Original Article

Cell Transplantation
2018, Vol. 27(2) 275–284
A PEG-Based Hydrogel for Effective ª The Author(s) 2018
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Wound Care Management DOI: 10.1177/0963689717749032
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Sen-Lu Chen1, Ru-Huei Fu2,3,4, Shih-Fei Liao1, Shih-Ping Liu2,3,

Shinn-Zong Lin5, and Yu-Chi Wang1

Abstract
It is extremely challenging to achieve strong adhesion in soft tissues while minimizing toxicity, tissue damage, and other side
effects caused by wound sealing materials. In this study, flexible synthetic hydrogel sealants were prepared based on poly-
ethylene glycol (PEG) materials. PEG is a synthetic material that is nontoxic and inert and, thus, suitable for use in medical
products. We evaluated the in vitro biocompatibility tests of the dressings to assess cytotoxicity and irritation, sensitization,
pyrogen toxicity, and systemic toxicity following the International Organization for Standardization 10993 standards and the in
vivo effects of the hydrogel samples using Coloskin liquid bandages as control samples for potential in wound closure.

Keywords
hydrogel, polyethylene glycol, wound closure, biocompatibility

Introduction bodily fluids and the highly dynamic areas of the body5.
Most of the clinically available glues and sealants do not
One way to treat wounds is to apply a dressing, and conventional offer both elasticity and good adhesion. For example, cya-
dressings such as gauze and cotton are frequently used. Over the noacrylates have high stiffness and adhesion strength but are
past 2 decades, modern dressings have been used which provide
not elastic and are toxic8. On the other hand, fibrin-based
a humid environment for the healing of the wound1,2.
sealants are more flexible but have low stiffness and adhe-
Wound sealants can be made using natural or synthetic
sion strength9. There is an unmet need for tissue sealants that
polymers or a combination of both. The market for surgical
can provide an effective barrier for bodily fluids with flex-
sealants and hemostats is growing rapidly, increasing from
ibility and without compromising strength10.
$4 (USA) billion in 2012 to $7 billion in 2017 worldwide3.
Although several tissue adhesives are commercially avail-
able, none of them are ideal for use as a tissue sealant for
wound repair4.
1
Biomaterials Research and Development Department, Biomedical
The currently available technologies for reconnecting and Technology and Device Research Laboratories, Industrial Technology
Research Institute, Hsinchu, Taiwan
sealing tissues after surgical procedures, such as sutures, 2
Graduate Institute of Biomedical Sciences, China Medical University,
wires, and staples, have several limitations, especially in Taichung, Taiwan
minimally invasive procedures5,6. For example, the use of 3
Translational Medicine Research Center, China Medical University
sutures for wound closure is time-consuming, may cause Hospital, Taichung, Taiwan
4
further tissue damage, may result in infection, and does not Department of Psychology, Asia University, Taichung, Taiwan
5
Department of Neurosurgery, Bioinnovation Center, Tzu Chi
provide immediate sealing to prevent leakage of bodily Foundation, Buddhist Tzu Chi General Hospital, Tzu Chi University,
fluids or exposure to air. The application of adhesives is a Hualien, Taiwan
convenient alternative method for wound closure because of
Submitted: September 23, 2017. Revised: January 15, 2017. Accepted:
the simple implementation procedure, shorter healing time,
March 11, 2017.
less pain for patients, and lack of need for removal7. It is
extremely challenging to achieve strong adhesion in soft Corresponding Author:
tissues while minimizing toxicity, tissue damage, and other Yu-Chi Wang, Biomaterials Research and Development Department,
Biomedical Technology and Device Research Laboratories, Industrial
side effects caused by the sealing materials. Another limita- Technology Research Institute, No. 195, Sec. 4, Chung Hsing Rd.,
tion is the low adhesion strength of most commercially avail- Chutung, Hsinchu 31040, Taiwan.
able sealants in wet environments due to the presence of Email: yuchiw@itri.org.tw

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276 Cell Transplantation 27(2)

