Introduction
Tympanic membrane perforation is a common entity in otology clinics. Most traumatic tympanic membrane perforations heal spontaneously in a few weeks. However, if the lesion does persist, surgical intervention is needed. Surgical techniques are invasive, require hospitalisation, can lead to complications and are associated with higher medical costs.
In recent years, exogenous growth factors (e.g. epidermal growth factor and fibroblast growth factor-2) have been adopted to repair tympanic membrane perforations. Among them, fibroblast growth factor-2 is commonly used to repair the eardrum. Fibroblast growth factor-2 was the first cellular growth factor to be evaluated for wound repair and regeneration.Reference Buntrock, Buntrock, Marx, Kranz, Jentzsch and Heder1, Reference Davidson, Klagsbrun, Hill, Buckley, Sullivan and Brewer2 Although not initially present at the wound site, the mitogenic and angiogenic properties of this cytokineReference Baird and Walicke3 have suggested that it could have properties associated with the augmentation of granulation tissue formation, and the promotion of organ and connective tissue repair. Although the concept of growth factors or cytokines as mediators of this process has been espoused for many years, only in the last decade has there been sufficient biochemical characterisation of these activities to permit their application, as recombinant gene products, to the process of wound repair.
In this mini-review, we focus on the role of fibroblast growth factor-2 in the repair of tympanic membrane perforations (Figure 1). In addition, some questions concerning fibroblast growth factor-2 are discussed.
Diagram of traumatic tympanic membrane perforation repaired with fibroblast growth factor-2 (FGF-2).
Materials and methods
A comprehensive search of the literature was conducted using the PubMed (US National Library of Medicine) database. The key words used were: ‘tympanic membrane perforation’, ‘fibroblast growth factor-2’ and ‘basic fibroblast growth factor’. Only English-language literature was included, but there was no restriction on the study design or date of publication. The final search was conducted on 30 January 2017. The inclusion criteria were: (1) English language; (2) inclusion of an abstract; (3) inclusion of a healing outcome (closure rate and/or closure time); (4) description of complications; and (5) acute or chronic tympanic membrane perforation. The exclusion criteria were: (1) performance of a histological or morphological study only; and (2) a review or commentary.
The titles and abstracts were screened independently by two researchers to identify potentially relevant articles, and the full-text articles were then obtained. The bibliography of each article was also searched for further potentially relevant studies. All articles that met the inclusion criteria were reviewed for data extraction and quality assessment. Data extracted from each article included: patient demographics, study design, type of surgical intervention performed, length of follow up and measured outcomes.
Results
A total of 42 articles were obtained from the initial literature search. After reviewing their citations and abstracts, 10 studies did not meet the inclusion criteria. Thirty-two studies were deemed to be potentially relevant and the full texts of these articles were reviewed. After further review of the remaining articles (n = 32), three were found to be reviews and were therefore removed.
