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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 28  |  Issue : 4  |  Page : 301-305

Efficacy of human epidermal growth factor in the regeneration of tympanic membrane perforation: A randomized clinical study


Department of Otorhinolaryngology, Dr D Y Patil Medical College, Kolhapur, Maharashtra, India

Date of Submission29-Sep-2022
Date of Decision16-Oct-2022
Date of Acceptance30-Oct-2022
Date of Web Publication29-Dec-2022

Correspondence Address:
Dr. Anjana A Mohite
Department of Otorhinolaryngology, Dr D Y Patil Medical College, Kolhapur, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/indianjotol.indianjotol_163_22

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  Abstract 


Introduction: Majority of tympanic membrane perforations require myringoplasty for closure. Recently, epidermal growth factor (EGF) has been shown to promote the healing of tympanic membrane perforations. Aim: The aim of this study was to find out a simple nonsurgical outpatient procedure to close one-quadrant tympanic membrane perforations that could reduce the hospital stay, medical cost, and morbidity in these patients. Materials and Methods: An interventional prospective randomized clinical study was done on 120 patients at our tertiary hospital. The allocation ratio was 3:1. Pure-tone audiometry, otomicroscopy, and otoenodoscopic recording were performed in all eligible patients who consented to take part in the study. Ninety cases received EGF gel application, whereas 30 controls received antibiotic ofloxacin application. Trichloroacetic acid chemical cautery and fibrin glue application were done in patients of both groups. Results: The closure rate was 97.7% in the EGF group and 70% in the ofloxacin group. The time taken for closure of perforations was 10 to 14 days in the EGF group and 3–4 weeks in the ofloxacin group. Hearing gain was observed in healed perforations of both groups. Conclusion: EGF application enhances the healing effect of one-quadrant nonhealing tympanic membrane perforations. It showed encouraging results and reliable safety in the regeneration of tympanic membrane. Clinical Significance: Apart from its use in single quadrant perforation, EGF may be considered for treating residual perforations after failed tympanoplasty.

Keywords: Epidermal growth factor, fibrin glue, ofloxacin, one quadrant perforations, trichloracetic acid


How to cite this article:
Mohite AA, Shrestha B, Mane RS, Patil BC, Varute VP, Yasatwar AP. Efficacy of human epidermal growth factor in the regeneration of tympanic membrane perforation: A randomized clinical study. Indian J Otol 2022;28:301-5

How to cite this URL:
Mohite AA, Shrestha B, Mane RS, Patil BC, Varute VP, Yasatwar AP. Efficacy of human epidermal growth factor in the regeneration of tympanic membrane perforation: A randomized clinical study. Indian J Otol [serial online] 2022 [cited 2023 Feb 5];28:301-5. Available from: https://www.indianjotol.org/text.asp?2022/28/4/301/365957




  Introduction Top


Surgical repairs, such as myringoplasty or tympanoplasty, are usually employed for patients who are suffering from chronic tympanic membrane perforation using a tissue graft. This study aimed to find out a simple nonsurgical outpatient procedure to close the tympanic membrane perforations that could reduce the hospital stay, medical costs, and morbidity in these patients.

Growth factors stimulate wound healing in many tissues and are currently being used in the treatment of diabetic skin ulcers or decubitus.[1],[2],[3] Perforation closure in chronic otitis media occurs by epithelial proliferation and migration. Epidermal growth factor (EGF) and fibroblast growth factor are polypeptides that are expressed during the regeneration process of the tympanic membrane as reported in studies.[4] They can be applied either in drops or in a scaffold soaked with them. On local application, these growth factors induce the proliferation and migration of epithelial cells and fibroblasts and stimulate angiogenesis, thereby facilitating wound healing and regeneration of the tympanic membrane.[4],[5],[6],[7]

Ofloxacin (0.3% w/w) is a broad-spectrum quinolone antibiotic widely used in the treatment of acute and chronic suppurative otitis media and otitis externa. Experimental studies have found that ofloxacin accelerates the closure of tympanic membrane perforations.[4]

Human EGF in gel form was used in our study. It has an inductive effect on epithelial cells and blood capillaries. EGF and gel foam patch soaked with fibrin glue have shown to have better outcomes in tympanic membrane regeneration.


