NEW METHODS

A novel fully synthetic and self-assembled peptide solution for

endoscopic submucosal dissection-induced ulcer in the stomach
Toshio Uraoka, MD, PhD,1,2 Yasutoshi Ochiai, MD, PhD,1 Ai Fujimoto, MD, PhD,1 Osamu Goto, MD, PhD,1
Yoshiro Kawahara, MD, PhD,3 Naoya Kobayashi, MD, PhD,4 Takanori Kanai, MD, PhD,5
Sachiko Matsuda, PhD,6 Yuko Kitagawa, MD, PhD,6 Naohisa Yahagi, MD, PhD1
Tokyo, Okayama, Japan

Background and Aims: Endoscopic submucosal dissection (ESD) can remove early stage GI tumors of various
sizes en bloc; however, success requires reducing the relatively high postprocedure bleeding rate. The aim of this
study was to assess the safety and efcacy of a novel, fully synthetic, and self-assembled peptide solution that functions as an extracellular matrix scaffold material to facilitate reconstruction of normal tissues in ESD-induced
ulcers.
Methods: Consecutive patients who underwent gastric ESD were prospectively enrolled. Immediately after the
resection, the solution was applied to the site with a catheter. Gastric ulcers were evaluated by endoscopy and
classied as active, healing, or scarring stages at weeks 1, 4, and 8 after ESD.
Results: Forty-seven patients with 53 lesions, including 14 (29.8%) previously on antithrombotic therapy and 2
(4.3%) requiring heparin bridge therapy, were analyzed; 2 patients were excluded, 1 with perforations and 1 with
persistent coagulopathy. The mean size of the en bloc resected specimens was 36.5  11.3 mm. The rate of postESD bleeding was 2.0% (1/51; 95% CI, 0.0310.3). Transitional rate to the healing stage of ESD-induced ulcers at
week 1 was 96% (49/51). Subsequent endoscopies demonstrated the scarring stage in 19% (9/48) and 98% (41/42)
at weeks 4 and 8, respectively. No adverse effects related to this solution occurred.
Conclusions: The use of this novel peptide solution may potentially aid in reducing the delayed bleeding rate by
promoting mucosal regeneration and speed of ulcer healing after large endoscopic resections in the stomach.
Further studies, particularly randomized controlled studies, are needed to fully evaluate its efcacy. (Clinical trial
registration number: 000011548.)

INTRODUCTION
Endoscopic submucosal dissection (ESD) can remove early stage GI tumors of varying sizes en bloc;
the procedure can be curative or at least reduce local
recurrence and facilitate more accurate histopathologic
assessment.1-3 However, delayed bleeding can occur
days after the procedure and success requires this rela-

Abbreviations: ESD, endoscopic submucosal dissection; PPI, proton

pump inhibitor; ECM-SM, extracellular matrix scaffold material; HBT,
heparin bridge therapy; PGA, polyglycolic acid.
This work was supported by MEXT KAKENNHI Grant-in-Aid for Scientific
Research (C), grant number 24591028.
DISCLOSURE: All authors disclosed no financial relationships relevant
to this publication.
Copyright 2015 by the American Society for Gastrointestinal Endoscopy
0016-5107/$36.00
http://dx.doi.org/10.1016/j.gie.2015.11.015

www.giejournal.org

tively high postprocedure bleeding rate to be reduced,

particularly in the stomach (4.6%15.6%).4-7 Although
gastric ESD-induced ulcers are treated with proton
pump inhibitors (PPIs) for at least 8 weeks in most hospitals, this treatment does not eliminate the risk of
bleeding.8 Prevention of post-ESD bleeding is important because it can potentially result in signicant
morbidity from acute blood loss and the need for

Current affiliations: Division of Research and Development for Minimally

Invasive Treatment, Cancer Center, Keio University School of Medicine,
Tokyo, Japan (1); Department of Gastroenterology, National Hospital
Organization Tokyo Medical Center, Tokyo, Japan (2); Department of
Endoscopy, Okayama University Hospital, Okayama, Japan (3); Okayama
Saidaiji Hospital, Okayama, Japan (4); Division of Gastroenterology and
Hepatology, Department of Internal Medicine, Keio University School of
Medicine, Tokyo, Japan (5); Department of Surgery, Keio University
School of Medicine, Tokyo, Japan (6).
Reprint requests: Toshio Uraoka, MD, PhD, Department of
Gastroenterology, National Hospital Organization Tokyo Medical Center,
2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan.