A total of 29 studies were available for the final review and analysis; of these, 10 were experimental studies (Table I),Reference Mondain, Saffiedine and Uziel4–Reference Santa Maria, Weierich, Kim and Yang13 11 were human traumatic tympanic membrane perforation studies (Table II)Reference Lou14–Reference Lou, Lou, Liu and Chang24 and 8 were human chronic tympanic membrane perforation studies (Table III).Reference Kanemaru, Umeda, Kitani, Nakamura, Hirano and Ito25–Reference Hakuba, Hato, Okada, Mise and Gyo32 Of the 10 experimental studies, 7 examined the effect of fibroblast growth factor-2 on acute tympanic membrane perforationsReference Mondain, Saffiedine and Uziel4–Reference Zhang, Huang, Sun, Huang, Zhang and Dai10 and 3 focused on the effect of fibroblast growth factor-2 on chronic tympanic membrane perforations.Reference Kato and Jackler11–Reference Santa Maria, Weierich, Kim and Yang13 Of the 11 studies on traumatic tympanic membrane perforation in humans, 3 were randomised controlled trials (RCTs),Reference Lou14, Reference Lou and Wang19, Reference Zhengcai-Lou, Zihan-Lou and Yongmei-Tang23 4 were prospective controlled studies,Reference Lou, Tang and Wu15, Reference Zhang and Lou16, Reference Lou, Wang and Yu18, Reference Lou, Huang, Yang, Xiao and Chang22 1 was a single-arm and exploratory clinical trial,Reference Lou, Lou, Tang and Xiao20 2 were prospective, quasi-randomised, controlled clinical studies,Reference Lou and Wang17, Reference Lou, Lou, Liu and Chang24 and 1 was a retrospective cohort study.Reference Lou, Yang, Tang and Xiao21 Of the eight studies on chronic tympanic membrane perforation in humans, one was an RCT,Reference Kanemaru, Umeda, Kitani, Nakamura, Hirano and Ito25 four were prospective single-arm studies,Reference Acharya, Coates, Tavora-Vièira and Rajan26–Reference Hakuba, Iwanaga, Tanaka, Hiratsuka, Kumabe and Konishi29 one was a prospective controlled studyReference Hakuba, Hato, Omotehara, Okada and Gyo30 and two were retrospective studies.Reference Hakuba, Ikemune, Okada and Hato31, Reference Hakuba, Hato, Okada, Mise and Gyo32
Summary of fibroblast growth factor-2 effects on experimental tympanic membrane perforation
bFGF = basic fibroblast growth factor; FGF-2 = fibroblast growth factor-2; PBS = phosphate-buffered saline; TMP = tympanic membrane perforation; HB-EGF = heparin-binding epidermal growth factor-like growth factor; EGF = epidermal growth factor
Summary of fibroblast growth factor-2 effects on human traumatic tympanic membrane perforation
TMP = tympanic membrane perforation; FGF-2 = fibroblast growth factor-2; bFGF = basic fibroblast growth factor; EGF = epidermal growth factor
Summary of fibroblast growth factor-2 effects on tympanic membrane perforation with chronic suppurative otitis media
TMP = tympanic membrane perforation; FGF-2 = fibroblast growth factor-2; bFGF = basic fibroblast growth factor
Of the 10 experimental studies, 5 showed that subjects in the fibroblast growth factor-2 group with or without a patch (Gelfoam or gelatine hydrogel) had a significantly shortened closure time and improved closure rate for acute tympanic membrane perforations compared with the control group (saline, phosphate-buffered saline, or glycerol with or without a patch).Reference Mondain, Saffiedine and Uziel4–Reference Chauvin, Bratton and Parkins8 Chauvin et al. showed that fibroblast growth factor-2 reduced the closure rate of acute tympanic membrane perforations compared with 1 per cent hyaluronic acid and epidermal growth factor, but improved the closure rate compared with subjects who spontaneously healed.Reference Chauvin, Bratton and Parkins8 However, collagen membrane integrated with collagen-binding basic fibroblast growth factor promoted the healing rate at an early stage (within 7 days) and reduced the healing time in acute tympanic membrane perforations.Reference Zhang, Huang, Sun, Huang, Zhang and Dai10 In addition, two studies on chronic tympanic membrane perforations showed that fibroblast growth factor-2 with or without Gelfoam facilitated the closure rate of chronic tympanic membrane perforations compared with a saline solution.Reference Kato and Jackler11, Reference Ozkaptan, Gerek, Simşek and Deveci12 However, one comparative study of chronic tympanic membrane perforations found that the closure rate in the fibroblast growth factor-2 group was lower than that of the heparin-binding epidermal growth factor-like growth factor group, but was similar to the polymer-only group.Reference Santa Maria, Weierich, Kim and Yang13
