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ISSN: 0897-7194 (print), 1029-2292 (electronic)

Growth Factors, 2015; 33(2): 6570

! 2014 Informa UK Ltd. DOI: 10.3109/08977194.2014.980905

RESEARCH PAPER

Evaluation of the optimum time for direct application of fibroblast

growth factor to human traumatic tympanic membrane perforations
Zhengcai Lou and Yubizhuo Wang

Department of Otorhinolaryngology, The Affiliated YiWu Hospital of Wenzhou Medical College, Yiwu, China

Abstract Keywords
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Objective: The aim of this study was to determine the optimum time for direct application of Basic fibroblast growth factors, time window,
basic fibroblast growth factor (bFGF) on large traumatic tympanic membrane perforations traumatic, tympanic membrane
(TMPs). Study design: Prospective clinical study. Setting: Tertiary University Hospital. Methods: perforation
Ninety-three patients, with traumatic TMPs greater in extent than 25% of the entire tympanic
membrane, were randomized into observation and bFGF-treated groups (0.20.25 mL of bFGF History
solution was applied directly onto the TM once daily and continued until the perforation
closed). Initial visit times were subcategorized into perforation durations of 3 and 43 days, Received 13 August 2014
thereby rendering two subgroups, as follows: A and B in the observation group; and C and D Revised 20 October 2014
in the bFGF-treated group. The closure rate and mean closure time were evaluated after Accepted 21 October 2014
6 months. Results: Eighty-six patients were finally analyzed. After 6 months, the bFGF-treated Published online 6 November 2014
group exhibited a significantly higher total closure rate (97.8 versus 82.5%, p50.05) and a
shorter mean closure time (12.5 3.4 versus 34.0 5.9 days, p50.05) compared with the
For personal use only.

spontaneous healing group. In addition, in the observation group, visiting time was not
associated with differences in closure rate (p40.05) and mean closure time (p40.05), between
the A and B subgroups. Similarly, in the bFGF-treated group, visiting time was not associated
with differences in closure rate (p40.05) between the C and D subgroups. However, the D
subgroup was characterized by significantly shortened mean closure time compared with the C
subgroup (p50.05). Conclusions: This study shows the beneficial effect of bFGF on human
traumatic large TMPs when applied after the 3rd day post-injury had passed (i.e. during
the proliferative stage of wound healing). The procedure can not only significantly shorten
closure time but can also reduce both the clinical administration duration and occurrence of
side-effects associated with bFGF.

