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Guo JY, Dong XY, Li S, Tang JF, Zhou CF. Chinese patent medicine: Opening new perspectives for treatment of post-endoscopic submucosal dissection esophageal stricture in esophageal cancer patients. World J Gastroenterol 2025; 31:102943. [PMID: 40248381 PMCID: PMC12001194 DOI: 10.3748/wjg.v31.i14.102943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 02/28/2025] [Accepted: 03/10/2025] [Indexed: 04/11/2025] Open
Abstract
Endoscopic submucosal dissection (ESD) is an effective technique for treating early esophageal cancer, and the prevention of postoperative esophageal stricture has emerged as a significant research topic. Zhou et al utilized an experimental minipig model to demonstrate that Kangfuxin (KFX) can improve postoperative esophageal stricture following ESD by inhibiting transforming growth factor-β1-driven fibrosis and the downstream fibrotic mediators Smad2/3. In this letter, we primarily discuss recent advancements in the treatment of esophageal stricture, the clinical applications of KFX, and the mechanisms involved in alleviating postoperative esophageal stricture, aiming to provide insights for advancing clinical practice and research in esophageal stricture after ESD.
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Affiliation(s)
- Jie-Yu Guo
- School of Life and Health Sciences, Institute of Biomedical Research, Wuhan 430068, Hubei Province, China
| | - Xue-Ying Dong
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, School of Life and Health Sciences, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, Hubei Province, China
| | - Shi Li
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, School of Life and Health Sciences, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, Hubei Province, China
| | - Jing-Feng Tang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, School of Life and Health Sciences, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, Hubei Province, China
| | - Ce-Fan Zhou
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, School of Life and Health Sciences, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, Hubei Province, China
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Liu J, Jiang Y, Chen X, Wei X, Wang X, Yang Z, Yang J, Zhang J, Peng Y, Lin C, Chen Q, Yu G, Chen Y, Wei Q, Zheng X, Zheng S. Adipose stem cells prevent esophageal strictures after extensive endoscopic submucosal dissection - experimental research. Int J Surg 2025; 111:1836-1846. [PMID: 39693486 DOI: 10.1097/js9.0000000000002148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 11/06/2024] [Indexed: 12/20/2024]
Abstract
BACKGROUND AND AIMS Endoscopic submucosal dissection (ESD) is a pivotal technique for excision of early-stage esophageal tumors. However, its primary complication, postoperative esophageal stricture, is a significant challenge owing to the absence of effective preventive measures. Adipose-derived stem cells (ADSCs) have emerged as a promising treatment modality to address this concern. In this study, we aimed to investigate, for the first time, the efficacy of allogenic ADSC injections in preventing esophageal stenosis after ESD. METHODS We administered allogeneic ADSC injections (same-species but different individual) to a porcine model of ESD as a way to observe the role of ADSC in preventing esophageal stricture. We also co-cultured rats' ADSCs with rats' esophageal fibroblasts and esophageal mucosal epithelial cells to investigate the mechanism. RESULTS ADSCs notably facilitated epithelial-mesenchymal transition of epithelial cells. Furthermore, ADSC-conditioned medium exhibited a substantial inhibitory effect on fibroblast proliferation and migration, which was mediated by the transforming growth factor-beta pathway. CONCLUSIONS Our findings underscore the potential of ADSC injections as a promising therapeutic intervention to enhance recovery and prevent post-ESD complications.