All 11 clinical studies investigating the effect of fibroblast growth factor-2 on traumatic tympanic membrane perforations in humans were reported by Lou and colleagues (Table II), between 2012 and 2016, at the same medical institution.Reference Lou14–Reference Lou, Lou, Liu and Chang24 The authors found that the topical application of fibroblast growth factor-2 with or without Gelfoam significantly shortened the closure time and improved the closure rate of large traumatic tympanic membrane perforations in humans compared with the control group, regardless of the cause of trauma (penetrating perforations or blast injury) and the duration of trauma (acute or subacute). The closure rate of large perforations ranged from 89.3 to 100 per cent, and the closure time was around two weeks in most large perforation cases.Reference Lou14–Reference Zhengcai-Lou, Zihan-Lou and Yongmei-Tang23 However, surprisingly, they also found, in a prospective, quasi-randomised, controlled clinical study, that the closure rate and closure time in the fibroblast growth factor-2 group were similar to those of the ofloxacin eardrops treatment group.Reference Lou, Lou, Liu and Chang24
Patching with biological materials (gelatine sponge and fibrin glue, an atelocollagen/silicone bilayer membrane patch) was applied in eight clinical studies investigating the effect of fibroblast growth factor-2 on chronic tympanic membrane perforation in humans.Reference Kanemaru, Umeda, Kitani, Nakamura, Hirano and Ito25–Reference Hakuba, Hato, Okada, Mise and Gyo32 However, no studies reported the effect of applying fibroblast growth factor-2 alone. Three studies examining fibroblast growth factor-2 combined with Gelfoam showed that the success rate of treating chronic tympanic membrane perforations was 83–98.1 per cent in the fibroblast growth factor-2 group, but 10 per cent in the gelatine sponge and fibrin glue group.Reference Kanemaru, Umeda, Kitani, Nakamura, Hirano and Ito25–Reference Omae, Kanemaru, Nakatani, Kaneda, Nishimura and Tona27 Another five studies evaluating the effect of fibroblast growth factor-2 on chronic tympanic membrane perforation in humans were reported by Hakuba and colleagues, during the period 2003–2015, at the same medical institution.Reference Hakuba, Taniguchi, Shimizu, Sugimoto, Shinomori and Gyo28–Reference Hakuba, Hato, Okada, Mise and Gyo32 They reported a success rate of 62–100 per cent in the fibroblast growth factor-2 combined with an atelocollagen/silicone bilayer membrane patch group, compared to a success rate of only 40 per cent in the control group.
Discussion
Experimental tympanic membrane perforation
First, we consider the effect of fibroblast growth factor-2 on the regeneration of an experimental tympanic membrane perforation. Historically, the growth factor activity of fibroblast growth factors was the first to be identified.Reference Buntrock, Buntrock, Marx, Kranz, Jentzsch and Heder1 Within the fibroblast growth factor family, fibroblast growth factor-2 has been the most investigated.Reference Burgess and Maciag33, Reference Bashkin, Doctrow, Klagsbrun, Svahn, Folkman and Vlodavsky34 Fibroblast growth factor-2 is an 18 kD protein. At physiological pH and temperature, the in vitro half-life time of fibroblast growth factor-2 activity is approximately 12 hours. The normal function of basic fibroblast growth factor is unknown to date. When the vascular wall is damaged, fibroblast growth factor-2 can be released through several mechanisms. Fibroblast growth factor-2 is a potent stimulator of endothelial cells and neovessel formation in in vitro and in vivo models of angiogenesis.Reference Baird and Walicke3, Reference Burgess and Maciag33 Similarly, fibroblast growth factor-2 stimulates the proliferation of endothelial cells, fibroblasts, smooth muscle cells and chondrocytes, but also induces the production of proteases, including collagenases, in vitro.Reference Bashkin, Doctrow, Klagsbrun, Svahn, Folkman and Vlodavsky34–Reference Baird36