Introduction reduces the closure time and improves the closure rate of
TMPs (Fina et al., 1991; Lou, 2012; Lou & Wang, 2013). The
Traumatic tympanic membrane perforation (TMP) is com-
best dosage and application time of bFGF have been
monly seen in the otology clinic. Although the eardrum
investigated using experimental eardrum perforations.
has the capacity for regenerative healing, the spontaneous
Chauvin et al. (1999) reported that the initial application of
closure rate of large perforations is considerably lower (Lou,
bFGF significantly improved the closure rate of guinea pig
2012; Lou et al., 2011; Orji & Agu, 2008). Therefore, most
eardrum perforations; however, continued use after day 7 did
otolaryngologists prefer more immediately invasive micro-
not further improve the closure rate. Other studies have
surgical procedures, such as early patch and surgical
reported opposing results (Ishibashi et al., 1998; Ozkaptan
intervention (Lou & He, 2011; Park et al., 2011; Sprem
et al., 1997; Vrabec et al., 1994). They found that bFGF
et al., 2001). However, patching only reduces the healing time
mediated primarily the connective tissue reaction in the
and does not improve the closure rate (Jun et al., 2014; Lou &
middle layer at the proliferative and remodeling stages of the
He, 2011; Park et al., 2011). Surgery involves higher costs
healing process, and bFGF had a beneficial effect when
and more effort in addition to the associated risks.
applied after the inflammatory stage of wound healing by
Clinical and experimental studies have confirmed that
delaying treatment for 48 h after injury. Buntrock et al.
topical application of basic fibroblast growth factor (bFGF)
(1982), in their study of wound repair, also found that bFGF
accelerated the formation of granulation tissue and promoted
wound healing when applied on postoperative days 3 and 7.
Address for correspondence: Zheng Cai Lou, PhD, Department of In addition, bFGF ototoxicity has been evaluated extensively;
Otorhinolaryngology, The Affiliated YiWu Hospital of Wenzhou
Medical College, 699, Jiangdong Road, Yiwu 322000, China. E-mail: most of the studies reported that topical application of bFGF
louzhengcai@163.com exerted no ototoxicity (Hakuba et al., 2010; Kanemaru et al.,
 66 Z. Lou & Y. Wang
2011; Kase et al., 2008); however, a few studies reported that
long-time administration of bFGF resulted in impairment of
collagen synthesis and development of middle ear cholestea-
toma (Kato et al., 1996; Lazarou et al., 1989; Mondain &
Ryan, 1994). Thus, determination of the optimum application
time of bFGF on human TMPs is important to achieve the
greatest treatment effect and reduces the complication rate.
To our knowledge, few studies to date have evaluated
the optimum time for bFGF application to human large
TMPS. Although our recent study reported the optimum time
for gelfoam patching with bFGF application to human TMPs
(Lou et al., 2012), gelfoam patching could itself accelerate
eardrum healing and affect the effect evaluation of direct
application of bFGF. In addition, skin wound healing and
eardrum repair (Lou & Wang, 2013) studies have reported
that direct application of bFGF resulted in more rapid healing
than gelfoam patching with bFGF. Gelfoam can induce
Growth Factors Downloaded from informahealthcare.com by Nyu Medical Center on 05/27/15
scar formation of the eardrum and affect sound conduction
(Fina et al., 1991). The aim of the present study was to
determine the optimum time for direct application of bFGF to
human large TMPs.
Materials and methods
The present study was reviewed and approved by the
Institutional Ethical Review Board of Wenzhou Medical
College-Affiliated Yiwu Hospital in Yiwu, Zhejiang, China.
For personal use only.
Informed consent was obtained from all participants. Study
subjects were recruited from consecutive patients diagnosed
with traumatic TMP who visited the Department of
Otorhinolaryngology, Head and Neck Surgery at the
Affiliated Yiwu Hospital of WenZhou Medical College
between January 2012 and December 2013. The inclusion
criteria were the following: (1) traumatic TMPs resulting from
blunt injuries such as physical blows (e.g. open-hand slap, fist
strikes or ball hits) and explosive noise (e.g. blast of
firecrackers or fireworks); (2) a perforation size of at least
one quarter of the pars tensa and (3) no middle ear infection at
the time of hospital visit.
Age, gender, date of injury, cause of traumatic injury, size
of TMP and presence or absence of otorrhoea were recorded
at the time of the visit. All patients were examined with
an endoscope after cleaning cerumen or blood clots from the
external auditory canal (EAC), using a cotton bud soaked
in povidone iodine solution, and the site and size of the
perforation were documented. A large perforation was defined
as exceeding 25% of the entire tympanic membrane when
viewed using the ImageJ software package (NIH, Bethesda,
MD) (Lou et al., 2011; Saito et al., 1990).
Patients were randomized into observation only and
direct application of bFGF treatment groups.
Randomization was performed using a table of random
numbers in conjunction with the SPSS for Windows software
package (ver. 11.0; SPSS, Inc., Chicago, IL). Based on
the initial visit time, patients in the observation group
were subsequently divided into two sub-groups: A and B
(A: perforation duration of 3 days; B: perforation duration
of 43 days). Patients in the bFGF-treated group were also