Recently, extensive research efforts have been made to Table 1. Cytotoxicity Evaluated Using Neutral Red Stain.
engineer biocompatible, biodegradable, and flexible sealants
Test Item Cell Lysis (%) Grade
that can form leak-free closures in soft tissues6,11–13. The
sealant materials must be elastic and compliant to allow Blank (B) 0 0
normal functioning and movement of elastic native tissues, Negative control (NC) 1 0
such as blood flow and the tissues surrounding the wound. Positive control (PC) 100 4
In this study, flexible synthetic hydrogel sealants were Test sample (S) 5 0
prepared based on polyethylene glycol (PEG) materials.
PEG is a synthetic material that is nontoxic and inert and,
thus, suitable for use in medical products10. All samples monolayer confluency were scored under a microscope.
were characterized and assessed in swelling studies to eval- Cryopreserved L929 cells were thawed and cultured in min-
uate their performance as wound sealants. imum essential media/alpha modification medium (Invitro-
In vitro biocompatibility tests of the dressings were per- gen, Carlsbad, CA, USA) at 37 + 1  C in a 5% CO 2
formed to assess cytotoxicity and irritation, sensitization, atmosphere. When the cell monolayer reached 80% con-
pyrogen toxicity, and systemic toxicity following the Inter- fluency as assessed with a microscope, the cells were sub-
national Organization for Standardization (ISO) 10993 stan- cultured until reaching passage 2 or 3 prior to use. The
dards for safety in wound closure14. We also evaluated the in culture medium was replaced twice a week. According to
vivo effects of the hydrogel samples using Coloskin liquid ISO 10993-12, the surface ratio of the test compound/culture
bandages as control samples. medium was 0.2 g/1 mL. Accordingly, 3.6 g of each test
sample (S) was extracted with 18 mL of culture medium at
a rotation speed of 1,000g at 37 + 1  C for 24 + 2 h. A 10%
Materials and Methods (v/v) solution of dimethyl sulfoxide (DMSO Sigma-Aldrich)
Materials prepared using culture medium was used as the positive
PEG (M.W. 35,000) was purchased from Sigma-Aldrich (St. control (PC). Based on ISO 10993-12, the extraction ratio
Louis, MO, USA). First, aqueous PEG solutions were pre- was 0.2 g/mL, and 1.0 g of high-density polyethylene
pared, and then, homogeneous solutions were obtained by (Sigma-Aldrich) was used as a negative control (NC). Each
dissolving and mixing the materials at a constant tempera- sample was immersed in 5 mL of culture medium and
ture. The solutions were poured into molds, and after the extracted at a rotation speed of 1,000g at 37 + 1  C for
solutions cooled down, they formed a gel structure with high 24 + 2 h. In addition, 5 mL of culture medium was used
viscosity. Finally, the samples were sterilized under an as a blank (B) and then incubated at a rotation speed of 100
appropriate dose of radiation. To assess the wound-healing rpm at 37 + 1 C for 24 + 2 h.
effects of the hydrogel samples, the results were compared The MTT (Sigma-Aldrich) assay was performed to
with those of the Coloskin liquid bandages (Tokyokoshisha quantitatively assess the cytotoxicity of the test sample
Co., Ltd., Tokyo, Japan). extracts. For the assay, 5  104 L929 mouse fibroblast cells
were seeded in 24-well culture plates and then incubated at
37 + 1  C in a 5% CO2 atmosphere for 24 + 2 h to obtain
Swelling Studies and Degradation Analysis confluent cell monolayers. After cell attachment, the orig-
The samples were placed in a vacuum oven at 37  C for 24 h, inal culture medium in each well was removed and replaced
and then their apparent dry weights (Wd) were measured. with 0.5 mL of the respective test medium (B, PC, NC, and
The samples were then placed in distilled water to determine S). Then, the test plates were incubated at 37 + 1  C in a
their water uptake (Ws) after drying at 37  C. 5% CO2 atmosphere for 24 + 2 h. The plate was incubated
Mass loss was measured using a balance. At each time for 24 h. After 24 h, the cells in each well were stained with
point, the samples were weighed after drying, and neutral red solution (Sigma-Aldrich) and scored according
mass loss was calculated by comparing the initial mass to the change in cell morphology and viability under an
with that at a given time point. Measurements were per- inverted microscope (Carl Zeiss MicroImaging GmbH,
formed while maintaining the samples at 3 temperatures, Göttingen, Germany) in accordance with the criteria in
37  C, 50  C, and 65  C, and the results are presented as Table 1. At the end of the incubation period, 10 mL of MTT
the mean. reagent was added to each well, which contained 100 mL of
medium. The reaction was performed at 37  C in a 5% CO2
atmosphere for 2 h in the dark. Then, 0.1 mL of detergent
Cytotoxicity Analysis and 3-(4,5-Dimethyl-Thiazol-2-yl)-
reagent (Sigma-Aldrich) was added to each well followed
2,5-Diphenyltetrazolium (MTT) Assay by incubation in the dark for 2 h, after which the absorbance
The cytotoxicity analysis was performed according to ISO was measured. The absorbance of test samples was mea-
10993-5:2009. Using a mouse fibroblast cell line (L929; sured at 570 nm (reference wavelength: 630 nm) with a
Bioresources Collection and Research Center, Hsin Chu, microplate reader (Molecular Devices, Silicon Valley,
Taiwan), qualitative measures of cell morphology and CA, USA).
Chen et al 277

