High-density collagen patch prevents stricture after endoscopic circumferential submucosal dissection of the esophagus: a porcine model

doi:10.1016/j.gie.2016.10.012

Gastrointestinal Endoscopy

Volume 85, Issue 5, May 2017, Pages 1076-1085

https://doi.org/10.1016/j.gie.2016.10.012 Get rights and content

Background and Aims

Extensive excision of the esophageal mucosa by endoscopic submucosal dissection (ESD) frequently evokes a luminal stricture. This study aimed to determine the efficacy of a high-density collagen patch for the prevention of esophageal stricture in extensive ESD.

Methods

Six pigs underwent circumferential esophageal ESD under general anesthesia. In 3 pigs, artificial ulcers were covered by 2 collagen patches. The other 3 pigs underwent circumferential ESD only.

Results

The 2 collagen patches were settled onto the ulcer surface using a general endoscope and instruments. The collagen patch-treated group showed significantly better patency rates on both the oral and anal sides of the wound area compared with the control group at day 14. The mucosal re-epithelization ratio was significantly promoted, and the extent of mucosal inflammation and fibrosis was significantly decreased with the collagen patch treatment in the wound area. The frequency of cells positive α-smooth muscle actin was significantly reduced in the collagen patch-treated group compared with the control group.

Conclusions

We have established a high-density collagen device that can reduce the esophageal stricture associated with extensive ESD. This easy-to-handle device would be useful during superficial esophageal cancer treatment by ESD.

Section snippets

Methods

All experimental procedures were approved by the Institutional Animal Ethics Committee of IVTec (Kobe, Japan) and Saga University. Six 24-week-old female pigs weighing 30.3 to 38.6 kg (LWD pigs; Aratoyama SPF Farm, Okayama, Japan) were used. The pigs were regarded as healthy based on daily visual inspections during an acclimatization period of 7 days. The pigs were fed a commercial semisolid swine feed (MP-A; Oriental Yeast, Tokyo, Japan) and housed in groups during the acclimatization period.

CVP prevents stricture after esophageal circumferential ESD

Circumferential ESD was performed safely in both the CVP-treated (n = 3) and control (n = 3) groups. The weight gain ratios from before surgery to postoperative day 14 did not differ between the CVP-treated and control groups (1.028 ± 0.032 vs 0.977 ± 0.029, P = .444) (Table 1). Two pigs in the control group showed increased leftovers of semisolid MP-A after day 4 and developed vomiting after day 9. In contrast, 2 pigs in the CVP group developed transient vomiting after day 12. These 2 pigs had

Discussion

In the present study, we devised an easy-to-use collagen device for reducing stricture after extensive esophageal ESD. In addition, we demonstrated that the device was capable of promoting epithelization of the wound area and inhibiting inflammation in a porcine model.

We accept that our study may have some limitations. First, the study was carried out with an animal (porcine) model, and the evaluations were performed on a small number of animals. Second, we did not evaluate the long-term data

Acknowledgments

We thank T. Sakumoto, S. Morito, M. Nishida, F. Mutoh, S. Nakahara, Y. Tateishi, and I. Nanbu for excellent technical assistance. We are grateful to Dr. T. Akutagawa for discussions and Mr. K. Tokaichi for refining the English in the manuscript. This work was supported in part by the Center for Clinical and Translational Research of Kyushu University Hospital (to S.A.), and a Grant-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology for Scientific Research