divided into two sub-groups: C and D (C: perforation duration
of 3 days; D: perforation duration of 43 days).
Growth Factors, 2015; 33(2): 6570
Technical method
Observation group
There was no intervention, but the patients underwent regular
follow-up.
bFGF-treated group
The EAC was cleaned with a cotton bud soaked in povidone-
iodine solution. Approximately 0.20.25 mL (45 drops) of
recombinant bovine bFGF solution (21 000 IU/5 mL)
(Yi Sheng, Zhuhai City, China) was applied directly onto
the TM once daily, and no scaffolding material was used.
The first application of bFGF drops was carried out by the
physician. Thereafter, bFGF drops were applied daily by the
patients themselves at home as instructed until complete
perforation closure was confirmed by the physician.
Oral amoxicillin was administered to all subjects for
1 week. All patients were regularly followed-up (twice per
week) in the 1 month following treatment, or at the initial
hospital visit and once per week thereafter, until the
perforation was completely closed, or for up to 6 months
following treatment. In the bFGF-treated group, the physician
determined whether the self-application of bFGF by patients
at home was correct and whether purulent otorrhoea
developed during the 23 days following treatment com-
mencement. Incorrect application of bFGF was corrected.
The patient was advised to discontinue the application of
bFGF if the ear symptom disappeared or purulent otorrhoea
occurred. To reduce clinician bias, closure of the tympanic
membrane and the occurrence of otorrhoea were photo-
documented using color slides during every follow-up visit.
Results are given as means SD or as percentage values.
Statistical analyses were performed using the SPSS for
Windows software package (ver. 11.0; SPSS, Inc., Chicago,
IL), and a paired chi-squared test and a t-test were used
to compare the closure time and closure rate, respectively.
A p value less than 0.05 was deemed to indicate statistical
significance.
Results
Demographic characteristics
In total, 93 patients were randomized into the study groups.
Seven patients were lost to follow-up, such that the final
analysis was performed on 86 patients (27 males and 59
females) with a diagnosis of large traumatic TMP. The mean
age of patients was 36.9 4.2 years (range: 1652 years).
Demographic data for the two groups are provided in Table 1.
There was no statistically significant group difference in age,
gender, duration, ear side, mean size of perforation or cause of
injury. Mean closure time was defined as the time between
treatment commenced and complete closure. The healing
outcomes of the two groups are described in Tables 2 and 3,
and Figure 1.
Healing outcome
After 6 months, the total closure rate of the bFGF-treated
group was significantly higher compared with the observation
group (97.8 versus 82.5%, p50.05). The bFGF-treated group
 DOI: 10.3109/08977194.2014.980905 Direct application of bFGF to human traumatic TMP 67
Table 1. Demographic data of patients in observation and bFGF-treated Of the 86 patients, purulent otorrhoea was observed in
groups.
three cases (3/40; 7.5%) in the observation group and in two
Observation bFGF-treated
cases (2/46; 4.3%) in the bFGF-treated group. Two perfor-
group group p Value ations with purulent otorrhoea achieved complete closure
within 10 days following treatment commencement, in the
Sex (male:female) 12:28 15:31 40.05
Age, years 32.4 3.8 31.9 5.2 40.05 bFGF-treated group; however, no perforation with purulent
The cause of injury 38:2 42:4 40.05 otorrhoea achieved complete closure in the observation group
(blunt:blast injury) during follow-up. No severe bFGF-related complications,
The ear side (L:R) 36:4 41:5 40.05
such as severe vertigo or abnormal thickening of the eardrum
Duration, days 5.7 1.9 6.6 1.2 40.05
The mean size of perforation 46.0 11.9 47.0 12.1 40.05 and EAC, were observed. Slight earache and ear fullness were
found in a few patients (these symptoms could be associated
with excessive accumulation of bFGF solution tympanic
Table 2. The healing outcome of observation group. cavity), these symptoms disappeared upon complete closure
of the perforation or stop the application of eardrops.
The mean Average Mean
size of the visiting Closure closure
Subgroup N perforation time rate time Otoendoscopic features
A 22 46.8 11.3 1.9 0.7 19 (82.5) 38.4 6.9 Of the 40 observation group patients, 22 had a perforation
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B 18 45.3 12.6 8.0 2.9 14 (77.8) 34.7 5.0 duration of 3 days, for whom oedema and exudates were
observed at the perforation margins during the first visit.
Table 3. The healing outcome of bFGF-treated group.
Oedema gradually disappeared and centripetal epithelium
proliferation and migration occurred approximately 45 days
The mean Average Mean following injury. The proliferative epithelium was very thin
size of the visiting Closure closure and transparent, and the centripetal migratory epithelium
Subgroup N perforation time rate time gradually increased, and finally closed the perforation, in 19
C 29 48.4 13.4 2.3 0.5 28 (96.6) 17.5 5.1 patients within the 6 months following injury. Of the 18
D 17 45.6 10.8 10.4 3.1 17 (100.0) 8.5 2.1 patients with a perforation duration of 43 days, oedema and
exudates had disappeared at the time of first visit, and only
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the proliferative and migratory epithelium were observed at