Skin Sensitization Study body temperature of the animals were calculated by subtract-
ing the control temperature from the highest temperature
For the study to comply with the “Good Laboratory Practice
among the 5 measurement times. The main test was per-
for Nonclinical Laboratory Study,” quality assurance unit
formed with 5 additional animals when the results of the
audited the facility, equipment, personnel, test methods, raw
preliminary test indicated a fever (a high temperature).
data, and records regularly. All animal experiments were
conducted according to a protocol approved by Master
Laboratory CO., Ltd (IACUC No.: MS20160706, Hsinchu Acute System Injection Study
County, Taiwan, People’s Republic of China). A system toxicity study following the ISO 10993-11:2006
The skin sensitization potential of the PEG-based sealant guidelines was performed to evaluate the toxicity response to
extracts was tested on guinea pigs (body weights [BWs; gen- the PEG-based sealant extracts in mice (ICR mice, Bio-
der]: 300 to 500 g [male]; age around 85 d, from the National LASCO Taiwan Co., Ltd, Taipei, Taiwan; BWs [gender]:
Laboratory Animal Center, Taiwan) following ISO 10993-10: 17 to 23 g [male]). The test compound extracts were injected
2010. After treatment with the test compound (polar and into mice at a dose of 50 mL test compound extract per
nonpolar extracts), the extracts were applied twice in the kilogram BW. Control solutions of 0.9% saline for intrave-
induction phase and once in the challenge phase. Then, 24 h nous injections and cottonseed oil for intraperitoneal injec-
and 48 h after the challenge phase, the treated areas were tions were given at a dose level of 50 mL/kg BW. Polar
assessed for visible changes according to the criteria of the extracts were used for the intravenous injections, and non-
Magnusson and Kligman scale, ISO 10993-10. polar extracts were used for the intraperitoneal injections.

Intracutaneous Irritation Study Wound Closure Animal Study

Intracutaneous irritation in response to the PEG-based sea- To evaluate the bioadhesive property and the biocompatibil-
lant extracts was assessed in New Zealand White rabbits ity of the PEG-based hydrogels, rats (normal Sprague-
(BWs [gender]: >2 kg [male]; age around 65 d, from the Dawley [SD] rats, 100 to 150 g, 4 wk old, male; BioLASCO
National Laboratory Animal Center, Taiwan). The testing Taiwan Co., Ltd) were anesthetized using Zoletil (Virbac,
was performed in compliance with ISO 10993-10. The rab- Taiwan, Taipei), and their backs were shaved. Skin incisions
bits were shaved to remove the fur at 5 sites and subse- that were 1.5 cm long and full-skin thickness deep were
quently injected with an extract of a test compound at each made on both sides of the backs of the rats. The skin inci-
site. The control solution (0.9% saline and cottonseed oil sions were quickly closed using Coloskin or the PEG-based
[Sigma-Aldrich]) was injected into the same side of each hydrogels. The PEG-based hydrogels were sterilized by fil-
rabbit, and dermal reactions were assessed at time points tration using 200-nm syringe filters and prepared with a dual
of 24, 48, and 72 h. syringe kit. A 50-mL aliquot of a hydrogel was applied to the
wound area. Immediately after wound closure and at 1 and
4 d postimplantation, the closed skin was harvested and fixed
Pyrogen Study in White Rabbits in paraformaldehyde (PFA) solution (3.7 wt.%) for histolo-
gical analysis after hematoxylin and eosin (H&E) staining
The guidelines of USP39/NF34(151) were followed to deter-
and Masson’s trichrome stain (Sigma-Aldrich). The growth
mine whether the test sample extracts passed the pyrogen
of collagen was calculated by using Image J software
evaluation in the New Zealand White rabbits (Hui Jun, BWs
(National Institutes of Health (NIH), Bethesda, MD, USA).
[gender]: >2 kg [male]; age around 65 d) following a single-
dose injection (10 mL/kg) in an ear vein. Three to 5 d before
the experiment, the body temperatures of the rabbits were Statistical Analysis
measured. The criteria for selecting rabbits for the pyrogen All data are presented as the mean (standard deviation). The
study were a body temperature that does not exceed 39.8  C significance of differences between results was assessed via
and no more than a 1  C difference between the highest and one-way analysis of variance (ANOVA) (EXCEL, Micro-
the lowest body temperatures among the 4 measurement soft, Seattle, WA, USA). For all tests, a P value < 0.05 was
times. During the study, only reverse osmosis water was considered statistically significant.
provided. The control temperature of each animal was deter-
mined using a rectal thermometer (accuracy + 0.1  C).
Every appliance used in the study was also pyrogen free. Results
In the preliminary test, the control temperatures of the
Formation and Characterization of Adhesive Sealants
3 animals were determined. Test samples (warmed up to
37  C + 2  C) were injected into an ear vein of an animal.
Composed of PEG-Based Hydrogels
The administration time did not exceed 10 min. Body tem- For optimal gelation, 10% to 35% weight/volume (w/v) solu-
peratures were measured 5 times at 30-min intervals at 1, tions of the PEG-based hydrogel were used because a solu-
1.5, 2, 2.5, and 3 h after administration. The elevations in tion of less than 5% (w/v) would not solidify. Figure 1a
278 Cell Transplantation 27(2)