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Affiliation(s)
- Jie Liu
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Yuting Jiang
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Xianzeng Chen
- Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Anesthesiology, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Xujin Wei
- The Graduate School of Fujian Medical University, Fuzhou, China
| | - Xiangyu Wang
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Zeliang Yang
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Jie Yang
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Jianhui Zhang
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Yunyi Peng
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Caihao Lin
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Qilin Chen
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Genmiao Yu
- Department of Plastic Surgery and Burns, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Plastic Surgery and Burns, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Yangyang Chen
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Qingqing Wei
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Xiaoling Zheng
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Endoscopy, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Shengwu Zheng
- Department of Plastic Surgery and Burns, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Plastic Surgery and Burns, Fujian Provincial Hospital, Fuzhou, Fujian, China
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Yano H, Sasaki F, Maeda H, Uehara S, Kabayama M, Fujino Y, Tanaka A, Hinokuchi M, Arima S, Hashimoto S, Kanmura S, Ito S, Nishiguchi A, Taguchi T, Ido A. Effect of sprayable, highly adhesive hydrophobized gelatin microparticles on esophageal stenosis after endoscopic submucosal dissection: an experimental study in a swine model. Esophagus 2025; 22:95-104. [PMID: 39404963 PMCID: PMC11717788 DOI: 10.1007/s10388-024-01090-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 09/16/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND Esophageal mucosal resection for superficial esophageal cancer can lead to postoperative esophageal stricture, with current preventive measures being insufficient. Sprayable wound dressings containing hydrophobized microparticles exhibit strong adhesion. This study aimed to investigate the preventive effects of hydrophobized microparticles on esophageal stenosis following endoscopic submucosal dissection. METHODS Circumferential esophageal endoscopic submucosal dissection was performed on miniature swine (n = 6). Swine were categorized into two groups: those sprayed with hydrophobized microparticles (sprayed group) and those not sprayed (non-sprayed group). Hydrophobized microparticles were sprayed onto the sprayed group on Days 0, 3, and 7 of endoscopic submucosal dissection. The non-sprayed group underwent endoscopy on the same days. Esophageal stricture rate, submucosal inflammatory cell infiltration, submucosal fibrosis, and thickening of the muscular layer were compared between the groups on Day 14 of endoscopic submucosal dissection. RESULTS Spraying of hydrophobized microparticles was easily performed using an existing endoscopic spraying device. The esophageal stricture rate was significantly lower in the sprayed group than in the non-sprayed group (76.1% versus 90.6%, p < 0.05). The sprayed group showed suppression of inflammatory cell infiltration in the submucosal layer (p < 0.01) and thickening of the muscular layer (p < 0.01). CONCLUSIONS Sprayable tissue-adhesive hydrophobized microparticles reduce the stricture rate after esophageal ESD by inhibiting inflammatory cell infiltration, submucosal fibrosis, and thickening of the muscular layer. The use of hydrophobized microparticles for preventing post-endoscopic submucosal dissection esophageal stenosis offers a promising avenue for clinical applications in endoscopic procedures, potentially improving patient outcomes.
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Affiliation(s)
- Hiroki Yano
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Fumisato Sasaki
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.
| | - Hidehito Maeda
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Shohei Uehara
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Masayuki Kabayama
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Yusuke Fujino
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Akihito Tanaka
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Makoto Hinokuchi
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Shiho Arima
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Shinichi Hashimoto
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Shuji Kanmura
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Shima Ito
- Research Center for Macromolecules and Biomaterials, National Institute for Materials Science, Tsukuba, Japan
- Graduate School of Science and Technology, Degree Programs in Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan
| | - Akihiro Nishiguchi
- Research Center for Macromolecules and Biomaterials, National Institute for Materials Science, Tsukuba, Japan
| | - Tetsushi Taguchi
- Research Center for Macromolecules and Biomaterials, National Institute for Materials Science, Tsukuba, Japan
- Graduate School of Science and Technology, Degree Programs in Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
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Uehara K, Oshiro E, Ochiai A, Takagi R, Yamato M, Kato A. Lessons learned from contamination with endotoxin originated from the supplement in the cell culture medium. Regen Ther 2024; 27:230-233. [PMID: 38596824 PMCID: PMC11002528 DOI: 10.1016/j.reth.2024.03.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/13/2024] [Accepted: 03/20/2024] [Indexed: 04/11/2024] Open
Abstract
Introduction Endotoxin is a typical pyrogen derived from the outer membrane of Gram-negative bacteria. In fabricating cell-based medicinal products, it is necessary to control endotoxin in the process and the products. In the quality control tests of our clinical study, endotoxin concentration in the culture supernatant of autologous oral mucosal epithelial cell sheets exceeded the criterion value. Therefore, endotoxin measurements were conducted to clarify the cause of the endotoxin contamination. Methods The reagents used to prepare the culture medium, the unused culture medium, and the culture supernatants were diluted with pure water. Endotoxin concentrations in the diluted samples were measured. Results Endotoxin was detected in both the unused culture medium and the culture supernatant of the epithelial cell sheets at higher concentrations than the criterion value. Therefore, endotoxin concentrations in the reagents used to prepare the culture medium were measured and were found to be below the criterion value, except for cholera toxin. On the other hand, three lots of cholera toxin products were used for the measurement, and the endotoxin concentrations were higher than the criterion value. The results indicate that the endotoxin contamination is caused by the cholera toxin product. Conclusions To prevent endotoxin contamination in cell-based medicinal products, endotoxin concentrations in reagents used for the fabrication should be measured in the facility conducting clinical research or confirmed by an adequate certificate of analysis from the manufacturers of the reagents.