Figure 1. Mean closure time each group. (A) Sub-group of observation
group (perforation duration of 3 days); (B) sub-group of observation
group (perforation duration of 43 days); (C) sub-group of bFGF-
treated group (perforation duration of 3 days); (D) sub-group of
bFGF-treated group (perforation duration of 43 days).
also exhibited significantly shortened mean closure times
compared with the observation group (12.5 3.4 versus
36.0 5.9 days, p50.05). In the observation group, visiting
time was not associated with differences in closure rate
(p40.05) and mean closure time (p40.05), among the A and
B subgroups. Similarly, in the bFGF-treated group, visiting
time was not associated with differences in closure rate
(p40.05) among the C and D subgroups (p40.05); however,
the D subgroup demonstrated significantly shortened mean
closure time compared with the C subgroup (p50.05). For
the 11 large perforations with a injury duration of 7 days,
the mean closure time was 8.0 1.6 days.
the perforation margins; however, outward migratory epider-
mis subsequently emerged in three patients, and the perfor-
ation failed to achieve complete closure.
Of the 46 treatment group patients, 29 had a perforation
duration of 3 days, for whom oedema and exudates were
also observed at the perforation margins at the time of the first
visit. The oedema began to subside, and no proliferative
epithelium was detected at the 3-day bFGF treatment follow-
up. However, the centripetal proliferative and migratory new
eardrum gradually emerged within 7 days after bFGF
treatment commenced: the new eardrum, which was thick
and opaque, gradually increased in size and completely closed
the perforation within 430 days after treatment commenced
(Figures 2 and 3). However, one perforation failed to achieve
closure at the 6-month follow-up. Of the 17 patients with a
perforation duration of 43 days, only centripetal proliferative
and migratory epithelium were observed. The epithelium was
very thin and transparent, but a new eardrum rapidly emerged
at the perforation margins within 3 days following bFGF
treatment commenced. The new eardrum was thick and
opaque, and completely closed the perforation within 514
days after treatment commenced (Figure 4).
Discussion
Clinical and experimental studies have confirmed that either
direct application of bFGF or the combination of bFGF
application with patching significantly improved the closure
rate and reduced the closure time of TMPs (Chauvin et al.,
1999; Lou, 2012; Lou & Wang, 2013; Ozkaptan et al., 1997;
Vrabec et al., 1994). However, the controversy concerning
ototoxicity and complications remains. Most studies have
 68 Z. Lou & Y. Wang Growth Factors, 2015; 33(2): 6570
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Figure 2. The healing process at various time points after direct application of FGF: (A) 1st after perforation; (BH) 3, 7, 10, 14, 17 and 23 days after
treatment and 2 months after treatment, respectively.
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Figure 3. The healing process at various time points after direct application of FGF: (A) 1st after perforation; (BE) 4, 11, 14 and 18 days after
treatment.