  Materials and Methods Top


A prospective, randomized control study was conducted on 120 patients at our tertiary care hospital for a period of 2 years. Patients in the age group 18–60 years, with one-quadrant dry perforation of tubotympanic type having conductive hearing loss within 40dB were included in the study. Patients with active ear discharge were excluded from the study.

Consecutive subjects fulfilling the inclusion criteria were subjected to detailed clinical history taking and examination after approval from the institutional ethical committee. Informed written consent was taken in vernacular language from all subjects willing to participate in the study. Detailed otoendoscopic examination was simultaneously followed by the photography of the ear perforation using the digital video camera. All patients underwent pure-tone audiometry for assessing the degree of hearing loss.

The patients were randomly allocated in a 3:1 ratio for EGF (cases) and ofloxacin (control) treatment, respectively. Thus, 90 patients underwent EGF therapy and 30 underwent ofloxacin therapy.

Application of the study treatment was done to both groups under local anesthesia. The intervention procedure in the case group involved chemical cauterization of the perforation edges with 50% trichloracetic acid (TCA), followed by the application of EGF gel and sealing it in position with fibrin glue-soaked gel foam. Whereas in the control group, chemical cauterization of perforation edges with 50% TCA was followed by the application of ofloxacin antibiotic ointment and sealing it in position with fibrin glue-soaked gel foam [Figure 1]. The follow-up visits occurred from 10 days to 3 months. During these visits, the patient's tympanic membrane was examined and photographed. If the perforation was found to be closed, then the patient reported after 3 months for a final follow-up. If the perforation persisted after the first 3 weeks, the procedure was repeated. The study was completed for reporting purposes after all patients had completed the 3-month follow-up. If perforation persisted after 3 months, the patient was offered standard of care.
Figure 1: Steps in procedure of EGF therapy. (1) 4% xylocaine cotton ball for surface anesthesia of TM. (2) Perforation occupying the anteroinferior quadrant of Lt TM. (3) Blanched rim of perforation after TCA cauterization. (4) Gelfoam placed just below the perforation. (5) EGF gel application to rim. (6) Fibrin sealant loaded in double plunger syringe. (7) Gelfoam moistened with Fibrin glue drops. (8) Ear wick moistened with Antibiotic drops. (9) External dressing. EGF: Epidermal growth factor, TCA: Trichloracetic acid. TM: Tympanic membrane

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Statistical analysis

Z-test for comparing two proportions was used to compare the recovery rate P < 0.05 was considered statistically significant at a 5% level of significance.


  Results Top


Demographic characteristics

Of 90 patients who underwent EGF therapy, 52 (57.8%) were males and 38 (42.2%) were females. In the ofloxacin group, 18 (60%) were males and 12 (40%) were females. The age ranged from 16 to 55 years. Mean ages of the EGF group were 37.08 years and the control was 42.26 years, respectively. Overall right ear was affected in 64 patients (53.33%) and the left ear in 56 patients (46.67%). Regarding the site, anteroinferior quadrant perforation was seen in 34 (28.83%) patients, posteroinferior in 32 (26.67%), centrimalleolar in 29 (24.17%), anterosuperior in 19 (15.83%), and posterosuperior in 6 (5%) patients. Seventy-two patients (60%) showed conductive hearing loss in the range of 15–30dB while 48 patients (40%) showed hearing loss in the range of 30–45dB [Table 1].
Table 1: Demographic data of patients in epidermal growth factor and ofloxacin groups