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Affiliation(s)
- Koaki Uehara
- Social Medical Corporation Yuuaikai, Yuuai Medical Center, Advanced Medical Research Center, 50-5, Yone, Tomigusuku-shi, Okinawa 901-0224, Japan
| | - Eriko Oshiro
- Social Medical Corporation Yuuaikai, Yuuai Medical Center, Advanced Medical Research Center, 50-5, Yone, Tomigusuku-shi, Okinawa 901-0224, Japan
| | - Atsushi Ochiai
- Social Medical Corporation Yuuaikai, Yuuai Medical Center, Advanced Medical Research Center, 50-5, Yone, Tomigusuku-shi, Okinawa 901-0224, Japan
| | - Ryo Takagi
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Atsunaga Kato
- Social Medical Corporation Yuuaikai, Yuuai Medical Center, Advanced Medical Research Center, 50-5, Yone, Tomigusuku-shi, Okinawa 901-0224, Japan
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Ye S, Hu J, Zhang D, Zhao S, Shi X, Li W, Wang J, Guan W, Yan L. Strategies for Preventing Esophageal Stenosis After Endoscopic Submucosal Dissection and Progress in Stem Cell-Based Therapies. TISSUE ENGINEERING. PART B, REVIEWS 2024; 30:522-529. [PMID: 38243787 DOI: 10.1089/ten.teb.2023.0316] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2024]
Abstract
Endoscopic submucosal dissection (ESD) has been widely used in the early neoplasia of the esophagus. However, postoperative esophageal stenosis is a big problem, particularly when a large circumferential proportion of esophageal mucosa is resected. Currently, there are several methods available to prevent esophageal stenosis after ESD, including steroid administration, esophageal stent implantation, and endoscopic balloon dilation (EBD). However, the therapeutic effects of these are not yet satisfactory. Stem cell-based therapies has shown promising potential in reconstructing tissue structure and restoring tissue function. In this study, we discussed the current strategies for preventing esophageal stenosis after ESD and perspectives of stem cell-based therapies for the prevention of esophageal stenosis.
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Affiliation(s)
- Shujun Ye
- Department of Geriatric Gastroenterology, the Second Medical Center and National Clinical Research Center of Geriatric Diseases, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Jingjing Hu
- Department of Geriatric Gastroenterology, the Second Medical Center and National Clinical Research Center of Geriatric Diseases, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Daxu Zhang
- Department of Geriatric Gastroenterology, the Second Medical Center and National Clinical Research Center of Geriatric Diseases, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Shuo Zhao
- Department of Geriatric Gastroenterology, the Second Medical Center and National Clinical Research Center of Geriatric Diseases, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Xiaonan Shi
- Department of Geriatric Gastroenterology, the Second Medical Center and National Clinical Research Center of Geriatric Diseases, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Weilong Li
- Department of Geriatric Gastroenterology, the Second Medical Center and National Clinical Research Center of Geriatric Diseases, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Jingyi Wang
- Department of Geriatric Gastroenterology, the Second Medical Center and National Clinical Research Center of Geriatric Diseases, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Weiping Guan
- Department of Geriatric Neurology, the Second Medical Center and National Clinical Research Center of Geriatric Diseases, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Li Yan
- Department of Geriatric Gastroenterology, the Second Medical Center and National Clinical Research Center of Geriatric Diseases, Chinese PLA General Hospital, Beijing, People's Republic of China
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Xu N, Li L, Zou J, Yue W, Wang P, Chai M, Li L, Zhang L, Li X, Cheng Y, Wang Z, Wang X, Wang R, Xiang J, Linghu E, Chai N. PRP improves the outcomes of autologous skin graft transplantation on the esophagus by promoting angiogenesis and inhibiting fibrosis and inflammation. J Transl Int Med 2024; 12:384-394. [PMID: 39360159 PMCID: PMC11444473 DOI: 10.2478/jtim-2023-0126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Autologous skin graft (ASG) transplantation is a challenging approach but a promising option for patients to prevent postoperative esophageal stricture. Nonetheless, the current strategies require improvement. We aimed to investigate the effectiveness of the injection of platelet-rich plasma (PRP) before skin graft transplantation for extensive esophageal defects after endoscopic resection. METHODS Standardized complete circular endoscopic resection (5 cm in length) was performed in 27 pigs allocated into 3 groups. The artificial ulcers were treated with a fully covered esophageal stent (control group), ASG (ASG group), and submucosal injection of PRP with ASG (PRP-ASG group). Macroscopic evaluation and histological analysis of the remolded esophagus were performed 7, 14, and 28 days after surgery. RESULTS The macroscopic evaluation indicated that submucosal injection of PRP before transplantation effectively promoted the survival rate of skin grafts and decreased the rate of mucosal contraction compared with those treated with ASG or stent alone. Histological analysis of submucosal tissue showed that this modified strategy significantly promoted wound healing of reconstructed tissues by enhancing angiogenesis, facilitating collagen deposition, and decreasing inflammation and fibrogenesis. CONCLUSIONS These findings suggested that PRP might be used as a biological supplement to increase the esophageal skin graft survival rate and improve submucosal tissue remolding in a clinically relevant porcine model. With extremely low mucosal contraction, this novel combination strategy showed the potential to effectively prevent stenosis in extensive esophageal ulcers.