Figure 4. The healing process at various time points after direct application of FGF: (A) 6 weeks after perforation; (BE) 3, 7, 10 and 14 days after
treatment.

shown that topical application of bFGF demonstrates no
ototoxicity to the middle and inner ear (Buntrock et al., 1982;
Hakuba et al., 2010; Kase et al., 2008). Nevertheless, a few
studies have suggested that continuous application of bFGF
could inhibit collagen synthesis and deposition, prolonging
the closure time and leading to the development of middle
ear cholesteatoma and an atrophic eardrum. Thus, determin-
ation of the optimum time for bFGF application to human
TMPs is vital.
Our result further confirms that direct application of bFGF
leads to a significantly higher closure rate, and a reduced
closure time of traumatic large TMPs, compared to spontan-
eous healing. Regarding perforation of spontaneous healing,
visiting time following injury did not affect either the closure
rate or mean closure time. This could be due to the
spontaneous healing mechanism. Several experimental
studies (Santa Maria et al., 2010; Wang et al., 2004)
have demonstrated that perforations heal more rapidly
within 1 week following injury; the speed of perforation
healing decreases after this time.
In our study, the most important finding was that
perforations with a duration of 43 days were characterized
by significantly shortened mean closure times compared
with perforations with a duration of 3 days, in the bFGF-
treated group, although visiting time did not affect the
closure rate. In the 11 perforations with an injury duration
of 7 days, the mean closure time was 8.0 1.6 days. A
perforation larger than 50% of the entire tympanic
 DOI: 10.3109/08977194.2014.980905
membrane achieved complete closure within 10 days after
treatment commenced.
An important question concerns the reason why direct
application of bFGF at different times post-injury produced
different treatment results. We speculate that these time-
dependent effects could be related to the pathological changes
occurring during different stages of traumatic TMP healing,
and also to the particular pharmacological mechanism of
bFGF. Previous studies (Santa Maria et al., 2010; Wang et al.,
2004) have demonstrated that the perforation margin exhibits
an inflammatory reaction within 4872 h post-perforation; i.e.
swelling and an exudative reaction within the perforation
margin; however, the squamous epithelium did not exhibit
hyperplasia. After approximately 34 days of injury, prolif-
eration and migration of the squamous epithelium began to
manifest at the germinal centre of the TM, with thin and
transparent centripetal migratory epithelium observed at the
Growth Factors Downloaded from informahealthcare.com by Nyu Medical Center on 05/27/15
perforation margin. In addition, other studies have reported
that bFGF expression occurred primarily in the area of
epithelial proliferation 3 days after perforation and peaked at
day 5 post-injury (Ishibashi et al., 1998; Werner et al., 1992).
Therefore, although the inflammatory and proliferative stages
occur at different times among patients (based on this result
and the spontaneous healing mechanism of traumatic TMPs),
our study suggests that direct application of bFGF will
produce the optimal therapeutic effect only when applied
during the proliferative stage. This conclusion is in agreement
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with previous animal studies (Ozkaptan et al., 1997; Vrabec
et al., 1994). Ishibashi et al. (1998) reported that bFGF might
primarily mediate the reaction of connective tissue, in the
middle layer, during proliferative and remodeling stages of
healing, in rat eardrum perforations. This result could be used
as a guide regarding the duration of clinical administration,
thereby reducing the total number of side effects associated
with bFGF.
One limitation of the present study was the small sample
size and non-standardized hospital visit times. Additionally,
the division of patients into groups, with perforation durations
of either 3 or 43 days, might have affected the accuracy of
the application time evaluation. Regardless of the precise
method chosen, however, classifying the timing of the
inflammatory and proliferative stages of the healing process,
in human traumatic TMPs, is challenging. Second, the
number of bFGF and difference in EAC structure (which
could affect the final dose in the eardrum perforation margin)
might have influenced the healing effect. Third, several
patients discontinued their eardrop application due to slight
earache and otorrhoea, occurring between the first treatment
and first follow-up. However, the majority of these patients
resumed their eardrop use following an explanation from a
physician during the follow-up.
Conclusion
This study shows the beneficial effect of bFGF on human
traumatic large TMPs when applied after the 3rd day post-
injury had passed (or the proliferative epithelium can be
observed at the perforation margin). This might not only
result in more-rapid healing but could also shorten the
duration of clinical administration and reduce the total
Direct application of bFGF to human traumatic TMP 69
number of side-effects caused by long-term application of
bFGF.
Declaration of interest
The authors report no conflicts of interest. The
authors alone are responsible for the content and writing of
this article.
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