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additional endoscopic intervention and extended

hospitalization.
Recently, tissue engineering and regenerative substances, such as extracellular matrix scaffold material
(ECM-SM), have been developed to target the reconstruction of structurally and functionally normal tissues.9 In
addition, a fully synthetic and self-assembled peptide solution that functions like ECM-SM to replace collagen has
been developed.10,11
We conducted this clinical trial with the aim of assessing
the safety and efcacy of this novel peptide solution for the
management of ESD-induced gastric ulcers.

TABLE 1. Baseline characteristics

Patients
Age, mean (SD)
Male sex (%)
Current use of antithrombotic agents, n (%)
Administration of heparin bridge therapy, n (%)
Gastric lesions
Location: U/M/L

45
71.9 (8.8)
73.3
14 (29.8%)
2 (4.3%)
51
16/17/18

Outcome of ESD
En bloc resection (%)

51 (100)

SD, Standard deviation; U, upper third of the stomach; M, middle third of the
stomach; L, lower third of the stomach; ESD, endoscopic submucosal dissection.

METHODS
The study protocol was approved by the institutional review board of Keio University Hospital. Consecutive patients who underwent ESD for intraepithelial gastric
tumors12 performed by 8 endoscopists of various levels
of experience were enrolled.
Patients receiving antithrombotic therapy were
included in this study; however, this was discontinued
before the procedure in patients at low risk for thromboembolism according to the current guidelines of the
Japan Gastroenterological Endoscopy Society.13 Heparin
bridge therapy (HBT) was administered to patients who
were considered high risk for thromboembolism up to
6 hours before ESD, and restarted on the rst postprocedure day. Patients with a platelet count <50,000/mm3
were excluded from this trial. In addition, cases with
coagulopathy (international normalized ratio >2) despite
appropriate management and those with perforations
were excluded from the analysis.
Informed signed consent for the procedure and use of
the peptide solution was obtained from all patients.

Fully synthetic and self-assembled peptide

solution
A novel fully synthetic material consisting of a 16-amino
acid peptide solution (PuraMatrix; 3-D Matrix, Tokyo,
Japan) self-assembles at physiologic pH and forms a hydrogel comprising a network of nanobers. This rapidly
seals open blood vessels when exposed to blood or tissue
uids. In addition, the important feature of PuraMatrix is
its nanostructure, which is equivalent to natural ECM-SM
(nanober) and results in adequate adherence of cells
and tissue.14

Post-ESD bleeding was dened as bleeding that

required endoscopic or surgical intervention, or a
decrease in hemoglobin level of 2 g/dL and hemodynamic
instability. Images of ESD-induced ulcers were collected
prospectively and digitally stored, and post-ESD gastric ulcer stages were evaluated by endoscopy and classied as
active, healing, or scarring at weeks 1, 4, and 8. The healing stage of gastric ESD-induced ulcer was dened as an
ulcer without a mucous coating and increased margin according to the Sakita and Fukutomi classication.15 The
stage was classied at follow-up endoscopy after careful inspection and thorough review by 2 experienced endoscopists who did not participate in the ESD procedure.
Although this classication is generally used to assess
the healing process of a peptic gastric ulcer, we used
this classication for ESD-induced ulcers in this study
because it is the most objective guide published. When
the opinions on stage differed between the 2 endoscopists, they discussed their ndings until consensus was
reached on a mutually agreeable and best staging.
Although the Sakita and Fukutomi classication is directly
related to peptic ulcer disease, the pathophysiology of
which is certainly different from that of an iatrogenicinduced ulcer/mucosal defect after ESD, tissue regeneration and healing requires the same process from a histologic perspective. Therefore, given that it is the only
objective staging guide available, this classication was
used in this study to reduce interobserver interpretation
variability.
The primary end point was the rate of post-ESD
bleeding. The secondary end points included the transitional rate to the healing and scarring stages of gastric
ESD-induced ulcers.