Fig. 1. The characteristics of polyethylene glycol (PEG)-based hydrogel. (A) The picture displays the elasticity of PEG-based hydrogel
containing 30% PEG-based hydrogel. A hydrogel strip can be easily stretched to about 10 times its initial length without visible or permanent
deformation. (B) Swelling ratios of PEG-based hydrogel at different time points. (C) The relative mass of PEG-based hydrogel decreased over
time due to degradation in the difference temperature.

presents the adhesion and stretching results of a line-shaped Qualitative determination. A morphological assessment of
hydrogel attached to a 1.5 mL Eppendorf tube. The elon- L929 cells using an inverted microscope (100) was per-
gated hydrogel adhered easily to skin even when part of it formed after treating them with B, NC, PC, or S for 3 h and
was removed. Figure 1b shows the hydrogel before and after staining them with neutral red. The morphology of B- and
immersion in water. The hydrogel swelled to 11 times its NC-treated cells revealed a long spindle shape with obvious
initial weight in the first 2 h (Fig. 1b). lamellipodia and filopodia instead of a lysed, rounded shape
The mass loss data for hydrogels degraded at tempera- and inhibited growth. However, PC-treated cells showed a
tures of 37  C, 50  C, and 65  C are summarized in Fig. 1C. nearly complete rounded lysed morphology; cell layers were
During the first 3 d, similar mass losses were observed for almost completely destroyed, and growth inhibition was
hydrogels maintained at temperatures of 37  C and 50  C. At observed. The cells treated with the test samples showed the
day 7, samples maintained at a temperature of 65  C exhib- same long spindle shape as cells treated with B and NC.
ited faster rates of mass loss, losing a total of 20% of their According to the results of the microscopic assay, the per-
original mass. At day 14, samples maintained at 65  C centages of rounded or lysed cells in the B, NC, PC, and S
showed a faster mass loss rate at day 12 of degradation, groups were 0%, 1%, 100%, and 5%, respectively. There-
losing more than 95% of their original weight. The mass loss fore, the cytotoxicity of B, NC, PC, and S was graded at 0, 0,
rate of hydrogels maintained at 65  C was higher than those 4, and 0, respectively (Table 1 and Fig. 2).
of hydrogels maintained at 37  C and 50  C.
Quantitative determination. L929 cells were treated with B,
NC, PC, and S for 24 h, and cell viability was evaluated with
an MTT cell proliferation/viability assay. The absorbance
In Vitro Cell Viability and MTT Assay
values of the B, NC, PC, and S groups at 570 nm were
To evaluate the cytotoxicity of the PEG-based hydrogels, the 1.065 + 0.071, 1.051 + 0.056, 0.294 + 0.038, and 0.861
effects of the samples on cell growth, morphology, and via- + 0.053, respectively; the respective cell viability values
bility were evaluated. After cells were exposed to the were 100%, 99%, 28%, and 81%, and the respective mortal-
extracts for 24 h, the following items were evaluated: ity values were 0%, 1%, 72%, and 19%.
Chen et al 279

Fig. 2. In vitro cell viability and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The observed cell morphology
of L929 cells (mouse fibroblast cell line) after being treated for 24 h under 100 inverted microscope. (A) Blank (B): culture medium.
(B) Negative control (NC): high-density polyethylene. (C) Positive control (PC): 10% dimethyl sulfoxide (DMSO). (D) Test sample
(S): polyethylene glycol (PEG)–based hydrogel.