The mechanism underlying fibroblast growth factor-2 facilitation of eardrum healing is unclear. A previous study showed that fibroblast growth factor-2 is produced after tympanic membrane perforation and facilitates perforation closure through various mechanisms. The progress of tympanic membrane healing is also accelerated, but the basic healing process is unchanged after fibroblast growth factor-2 treatment.Reference Mondain and Ryan37 Fibroblast growth factor-2 mainly activates mitosis in fibroblast and endothelial cells, induces neovascularisation and better arrangement of collagenous fibres, and facilitates the proliferation of the fibrous layer, thereby providing the scaffold of epithelial migration and preventing eardrum atrophy.Reference Fina, Bresnick, Baird and Ryan5, Reference Chauvin, Bratton and Parkins8, Reference Mondain and Ryan37, Reference Mondain and Ryan38 However, although the average area of blood vessels in the eardrum was greater after fibroblast growth factor-2 application, the number of vessels remained unchanged.Reference Fina, Bresnick, Baird and Ryan5, Reference Mondain and Ryan37
Some scholars reported that the fibroblast growth factor-2 group showed a significantly improved closure rate and shorted the closure time in subjects with acute tympanic membrane perforations compared with the phosphate-buffered saline treated group or glycerol group.Reference Mondain, Saffiedine and Uziel4, Reference Fina, Bresnick, Baird and Ryan5, Reference Vrabec, Schwaber, Davidson and Clymer7–Reference Hakuba, Tabata, Hato, Fujiwara and Gyo9 In addition, fibroblast growth factor-2 treatment also promotes the healing of glucocorticoid-induced tympanic membrane perforations.Reference Ishimoto and Ishibashi39, Reference Ishimoto, Ishibashi, Bottaro and Kaga40 Two studies demonstrated that the topical application of fibroblast growth factor-2 facilitated the closure of chronic tympanic membrane perforations.Reference Kato and Jackler11, Reference Ozkaptan, Gerek, Simşek and Deveci12 Kato and Jackler treated chronic tympanic membrane perforations by applying 25 µl fibroblast growth factor-2 to a Gelfoam pledget every other day for 6 days in an experimental group, and administered 25 µl phosphate-buffered saline alone to a control group.Reference Kato and Jackler11 The closure rate was 81 per cent in the fibroblast growth factor-2 group and 41 per cent in the control group. However, in an experimental study of chronic tympanic membrane perforations similar to human chronic tympanic membrane perforations with chronic suppurative otitis media, Santa Maria et al. found that the success rate in the fibroblast growth factor-2 group was only 31.6 per cent at four weeks, which was similar to that of the control group (27.8 per cent).Reference Santa Maria, Weierich, Kim and Yang13
Human tympanic membrane perforation
Second, we consider the effect of fibroblast growth factor-2 on the regeneration of tympanic membrane perforation in humans. Fibroblast growth factor-2 has been used widely to repair large traumatic and subacute tympanic membrane perforations in humans, in studies conducted by Lou et al.Reference Lou14–Reference Lou, Lou, Liu and Chang24 They reported a closure rate of 89.3–100 per cent in the fibroblast growth factor-2 treated group, compared to closure rates of 60 per cent in the edge approximation group and 55–72.4 per cent in the spontaneous healing group, in prospective clinical studies.Reference Lou14–Reference Lou and Wang19, Reference Lou, Yang, Tang and Xiao21, Reference Zhengcai-Lou, Zihan-Lou and Yongmei-Tang23, Reference Lou, Lou, Liu and Chang24 Topical application of fibroblast growth factor-2 also improved the closure rate of blast-induced total or near-total tympanic membrane perforations and subacute traumatic tympanic membrane perforations.Reference Lou, Lou, Tang and Xiao20, Reference Lou, Huang, Yang, Xiao and Chang22
