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Evaluation of the Poly(lactic-co-glycolic acid)/Pluronic F127 for Injection

Laryngoplasty in Rabbits

Article in Otolaryngology Head and Neck Surgery · September 2014

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Original Research—Laryngology and Neurolaryngology
Evaluation of the Poly(lactic-co-glycolic
acid)/Pluronic F127 for Injection
Laryngoplasty in Rabbits
Jin Ho Lee, PhD1*, Dong Wook Kim, MD2*, Eun Na Kim, MD3,
Seok-Won Park, MD, PhD4, Hee-Bok Kim, MS4, Se Heang Oh, PhD5,
and Seong Keun Kwon, MD, PhD2,6,7
Sponsorships or competing interests that may be relevant to content have
been disclosed at the end of the article.
Abstract
Objective. Poly(lactic-co-glycolic acid) (PLGA) is an aliphatic
polyester and one of the most commonly used synthetic
biodegradable polymers for tissue engineering. The objec-
tives of this study were to evaluate the biocompatibility of
PLGA/Pluronic F127 in the vocal fold.
Study Design. A randomized, prospective, controlled animal
study.
Setting. University laboratory.
Subjects and Methods. We used 18 New Zealand white rab-
bits, which were divided into 5% PLGA solution (n = 9) and
10% PLGA solution (n = 9) groups. The PLGA/Pluronic
F127 solutions were injected into the rabbit vocal fold.
Laryngoscopic exams were performed at 1, 4, and 8 weeks
after implantation; then larynx specimens were sampled.
High-speed video camera examination was performed for
functional analysis of vocal mucosa vibration at 8 weeks
after implantation. Also, we evaluated the amplitude of the
mucosal wave from the laryngeal midline on high-speed
recording. Histologic study of larynx specimen was per-
formed at 4 and 8 weeks.
Results. All animals survived until the scheduled period.
Laryngoscopic analysis showed that both 5% and 10%
PLGA/Pluronic F127 maintained after 8 weeks after injection
without significant inflammatory response. On functional
analysis, high-speed camera examination revealed regular
and symmetric contact of vocal fold mucosa without a dis-
torted movement by injected PLGA/Pluronic F127.
Histologically, no significant inflammation was observed in
the injected vocal fold.
Conclusion. As a vocal fold injection material, PLGA/Pluronic
F127 showed a good bio-compatibility without significant
inflammatory response. Further experiment will follow to
elucidate its role for drug or gene delivery into the vocal
fold.
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Otolaryngology–
Head and Neck Surgery
2014, Vol. 151(5) 830–835
Ó American Academy of
Otolaryngology—Head and Neck
Surgery Foundation 2014
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0194599814549527
http://otojournal.org
Keywords
Poly(lactic-co-glycolic acid), vocal fold palsy, injection laryn-
goplasty, augmentation, drug delivery system
Received December 21, 2013; revised July 8, 2014; accepted August
11, 2014.
Introduction
A number of injectable materials including autologous tis-
sues (ie, fascia and fat) and calcium hydroxyapatite (CaHA)
were introduced for augmentation of vocal fold paralysis.
However, none of them succeeded in showing the ideal
characteristics required for permanent injection laryngo-
plasty material, such as restoring a vibratory membrane in
an atrophied vocal fold while maintaining its volume perma-
nently without inflammation or migration.1,2 Due to the lim-
itation of current injection materials for augmentation
laryngoplasty, development of injection materials, which
induce a simultaneous effect of augmentation by itself and
tissue regeneration in the atrophied vocal fold, could be
1
Department of Advanced Materials, Hannam University, Daejeon, Republic
of Korea
2
Department of Otorhinolaryngology–Head and Neck Surgery, Seoul
National University Hospital, Seoul National University College of
Medicine, Seoul, Republic of Korea
3
Department of Pathology, Asan Medical Center, University of Ulsan
College of Medicine, Songpa-gu, Seoul, Republic of Korea
4
Department of Otorhinolaryngology–Head and Neck Surgery, Dongguk
University Ilsan Hospital, Goyang, Republic of Korea
5
Department of Nanobiomedical Science, Dankook University, Cheonan,
Republic of Korea
6
Cancer Research Institute, Seoul, Republic of Korea
7
Seoul National University Medical Research Center, Seoul, Republic of
Korea
*
These two authors contributed equally to this work
Corresponding Author:
Seong Keun Kwon, MD, PhD, Associate Professor, Department of
Otorhinolaryngology–Head and Neck Surgery, Seoul National University
Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea.