Table 2. The Results of MTT Assay for Evaluation of Cell Viability. Table 3. Skin Reaction in Guinea Pigs.

Absorbance Viability Mortality Group (0.9% saline) Control Treatment

Test Item (OD570 nm) (%) (%)
Gender Male Male
Blank (B) 1.065 + 0.071 100 0 Number of animals 5 10
Negative control (NC) 1.051 + 0.056 99 1 Erythema and eschar 0/5 0/10
Positive control (PC) 0.294 + 0.038 28 72 Edema 0/5 0/10
Test sample (S) 0.861 + 0.053 81 19 Group (cottonseed oil) Control Treatment
Gender Male Male
Abbreviation: MTT, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium. Number of animals 5 10
Erythema and eschar 0/5 0/10
Edema 0/5 0/10
The qualitative and quantitative assay results (Tables 1
and 2) indicated zero reactivity. Therefore, the extract solu- Note. n/n, no. of guinea pigs with abnormal clinical signs/no. of guinea pigs
tions of the PEG-based hydrogels were considered to have per group.
no in vitro cytotoxicity.
Intracutaneous Irritation Study
Skin Sensitization Study The intracutaneous irritation results showed that there were
The skin sensitization potential of the PEG-based hydrogels no significant clinical signs or gross findings in the control or
was tested on guinea pigs. Following extraction of the test treatment groups, and there was no mortality in any of the
samples, the extracts were applied twice in the induction tested groups. Therefore, a single topical application of
phase and once in the challenge phase. Then, 24 h and 48 h 0.2 mL of the test compound extracts did not cause intracu-
after the challenge phase, neither the control nor the treatment taneous irritation in New Zealand White rabbits. The intra-
group showed visible changes in the skin response on the cutaneous irritation results showed that a single application
treated areas (Table 3 and Fig. 3). The results indicated that of the test compound extracts induced neither observable
the test samples (polar or nonpolar) did not cause delayed clinical signs nor dermal gross changes in New Zealand
hypersensitivity on the skin of the tested guinea pigs. White rabbits at any time point. Therefore, a single topical
280 Cell Transplantation 27(2)

Fig. 3. Skin sensitization study. (A) Pictures for observation of skin reaction (0.9% saline). (B) Pictures for observation of skin reaction
(cottonseed oil). (C) Pictures for observation of skin reaction (positive control).

application of a PEG-based hydrogel did not cause observa- of the 3 animals were 39.42  C, 39.37  C, and 39.25  C. Any
ble irritation in New Zealand White rabbits (Fig. 4). elevation of body temperature for the 3 rabbits was below
0.5  C (Table 5; Animal No.79-1001: 0.46  C, Animal
No.79-1002: 0.10  C, and Animal No.79-1003:
Pyrogen Study in White Rabbits 0.05  C; Table 5).
The BWs of 3 New Zealand White rabbits were above 1.5 The body temperatures of the 3 qualifying White rabbits
kg, qualifying them for the study. The control temperatures were measured 5 times after a single dose (10 mL/kg) of a
Chen et al 281

Table 4. Acute System Injection Study.