A higher success rate has also been obtained in chronic tympanic membrane perforations in humans after fibroblast growth factor-2 administration. The efficacy of fibroblast growth factor-2 in the repair of chronic tympanic membrane perforations was reported by Hakuba et al.Reference Hakuba, Taniguchi, Shimizu, Sugimoto, Shinomori and Gyo28–Reference Hakuba, Hato, Okada, Mise and Gyo32 They reported a regeneration success rate of 62–100 per cent in patients treated using fibroblast growth factor-2 combined with an atelocollagen/silicone bilayer membrane patch, whereas the success rate was only 40 per cent (two out of five) in the saline control group.Reference Hakuba, Taniguchi, Shimizu, Sugimoto, Shinomori and Gyo28 Kanemaru et al., in a randomised controlled trial (RCT), reported a higher success rate of 98.1 per cent (52 out of 53) in the gelatine sponge and fibrin glue with fibroblast growth factor-2 group, but the success rate was only 10 per cent (1 out of 10) in the gelatine sponge and fibrin glue only group.Reference Kanemaru, Umeda, Kitani, Nakamura, Hirano and Ito25 Other prospective single-arm and exploratory clinical trials recently reported success rates of 83 per cent and 88.9 per cent in the regeneration of chronic tympanic membrane perforations in humans using gelatine sponge and fibrin glue with fibroblast growth factor-2.Reference Acharya, Coates, Tavora-Vièira and Rajan26, Reference Omae, Kanemaru, Nakatani, Kaneda, Nishimura and Tona27
Confounding factors were obvious in these clinical studies on chronic tympanic membrane perforation. In addition, some studies reported higher success rates for regeneration in cases of chronic tympanic membrane perforation using Gelfoam or an atelocollagen/silicone bilayer membrane patch alone.Reference Niklasson and Tano41, Reference Tamae and Komune42 Thus, the specific effects of fibroblast growth factor-2 on chronic tympanic membrane perforations have not previously been well-demonstrated. The application of fibroblast growth factor-2 only to treat clinical chronic tympanic membrane perforations has not been performed, to date.
Fibroblast growth factor-2 administration and release
Normally, growth factors enhance wound healing. However, one important consideration is that many growth factors require prolonged exposure to wound cells to stimulate a response.Reference Bennett and Schultz43, Reference Lynch, Colvin and Antoniades44 The middle ear is connected to the Eustachian tube; eardrops or gel can partly flow into the nasopharynx, which could rapidly clear fibroblast growth factor-2. Several studies have suggested that fibroblast growth factor-2 should be administered once daily until the perforation is completely closed. However, daily topical application would increase the inconvenience to patients, who might even discontinue the treatment, particularly those with chronic tympanic membrane perforation in need of a long healing time.
Studies have suggested that local sustained release from a suitable matrix is the most effective method of fibroblast growth factor-2 administration in vivo.Reference Bennett and Schultz43, Reference Rifkin and Moscatelli45 In several clinical studies of chronic tympanic membrane perforations, biological materials combined with fibroblast growth factor-2 were found to be effective for sustained-release and bioactive maintenance of fibroblast growth factor-2.Reference Kanemaru, Umeda, Kitani, Nakamura, Hirano and Ito25–Reference Hakuba, Hato, Okada, Mise and Gyo32, Reference Goldman, Siegfried, Scoleri, Aydogen and Cass46 The vehicles not only provide scaffolds for epithelial migration, but also store and offer sustained release of fibroblast growth factor-2. However, clinical studies on traumatic tympanic membrane perforations treated with fibroblast growth factor-2 found that the healing outcome was not different between fibroblast growth factor-2 with or without a vehicle.Reference Lou14, Reference Zhang and Lou16, Reference Lou and Wang17, Reference Lou and Wang19–Reference Lou, Yang, Tang and Xiao21 Thus, an RCT investigating single and cyclic application of fibroblast growth factor-2 with or without biomaterial is needed in the future to determine the effectiveness of fibroblast growth factor-2 alone on chronic perforations.
Application time, dosage and duration
The best dosage and application time for fibroblast growth factor-2 for the regeneration of tympanic membrane perforations are unclear. The application dosage and time given in some previous studies are shown in Table IV.Reference Mondain, Saffiedine and Uziel4–Reference Hakuba, Tabata, Hato, Fujiwara and Gyo9, Reference Kato and Jackler11–Reference Hakuba, Hato, Okada, Mise and Gyo32 The dosage in these studies was not uniform. Briefly, although fibroblast growth factor-2 promoted regeneration in cases of traumatic and chronic tympanic membrane perforation, it remains unclear whether a single or repeated dosage is best.