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Healing outcomes

In the EGF group, 88 (97.78%) patients showed complete closure of perforation while 2 (2.22%) had residual perforation after 3 months of final follow-up. In 88 patients of the EGF group, 8 patients had to undergo repeat procedures for the second time, while 2 needed the third application. While in the ofloxacin group, 21 (70%) patients showed complete closure of perforation and 9 (30%) had residual perforation at the final follow-up [Figure 2].
Figure 2: Preoperative picture of perforation and postoperative healed perforation

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Closure time was significantly longer in the ofloxacin group. The mean closure time was 10–12 days in the EGF group and 14–21 days in the ofloxacin group [Table 2].
Table 2: The healing outcome in epidermal growth factor and ofloxacin groups

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Hearing gain was observed in all healed perforations of both groups. More than 10 dB of hearing gain was seen in 29 patients of the EGF group and 5 patients of the control group. Up to 10 dB of hearing gain was observed in 61 patients of the EGF group and in 25 patients of the ofloxacin group [Figure 3].
Figure 3: Postprocedure hearing gain in the two groups

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Complications

During follow-up, some patients reported ear discomfort, but no serious complications were observed. Minor complications such as otomycosis were seen in 3 patients of each group. Myringitis was seen in 2 patients of the ofloxacin group. All these complications responded to treatment well.


  Discussion Top


Over the years, surgical myringoplasty has been the treatment of choice for patients with chronic tympanic membrane perforations. No matter how much ever efforts are put in by a surgeon, his success is always measured in terms of the results of his surgery and the compliance of the patient.[8] This has led to the search for more practical and conservative surgical techniques rather than radical and time-consuming procedures. It is always justified in giving a chance before moving on to major surgical procedures such as tympanoplasty. The use of EGFs thus could be a game changer in the management of small perforations.

Topical treatment with EGF for tympanic membrane regeneration has been reported since the 1990s. Our study shows that EGF significantly improved the closure rate (97.78%) of chronic one-quadrant perforations with no major complications. It also demonstrated that topical application of growth factors (EGF) has a speedy closure time with an average of 10–12 days as compared to ofloxacin treatment. There are several evidences in the literature that demonstrate the efficacy of topical EGF in the healing of tympanic membrane perforations. A comparison of our results is made with recent other EGF studies in [Table 3].
Table 3: Epidermal growth factor results in various studies

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[14],[15],[16]

Our study is in agreement with studies done by Lou and Lou,[4] Bongale et al.,[9] Zhengcai-Lou et al.,[10] Bhat et al.,[11] and Nayak et al.,[12] who found that topical application of EGF shortens the healing time and promotes closure of tympanic membrane perforations. These studies concluded that direct application of EGF over the tympanic membrane appears to be safe and effective.

Repeat application of EGF was done in few of our cases. In them, though the perforation persisted, the size of the perforation had reduced. Djamin et al.[13] reported that EGF had a role in shrinking the perforation diameter, if not closing it completely. We too have observed the same and noticed that EGF helped reduce the size of the perforation if not closing it completely.


  Conclusion Top


The closure rate of perforations was found to be significantly higher in the EGF group within a shorter period of time than in the ofloxacin group. We also observed that EGF had a role in reducing the perforation size if not closing it completely. Hearing gain was observed in closed perforations of both groups. Our study shows encouraging results and reliable safety with topical EGF in the regeneration of tympanic membrane perforations.

In future, the inspiring results of EGF can have vast applications intraoperatively to improve the outcome of tympanoplasty and to treat residual perforations of tympanoplasty surgery.

Clinical significance

EGF can promote and hasten the closure of tympanic membrane perforations. In future, it has scope for intraoperative use to increase the success rate during tympanoplasty surgery and also to treat residual perforations posttympanoplasty.

Acknowledgments

We gratefully acknowledge the funding for this research project by D Y Patil University, Kolhapur, Maharashtra.

