Health Policy Advisory Committee on
Technology
Technology Brief Update
Basic fibroblast growth factor (b-FGF) for the treatment of
tympanic membrane perforation
July 2015
© State of Queensland (Queensland Department of Health) 2015
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DISCLAIMER: This Brief is published with the intention of providing information of interest. It is
based on information available at the time of research and cannot be expected to cover any
developments arising from subsequent improvements to health technologies. This Brief is based on
a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered.
The State of Queensland acting through Queensland Health (“Queensland Health”) does not
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This Brief was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy
Advisory Committee on Technology (HealthPACT). The production of this Brief was overseen by
HealthPACT. HealthPACT comprises representatives from health departments in all States and
Territories, the Australian and New Zealand governments and Medical Services Advisory Committee
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This brief was prepared by Jonathan Henry Jacobsen from ASERNIP-s.
2015 Summary of findings
Basic-FGF is a novel method of closing perforated tympanic membranes. Evidence from the
published literature is limited by short follow-up, inappropriate comparators, the use of
bovine rather than human b-FGF and a single author conducting all the trials. Two
randomised controlled trials demonstrated a shorter perforation closure time and a higher
overall closure rate with b-FGF, compared with no intervention. However, there was
variability in the rate of purulent otorrhoea following b-FGF treatment with higher doses of
b-FGF resulting in more occurrences. It would be prudent to await the results of the
Australian RCT examining the method of human FGF application, which is due to be
completed within eight months and is collecting more clinically relevant outcomes, such as
hearing threshold post-intervention.
2015 HealthPACT Advice
HealthPACT noted that this technology is a novel, low cost approach for the treatment of
otitis media, a condition that is associated with high morbidity particularly in the rural and
remote Aboriginal population. However, HealthPACT does not support the introduction of
this technology into clinical practice at this time and recommend that a further review of
the evidence be conducted in 24 months once the results of the ongoing Australian RCT are
published.
b-FGF for tympanic membrane regeneration: Update July 2015
i
TECHNOLOGY BRIEF UPDATE 2015
Technology, Company and Licensing
Register ID
WP129
Technology name
Gelatin foam impregnated with basic fibroblast growth
factor (b-FGF) solution (update)
Patient indication
Tympanic membrane perforation due to trauma or severe
otitis media
Reason for assessment
In 2012, a Technology Brief was completed to investigate the use of gelatin foam
impregnated with basic fibroblast growth factor, a protein implicated in wound healing, in
the treatment of tympanic membrane perforation. In light of the developing evidence on
the subject, the Brief recommended that this technology be monitored for further evidence
in 24 months. In line with this recommendation, the purpose of the current Update is to
consider the evidence that has emerged since 2012, and determine whether this new
evidence may provide additional information to inform policy decisions.
Description of the technology
The technology is a new method for closing tympanic membrane perforations using a
gelatin sponge impregnated with basic fibroblast growth factor (b-FGF) as a patch. The aim
of the procedure is to encourage healing of the perforation by providing the conditions
necessary for tissue regeneration (cells, scaffolds and chemical mediators which regulate
cell growth). The b-FGF stimulates proliferation of epidermal and connective tissue cells and
the gelfoam acts as a sustained release substrate for the b-FGF. Table 1 details the
components of the intervention and their relationship to the principles of tissue
engineering.
Table 1
Components of the intervention
Tissue engineering component
Intervention material
Scaffold and sustained release substrate
for b-FGF
Gelatin sponge is often used in medical procedures due to its
homeostatic properties and is absorbable in vivo. The sponge
1
may be cut to size in order to fit the perforation.
Gelatin sponge or ‘gelfoam’
Regulatory factors
Basic fibroblast growth factor
Cells
Supplied by the perforation margin
Recombinant human or bovine b-FGF (derived from genetically
engineered E.coli), is a polypeptide growth factor that
stimulates the proliferation of epidermal and connective tissue
cells. It has an inductive effect on fibroblasts and blood
capillaries. Current clinical applications of b-FGF include the
1
treatment of skin ulcers or decubitis.
Endogenously supplied by the perforation margin which is
mechanically disrupted during the procedure. The mechanical
disruption of the perforation edge is thought to stimulate the
b-FGF for tympanic membrane regeneration: November 2012
1
activity of stem cells of the tympanic membrane.
1
b-FGF: basic fibroblast growth factor.
The intervention involves placing a gelfoam sponge soaked in b-FGF at the perforation and
sealed in position with fibrin glue. Local anaesthesia is administered and the perforation
margin is trimmed before the sponge is placed. In paediatric patients the procedure may be
performed under general anaesthesia. Patients return three weeks post-procedure for
assessment and removal of any residual crust. Figure 1 is a schematic diagram of the
procedure.1
Figure 1
A schematic diagram showing the method of treatment 1 (TM: tympanic membrane).
The procedure may be performed in an outpatient setting and is an alternative to
myringoplasty, a surgical procedure which repairs the perforated membrane using a tissue
graft. The graft is most commonly autologous tissue sourced from the temporalis fascia,
although reports in the literature of optimal graft materials to achieve complete closure and
restore hearing are varied.2 Myringoplasty is performed under a general anaesthetic and
may be conducted as a same-day procedure or involve an overnight stay.
The potential advantages of b-FGF over conventional surgical treatment include:
reduced operative time
avoidance of invasive incision
reduced risk of infections, as harvesting of an autologous graft is not necessary
the option of local anaesthesia versus general anaesthesia
increased accessibility for remote and rural patients
reduced costs.3
The intervention is similar to wound healing applications used for burns or diabetic foot
ulcers.3 It is claimed that the procedure is associated with success rates of over 90 per
b-FGF for tympanic membrane regeneration: November 2012
2
cent.1, 4, 5 The Australian Institute of Health and Welfare reports 4,052 myringoplasties were
performed in the 2012-13 financial year.6
2015 Stage of development in Australia
Yet to emerge
Established
Experimental
Established but changed indication
or modification of technique
Should be taken out of use
Investigational
Nearly established
2015 Licensing, reimbursement and other approval
b-FGF for tympanic membrane perforation has not received FDA approval or a CE mark.
A Japanese pharmaceutical company, Kaken Pharmaceutical Co, Ltd. holds the only
identifiable patent of an agent (gelatin sponge impregnated with b-FGF and a covering
material) for regenerating tympanic membranes or external auditory canals.7
2015 Australian Therapeutic Goods Administration approval
Yes
ARTG number (s)
No
Not applicable
2015 Diffusion of technology in Australia
b-FGF for tympanic membrane perforation is considered an investigational technology in
Australia and its use is limited to clinical trials.
2015 International utilisation
Country
Level of use
Trials underway or
completed
Australia