Summary of effects for fibroblast growth factor-2 dosage and application time on tympanic membrane perforation
FGF-2 = fibroblast growth factor-2; TMP = tympanic membrane perforation; bFGF = basic fibroblast growth factor; TM = tympanic membrane
Lou et al. found that the closure rate and average closure time were not significantly different between high- and low-dosage fibroblast growth factor-2 treatments.Reference Lou, Wang and Yu18, Reference Lou, Yang, Tang and Xiao21 A high dosage of fibroblast growth factor-2 induced infection of the middle ear and discomfort, thereby prolonging the closure time. The authors suggested that the best dosage condition was the maintenance of a moist perforation edge. Kälicke et al. also found that the local application of basic fibroblast growth factor increases the risk of local infection after trauma.Reference Kälicke, Köller, Frangen, Schlegel, Sprutacz and Printzen47 A dose-dependent, sometimes highly significant increase in the infection rate occurs after soft tissue trauma.
Thus, the best dosage and duration of application needs to be studied further, as fibroblast growth factor-2 solution rapidly flows into the Eustachian tube when applied as ear drops.
The best application time for fibroblast growth factor-2 has yet to be completely elucidated, particularly for acute tympanic membrane perforations. Vrabec et al. reported that the timing of application may influence the repair process, with a beneficial effect of fibroblast growth factor-2 when applied after the inflammatory stage of wound healing has passed.Reference Vrabec, Schwaber, Davidson and Clymer7 Ishibashi et al. suggested that fibroblast growth factor-2 may mediate the connective tissue reaction in the middle layer in the proliferation stage, and indicated that the best commencement time of application for traumatic tympanic membrane perforations should be during the proliferation stage of the healing process.Reference Ishibashi, Shinogami, Ishimoto, Yoshida and Kaga48
In clinical studies, Lou et al. reported that the best time to apply it was 3 days after perforation.Reference Lou and Wang19, Reference Lou, Yang, Tang and Xiao21 Fibroblast growth factor-2 had a normal biological effect only when the epithelium of the perforation edge showed signs of proliferation. The acute inflammatory response of the perforation edge occurred for 1–2 days after the perforation, and proliferation and migration of the epithelium in the germinal centre began 3–4 days after perforation, at which point the eardrum healing process entered the proliferation stage. During the proliferation stage, inflammatory cells are reduced, and fibroblasts are activated and gradually increase.Reference Mondain and Ryan38, Reference Santa Maria, Redmond, Atlas and Ghassemifar49
Exogenous application of fibroblast growth factor-2 can have the best biological effect. Nevertheless, it is difficult to differentiate among the different stages of the healing process of tympanic membrane perforations in humans.
Adverse effects on regeneration
The safety of fibroblast growth factor-2 regarding the tympanic membrane has been widely investigated. Otorrhoea is a common complication that may result from excessive application of a single dosage. However, interestingly, otorrhoea only prolonged the closure time and did not affect the closure rate.Reference Lou14, Reference Lou, Yang, Tang and Xiao21, Reference Lou, Huang, Yang, Xiao and Chang22 Previous studies have shown that fibroblast growth factor-2 may overcome the inhibition of wound contraction associated with bacterial infection.Reference Stenberg, Phillips, Hokanson, Heggers and Robson50, Reference Hayward, Hokanson, Heggers, Fiddes, Klingbeil and Goeger51
Chauvin et al. reported hypertrophy of the external auditory canal after treatment with hyaluronic acid and fibroblast growth factor-2, but not with epidermal growth factor.Reference Chauvin, Bratton and Parkins8 The mild complication may have been due to injury of the external auditory canal during the process of model work.
Mondain et al. reported myringitis; however, other studies have not reported similar findings.Reference Mondain, Saffiedine and Uziel4 Lou et al. found myringitis in the fibroblast growth factor-2 plus Gelfoam group, but not in the fibroblast growth factor-2 only group.Reference Lou14 We speculate that the incidence of myringitis is not characteristic of fibroblast growth factor-2 treatment and is not associated with the dosage of fibroblast growth factor-2.
