therapy using an atelocollagen and basic fibroblast growth factor. JAMA Otolaryngol Head Neck Surg 2015;141:60–6
33Burgess, WH, Maciag, T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem 1989;58:575606
34Bashkin, P, Doctrow, S, Klagsbrun, M, Svahn, CM, Folkman, J, Vlodavsky, I. Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by heparitinase and heparin-like molecules. Biochemistry 1989;28:1737–43
35DeBlois, C, Cote, MF, Doillon, CJ. Heparin-fibroblast growth factor-fibrin complex: in vitro and in vivo applications to collagen-based materials. Biomaterials 1994;15:665–72
36Baird, A. Potential mechanisms regulating the extracellular activities of basic fibroblast growth factor (FGF-2). Mol Reprod Dev 1994;39:43–8
37Mondain, M, Ryan, A. Histological study of the healing of traumatic tympanic membrane perforation after basic fibroblast growth factor application. Laryngoscope 1993;103:312–18
38Mondain, M, Ryan, A. Effect of basic fibroblast growth factor on normal tympanic membrane. Am J Otolaryngol 1994;15:344–50
39Ishimoto, S, Ishibashi, T. Induction of growth factor expression is reduced during healing of tympanic membrane perforations in glucocorticoid-treated rats. Ann Otol Rhinol Laryngol 2002;111:947–53
40Ishimoto, S, Ishibashi, T, Bottaro, DP, Kaga, K. Direct application of keratinocyte growth factor, basic fibroblast growth factor and transforming growth factor-alpha during healing of tympanic membrane perforation in glucocorticoid-treated rats. Acta Otolaryngol 2002;122:468–73
41Niklasson, A, Tano, K. The Gelfoam® plug: an alternative treatment for small eardrum perforations. Laryngoscope 2011;121:782–4
42Tamae, A, Komune, S. Clinical study of transcanal closure of tympanic membrane perforations using a collagen sponge. J Laryngol Otol 2015;129:S216
43Bennett, NT, Schultz, GS. Growth factors and wound healing: part II. Role in normal and chronic wound healing. Am J Surg 1993;166:7481
44Lynch, SE, Colvin, RB, Antoniades, HN. Growth factors in wound healing. Single and synergistic effects on partial thickness porcine skin wounds. J Clin Invest 1989;84:640–6
45Rifkin, DB, Moscatelli, D. Recent developments in the cell biology of basic fibroblast growth factor. J Cell Biol 1989;109:16
46Goldman, SA, Siegfried, J, Scoleri, P, Aydogen, LB, Cass, SP. The effect of acidic fibroblast growth factor and live yeast cell derivative on tympanic membrane regeneration in a rat model. Otolaryngol Head Neck Surg 1997;117:616–21
47Kälicke, T, Köller, M, Frangen, TM, Schlegel, U, Sprutacz, O, Printzen, G et al. Local application of basic fibroblast growth factor increases the risk of local infection after trauma: an in vitro and in vivo study in rats. Acta Orthop 2007;78:6373
48Ishibashi, T, Shinogami, M, Ishimoto, SI, Yoshida, K, Kaga, K. Induction of KGF, basic FGF, and TGFalpha mRNA expression during healing of experimental TM perforations. Acta Otolaryngol 1998;118:701–4
49Santa Maria, PL, Redmond, SL, Atlas, MD, Ghassemifar, R. Histology of the healing tympanic membrane following perforation in rats. Laryngoscope 2010;120:2061–70
50Stenberg, BD, Phillips, LG, Hokanson, JA, Heggers, JP, Robson, MC. Effect of bFGF on the inhibition of contraction caused by bacteria. J Surg Res 1991;50:4750
51Hayward, P, Hokanson, J, Heggers, J, Fiddes, J, Klingbeil, C, Goeger, M et al. Fibroblast growth factor reserves the bacterial retardation of wound contraction. Am J Surg 1992;163:288–93
52Kase, K, Iwanaga, T, Terakado, M, Tanaka, F, Takasaki, K, Kumagami, H et al. Influence of topical application of basic fibroblast growth factor upon inner ear. Otolaryngol Head Neck Surg 2008;138:523–7
53Zhai, SQ, Wang, DJ, Wang, JL, Han, DY, Yang, WY. Basic fibroblast growth factor protects auditory neurons and hair cells from glutamate neurotoxicity and noise exposure. Acta Otolaryngol 2004;124:124–9
54Low, W, Dazert, S, Baird, A, Ryan, AF. Basic fibroblast growth factor (FGF-2) protects rat cochlear hair cells in organotypical culture from aminoglycoside injury. J Cell Physiol 1996;167:443–50
55Sekiya, T, Shimamura, N, Yagihashi, A, Suzuki, S. Effect of topically applied basic fibroblast growth factor on injured cochlear nerve. Neurosurgery 2003;52:900–7
56Friedman, NR, Wright, CG, Pawlowski, KS, Meyerhoff, WL. Effect of basic fibroblast growth factor on perforated chinchilla tympanic membranes. Ear Nose Throat J 1997;76:559–64
57Hennessey, PJ, Nirgiotis, JG, Shinn, MN, Andrassy, RJ. Continuous EGF application impairs long-term collagen accumulation during wound healing in rats. J Pediatr Surg 1991;26:362–5
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