China

Japan

South Korea

United States

Limited use
Widely diffused
2015 Cost infrastructure and economic consequences
The cost of the technology and its economic consequences are presently unknown.
However, additional infrastructure or training is unlikely to be required for this simple
intervention. The main cost factors will be the price of the b-FGF, avoidance of general
b-FGF for tympanic membrane regeneration: November 2012
3
anaesthesia and any differences in rates of success and complications compared with
myringoplasty.
2015 Evidence and Policy
Safety and effectiveness
Two randomised controlled trials (RCTs) (level II interventional evidence) and one pseudorandomised comparative study (level III-1 interventional evidence) (Table 2) were included
in the technology brief update. The studies evaluated the safety and efficacy of b-FGF for
tympanic membrane perforation. However, the method of applying b-FGF to the membrane
and the dose administered differed between the studies. Both randomised controlled trials
used observation as the control group. However, myringoplasty or application of a solution
without b-FGF are more appropriate controls. In addition, all of the included studies were
conducted by a single author and therefore represent a significant bias in the published
literature.
The primary outcome of all three studies was the rate of tympanic membrane closure and
adverse events attributable to b-FGF.
Table 2
Characteristics of included studies
Study / Design
Lou 2012
8
China
II (RCT)
Lou & Wang
9
2014
China
II (RCT)
Lou et al. 2014
China
III-1 (pseudorandomised)
9
Inclusion criteria
Exclusion
criteria
Intervention/
Number of
patients
Conflicts of
interest
TM perforation
involving ≥50% of
the entire TM and
presentation
within 14 days of
injury.
Granulation
tissue or purulent
discharge from
the ear
(otorrhoea),
severe vertigo,
profound hearing
loss or ossicular
disruption.
b-FGF solution
(n=32)
b-FGF gelfoam
(n=33)
No intervention
(n=29)
Losses to followup = 13
Not reported.
Traumatic TM
perforation
resulting from
blunt injury, a
perforation size of
≥25% of the pars
tensa (large area
of the TM) without
middle-ear
infection.
Not reported.
b-FGF solution
(n=46)
No intervention
(n=40)
Losses to followup = 7
None.
Low dose b-FGF
(n=76)
High dose b-FGF
(n=55)
Losses to followup =15
Not reported.
Traumatic TM
perforation
resulting from
blunt injury, a
perforation size
≥one eighth of the
pars tensa and dry
perforation without
middle-ear
infection.
Not reported.
b-FGF for tympanic membrane regeneration: November 2012
4
b-FGF: basic fibroblast growth factor, RCT: randomised controlled trial, TM: tympanic membrane
Lou 20128
One hundred and seven patients were enrolled into a RCT (level II interventional evidence)
evaluating two different methods of applying b-FGF to perforated tympanic membranes.
Patients were randomly assigned (via a series of computer-generated numbers) to one of
three cohorts: b-FGF solution applied directly, b-FGF impregnated in gelfoam or observation
(no intervention).
Patients assigned to either of the b-FGF groups (direct or gelfoam) received 4 to 5 drops (0.2
– 0.25ml at 21,000 IU/5 mL) of recombinant bovine b-FGF (Yi sheng Biological
Pharmaceutical Co., Ltd, Zhuhai, China) daily. The direct group received b-FGF solution onto
the tympanic membrane via ear drops, whereas the patients in the gelfoam group received
a gelatin sponge soaked in b-FGF which was placed on the tympanic membrane. Patients in
both direct groups continued daily application of b-FGF until the tympanic membrane closed
or three months had elapsed.
A power calculation determined the total number of patients required for the trial was 57.
One hundred and seven patients were enrolled, with 94 patients completing the threemonth follow-up. No further details regarding the losses to follow up were reported.
Patient demographics are outlined in Table 3. The included patients were on average 33
years of age, had their injury for four days and were considered hearing impaired (>25 dB,
the threshold for unimpaired hearing). There were no significant differences between the
groups with respect to any demographic variable.
Table 3
Baseline patient demographics in Lou 2012
8
b-FGF applied
directly
b-FGF applied
via gelfoam
Observation
32
33
29
32.8 [13.7]
35.3 [14.3]
33.6 [11.2]
p=0.53
29:3
31:2
27:2
p=0.97
Mean duration of injury (days)
[SD]
3.6 [1.4]
4.3 [2.2]
3.8 [1.6]
p=0.26
Mean hearing level (dB) [SD]
31.6 [ 8.0]
31.9 [7.1]
30.5 [9.5]
p=0.91
Demographic variable
Number of patients
Mean age (years) [SD]
Cause of injury (blunt injury: blast
injury)
p-value
b-FGF: basic fibroblast growth factor, SD: standard deviation
Effectiveness
There was no difference in mean hearing improvement between the three groups at the
three month follow-up (p=0.73) (Table 4). Both b-FGF groups had a shorter healing time and
a higher tympanic membrane closure rate at three months than the observational group
b-FGF for tympanic membrane regeneration: November 2012
5
(p<0.05). However, the method of b-FGF application was not a significant variable for either
the rate of closure or closure time (p>0.05).
Table 4
8
Efficacy outcomes reported in Lou 2012
Efficacy outcome
Mean hearing improvement (dB)
[SD]
b-FGF applied
directly
b-FGF applied
via gelfoam
Observation
p-value
12.7 [2.9]
13.1 [3.3]
12.4 [3.1]
p=0.73
Mean time until tympanic
membrane closed (days) [SD]
11.06 [1.52]
11.14 [ 2.28]
46.25 [8.71]
p<0.05
Tympanic membranes closed at 3
months (%)
32/32 (100)
32/33 (97)
16/29 (55)
p<0.05
b-FGF: basic fibroblast growth factor, SD: standard deviation
Safety
Each treatment group had two patients with purulent ear discharge (otorrhoea), of which
only the patients receiving direct application of b-FGF reported complete tympanic
membrane closure in the infected ears. The gelfoam and the observation groups reported
complete closure rates of 50 and 0 per cent, respectively, following the infection.
Inflammation of the tympanic membrane (myringitis) was reported in 17 patients in the bFGF gelfoam group. By contrast, myringitis was not observed in the other two groups,
indicating that the gelfoam was the likely source of the tympanic membrane inflammation.
Calcification of the tympanic membrane (tympanosclerosis) developed in one patient from
the observational cohort. No other adverse events or deaths were reported during the
three-month follow-up.
Lou & Wang 20149
Ninety-three adults with a tympanic membrane perforation covering at least one quarter of
the eardrum were recruited into this RCT (level II interventional evidence). Patients were
randomly assigned to either b-FGF treatment or observation (no intervention).
Randomisation was achieved using a table of random numbers in conjunction with a
statistics program.
Patients assigned to the treatment group received daily applications of recombinant bovine
b-FGF solution (0.2 to 0.25 mL of 21,000 IU/5 mL solution) (Yi sheng Biological
Pharmaceutical Co., Ltd, Zhuhai, China) to the tympanic membrane. The b-FGF solution was
applied via ear drops by the attending physician during the patient’s first visit. Patients were
responsible for applying the solution thereafter. No further application details were
reported. The b-FGF solution was applied until the tympanic membrane closed or until six
b-FGF for tympanic membrane regeneration: November 2012
6
months had elapsed. Patients in the observational cohort received monthly follow-up
appointments.
Seven patients were lost to follow-up; the final analysis was performed on 86 patients. No
further detail regarding the losses to follow-up was reported. There were no statistically
significant differences between the interventional or observational cohorts with respect to
age, sex, cause or side of injury, or mean perforation size (Table 5).
Table 5
Baseline patient demographics in Lou & Wang 2014
Demographic variable
9
b-FGF solution
Observation
46
40
31.9 [5.2]
32.4 [3.8]
p>0.05
42:4
38:2
p>0.05
6.6 [1.2]
5.7 [1.9]
p>0.05
Perforation ≤3 days
29
22
NR
Perforation ≥3 days
17
18
NR
47.0 [12.1]
46.0 [11.9]
p>0.05
Number of patients
Mean age (years) [SD]
Cause of injury (blunt injury, blast
injury)
Mean duration of injury (days) [SD]
2
Mean perforation size (mm ) [SD]
p-value
b-FGF: basic fibroblast growth factor, SD: standard deviation
Effectiveness
At the six-month follow-up, the rate of tympanic membrane closure was significantly higher
in the group treated with b-FGF compared with the non-treatment group (98% versus 83%;
p<0.05) (Table 6). Similarly, the b-FGF group reported shorter closure times compared to the
observational group (p<0.05). Tympanic membrane perforations that were less than three
days old at the time of treatment closed significantly faster than older perforations,