Study protocol

Statistical analysis

For every 1 cm of resected tumor, 1 mm3 of PuraMatrix

was applied immediately to the resection site using a catheter (TOP Endoscopic Spraying Tube; Top, Tokyo, Japan).
All patients received a single-dose PPI for 8 weeks beginning on the morning of the procedure.

The continuous values were expressed as means  standard deviation (SD). JMP, version 8, software (SAS Institute, Cary, NC) was used to analyze the data and the
signicance level was set at 5% for each analysis; P < .05
was considered statistically signicant.

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A novel peptide solution after ESD

TABLE 2. Comparison of transitional rates to stages of gastric ESD-induced ulcers with proton pump inhibitor treatment
Study

Mean resected size (mm)

1 week

4 weeks

39.1

NA

NA

20

Park et al

8 weeks
Active 0%
Healing 31%
Scarring 69%

Uedo et al21

41.0

NA

NA

Active 0%
Healing 17%
Scarring 83%

Ye et al22

NA

NA

Active 4%

NA

Healing 92%
Scarring 4%
23

NA

Kawano et al

Kakushima et al

Our study

34.7

36.5

NA

Active 3%

Active 0%

Healing 85%

Healing 11%

Scarring 11%

Scarring 89%

Active 100%

Active 0%

Active 0%

Healing 0%

Healing 99%

Healing 0%

Scarring 0%

Scarring 1%

Scarring 100%

Active 4%

Active 0%

Active 0%

Healing 96%

Healing 81%

Healing 2%

Scarring 0%

Scarring 19%

Scarring 98%

NA, Not applicable.

RESULTS
Baseline characteristics
A total of 47 patients were recruited and 45 patients
with 51 lesions were enrolled for the outcome analysis.
Two patients were excluded because of perforation and
coagulopathy. Of the 45 patients, 14 (29.8%) were previously on antithrombotic therapy, including 2 (4.3%)
requiring HBT. En bloc resection was achieved in all cases
(Table 1). The mean size of the resected specimens was
36.5  11.3 mm.

Post-ESD bleeding
Post-ESD bleeding was observed in 1 case (1/51, 2.0%;
95% CI, 0.0310.3). The only case of post-ESD bleeding
was successfully managed by endoscopic intervention
alone.

Transitional rates to stages of gastric ESDinduced ulcers

A total of 51 gastric ESD-induced ulcers had scheduled
follow-up endoscopy at 1, 4, and 8 weeks after ESD. Complete follow-up was not possible in 8 patients, 4 of whom
underwent surgery for noncurative resection and 2
required pyloric ring dilation for stricture management
during the follow-up period. The other 2 patients declined
subsequent endoscopy.
The transitional rate to the healing stage at 1 week
was 96% (49/51). Further follow-up gastroscopies demonwww.giejournal.org

strated scarring stage in 19% (9/48) and 98% (41/42) at

weeks 4 and 8, respectively (Table 2 and Fig. 1).
No adverse effects related to the use of PuraMatrix
occurred in this study.