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Affiliation(s)
- Ning Xu
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Longsong Li
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Jiale Zou
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Wenyi Yue
- Department of Radiology, Chinese PLA General Medical School, Beijing100853, Beijing, China
| | - Pengju Wang
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Mi Chai
- Department of Plastic Surgery, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Li Li
- Department of Plastic Surgery, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Lihua Zhang
- Department of Pathology, The Fourth Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Xiao Li
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Yaxuan Cheng
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Zixin Wang
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Xueting Wang
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Runzi Wang
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Jingyuan Xiang
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Enqiang Linghu
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
| | - Ningli Chai
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing100853, Beijing, China
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Yang F, Hu Y, Shi Z, Liu M, Hu K, Ye G, Pang Q, Hou R, Tang K, Zhu Y. The occurrence and development mechanisms of esophageal stricture: state of the art review. J Transl Med 2024; 22:123. [PMID: 38297325 PMCID: PMC10832115 DOI: 10.1186/s12967-024-04932-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 01/26/2024] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Esophageal strictures significantly impair patient quality of life and present a therapeutic challenge, particularly due to the high recurrence post-ESD/EMR. Current treatments manage symptoms rather than addressing the disease's etiology. This review concentrates on the mechanisms of esophageal stricture formation and recurrence, seeking to highlight areas for potential therapeutic intervention. METHODS A literature search was conducted through PUBMED using search terms: esophageal stricture, mucosal resection, submucosal dissection. Relevant articles were identified through manual review with reference lists reviewed for additional articles. RESULTS Preclinical studies and data from animal studies suggest that the mechanisms that may lead to esophageal stricture include overdifferentiation of fibroblasts, inflammatory response that is not healed in time, impaired epithelial barrier function, and multimethod factors leading to it. Dysfunction of the epithelial barrier may be the initiating mechanism for esophageal stricture. Achieving perfect in-epithelialization by tissue-engineered fabrication of cell patches has been shown to be effective in the treatment and prevention of esophageal strictures. CONCLUSION The development of esophageal stricture involves three stages: structural damage to the esophageal epithelial barrier (EEB), chronic inflammation, and severe fibrosis, in which dysfunction or damage to the EEB is the initiating mechanism leading to esophageal stricture. Re-epithelialization is essential for the treatment and prevention of esophageal stricture. This information will help clinicians or scientists to develop effective techniques to treat esophageal stricture in the future.
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Affiliation(s)
- Fang Yang
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
| | - Yiwei Hu
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
| | - Zewen Shi
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
- Ningbo No.2 Hospital, Ningbo, 315001, People's Republic of China
| | - Mujie Liu
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
| | - Kefeng Hu
- The First Affiliated Hospital of Ningbo University, Ningbo, 315000, People's Republic of China
| | - Guoliang Ye
- The First Affiliated Hospital of Ningbo University, Ningbo, 315000, People's Republic of China
| | - Qian Pang
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
| | - Ruixia Hou
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China
| | - Keqi Tang
- Institute of Mass Spectrometry, School of Material Science and Chemical Engineering, Ningbo University, Ningbo, 315211, People's Republic of China.
| | - Yabin Zhu
- Health Science Center, Ningbo University, Ningbo, 315211, People's Republic of China.