Email: otolarynx@hanmail.net
Lee et al
more feasible and physiologic. Because that appropriate
tissue regeneration could be achieved with combination of
biosynthetic scaffold, cells, and regulatory factors,3-7 we
introduced a poly(lactic-co-glycolic acid) (PLGA)/Pluronic
F127 as an injectable scaffold of bioactive agents for regen-
eration of the atrophied vocal fold.
The PLGA as well as Pluronic F127 are well-known
polymers and were approved by the US Food and Drugs
Administration (FDA) for several therapeutic applications
because of their biodegradability, biocompatibility, and a
long history of safe use in humans. PLGA is synthesized by
means of co-polymerization of 2 different monomers, glyco-
lic acid (GA) and lactic acid (LA). The degradation rate and
mechanical properties of PLGA can be controlled by vary-
ing the ratio of GA to LA, and this polymer has been more
extensively investigated than PGA and PLA homopolymers
in numerous biomedical applications, such as cell/tissue
scaffolds, drug delivery carriers, and sutures.8-13 The degra-
dation rates of conventionally used PLGA in biomedical
fields are as follows: 50/50 (lactide to glycolide ratio), 1 to
2 months; 75/25, 4 to 5 months; 85/15, 5 to 6 months.14
PLGA with a lactide/glycolide ratio of 10/90 was initially
approved by the FDA for use as a suture (Vicryl), and other
PLGAs with different GA to LA ratios are currently being
approved for use as guided tissue regeneration substances;
vascular grafts, urological stents, skin substrates, and 3D
porous scaffolds for tissue reconstruction;8,9 and drug deliv-
ery carriers.10,11 However, it was reported that acidic by-
products of PGA, PLA, and PLGAs during degradation can
sometimes lead to an inflammatory response in the human
body.12,13 Pluronic F127 as a hydrophilic additive for hydro-
phobic PLGA can enhance the water diffusion into the
PLGA matrix and thus can allow continuous release of cer-
tain bioactive molecules from the hydrophobic PLGA, in
particular at the initial stage of release.15 It did not lead to
any adverse tissue responses, probably because of its fast
absorption in the body (within a few days) as well as its
own biocompatibility.1,16
In this study, we devised the injectable PLGA/Pluronic
F127 solution as a material for injection laryngoplasty, and
their biocompatibility was investigated.
Material and Methods
The experiments performed in the present study were
approved by the Animal Research Committee of Dongguk
University Ilsan Hospital (approval number: 2011-0154) and
performed in accordance with the ethical guidelines of the
Animal Research Committee.
Preparation of PLGA/Pluronic F127 Solutions
PLGA (lactic to glycolic acid, mol ratio, 75:25; Lakeshore
Biomaterials, Birmingham, Alabama) and Pluronic F127
(EG99PG65EG99; BASF, Florham Park, New Jersey) were
used to prepare injectable PLGA/Pluronic F127 solution.
Tetraglycol (glycofurol) as a nontoxic cosolvent for PLGA
and Pluronic F127 was purchased from Sigma (St Louis,
Missouri).8 Pluronic F127 was used for hydrophilization of
Downloaded from oto.sagepub.com at UNIVERSITY OF ULSAN COLLEGE OF MEDICINE on August 12, 2015
831
the PLGA. All other chemicals were of analytical grade and
used as received. For the animal study, PLGA and
Pluronic F127 powder were sterilized by ethylene oxide
(EO) gas. Tetraglycol was sterilized through a syringe-
driven filter unit (0.2 mm Millex-FG, Millipore, Billerica,
Massachusetts). PLGA pellet and Pluronic F127 powder
mixture (PLGA/Pluronic F127 [w/w], 95/5) was completely
dissolved in tetraglycol to 5% and 10% concentration in the
room temperature, then the mixture solution was transferred
into a syringe for further investigations.
Injection of PLGA/Pluronic F127 into the
Rabbit Vocal Fold
Eighteen male New Zealand white rabbits (Koatech
Laboratory Animal Company, Korea) weighing 3.0 to 3.5
kg were anesthetized with a combination of zoletile 50 (50
mg/kg), administrated intramuscularly. By using a blocked
randomization method, all the rabbits were randomly
divided into equal 2 groups; 5% and 10% PLGA groups. In
5% PLGA group, the 5% PLGA/Pluronic F127 solution was
carefully injected into the left vocal fold of 9 rabbits. Each
injection (100 mL/rabbit) was given through a syringe with
a 25 G spinal needle under the guidance of a 4.0 mm 30
degree rigid endoscope (Richards, Knittlingen, Germany).