DISCUSSION
In this feasibility study, the application of a novel, fully
synthetic, and self-assembled peptide solution, PuraMatrix,
was found to reduce the rate of delayed bleeding and promote mucosal regeneration and speed of ulcer healing after large endoscopic resections in the stomach. The rate of
bleeding was 2.0% (1/51). These post-ESD bleeding rates
are lower than in previous reports.4-7
The synthetic peptide solution was tested as a hemostatic material in pilot studies; a small number of cases
demonstrated hemostasis of active oozing/bleeding during
gastric ESD and in vascular anastomotic graft sites.16,17
Both studies demonstrated more effective and reliable hemostasis than other commonly used general hemostatic
agents. In addition, Kondo et al18 reported the safety and
effectiveness of PuraMatrix as a biocompatible sealing material for the management of postoperative peritoneal effusion after pelvic surgery. No reports exist on the use of this
solution for promoting wound healing by sequential observation in any of the medical elds.
Recently, a shielding method using polyglycolic acid
(PGA) sheets and brin glue for gastric ESD-induced ulcer
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Figure 1. Transition of gastric ESD-induced ulcers in the gastric angle after ESD. A, An early stage cancer on the posterior of the gastric angle. B, Endoscopic image after acetic acid and indigo-carmine dye spay. C, ESD-induced ulcer immediately after ESD. D, Application of PuraMatrix. E, One week after
ESD, the ulcer was at the healing stage according to the Sakita and Fukutomi classication. F, At 4 weeks, the scarring stage was observed. G, At 8 weeks,
the scarring stage was observed.

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to prevent post-ESD bleeding in high-risk patients was reported by Tsuji et al.19 They reported a decreased postESD bleeding rate (6.7%) in high-risk patients who were
taking antithrombotic drugs (antithrombotic drugs were
discontinued before the procedure) or were expected
to undergo large mucosal resection (40 mm).
Compared with our cases of gastric ESD, with a mean resected specimen size of 36.5 mm and 21% patients
currently using antithrombotic agents, their post-ESD
bleeding rate was not superior. The shielding method using PGA sheets and brin glue has some disadvantages,
including the risk of unknown infection and longer procedure time. According to their report, the mean procedure
time for applications of the sheets and glue was 20.4  9.5
min. Because PuraMatrix is a fully synthetic solution, the
risk of infection is not a concern. In addition, the application of PuraMatrix using a catheter is completed within a
minute.
Gastric ESD-induced ulcers were specically evaluated after ESDs. Because the risk of delayed bleeding
is higher with gastric ESDs than esophageal or colorectal
ESDs, despite the routine use of PPIs, the evaluation of
gastric ESD-induced ulcers is clinically important to
reduce morbidity. Compared with previous reports,8,2023
the rate at the healing stage at 1 week and the rate
at the scarring stage at 4 weeks were higher (Table 2).
In addition, the rate of scarring even at 8 weeks was relatively higher in our study than in previous reports. PuraMatrix seems to promote ulcer healing according to
these comparisons because objective assessment was
done according to the Sakita and Fukutomi
classication.
The advantages of PuraMatrix for ESD-induced ulcers
are as follows: (1) PuraMatrix functions as a synthetic extracellular matrix to replace collagen, tissue engineering, and
regenerative substances, (2) risk of infection does not arise
because PuraMatrix is a fully synthetic solution, (3) PuraMatrix is a transparent aqueous solution that rapidly forms
into hydrogel in the body at physiologic pH, and (4) PuraMatrix is an aqueous solution easily applied through a catheter from a prelled syringe.
This study has some limitations: it is a single-center
study with a relatively small number of patients, and the
protocol was not randomized. In addition, in this study,
we used a standard catheter but we have been developing
a special delivery catheter and expect to achieve more
effective results by better application of PuraMatrix using
this novel catheter.
In conclusion, the use of this novel, fully synthetic, and
self-assembled peptide solution may potentially help
reduce the rate of post-ESD bleeding and promote healing of ESD-induced gastric ulcers. Further studies, particularly randomized controlled studies, are needed to fully
evaluate its efcacy. Therefore, a multicenter, randomized
controlled trial should be considered to fully evaluate the
efcacy of this novel peptide solution.
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A novel peptide solution after ESD

ACKNOWLEDGMENT
We express our appreciation to Dr Hemchand Ramberan
for the revision of this manuscript.

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