irrespective of the intervention (p<0.05 for both intervention and comparator groups).
Table 6
Efficacy outcomes reported in Lou & Wang 2014
Efficacy outcome
9
b-FGF solution
Observation
p-value
Tympanic membranes
closed at 3 months (%)
45/46 (97.8)
33/40 (82.5)
p<0.05
Perforation ≤3 days
28/29 (96.6)
19/22 (82.5)
Perforation ≥3 days
17/17 (100)
14/18 (77.8)
12.5 [ 3.4]
36.0 [ 5.6]
17.5 [ 5.1]
38.4 [ 6.9]
8.5 [ 2.1]
34.7 [ 5.0]
Mean closure time
(days) [SD]
Perforation ≤3 days
Perforation ≥3 days
p<0.05
b-FGF: basic fibroblast growth factor, SD: standard deviation
b-FGF for tympanic membrane regeneration: November 2012
7
Safety
All reported adverse events were minor, including slight earache and ear fullness. All events
resolved following the closure of the tympanic membrane or ceasing application of the bFGF solution. However, the number of patients affected by these events was not reported.
Purulent otorrhoea was present in 4.3 per cent (2/46) of patients treated with b-FGF and in
7.5 per cent (3/40) of patients who did not receive treatment (p-value not reported). No
major adverse events were reported.
Lou et al. 20149
A dose response trial examining the closure rates of perforated tympanic membranes
between patients treated with low (0.1 – 0.15 mL) or high (0.25 – 0.3 mL) doses of
recombinant bovine b-FGF (21,000 IU/5mL) (Yi sheng Biological Pharmaceutical Co., Ltd,
Zhuhai, China) was conducted by Lou et al. 2014 (level III-1 interventional evidence). One
hundred and forty-one patients were consecutively enrolled and alternately allocated to
receiving either the low or high b-FGF dose applied directly via ear drops daily. Patients
received monthly follow-ups throughout the three-month trial period.
One hundred and twenty-six patients completed the three-month follow-up and were
included in the analysis. There were no statistically significant differences between the
patient groups with respect to age, sex, ear side or cause of perforation. However, the
precise values were not reported. Two sub-groups were examined: patients with mediumor larger-sized perforations. Medium-sized perforations covered one eighth to one quarter
of the tympanic membrane, while large-sized perforations were more than one quarter of
the membrane. Fifteen patients were lost during the follow-up period. No further details
regarding losses to follow-up were reported.
Table 7
Baseline patient demographics in Lou et al. 2014
9
Demographic variable
Low dose b-FGF
High dose b-FGF
Patient numbers
71
55
42
33
29
22
33.6 [11.2]
33.9 [14.7]
32.8 [13.7]
34.1 [15.6]
4.2 [3.7]
5.6 [4.7]
4.5 [2.4]
6.6 [6.1]
Medium-sized perforations
Large-sized perforations
Mean age (years) [SD]
Medium-sized perforations
Large-sized perforations
Mean duration of injury (days)
[SD]
Medium-sized perforations
Large-sized perforations
b-FGF: basic fibroblast growth factor, SD: standard deviation
Effectiveness
Closure rates did not differ between the low- and high-dose group for large-sized tympanic
membrane perforations (p>0.05) (Table 8). The lower dose group however, reported shorter
b-FGF for tympanic membrane regeneration: November 2012
8
closure times compared to the high-dose group for medium-sized tympanic membrane
perforations (p<0.05).
Table 8
Efficacy outcomes in Lou et al. 2014
Demographic variable
9
Low dose b-FGF
High dose b-FGF
7.9 [2.5]
12.5 [ 6.5]
11.8 [4.7]
15.1 [6.1]
42/42 (100)
27/29 (92)
31/33 (93)
0/42 (0)
13/33 (39)
0/29 (0)
9/22 (41)
Mean closure time (days) [SD]
Medium-sized perforations
Large-sized perforations
Closure rate (%)
Medium-sized perforations
Large-sized perforations
22/22 (100)
Purulent otorrhoea (%)
Medium-sized perforations
Large-sized perforations
b-FGF: basic fibroblast growth factor, SD: standard deviation
Safety
No major adverse events were reported. Watery otorrhoea was not reported in patients
receiving low dose b-FGF, but it was present in all patients in the high-dose group. Purulent
otorrhoea did not occur in the low-dose group. Conversely, nine and 41 per cent of the highdose patients with medium- and large-sized perforations developed purulent otorrhoea,
respectively. At the end of the three-month follow-up, 84 and 100 per cent of medium- and
large-sized perforations were closed, respectively.
The use of b-FGF for the treatment of chronic tympanic membrane perforations was
reported in three cases series. Hakbua et al. 2013 and 201513, 14 examined the efficacy of bFGF in 116 and 153 patients with chronic tympanic membrane perforations (>6 months)
respectively. By contrast, Archarya et al. reported the efficacy of b-FGF in 12 paediatric
patients with tympanic membrane perforations lasting three months.15 All studies utilised
similar a surgical procedure. In brief, a gelatin sponge was placed over the perforated
tympanic membrane. Basic fibroblast growth factor (0.1 – 0.2mL, 100ug/mL) was
subsequently applied to the sponge to facilitate faster healing. Hakuba et al. 2015 applied
recombinant human b-FGF to the sponge. However, it is unclear whether the remaining
case series used human or bovine b-FGF. Approximately 12 months following the
intervention, the rate of complete closure varied between 62 (73/116)14 and 66 (101/153)13
per cent in the larger case series. The smallest case series reported a higher closure rate of
83 per cent (10/12), with the successfully treated patients reporting a mean hearing
improvement of 9.1dB HL (range 0 -27.5 dB HL).15 Otorrhoea and post-operative epithelial
pearl formation was reported in 11 (17/153) 14 and 5 (6/116)13 per cent of patients.
2015 Economic evaluation
No economic evaluations were identified in the literature.
b-FGF for tympanic membrane regeneration: November 2012
9
2015 Ongoing research
Searches of ClinicalTrials.gov and the Australian and New Zealand Clinical Trials Register
identified two clinical trials investigating the b-FGF for the treatment of tympanic
membrane perforation in the Australia and the United States of America (Table 9).
Table 9
Registered clinical trial characteristics
Study
Design
Rajan et al.
10
2012
RCT
Parallel
assignment
Number of
patients
Intervention
60
FGF in a
gelfoam
scaffold
Australia
FGF in a fibroin
scaffold
Welling
11
2014
Nonrandomised
controlled trial
40
Trial status
(Estimated
completion
date)
FGF in a
collagen
scaffold
ACTRN126130
01338752
Outcomes
FGF-1
25µg/mL
United States
of America
FGF-1
50µg/mL
NCT02307916
FGF-1
100µg/mL
Primary:
Rate of
perforation
closure 12
months post
intervention
Recruiting
(November
2015)
Secondary:
Hearing
thresholds 12
months post
intervention
Primary:
Number of
adverse events
and closure
rates at 60
days post
intervention
Recruiting
(September
2018)
Secondary:
Pure-tone and
speech
discrimination
scores at 60
days post
intervention
FGF: human fibroblast growth factor; USA: United States of America
2015 Other issues
The included trials lack detailed safety evidence. Clinician input recommends ototoxicity and
systemic absorption studies should be performed to address this concern.
Local clinician input further suggests that b-FGF should only be used for chronic tympanic
membrane perforations and the evidence available from the acute studies could not be
used to infer the use of b-FGF for chronic indications.12 An overview of studies examining bFGF for chronic tympanic membrane regeneration are outlined below.
A study investigating preoperative factors affecting tympanic membrane regeneration
concluded that calcification and perforation of the tympanic annulus were significant factors
b-FGF for tympanic membrane regeneration: November 2012
10
affecting membrane closure. Perforation margin identified on microscopy, margin without
epithelial migration, absence of preoperative otorrhoea, no previous ear operations,
perforation size and patient age did not affect membrane closure.13
Pain and discomfort caused by the b-FGF was not clearly documented in the included
studies.
The effects of prolonged application of (>12 months) b-FGF to the middle ear mucosa,
particularly when drops are used rather than direct application, is unknown and any adverse
events may not be readily apparent unless imaging of the middle ear is performed.
It should be noted that a recent publication16 indicates that a novel myringoplasty technique
(hyaluronic acid fat graft myringoplasty) can be performed under local anaesthetic and is
associated with reduced surgical time and cost savings as compared to traditional
myringoplasty. The diffusion status of this technique could not be ascertained.
2015 Number of studies included
All evidence included for assessment in this Technology Brief has been assessed according
to the revised NHMRC levels of evidence. A document summarising these levels may be
accessed via the HealthPACT web site.
Total number of studies 3
Total number of Level II studies: 2