The injection needle was placed just lateral to the tip of the
vocal process so that the vocal process could rotate medi-
ally. Because the PLGA/Pluronic F127 solutions were
directly solidified in contact with body fluid after injection,
there was no definite back flow of injection materials. The
same procedure was performed to the other 9 rabbits with
10% PLGA/Pluronic F127 solution. Postoperatively, the ani-
mals were observed for 2 hours before being returned to
their cages, where water and standard feed were available.
For the following 3 days, the rabbits were given 20 mg/kg
kanamycin as prophylaxis. Clinical signs were monitored
daily, with special attention to weight, cough, sputum pro-
duction, wheezing, and dyspnea.
Laryngoscopic Evaluation
Immediately after the injection of PLGA/Pluronic F127, a
laryngeal endoscopic exam was done with a 4.0 mm 30
degree rigid endoscope (Richards, Knittlingen, Germany).
Images of each animal’s vocal fold were taken with a digital
camera (E4500, Nikon, Tokyo, Japan) attached to the rigid
endoscope. One, 4, and 8 weeks after injection of the
PLGA/Pluronic F127, rabbits were anesthetized via the
same method and laryngeal endoscopic exam and images of
each animal’s vocal fold were done with same process.
Histology
In each injection of 5% and 10% PLGA/Pluronic F127
groups, the animals were humanely sacrificed at 4 (n = 5)
and 8 (n = 4) weeks after injection, and the larynges were
removed by a procedure like a total laryngectomy.
Especially in 8 weeks after injection of PLGA/Pluronic
F127, functional analysis with high-speed camera recording
was followed by histologic study. Laryngeal specimens
832
were fixed in for 24 hours in 10% formalin, embedded in
paraffin, and sliced at 5 mm thick thickness using a micro-
tome. The sections were deparaffinized and dehydrated
through a series of graded ethanol. Standard hematoxylin
and eosin (H&E) staining was used to evaluate the remain-
ing injection materials and to detect the presence of inflam-
matory tissue reaction in the epithelium, lamina propria, and
muscular layer of vocal fold. To descript of inflammatory
degree of vocal fold, usual Kumar’s acute inflammatory
reaction classifications were used.17 For reliable review, a
pathologist (ENK) was blinded to the information related to
grouping of laryngeal sampling.
Recording of Induced Vocal Fold Vibration with High
Speed Camera and Functional Analysis
Vocal fold vibrations of excised laryngeal setup were exam-
ined with high-speed camera as our previously published
methods.1,2 In each injection of 5% and 10% PLGA/Pluronic
F127 groups, the animals were humanely sacrificed at 8 (n =
4) weeks after injection, and the larynges were removed by a
procedure like a total laryngectomy. For better visualization
of the vocal fold, the superior portion of the thyroid cartilages
and supraglottic structures were removed. The arytenoid car-
tilages were sutured together using a Prolene 6-0 suture to
close the both vocal folds. The trimmed larynx was mounted
on a holder and humidified air was injected into the larynx to
generate the vocal fold vibration.
Imaging of rabbit’s vocal fold vibration during induced
phonation was accomplished by a MotionXtra NR4S2 high-
speed video camera (DEL Imaging Systems, Cheshire,
Connecticut). High-speed video data were recorded at 8000
images per second and a spatial resolution of 256 horizontal
3 512 vertical pixels. Illumination was provided by 300-W
xenon light source. Each high-speed video data segment
consisted of 8000 images per second.
From the high-speed imaging, the maximal amplitude
of vocal vibration was measured to evaluate the elasticity
of the vocal fold mucosa with Image J software.18 The
distance from the midline of the glottis to the free edge of
the vocal fold was measured at the mid antero-posterior
portion of the vocal fold during the open phase. Because
this measured value was defined by pixels on Image J
software, it was adjusted by dividing this number by
length of the each vocal fold, from anterior commissure
to vocal process, and this adjusted value was redefined as
an amplitude ratio. For reliable interpretation of vocal
mucosal vibration measuring, interpreter (DWK) was
blinded to the information related to grouping of laryn-
geal sampling.
Statistical Analysis
Experimental data are expressed as means 6 standard
deviation. The Wilcoxon signed rank test and Mann-
Whitney test with SPSS 17.0 statistical software (SPSS) was
used for comparison and statistical significance was
accepted at P \ .05.