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A novel tetra-PEG based hydrogel for prevention of esophageal stricture after ESD in a porcine model
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Endoscopic submucosal dissection (ESD) is an accepted treatment for early esophageal cancer and precancerous lesions, but resection of a large mucosal area often leads to postoperative esophageal stricture. Biomaterials provide a new option for the treatment of post-ESD ulcers. In this study, we developed a well-defined ammonolysis-based tetra-armed poly (ethylene glycol) (Tetra-PEG) hydrogel and investigated its efficacy and related mechanisms for preventing esophageal ESD-induced stricture in a porcine model. In terms of material properties, Tetra-PEG hydrogel present great biocompatibility，great capability to retain moisture, strong tissue adhesion and high mechanical strength. Then, six domestic female pigs were randomly divided into PEG (n = 3) and control groups (n = 3). A 3/4 of the esophageal circumference ESD was performed in all pigs. In PEG group, Tetra-PEG hydrogel was easily delivered via endoscopy and adhered to the ulcer bed tightly. Compared to control group, Tetra-PEG hydrogel accelerated esophageal ulcer healing at an early stage with enhanced epithelium regeneration, milder inflammation and lesser fibrosis by regulating TGF-β/Smad2 signaling. Taken together, our findings reveal Tetra-PEG hydrogel is a promising and attractive candidate for preventing the formation of fibrotic stricture in the process of esophageal ESD-induced ulcer repair.
Progress of esophageal stricture prevention after endoscopic submucosal dissection by regenerative medicine and tissue engineering
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Citation Excerpt :
Aoki et al. performed circumferential esophageal mucosa dissection on six pigs and treated the wounds in the treatment group with high-density collagen patches. Compared to the control group, the treatment group had a significantly higher patency rate on both the traumatic oral and anal sides at day 14 and a significantly higher rate of mucosal reepithelialization [97]. Similar results were also observed in Mizushima et al.’s study, who found that mesenchymal stem cell CM can prevent the formation of stricture after submucosal dissection of esophagus in pigs [98].
Endoscopic submucosal dissection (ESD) has been widely accepted as an effective treatment for early esophageal cancer. However, post-ESD esophageal stricture remains a thorny issue. We herein review many strategies for preventing post-ESD esophageal stricture, as well as discuss their strengths and weaknesses. These strategies include pharmacological prophylaxis, esophageal stent and tissue engineering and regenerative medicine treatment. In this review, we summarize these studies and discuss the underlying progress and future directions of tissue engineering and regenerative medicine treatment.
Esophageal regenerative therapy using cell sheet technology
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Citation Excerpt :
This is a very interesting method and we expect further reports in the future. Other studies using animal models, amniotic membrane grafts [84], high-density collagen patch [85], autologous flap [86], and carboxymethyl cellulose (CMC) sheets [87], were also published previously. Lua et al. [88] reported the use of CMC sheets in seven patients in a randomized controlled study, in which the incidence rate of post-ESD stricture was 57% (4/7 patients).
We have been conducting research on esophageal regenerative therapy using cell sheet technology. In particular, in the endoscopic field, we have pushed forward clinical research on endoscopic transplantation of cultured autologous oral mucosal epithelial cell sheets to esophageal ulcer after endoscopic submucosal dissection (ESD). We started research in this direction using animal models in 2004 and performed clinical research in 2012 in collaboration with Nagasaki University and Karolinska Institute. Although in full-circumferential cases it was difficult to prevent esophageal stricture after ESD, there were no complications and stricture could be suppressed. The cell sheet technology is still in its infancy. However, we are convinced that it has a high potential for application in various areas of gastrointestinal science. In this review, we focus on the pre-clinical and clinical trial results obtained and on the theoretical aspects of (1) stricture prevention, (2) esophageal tissue engineering research, and (3) endoscopic transplantation, and review the esophageal regenerative therapy by cell sheet technology.
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As an alternative to fabricated cell sheets, commercially available dermal matrices (ECMs) can be effective in preventing post-ESD strictures.40,41 Recently, a collagen-based synthetic biomaterial placed at the ESD site in pigs induced mucosal re-epithelization with less fibrosis compared with controls.42 Although approaches not based on scaffolds, like applying autologous pluripotent cells to the site of injury or using tissue-engineered autologous cell sheets, as described earlier, have shown promising results, the majority of these studies have been on a small number of animals with very short survival follow-up.
Acellular dermal matrix for esophageal stricture prevention after endoscopic submucosal dissection in a porcine model
2017, Gastrointestinal Endoscopy
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The animals had to be killed because they were unable to feed.30,31 The time was too short to investigate the healing process.32 In our study a semicircumferential ulcer was made to prolong the observation time.
Endoscopic submucosal dissection (ESD) is considered an effective treatment for early esophageal cancer and precancerous lesions. Esophageal stenosis is closely associated with quasi-circumferential ESD. We examined whether post-ESD esophageal stricture can be prevented by grafting an acellular dermal matrix (ADM) membrane.
Fourteen Bama miniature pigs were randomly divided into an ADM group (n = 7) and a control group (n = 7). Semicircumferential ESD was performed at the distal esophagus in all animals, and in the ADM group an ADM patch graft was placed at the resection site and secured innovatively with metal clips. Animals in the control group underwent ESD only. Endoscopy was performed at 3 days, 1 week, 2 weeks, and 4 weeks post-ESD, and fluoroscopy was performed at 4 weeks for assessment of the degree of stenosis, after which the remodeled esophageal tissues were excised for histologic analysis.
No animals in the ADM group developed clinically significant esophageal stenosis, whereas 42.8% (3/7) in the control group did. The degree of stenosis was severe in the control group (39.8% vs 17.2%, respectively; P = .01). Animals in the ADM group had less feeding difficulty and lost less weight (−.9 kg vs −4.1 kg, respectively; P = .007). Histologically, complete mucosal epithelium, slight local inflammation, and organized collagenous fibers were observed in the ADM group.
ADM patch graft appears, after short-term observation, to be a potentially useful new treatment strategy for prevention of esophageal stricture after ESD. A metal clip fixation technique is effective for endoscopic graft attachment.

View all citing articles on Scopus

: DISCLOSURE: All authors disclosed no financial relationships relevant to this publication.

^∗: Drs Aoki and Sakata contributed equally to this article.

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Original articleExperimental endoscopyHigh-density collagen patch prevents stricture after endoscopic circumferential submucosal dissection of the esophagus: a porcine model

Background and Aims

Methods

Results

Conclusions

Section snippets

Methods

CVP prevents stricture after esophageal circumferential ESD

Discussion

Acknowledgments

Clin Gastroenterol Hepatol

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc Clin N Am

Gastroenterology

Lancet

Gastrointest Endosc

Endoscopic mucosal resection for treatment of early gastric cancer

Gut

Endoscopic submucosal dissection for esophageal squamous cell neoplasms

Dig Endosc

Preventing esophageal stricture after endoscopic submucosal dissection: steroid injection and shielding with polyglycolic acid sheets and fibrin glue

Endoscopy

Collagen vitrigel: a novel scaffold that can facilitate a three-dimensional culture for reconstructing organoids

Cell Transplant

A protein-permeable scaffold of a collagen vitrigel membrane useful for reconstructing crosstalk models between two different cell types

Cells Tissues Organs

A novel material of high density collagen fibrils: a collagen xerogel membrane and its application to transplantation in vivo and a culture chamber in vitro. 24th European Conference on Biomaterials, Dublin, Ireland

A new cell-free bandage-type artificial skin for cutaneous wounds

Wound Repair Regen

Histology for pathologists

Original article
Experimental endoscopy
High-density collagen patch prevents stricture after endoscopic circumferential submucosal dissection of the esophagus: a porcine model