Total number of Level III-2 studies: 1
2015 Search Date
16/02/2015
2015 References
1.
2.
3.
4.
5.
Kanemaru, S., Umeda, H. et al (2011). 'Regenerative treatment for tympanic
membrane perforation'. Otol Neurotol, 32 (8), 1218-23.
Levin, B., Rajkhowa, R. et al (2009). 'Grafts in myringoplasty: utilizing a silk fibroin
scaffold as a novel device'. Expert Rev Med Devices, 6 (6), 653-64.
The University of Western Australia (2012). "Smart" ear fix trial to begin at
Fremantle Hospital. [Internet]. The University of Western Australia,. Available from:
http://www.news.uwa.edu.au/201205084602/international/smart-ear-fix-trialbegin-fremantle-hospital [Accessed 2012].
Hakuba, N., Taniguchi, M. et al (2003). 'A new method for closing tympanic
membrane perforations using basic fibroblast growth factor'. Laryngoscope, 113 (8),
1352-5.
Lou, Z., Tang, Y.& Wu, X. (2012). 'Analysis of the effectiveness of basic fibroblast
growth factor treatment on traumatic perforation of the tympanic membrane at
different time points'. Am J Otolaryngol, 33 (2), 244-9.
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11
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16.
Australian Institute of Health and Welfare (2013). Procedures and healthcare
interventions (ACHI 7th edition), Australia, 2011−12 to 2012−13. [Internet].
Australian Institute of Health and Welfare,. Available from:
https://reporting.aihw.gov.au/Reports/openRVUrl.do?rsRID=SBIP%3A%2F%2FMETA
SERVER%2FAIHW%2FReleasedPublic%2FHospitals%2FReports%2FHDU_PROC+1113.
srx%28Report%29 [Accessed 18 May 2015].
Kanemaru, s.-i., inventor Google Patents, assignee. Agent for regenerating tympanic
membrane or external auditory canal2011.
Lou, Z. (2012). 'Healing large traumatic eardrum perforations in humans using
fibroblast growth factor applied directly or via gelfoam'. Otol Neurotol, 33 (9), 15537.
Lou, Z.& Wang, Y. (2014). 'Evaluation of the optimum time for direct application of
fibroblast growth factor to human traumatic tympanic membrane perforations'.
Growth Factors, 1-6.
Australian and New Zealand Clinical Trials Registry (2013). Tissue-engineered
Regeneration of Tympanic Membrane (Ear Drum) Perforations. Available from:
https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363843 [Accessed
23 Feb 2015].
National Institute of Health (2015). Open-label, Dose Response Study to Evaluate the
Safety and Optimal Biologic Dose of FGF-1 in Subjects With Chronic Non-Healing
Tympanic Membrane Perforations (TMPs). [Internet]. Clinicaltrials.gov. Available
from: https://clinicaltrials.gov/ct2/show/NCT02307916 [Accessed 23 Feb 2015].
Santa-Maria, P. NET-S Technology Brief Appraisal Form. In: ASERNIP-s, editor. 199
Ward St.: ASERNIP-s, 2015. p. 3.
Hakuba, N., Hato, N. et al (2015). 'Preoperative factors affecting tympanic membrane
regeneration therapy using an atelocollagen and basic fibroblast growth factor'.
JAMA Otolaryngology - Head and Neck Surgery, 141 (1), 60-6.
Hakuba, N., Hato, N. et al (2013). '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'. Clinical Otolaryngology, 38 (5), 394-7.
Acharya, A. N., Coates, H. et al (2015). 'A pilot study investigating basic fibroblast
growth factor for the repair of chronic tympanic membrane perforations in pediatric
patients'. International Journal of Pediatric Otorhinolaryngology.
Koc, S., Akyuz, S. et al (2013). 'Fat graft myringoplasty with the newly developed
surgical technique for chronic tympanic membrane perforation'. Eur Arch
Otorhinolaryngol, 270 (5), 1629-33.
b-FGF for tympanic membrane regeneration: November 2012
12
TECHNOLOGY BRIEF 2012
Technology, Company and Licensing
Register ID
WP129
Technology name
Gelatin foam impregnated with basic fibroblast growth factor
(b-FGF) solution
Patient indication
Tympanic membrane perforation due to trauma or severe
otitis media
Description of the technology
The technology is a new method for closing tympanic membrane perforations using a
gelatin sponge impregnated with basic fibroblast growth factor (b-FGF) as a patch material.
The aim of the procedure is to encourage healing of the perforation by providing the
conditions necessary for tissue regeneration (cells, scaffolds and chemical mediators which
regulate cell growth and proliferation). The b-FGF stimulates proliferation of epidermal and
connective tissue cells and the gelfoam acts as a sustained release substrate for the b-FGF.
Table 10 details the components of the intervention and their relationship to the principles
of tissue engineering.
Table 10
Components of the intervention
Tissue engineering component
Intervention material
Scaffold and sustained release substrate for b-FGF
Gelatin sponge is often used in medical procedures
due to its homeostatic properties and is absorbable in
vivo. The sponge may be cut to size in order to fit the
1
perforation.
Gelatin sponge or ‘gelfoam’
Regulatory factors
Basic fibroblast growth factor
Cells
Supplied by the perforation margin
Derived from genetically engineered E.coli human
DNA, b-FGF is a polypeptide mitogen that stimulates
proliferation of epidermal and connective tissue cells. It
has an inductive effect on fibroblasts and blood
capillaries, current clinical applications of b-FGF
1
include the treatment of skin ulcers or decubitis.
Endogenously supplied by the perforation margin
which is mechanically disrupted during the procedure.
The mechanical disruption of the perforation edge is
thought to stimulate the activity of stem cells of the
1
tympanic membrane.
b-FGF: basic fibroblast growth factor.
The intervention consists of a gelfoam sponge soaked in b-FGF which is placed at the
perforation and sealed in position with fibrin glue. Local anaesthesia is administered and the
perforation margin is trimmed before the sponge is placed. In paediatric patients the
procedure may be performed under general anaesthesia. Patients return three weeks post-
b-FGF for tympanic membrane regeneration: November 2012
1
procedure for assessment and removal of any residual crust. Figure 1 is a schematic diagram
of the procedure.1
Figure 2
1
A schematic diagram showing the method of treatment ; TM: tympanic membrane.
The procedure may be performed in an outpatient setting and is an alternative to
myringoplasty, a surgical procedure which repairs the perforated membrane using a tissue
graft. The graft is most commonly autologous tissue from the temporalis fascia, although
reports in the literature of optimal graft materials to achieve complete closure and restore
hearing are varied.2 Myringoplasty is performed under a general anaesthetic and may be
conducted as a same-day procedure or involve an overnight stay.
The potential advantages of b-FGF over conventional surgical treatment include:
reduced operative time
avoidance of invasive incision
reduced risk of infections, as harvesting of an autologous graft is not necessary
the option of local anaesthesia versus general anaesthesia
increased accessibility for remote and rural patients
reduced costs.17
The intervention is similar to wound healing applications used for burns or diabetic foot
ulcers and is reportedly both simple and cost effective.17 The procedure is also associated
with success rates of over 90 per cent.1, 4, 18 It should be noted that a recent publication19
indicates that a novel myringoplasty technique (hyaluronic acid fat graft myringoplasty) can
be performed under local anaesthetic and is associated with reduced surgical time and cost
b-FGF for tympanic membrane regeneration: November 2012
2
savings as compared to traditional myringoplasty. The diffusion status of this technique
could not be ascertained.
Company or developer
The intervention utilises existing medical devices and biological products for a novel
application and hence there is no single manufacturer or developer of the technology. The
table below details the components of the technology and several manufacturers as
identified within the included studies and by a search of the Australian Register of
Therapeutic Goods (ARTG).
Table 11
Company or developer of the intervention
1, 5, 20
Component
Name, manufacturer
ARTG number and
class
Products reported
by the included
studies
Sponge
Sponge, haemostatic,
absorbable
141962, Medical
Device Class III
Spongel, Astellas
Pharma, Inc., Tokyo,
Japan
Baxter Healthcare Pty Ltd
Plenac, Gunze Co.,
Kyoto, Japan
Basic fibroblast growth
factor
Search retrieved no
results
Search retrieved no
results
Fibrast, Kaken
Pharma Co., Ltd.,
Tokyo, Japan
Fibrin sealant
Tisseel
147141, Medicine
Bolheal, Kumamoto,
Japan
Baxter Healthcare Pty Ltd
ARTG: Australian Register of Therapeutic Goods.
Reason for assessment
A novel, lost cost approach for the treatment of otitis media, a condition that is associated
with high morbidity particularly in the rural and remote Aboriginal population.
Stage of development in Australia