Downloaded from oto.sagepub.com at UNIVERSITY OF ULSAN COLLEGE OF MEDICINE on August 12, 2015
Otolaryngology–Head and Neck Surgery 151(5)
Results
All animals survived without complications after injection
laryngoplasty. On endoscopic evaluation, injected PLGA/
Pluronic F127 showed augmentation effect in the left vocal
fold immediately after injection. The absorption of injected
materials was detected as function of times. The 5% PLGA/
Pluronic F127 group was more rapidly absorbed compared
with 10% one, and the biomaterials were disappeared on
endoscopic examination, at 8 weeks after injection, regard-
less of the polymer concentrations (Figure 1).
On histologic examination of 5% and 10% PLGA/
Pluronic F127, injected biomaterials (Figure 2, black
arrow) were remained until 8 weeks after injection. In both
of 5% and 10% PLGA/Pluronic F127, smaller amount of
injected biomaterials remained on histology of 8 weeks
after injection than that of 4 weeks. Also, the larger amount
of injected biomaterials in 10% PLGA/Pluronic F127 group
than 5% one was observed on histology of 8 weeks. On all
of the slide sections of 5% and 10% PLGA/Pluronic F127
group, mild to moderate inflammatory reactions including
giant cell formation (Figure 2, small arrow head) was
observed just around the injected biomaterials on 8 weeks
histology histologic analyses, and there was no difference
between groups. However (both 5% and 10% PLGA/Pluronic
F127), any significant inflammatory tissue reactions were not
revealed at surrounding intrinsic muscle, lamina propria, or
epithelium at 8 weeks (Figure 2, third column).
High-speed videos of vocal fold vibration, induced by
intratracheal airflow, showed regular and symmetrical con-
tact of both vocal folds. The left vocal fold that was injected
with PLGA/Pluronic F127 did not show the decreased level
of vibration compared with the right side vocal fold
(Figure 3). In 5% PLGA/Pluronic F127 injection, the
amplitude ratio of injected vocal fold (left) was not statisti-
cally decreased than that of non-injected (right) vocal fold
(0.720 6 0.007, 0.760 6 0.006, respectively, and P = .173
by Wilcoxon signed rank test, Figure 4A). Similar results
were identified in 10% PLGA/Pluronic F127 injection (left;
0.740 6 0.010, right; 0.760 6 0.009, respectively, and P =
.859 by Wilcoxon signed rank test, Figure 4B). In compari-
son of amplitude ratio between 5% and 10% PLGA/
Pluronic F127 groups, there was no significant difference
(P = .387 by Mann-Whitney test).
Discussion
Especially to evaluate the effect of PLGA/Pluronic F127 on
the movement of vocal fold wave, this study was conducted
with the normal vocal fold model rather than the vocal fold
palsy model.1 We focused more on the biocompatibility of
injected PLGA/Pluronic F127 as a bio-scaffolding matrix
rather than the augmentation effect because some inflamma-
tory tissue reactions related to the acidic monomer of
degrading PLGA in vivo were reported12,13 and these com-
plications could influence on vocal fold mucosa.
To the best of our knowledge, there has been no report
regarding vocal fold injection using injectable form of
Lee et al 833

Figure 1. Laryngoscopic images after injection laryngoplasty at the left vocal fold with 5% (upper row) and 10% PLGA/Pluronic F127
(lower row).

Figure 2. Standard hematoxylin and eosin (H&E) staining of rabbit larynx after injection laryngoplasty into the left vocal fold with 5%
(upper row) and 10% PLGA/Pluronic F127 (lower row).

soluble PLGA/Pluronic F127. This dissolved PLGA/

Figure 3. Representative serial images from the video of high-
speed camera recording at 8 weeks after injection of 5% PLGA/
Pluronic F127.
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Pluronic F127 in tetraglycol was different from previous
emulsion type of PLGA nanoparticle or microsphere that
was simply suspended in water-based medium.19,20 In our
study, the PLGA/Pluronic F127 as a scaffolding matrix for
injection laryngoplasty was prepared by dissolution of
PLGA and Pluronic F127 in a nontoxic tetraglycol. The
PLGA/Pluronic F127 solutions were easily injected through
a 25G needle into the left vocal fold of rabbit and stably
located at the injected site without back flow through the
channel formed by needle because of the fast solidification
of PLGA/Pluronic F127 solutions by the exchange of tetra-
glycol and body fluid (nonsolvent for PLGA). Therefore,
834
Figure 4. The amplitude ratio of the vocal fold. In (A) 5% and (B)
10% PLGA/Pluronic F127 injections, the amplitude ratio was not
significantly decreased than that of non-injected vocal fold.
this injectable solution type of PLGA/Pluronic F127 could
be a feasible form of an injecation laryngoplasty material.