It is important to know if fibroblast growth factor-2 is associated with ototoxicity of the middle and inner ear. Most studies have concluded that fibroblast growth factor-2 is not likely to be a candidate causative agent of ototoxicity.Reference Mondain, Saffiedine and Uziel4–Reference Hakuba, Hato, Okada, Mise and Gyo32 The topical application of fibroblast growth factor-2 preparation did not cause a significant reduction in the endocochlear direct current potential, and did not lead to damage of the stapes or signs of perilymph leakage when applied to the middle ear.Reference Kase, Iwanaga, Terakado, Tanaka, Takasaki and Kumagami52 In contrast, several interesting reports have described the protective effect of fibroblast growth factor-2 on sensory hair cells, rather than ototoxicity.Reference Zhai, Wang, Wang, Han and Yang53–Reference Sekiya, Shimamura, Yagihashi and Suzuki55
In addition, it is not completely understood whether cholesteatoma of the middle ear can develop after fibroblast growth factor-2 treatment. A few scholars have speculated that fibroblast growth factor-2 could induce the proliferation of squamous epithelial cells and ingrowth into the mucous layer, leading to the development of middle-ear cholesteatoma. However, most have suggested that fibroblast growth factor-2 strongly stimulates the regeneration of the intermediate layer composed of fibrous tissues produced by fibroblasts, thus limiting the potential for cholesteatoma formation.Reference Friedman, Wright, Pawlowski and Meyerhoff56 Lou et al. did not find cholesteatoma of the middle ear in a series of clinical studies.Reference Lou14–Reference Lou, Lou, Liu and Chang24
Some scholars have reported that large doses of fibroblast growth factor-2 in cases of acute and chronic tympanic membrane perforation may result in re-perforation of the eardrum. The long-term application of a large dose of fibroblast growth factor-2 can inhibit collagen synthesis and facilitate the catabolism of collagen.Reference Hennessey, Nirgiotis, Shinn and Andrassy57 The inhibitory effects of fibroblast growth factor-2 on collagen deposition imply that there would be little advantage to the regeneration of tympanic membrane perforations and that it might even be detrimental, resulting in re-perforation and atrophy of the eardrum. The long-term application of other growth factors may also result in eardrum re-perforation.
Prospects and outlook for clinical application
Fibroblast growth factor-2 has been used widely to treat cases of acute and chronic tympanic membrane perforation. Traumatic tympanic membrane perforations tend to spontaneously heal and some agent solutions of non-growth factors also facilitate eardrum healing;Reference Lou, Lou, Liu and Chang24 the regenerative effects of fibroblast growth factor-2 on traumatic tympanic membrane perforations may be minimal.
The important value of fibroblast growth factor-2 may be the regeneration in cases of chronic tympanic membrane perforation; however, the success rate of a single application of fibroblast growth factor-2 on chronic tympanic membrane perforations was very low. In addition, topical application of biomaterial alone could achieve a higher success rate.Reference Niklasson and Tano41, Reference Tamae and Komune42 Thus, the evidence for fibroblast growth factor-2 repairing chronic tympanic membrane perforations is limited.
Although the results of some previous studies have suggested that fibroblast growth factor-2 does have a positive effect on the tympanic membrane, these studies did not address the most important clinical problems: the minimal efficacious dose of fibroblast growth factor-2 for treating traumatic tympanic membrane perforations, the time of application, the total duration of application, and whether or not topical application alone without excision of the perforation edge can repair chronic tympanic membrane perforation. Randomised controlled trials of fibroblast growth factor-2 with and without biomaterial are scarce and are thus warranted.
Acknowledgements
This study was supported by: the Science and Technology Agency of Zhejiang Province, China (grant number: 2013C33176); the Science and Technology Agency of YiWu City, China (grant number: 15-3-306); and the Health and Medicine Agency of Zhejiang Province (grant number: 2015KYB420).
Competing interests
None declared