Yet to emerge

Established

Experimental

Established but changed indication or modification of
technique

Investigational

Should be taken out of use

Nearly established
Licensing, reimbursement and other approval
Table 11 contains information regarding the ARTG numbers associated with the
intervention. Fibroblast growth factor is a recombinant product; according to the Australian
regulatory guidelines for biologicals recombinant products are listed in the Therapeutic
Goods (Things that are not Biologicals) Determination and regulated as therapeutic goods.
b-FGF for tympanic membrane regeneration: November 2012
3
The approval status of fibroblast growth factor for tympanic membrane perforation could
not be ascertained. Fibrin sealants are regulated as Medicines on the ARTG and gelatin
sponges are regulated as class III medical devices.20
Australian Therapeutic Goods Administration approval

Yes

No

Not applicable
ARTG number (s) 141962, 157704
Technology type
Procedure
Technology use
Therapeutic
Patient indication and setting
Disease description and associated mortality and morbidity
The tympanic membrane is a thin layer of tissue which moves in response to variations in air
pressure; its vibrations are transmitted to the cochlea through the ossicular chain
stimulating the inner ear. Disruption of the tympanic membrane can compromise a patient’s
hearing and perforation compromises the barrier between the outer and middle ear,
increasing the risk of otitis media (middle ear infection). The membrane can be ruptured or
perforated as a result of:
trauma such inserting foreign objects into the ear
differences in pressure between the middle and outer ear which may occur as a
result of flying or scuba diving
exposure to severe atmospheric pressure such as an explosion
infection, such as acute infection of the middle ear.
Perforations vary in size and location on the drum surface and they may be temporary or
persistent. Most perforations due to trauma heal spontaneously; however, larger
perforations with everted or inverted eardrum flaps at the margin are less likely to heal
spontaneously and may necessitate surgical intervention.18 When a perforation is associated
with acute otitis media the perforation will usually resolve with treatment of the infection
although when infections are frequent patients may develop scarring of the eardrum and
middle ear (tympanosclerosis) which compromises the healing process. Recurrent ear
infections which do not resolve with medical therapy may be treated with ventilation tubes
(grommets); upon removal of the grommet the eardrum will usually heal spontaneously. 21
When the perforation does not close spontaneously following trauma or resolution of otitis
media the risk of hearing loss and subsequent otitis media infection is elevated. The
symptoms associated with perforation include decreased hearing and an increased risk of
b-FGF for tympanic membrane regeneration: November 2012
4
infection during colds and when water enters the ear canal. Effusion from the middle ear
(which may be sanguineous) confirms the existence of both perforation and infection.
A common cause of tympanic membrane perforation is otitis media. The condition
predominantly occurs in children (0-14 years of age) and recurring or chronic infection may
lead to hearing loss, deafness and associated complications such as learning difficulties.22
Hearing loss associated with otitis media generally averages 15-30 decibels and falls in the
mild to moderate category. There are three different types of otitis media associated with a
perforation of the tympanic membrane: acute otitis media complicated by perforation of
the tympanic membrane, presenting as otorrhea (discharge from the external ear); acute
otitis media in a patient with tympanostomy tubes; and chronic suppurative otitis media,
defined as tympanic membrane perforation with chronic inflammation of the middle ear
and persistent otorrhea for two weeks to three months.23
By the age of 12 months, 73 per cent of Australian children have experienced one episode of
otitis media and in 2008 temporary hearing loss was estimated to have affected more than
354, 475 children with 87, 655 children likely to have been affected by tympanic membrane
perforation.24 Aboriginal Australian children are disproportionately affected by otitis media
as compared to non-Aboriginal children; a national survey of general practice consultations
found that Indigenous children were significantly more likely to have severe otitis media
(chronic and/or suppurative and/or perforation; 8% versus 2%, p<0.001) than nonIndigenous children.25 Data from the Australian Institute of Health and Welfare (AIHW)
indicated that almost 12% of Indigenous children who received a Child Health Check on or
before 30 June 2009 had chronic suppurative otitis media, three times higher than the rate
(4%) classified by the World Health Organization as a massive health problem.14 The hearing
loss associated with infection represents a significant burden to the individual and
community as it is most prevalent during early years while children are developing their
speech and language capacity as well as having their first encounters with the education
system.26
Data from a retrospective general practice based study of otitis media in New Zealand
showed that the incidence of otitis media was 2.7 per 1,000 person years in children less
than two years of age, and was lower in older age groups (2.02– 2.04/1,000 person years in
2 to 5-year-olds, 0.74–0.81/1,000 person years in 6 to 15-year-olds, and 0.09–0.10/1,000
person years in >15-year-olds). Mahadevan et al12 also reports that a retrospective search of
hospital admission and mortality data due to otitis media was conducted (covering years
2000 to 2007); the otitis media hospital admission rate for children less than five years of
age was 11 per 1,000 and the annual myringoplasty rate in children less than two years of
age was 0.8 per 1,000. A recent cohort study to examine the incidence of acute otitis media
in children less than five years of age in New Zealand found that the raw incidence was 273
per 1,000 children.27 A publication from the Centre for Public Health Research (Massey
b-FGF for tympanic membrane regeneration: November 2012
5
University, New Zealand)17 analysed data from the New Zealand Ministry of Health to report
the incidence of otitis media among children aged 0-14 from 1994 to 2010 in New Zealand.
Overall the age-standardised rate of hospitalisations for otitis media decreased by 41 per
cent between 1994 and 2010 and 5,428 children were hospitalised with otitis media in 2010.
The highest rates of hospitalisation during 2006 were found in Maori children
(78.6 per 10,000) and Pacific children (64.1 per 10,000); these rates were noted to be
substantially higher than for European (46.3 per 10,000) or Asian (22.4 per 10,000)
children.17
Number of patients
The AIHW data cubes indicate that in 2009-10 there were 4,167 hospital separations for
perforation of the tympanic membrane; of those, 48 per cent were separations for children
aged between one and 14 years of age.28
Speciality
Surgical, ear, nose and throat (ENT)
Technology setting
General hospital, specialist hospital and ambulatory care
Impact
Alternative and/or complementary technology
The intervention is likely to substitute for current treatments of tympanic membrane
perforation. It is unlikely that failure of b-FGF for tympanic membrane perforation would
exclude subsequent myringoplasty.
Current technology
Conventional treatment for tympanic membrane perforation includes myringoplasty, a
surgical procedure which uses a tissue graft to reconstruct the tympanic membrane. Reports
in the literature indicate variation in the surgical techniques and graft materials used in
myringoplasty procedures; it is unclear whether this variation occurs in practice.
Patients with otitis media are generally managed in the first instance with observation and
analgesia; patients may be treated with amoxicillin if their infection is persistent or
associated with effusion. A patient may be referred for further intervention if the infection
resolves but the perforation does not, or if the infection is recurrent or persistent. 21 Closure
of the tympanic membrane is contraindicated in patients with purulent effusion from the
middle ear; patients with frequent episodes of otitis media, which does not resolve with
medical therapy, may receive ventilation tubes. Upon removal of the ventilation tubes a
perforation closure procedure may be indicated.
b-FGF for tympanic membrane regeneration: November 2012
6
Diffusion of technology in Australia
The technology appears to be in the investigational phase within Australia; there is currently
one clinical trial underway at Freemantle Hospital in Perth although it does not appeared to
be registered with the Australian and New Zealand Clinical Trials Registry.
International utilisation
A search of Clinicaltrials.gov and the Australian and New Zealand Clinical Trials Registry
retrieved no relevant results (search: tympanic membrane perforation, tympanic, fibroblast,
fibro*, membrane AND repair).
Country
Level of use
Trials underway or
completed
Australia