The injected 5% and 10% PLGA/Pluronic F127 remained
in the vocal fold for 8 weeks. Also, we identified that the
remained amount of PLGA was larger in a higher concen-
tration of PLGA. The sustainment duration of injected
PLGA/Pluronic F127 was shorter than those of calcium
hydroxyapatite, which maintained in the paralyzed rabbit
vocal fold over 12 weeks after injection (as our previous
published data1). This relatively short sustainment duration
would be easily modified by adjustment of PLA to PGA
ratio rather than injection of higher PLGA concentration
because higher PLGA concentration was difficult to use as
injection form.14
PLGA/Pluronic F127 showed only a few giant cell for-
mations and did not reveal any significant inflammatory
tissue reactions in the larynx of rabbit on histology, high-
speed recording, and analysis of the amplitude ratio. These
findings would be more favorable for normal vocal mucosal
wave than our other previous results related CaHA injection
laryngoplasty that showed abundant giant cell formations or
other complication reports.1,2,21 This biocompatibility of
PLGA/Pluronic F127 may be understood by the relatively
small amount of acidic by-products from the PLGA/
Pluronic F127 and their fast neutralization by excess tissue
buffers in the vocal fold.
Based on these findings, we could expect 2 sequential
effect of the injection laryngoplasty with PLGA/Pluronic
F127; the initial volume augmentation of diseased vocal
fold (vocal fold palsy or atrophied vocal fold) just after
injection for moderate duration (about 8 weeks) and the late
biodegradable scaffolding matrix that may release bioactive
Downloaded from oto.sagepub.com at UNIVERSITY OF ULSAN COLLEGE OF MEDICINE on August 12, 2015
Otolaryngology–Head and Neck Surgery 151(5)
molecules including specific growth factors that induce a
muscle cell differentiation of the intrinsic laryngeal muscles.
The capacity of PLGA scaffold for bioactive agent delivery
was already approved in many previous data.5-7 Though fur-
ther study on the PLGA/Pluronic F127 incorporated with
growth factors is needed to confirm the efficacy of tissue
regeneration of atrophic vocal fold, several recent studies
demonstrated that the growth factors or stem cell therapy
can promote laryngeal regeneration: Basic fibroblast growth
factor (bFGF) can compensate for diminished laryngeal
volume in vocal fold paralysis3: Injection of human
adipose-derived mesenchymal stem cells can contribute to
the functional restoration of vocal fold biomechanics.4
As another expected merit of PLGA/Pluronic F127,
short-term repeated injection of growth factors into the
target tissue (vocal fold) may be avoided or controlled
because bioactive molecules loaded in the PLGA/Pluronic
F127 scaffolding matrices could be delivered in the tissue
and continuously released for longer duration.11 It was
reported that repeated intralesional injections of hepatocyte
growth factor (HGF) allows the regenerative effects on
vocal fold scars in vocal fold scarring animal study.22,23
Hirano et al also demonstrated that a study of bFGF in the
clinical setting of human vocal disease with repeated injec-
tion of bFGF (weekly 4 times injections) and this repeated
regenerative treatments using growth factors have benefit
for improvement of vocal function.15 From the literatures,
we could expect that if appropriate growth factors or cell
types were adapted in our system, we may induce the effec-
tive management of vocal fold paralysis by initial augmen-
tation through initial volume effect of PLGA/Pluronic F127
itself and later regeneration of intrinsic laryngeal muscle.
Conclusion
From the observations in the present study, we conclude
that PLGA/Pluronic F127 be devised suitably for injection
laryngoplasty and PLGA/Pluronic F127 be biocompatible
for vocal fold. Further experiment will follow to elucidate
the PLGA/Pluronic F127 scaffolding matrix’s role related
with bioactive molecules including specific growth factors
or drugs in the vocal fold.
Author Contributions
Jin Ho Lee, data analysis and interpretation, article revision;
Dong Wook Kim, study design, data analysis and interpretation,
article drafting; Eun Na Kim, data analysis and interpretation, arti-
cle revision; Seok-Won Park, study design, data collecting, article
revision; Hee-bok Kim, data collecting, analysis and interpreta-
tion, article drafting; Se Heang Oh, data collecting, analysis and
interpretation, article revision; Seong Keun Kwon, study design,
data analysis, article revision.
Disclosures
Competing interests: None.
Sponsorships: None.
Funding source: National Research Foundation of Korea (NRF-
2014R1A2A2A04003979). No role in study.
Lee et al 835

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