The authors also wish to thank Honorable Chancellor Dr. Sanjay D. Patil, Vice Chancellor Dr. Rakesh Mudgal, Registrar Dr. V.V. Bhosale, Research Director Dr. C.V. Lokhande and Dean Dr. R.K. Sharma for their continuous encouragement and support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Carpenter G, Cohen S. Epidermal growth factor. J Biol Chem 1990;265:7709-12.  Back to cited text no. 1
    
2.
Tsang MW, Wong WK, Hung CS, Lai KM, Tang W, Cheung EY, et al. Human epidermal growth factor enhances healing of diabetic foot ulcers. Diabetes Care 2003;26:1856-61.  Back to cited text no. 2
    
3.
Djamin R, Aziza R, Rahardjo S, Savitri E, Punagi A, Patellongi I, et al. Topical application of epidermal growth factor (EGF) to changes in tympanic membrane perforation diameter. J Med Sci 2018;18:186-91.  Back to cited text no. 3
    
4.
Lou Z, Lou Z. A comparative study to evaluate the efficacy of EGF, FGF-2, and 0.3% (w/v) ofloxacin drops on eardrum regeneration. Medicine (Baltimore) 2017;96:e7654.  Back to cited text no. 4
    
5.
Berlanga-Acosta J, Gavilondo-Cowley J, López-Saura P, González-López T, Castro-Santana MD, López-Mola E, et al. Epidermal growth factor in clinical practice – A review of its biological actions, clinical indications and safety implications. Int Wound J 2009;6:331-46.  Back to cited text no. 5
    
6.
Wells A. EGF receptor. Int J Biochem Cell Biol 1999;31:637-43.  Back to cited text no. 6
    
7.
Bodnar RJ. Epidermal growth factor and epidermal growth factor receptor: The Yin and yang in the treatment of cutaneous wounds and cancer. Adv Wound Care (New Rochelle) 2013;2:24-9.  Back to cited text no. 7
    
8.
Jayakumar JK, Reghunathan D, Edacheriyan B, Divakaran B, Mukundan A. Closure of small central perforations of tympanic membrane with gelfilm patch and application of platelet rich plasma versus chemical cauterization: A comparative study. J Evol Med Dent Sci 2016;5:1004-8.  Back to cited text no. 8
    
9.
Bongale K, Bhat VK, Yadav M. The effect of epidermal growth factor on the outcomes of myringoplasty. Ann Otol Neurotol 2020;3:23-6.  Back to cited text no. 9
    
10.
Lou Zh, Lou Z, Tang Y. Comparative study on the effects of EGF and bFGF on the healing of human large traumatic perforations of the tympanic membrane. Laryngoscope 2016;126:E23-8.  Back to cited text no. 10
    
11.
Bhat VK, Veetil BV, Mathad VK. Effect of silver nitrate and epidermal growth factor on nonhealing tympanic membrane perforations: A randomized controlled study. Ann Otol Neurotol 2018;1:29-33.  Back to cited text no. 11
    
12.
Nayak P, Harugop A, Patil P, Prasad TV, Goswami L. Treatment of tympanic membrane perforation with topical epidermal growth factor: Progress towards clinical application. Int J Otorhinolaryngol Head Neck Surg 2021;7:768-71.  Back to cited text no. 12
    
13.
Djamin R, Aziza R, Rahardjo SP, Savitri E, Punagi A, Patellongi I, et al. Topical application of epidermal growth factor (EGF) to changes in tympanic membrane perforation diameter. J Medical Sciences 2018;18:186-91.  Back to cited text no. 13
    
14.
Yang J, Lou ZH, Fu Y, Lou ZC. A retrospective study of EGF and ofloxacin drops in the healing of human large traumatic eardrum perforation. Am J Otolaryngol 2016;37:294-8.  Back to cited text no. 14
    
15.
Lou ZC, Yang J, Tang Y, Fu YH. Topical application of epidermal growth factor with no scaffold material on the healing of human traumatic tympanic membrane perforations. Clin Otolaryngol 2016;41:744-9.  Back to cited text no. 15
    
16.
Lou ZC, Wei H, Lou ZH. Pretreatment factors affecting traumatic tympanic membrane regeneration therapy using epidermal growth factor. Am J Otolaryngol 2018;39:711-8.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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