Japan

China

Limited use
Widely diffused
Cost infrastructure and economic consequences
The new technique represents a simple intervention for tympanic membrane perforation
which affects a large number of patients worldwide and can be associated with lifelong
disability. No literature on the cost-effectiveness of the intervention was identified.
However, it appears that the immediate costs associated with the regenerative procedure
are reduced as compared to traditional surgery. Additionally the intervention may be more
accessible to remote and rural patients.17
Although the initial success rates of the procedure appear to be high, the available evidence
contains limited safety data; thus, it is difficult to identify the potential benefits and harms
associated with the technology. No evidence comparing b-FGF to myringoplasty
(conventional or novel) for tympanic membrane perforation was identified; hence the
reported advantages of the technology over conventional treatment cannot be quantified.
The table below summarises several aspects of the technology relevant to a consideration of
the economic impact of its introduction.
b-FGF for tympanic membrane regeneration: November 2012
7
Table 12
Considerations for cost of the procedure
Cost area
Impact
Further considerations
Infrastructure
The intervention uses current medical
technology in a novel manner; the
materials necessary are reportedly of low
cost.
Immediate costs may be lower than compared to
conventional surgery.
Complexity of
the procedure,
operative time
and
hospitalisation
The procedure is reportedly simple and
takes minimal time. No evidence to
suggest the need for inpatient treatment
was identified.
There may be cost savings associated with
reduced inpatient stays and operative time as
compared to conventional surgery. In practice
this intervention may be carried out more
frequently than surgical intervention due to its
reported simplicity.
Access
The intervention may be associated with
improved access for regional or remote
patients; thus a greater number of
patients may receive treatment and
potentially avoid the negative
downstream consequence of hearing loss
associated with perforation.
However, if a general anaesthetic was
required, this would require an inpatient
admission.
This is particularly relevant given the
overrepresentation of Indigenous Australians
amongst those affected by chronic otitis media in
Australia. However, it is important to consider the
potential advantages within the context of overall
service delivery; for a patient to receive the
intervention they must first be correctly
diagnosed and have access to further treatment.
Ethical, cultural or religious considerations
None identified
Evidence and Policy
Safety and effectiveness
Three studies have been included, one which assessed both the safety and effectiveness of
b-FGF for repair of tympanic membrane perforations and two which considered
effectiveness only. Table 13 outlines the characteristics of the included studies.
b-FGF for tympanic membrane regeneration: November 2012
8
Table 13
Characteristics of the included studies
Safety and
effectiveness
Author,
year,
country
Level of
evidence
n, Inclusion criteria
Kanemaru
1
et al. 2011
Level II
n=53
Chronic tympanic membrane perforation that was perfectly
dry and showed no active inflammation/infection. Inclusion
was also limited to patients who could fully understand the
procedure and gave ‘informed consent’.
Japan
Effectiveness
only (infection
reported)
Effectiveness
only
Lou et al.
5
2011
China
Lou et al.
7
2012
China
Level III – 3
n=136
Historical
control study
Traumatic tympanic membrane perforation patients who:
Level IV
n=147
Prospective
Traumatic tympanic membrane perforation patients who:
case series
were aged under 18 years
were without a previous history of middle ear
disease
had acute dry tympanic membrane perforations
had membrane perforations with everted edge
flaps at least 1/8 of the area of the tense part in
size
had a perforation that was managed within 72
hours of injury.
had no previous disease of middle ear and
were consulted within 3 months since they
experienced the perforation.
n; number of patients
Kanemaru1
In this study 56 patients (63 membrane perforations) were randomly selected from a group
of outpatients (n unspecified); the selected patients were then randomised to receive either
gelfoam with b-FGF (n=48; 53 perforations) or gelfoam without b-FGF (placebo; n=8; 10
perforations). The included patients had a mean age of 55 years (range 10 to 85) and of the
included ears (63), perforation was associated with otitis media (n=37), postoperative reperforation (n=6), old traumatic perforation (n=6), residual perforation after surgery (n=5)
and perforation after insertion of ventilation tubes (n=9).
Patients were classified into three grades based on the size of their perforation:
Grade I: perforations spanning less than 1/3 of the total membrane surface area (bFGF [n = 9]; control [n = 2]).
Grade II: perforations spanning from 1/3 to 2/3 of the total membrane surface area
(b-FGF [n = 25]; control [n = 6]).
Grade III: perforations spanning more than 2/3 of the total membrane surface area
(b-FGF [n = 19]; control [n = 2]).
b-FGF for tympanic membrane regeneration: November 2012
9
Safety
A total of eight patients experienced complications within the three-month follow-up
period; all eight experienced serious otorrhea (temporary effusion), six showed slight
retraction of the tympanic membrane and two patients with aural fullness (pressure or
fullness in the ear) had to be treated by puncture of the tympanic membrane. There were
no reports of infection within the study period. Overall the time required to complete each
procedure ranged from seven to 15 minutes and there were seven cases in which technical
difficulties arose. Of those seven difficult cases, five were Grade II and two were Grade III.
The total follow-up period was three months.
Effectiveness
The authors defined primary effectiveness as the following outcomes: closure rates, hearing
level, surgical sequelae, improvement of tinnitus and aural fullness three weeks after
treatment. The final evaluation was performed three months after the initial treatment with
hearing levels measured before treatment and at three months. The definition of success
was the rate of complete closure of the perforation within four courses of treatment. In
statistical analysis the Mann-Whitney U test was used. All outcomes are reported as number
of ears rather than number of patients. Table 14 shows effectiveness outcomes for patients
in the b-FGF group, overall the closure rate of the b-FGF group was 98 per cent as compared
to 10 per cent (1/10; 10%) in the control group. Average improvement in hearing loss
(measured in decibels) tended to be slightly greater in the lower frequency range as
compared to the higher frequency range (Table 14, LA versus NA).
Table 14
Effectiveness outcomes according to perforation grade in the b-FGF
treatment group
Closure rate
Total
52/53 (98.1)
Grade I
9/9 (100)
Grade II
25/25(100)
Grade III
18/19(94.7)
1 treatment
41/52 (77.4)
Required 2 treatments
7/52 (13.2)