(A) Incidence of Clinical Observation in Mice

Polar group

Number of animals 5 male 5 male

Treated article 0.9% saline PEG-based hydrogel
Toxicity reaction 0/5 0/5
Death 0/5 0/5
Nonpolar group
Number of animals 5 male 5 male
Treated article Cottonseed oil PEG-based hydrogel
Toxicity reaction 0/5 0/5
Death 0/5 0/5
(B) Incidence of Gross Finding
Polar group
Dose level (mL/kg) 50 50
Gender Male Male
Animal number 5 5
Symptom 0/5 0/5
Nonpolar group
Dose level (mL/kg) 50 50
Gender Male Male
Animal number 5 5
Symptom 0/5 0/5
Fig. 4. Intracutaneous irritation study. (A) Observation at the 24th
h of administration. (B) Observation at the 48th h of administration. Note. n/n, no. of mice with gross signs/no. of mice per group.
(C) Observation at the 72nd h of administration.

compound was injected in an ear vein. The pyrogen response Table 5. Pyrogen Study in White Rabbits.
was negative for all samples; therefore, the samples were (A) Control Temperature of Rabbits
considered to pass the pyrogen study.
Animal number Control temperature ( C)

Acute System Injection Study 79-1001 39.42

79-1002 39.37
The toxicity responses to the PEG-based hydrogels were 79-1003 39.25
assessed in mice after injecting the test samples and control (B) Temperature
solutions. The results showed that there were no significant Elevation
clinical signs or gross findings in the control or treatment Animal number Elevation (body temperature after
administration)
groups. Therefore, the test samples did not cause toxicity
79-1001 0.46  C
reactions or death after injection (Table 4). The study results 79-1002 0.10  C
showed that a single application of the hydrogels or the 79-1003 0.05  C
controls induced neither observable clinical signs nor gross
findings in the mice at any time point. Therefore, the PEG- Note. Temperature elevation ¼ the highest body temperature (among 5
times measurement) subtract control temperature.
based hydrogels did not cause a toxicity reaction or death
after injection (Table 4).
more collagen at the wound sites in the hydrogel-treated
groups than in the Coloskin-treated group (Fig. 5C). The
Wound Closure Animal Study average collagen in the Coloskin and PEG-based hydrogel
After applying the PEG-based hydrogels, bleeding from the groups were 65.2 and 77.2% (Image J), respectively (Fig.
incisions on the dorsum of SD rats immediately stopped, and 5D). We also calculated the wound area between 2 groups,
the wound openings closed within minutes. The wound and the average wound area in the Coloskin and PEG-based
openings did not close after applying Coloskin. Furthermore, hydrogel groups were 0.4 cm2 and 0.2 cm2, respectively,
visual examinations were performed at different time points after 7 d of treatment.
to compare the PEG-based hydrogel-treated incisions and
Coloskin (a commercial product)-treated incisions. The
results indicated that the PEG-based hydrogels enhanced the
Discussion
wound closure process (Fig. 5A and B). The histological In this study, the biocompatibility of hydrogel samples was
evaluation (H&E staining) showed that after 14 d, there was compared with that of control samples by assessing
282 Cell Transplantation 27(2)

Fig. 5. Animal experiment for wound closure. Photographs of wound closures. Skin incisions on back of the rats were treated by Coloskin
and hydrogel, (A) 1 and (B) 4 d postimplantation. The closure skin was harvested and fixed in p-formaldehyde solution (3.7 wt.%) for
histological analysis by hematoxylin and eosin and Masson’s trichrome stain (C) after 14 d. (D) The statistical results of collagen assay after
14 d treatment (P < 0.01). (E) The differences in wound area between the 2 treatments after 7 d (P < 0.01).

cytotoxicity, irritation, sensitization, pyrogen toxicity, and bleeding immediately ceased, and the wound opening closed
systemic toxicity, which are the most important factors in within a few minutes, whereas this did not occur with the
in vitro tests for wounds care14. According to the results of Coloskin-treated wounds. In addition, the PEG-based hydro-
these analyses, the PEG-based hydrogel showed good bio- gels led to improved and accelerated wound closure com-
compatibility and safety15. The animal study confirmed the pared to Coloskin. Interestingly, 14 d after application, no
effectiveness and convenience of using PEG-based hydro- trace of hydrogel was observed at the location of the healed
gels for wound closure and bleeding control and their tissues, indicating the complete in vivo degradation of the
enhanced performance over a commercial product. hydrogel. In vivo degradation rates of polymers could be
After applying the hydrogel solution to the full-skin faster than in vitro; the higher in vivo degradation rate has
thickness cutaneous incisions on the backs of SD rats, the been explained by the effects caused by cellular and
Chen et al 283

enzymatic activities found in the body16. Traditionally, it is Funding

believed that PEG-based hydrogels degrade due to ester The author(s) received no financial support for the research, author-
hydrolysis17 and hydroxyl radicals18. ship, and/or publication of this article.
The statistical results of the collagen assay showed the
statistically significant difference between the 2 groups,
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