Required 3 treatments
3/52 (5.7)
Required 4 treatments
1/52 (1.9)
Treatments, range (mean)
1-4(1.4)
1-3(1.3)
1-4(1.4)
1-4(1.6)
NA
21.7
18.3
21.2
25.8
LA
31.7
28.5
31.7
35.0
Improvement in hearing
loss, average (dB)
LA indicates average hearing level of 0.125, 0.25, and 0.5 kHz; NA, average hearing level of 0.5, 1, and 2 kHz.
b-FGF for tympanic membrane regeneration: November 2012
10
Table 15 summarises the improvement in subjectively measured effectiveness outcomes
between the b-FGF group and the control group; the outcomes were superior in the b-FGF
group for both improvement of tinnitus and aural fullness (p<0.0001 for both measures).
Table 15
Subjective effective outcomes in the b-FGF group versus the control group
Outcome
b-FGF group
Control
Improvement of tinnitus
50/51 (98.0%)
1/10 (10%)
Improvement of aural fullness
44/46 (95.6%)
1/9 (11.1%)
All data is reported as a proportion with percentage in brackets.
Lou et al 201118
This study is a retrospective review of patients with traumatic tympanic membrane
perforation (n=67); these patients were compared to those who underwent no treatment
and who spontaneously healed (n=69) at the same institution. The inclusion criteria are
detailed in Table 16; the study included a total of 136 patients with a mean age of 15.3 years
(range of 6 to 18 years). A total of three patients failed to complete treatment and were
excluded from the analysis (n=1 in the control group and n=2 in the b-FGF group). The
relative size of perforation was categorised as medium (1/8–1/4 of the surface area of the
tympanic membrane) or large (greater than 1/4 of the surface area of the tympanic
membrane). Of the group who chose to undergo spontaneous healing, 45 had a mediumsized perforation and 22 patients had a large-sized perforation. In the b-FGF group, 46 had a
medium-sized perforation and 23 patients had a large-sized perforation.
Perforation healing was confirmed by otoscope and acoustic immittance tests. Total followup time was not reported; however, the authors state that endoscopic examinations with
image capturing were conducted at least two times a week and outcomes appear to be
reported for up to three months. Patients appear to have undergone only a single treatment
session.
Safety
No safety outcomes were discussed. However, the results table included in the study
indicates that in the spontaneous healing group nine patients experienced infection of the
ear and in the b-FGF group one patient experienced infection. The exact nature of infection
and the time to occurrence was not reported.
Effectiveness
A comparison of the infection rate, the healing rate and the average perforation closure
time between the b-FGF group and the control group found that in all measures the b-FGF
group performed significantly better (p <0.05). Within each group, no statistically significant
difference was found between patients with an eardrum flap area to perforation area ratio
of less than 1/2 versus more than 1/2 across any measure. Table 16 summarises the
b-FGF for tympanic membrane regeneration: November 2012
11
effectiveness outcomes reported; results are assumed to be per patient as the number of
ears equates to the number of patients included.
Table 16
A comparison of the healing rate and average healing time at three months
Spontaneous healing
with eardrum flap area < 1/2
with eardrum flap area ≥ 1/2
Total spontaneous healing:
b-FGF
with eardrum flap area < 1/2
with eardrum flap area ≥ 1/2
Total b-FGF group
Total ears
Healed ears (%)
Average healing time, days
36
32
68
31/ 36 (86.1)
27/32 (84.4)
58/68 (85.3)
27.3 ± 2.4
28.6 ± 3.1
NA
35
30
65
34/35 (97.1)
30/30 (100)
64/65 (98.5)
10.4 ± 2.5
11.1 ± 1.9
NA
NA: not applicable
Lou et al 20125
In this study patients were prospectively enrolled to receive a treatment of b-FGF at
different time intervals (3 days, 4 to 7 days, 8 to 15 days and more than 4 weeks after the
injury). A total of 147 patients with a mean age of 32.1 years (range 5 to 56, standard
deviation 1.9 years) were included. The relative size of perforation was determined to be
either:
small (n=121), less than one fourth of the area of membrana tensa, or
large (n=26), at least one fourth of the area of membrana tensa.
Of the 147 patients, 136 were diagnosed as having dry perforation and 11 were diagnosed
as having secondary water or bloody otorrhea. Patients who were diagnosed as having
secondary purulent otorrhea were prescribed concurrent oral antibiotics for a period of one
to two weeks and the perforation was examined by otoscope twice a week until healing
occurred.
Safety
No safety outcomes were reported.
Effectiveness
Following treatment, 120 of the 121 small perforations (99%), and 24 of the 26 large
perforations (92%) were healed. Amongst the small perforations, the healing rates at three
days, four to seven days, 8 to 14 days and two to four weeks after injury were 98.2 per cent,
100 per cent, 100 per cent and 100 per cent respectively. Statistical significance between
the overall healing rate at different time intervals was not found (significance level p<0.05).
A comparison of the first three time intervals found that the average healing time was
shortest in patients admitted within eight to 14 days since injury (p<0.01). In the case of
admissions within three days after perforation, the average healing time from injury to
healing was the shortest. Using pairwise comparisons with the Student-Newman-Keuls
b-FGF for tympanic membrane regeneration: November 2012
12
method, the results of the first three groups with small perforations in time from treatment
to healing and from injury to healing were all significant (p<0.01).
In healed ears the pure tone hearing test showed that the airborne gap (conductive hearing
loss) was 25 ± 9 decibels at perforation, whereas it was 8 ± 8 decibels when it was healed
(p<0.01).
Table 17
Healing time and rate in small perforations
Consultation period
(post injury), size of
perforation
≤ 3 days, small
≤ 3 days, large
4–7 days, small
4–7 days, large
8–14 days, small
8–14 days, large
2–4 weeks, small
More than 4 weeks, large
Healing rate*
56
14
36
6
22
5
3
1
Time from treatment to
perforation healing
(days)
7.95 ± 2.07
13.14 ± 1.16
6.75 ± 2.67
11.4 ± 3.13
4.18 ± 0.91
10.5 ± 3.11
6.33 ± 0.91
11
Time from injury to
perforation healing
(days)
9.75 ± 2.04
14.57 ± 1.02
12.14 ± 2.28
17.6 ± 3.05
15.95 ± 2.21
21 ± 2.16
25 ± 2.64
72
* Healing rate is reported as the number of patients who experience closure of the perforation. Time from treatment to
perforation
healing and time from injury to perforation healing were both reported as mean days with standard deviation.
Economic evaluation
No literature on the cost-effectiveness of the intervention was identified. However, there
may be significant costs associated with the procedure including, but not limited to the:
cost of the growth factor
cost of general anaesthesia and associated hospital charges for paediatric patients.
Ongoing research
A current trial at Freemantle Hospital is underway and will involve both adults and children;
the trial will reportedly replicate that conducted by Kanemaru et al1 and has thus far treated
11 patients. A second trial will also begin at Princess Margaret Hospital for Children in Perth,
Western Australia.17
Phage pharmaceuticals Inc. is currently preparing to initiate a U.S. Department of Defence
funded Phase I study for the treatment of chronic tympanic membrane perforation.29
Other issues
In one of the included studies (Lou et al 2012) no safety data was included. It could not be
determined whether complications did not occur or whether complications were not
reported. In Lou et al (2011) infection was reported; however, it was unclear whether other
safety data was omitted.
All studies compared treatment with b-FGF and gelfoam to spontaneous healing or a control
group (who received a saline soaked gelfoam1); therefore, no direct comparison between
the effectiveness of this intervention versus myringoplasty, conventional or novel, can be
made.
b-FGF for tympanic membrane regeneration: November 2012
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The study by Kanemaru et al1 reported rates of closure in the control group of 10 per cent as
compared to 98 per cent. In contrast, Lou et al 201118 reports a closure rate in the control
group of 85 per cent. It is possible that the source of this disparity is the small sample size of
Kanemaru; however, this disparity may also illustrate a difference in the rate of
spontaneous closure in patients with perforation due to trauma versus infection. The size
and location of the perforation on the tympanic membrane was also a confounding factor
and the patient population most likely to benefit from this intervention is an area for further
research.
Lou et al (2012) examined the effect of delayed intervention in patients with traumatic
membrane perforation and found no statistically significant differences in the rate of
healing between the groups (3 days, 4 to 7 days, 8 to 15 days, and more than 4 weeks after
the injury). The measurement of conductive hearing loss in patients with a healed
membrane was significantly less after healing than prior to (p<0.01).
Summary of findings
Limited safety data related to the procedure were identified; in the single study reporting
safety data there were eight patients who experienced 16 complications within a threemonth follow-up period. The complications included serious otorrhea (n=8), slight retraction
of the tympanic membrane (n=6) and aural fullness (n=2). In a second study which reported
only infection, one patient in the treatment group experienced infection as compared to
nine patients in the control. No evidence to indicate that the procedure is associated with
severe safety concerns was identified.
The evaluation of efficacy is limited by the lack of comparative data, as no studies reported
the relative effectiveness of b-FGF treatment compared to myringoplasty. The included
studies found perforation closure rates associated with the procedure are over 90 per cent;
however, only two studies included a control group and in one the control sample size was
10 patients. In one study the average perforation closure time in patients treated with bFGF was significantly lower (p<0.05) as compared to patients whose perforations healed
spontaneously. Overall the procedure is reportedly simple to perform, does not appear to
be associated with major adverse events and results in higher rates of perforation closure
than untreated perforations (total treated patients = 262; total untreated = 79).
HealthPACT assessment
Based on the level and availability of evidence, and the potential for widespread uptake of
this technology, it is recommended that the technology be monitored for 24 months with a
view to obtaining evidence from the Australian trial currently underway.
b-FGF for tympanic membrane regeneration: November 2012
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Number of studies included
All evidence included for assessment in this Technology Brief has been assessed according
to the revised NHMRC levels of evidence. A document summarising these levels may be
accessed via the HealthPACT web site.
Total number of studies 3
Total number of Level II studies 1
Total number of level III-3 studies 1
Total number of level IV studies 1
References
1.
Kanemaru, S., Umeda, H. et al (2011). 'Regenerative treatment for tympanic
membrane perforation'. Otology & neurotology : official publication of the American
Otological Society, American Neurotology Society [and] European Academy of
Otology and Neurotology, 32 (8), 1218-23.
2.
Levin, B., Rajkhowa, R. et al (2009). 'Grafts in myringoplasty: utilizing a silk fibroin
scaffold as a novel device'. Expert review of medical devices, 6 (6), 653-64.
3.
The University of Western Australia (2012). "Smart" ear fix trial to begin at
Fremantle Hospital. [Internet]. The University of Western Australia,. Available from:
http://www.news.uwa.edu.au/201205084602/international/smart-ear-fix-trialbegin-fremantle-hospital [Accessed 2012].
4.
Hakuba, N., Taniguchi, M. et al (2003). 'A new method for closing tympanic
membrane perforations using basic fibroblast growth factor'. The Laryngoscope, 113
(8), 1352-5.
5.
Lou, Z., Xu, L. et al (2011). '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, 75 (10), 1285-8.
6.
Koc, S., Akyuz, S. et al (2013). 'Fat graft myringoplasty with the newly developed
surgical technique for chronic tympanic membrane perforation'. European archives
of oto-rhino-laryngology : official journal of the European Federation of Oto-RhinoLaryngological Societies (EUFOS) : affiliated with the German Society for Oto-RhinoLaryngology - Head and Neck Surgery, 270 (5), 1629-33.
7.
Lou, Z. (2012). 'Healing large traumatic eardrum perforations in humans using
fibroblast growth factor applied directly or via gelfoam'. Otology & neurotology :
official publication of the American Otological Society, American Neurotology Society
[and] European Academy of Otology and Neurotology, 33 (9), 1553-7.
8.
Lou, Z.& Wang, Y. (2014). 'Evaluation of the optimum time for direct application of
fibroblast growth factor to human traumatic tympanic membrane perforations'.
Growth factors (Chur, Switzerland), 1-6.
9.
Lou, Z., Wang, Y.& Yu, G. (2014). 'Effects of basic fibroblast growth factor dose on
traumatic tympanic membrane perforation'. Growth factors (Chur, Switzerland), 32
(5), 150-4.
10.
National Institute of Health (2015). Open-label, Dose Response Study to Evaluate the
Safety and Optimal Biologic Dose of FGF-1 in Subjects With Chronic Non-Healing
b-FGF for tympanic membrane regeneration: November 2012
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Tympanic Membrane Perforations (TMPs). [Internet]. Clinicaltrials.gov. Available
from: https://clinicaltrials.gov/ct2/show/NCT02307916 [Accessed 23 Feb 2015].
11.
Hakuba, N., Hato, N. et al (2015). 'Preoperative factors affecting tympanic membrane
regeneration therapy using an atelocollagen and basic fibroblast growth factor'.
JAMA Otolaryngology - Head and Neck Surgery, 141 (1), 60-6.
Search criteria to be used (MeSH terms)
Tympanic Membrane Perforation/therapy*
Fibroblast Growth Factor 2/therapeutic use*
Hearing Loss/therapy*
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