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Nishimura Y, Ono M, Okubo N, Sone T, Higashino M, Matsumoto S, Kubo M, Yamamoto K, Ono S, Ohnishi S, Sakamoto N. Application of polyglycolic acid sheets and basic fibroblast growth factor to prevent esophageal stricture after endoscopic submucosal dissection in pigs. J Gastroenterol 2023; 58:1094-1104. [PMID: 37635203 PMCID: PMC10590298 DOI: 10.1007/s00535-023-02032-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/05/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND Endoscopic submucosal dissection (ESD) has been the first-line treatment for early-stage esophageal cancer. However, it often causes postoperative stricture in cases requiring wide dissection. Basic fibroblast growth factor (bFGF) reportedly has anti-scarring effects during cutaneous wound healing. We hypothesized that suppressing myofibroblast activation will prevent stricture after esophageal ESD. METHODS We resected a complete porcine esophagus circumference section by ESD. To investigate the preventive effect of bFGF on esophageal stricture formation after ESD, we endoscopically applied bFGF-soaked poly-glycolic acid (PGA) sheets onto the wound bed after ESD and fixed them by spraying fibrin glue (PGA + bFGF group), PGA sheets alone onto the wound bed and fixed them by spraying fibrin glue (PGA group), or nothing (control group). After removing the esophagus on day 22, we evaluated the mucosal constriction rate. RESULTS Compared with those in the control group, esophageal stricture was significantly reduced in the PGA + bFGF group, and the areas stained with α-SMA and calponin-1 antibodies were significantly inhibited in the PGA + bFGF and PGA groups. The thickness of the fibrous layer in the PGA + bFGF group was uniform compared to that of the other groups. Thus, PGA + bFGF inhibited the development of unregulated fibroblasts in the acute phase, leading to uniform wound healing. CONCLUSIONS Stenosis after esophageal ESD is related to fibrosis in the acute phase. Administration of PGA and bFGF suppresses myofibroblast activation in the acute phase, thereby preventing esophageal constriction in pigs.
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Affiliation(s)
- Yusuke Nishimura
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-14-Jo Nishi-5-Chome Kita-Ku Sapporo, Hokkaido, 060-8648, Japan
| | - Masayoshi Ono
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-14-Jo Nishi-5-Chome Kita-Ku Sapporo, Hokkaido, 060-8648, Japan.
| | - Naoto Okubo
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Takayuki Sone
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-14-Jo Nishi-5-Chome Kita-Ku Sapporo, Hokkaido, 060-8648, Japan
| | - Masayuki Higashino
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-14-Jo Nishi-5-Chome Kita-Ku Sapporo, Hokkaido, 060-8648, Japan
| | - Shogo Matsumoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-14-Jo Nishi-5-Chome Kita-Ku Sapporo, Hokkaido, 060-8648, Japan
| | - Marina Kubo
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-14-Jo Nishi-5-Chome Kita-Ku Sapporo, Hokkaido, 060-8648, Japan
| | - Keiko Yamamoto
- Division of Endoscopy, Hokkaido University Hospital, Sapporo, Japan
| | - Shoko Ono
- Division of Endoscopy, Hokkaido University Hospital, Sapporo, Japan
| | - Shunsuke Ohnishi
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-14-Jo Nishi-5-Chome Kita-Ku Sapporo, Hokkaido, 060-8648, Japan
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Pan Q, Tsuji Y, Sreedevi Madhavikutty A, Ohta S, Fujisawa A, Inagaki NF, Fujishiro M, Ito T. Prevention of esophageal stenosis via in situ cross-linkable alginate/gelatin powder in a new submucosal exfoliation model in rats. Biomater Sci 2023; 11:6781-6789. [PMID: 37614197 DOI: 10.1039/d3bm00887h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Endoscopic submucosal dissection (ESD) for the treatment of esophageal mucosal lesions often leads to postoperative stenosis, causing difficulty in swallowing, known as dysphagia. In this study, we developed an in situ cross-linkable powder composed of alginate, gelatin, transglutaminase (TG), and calcium chloride ions (Ca2+), which can be administered through a 1.5 m-long and 3.2 mm-diameter endoscopic instrument channel. The powdered mixture of alginate and gelatin quickly formed a hydrogel by absorbing body fluids and was cross-linked by TG and Ca2+, which adhered ex vivo to porcine submucosal layers for over 2 weeks. In addition, we developed a new submucosal exfoliation model in rats that induced severe stenosis, similar to the ESD-induced stenosis models in clinical practice. When administered to the new rat model, the powder system effectively reduced the severity of esophageal stenosis based on body weight change monitoring, anatomical findings, and histological analysis. The body weight of the rats was maintained at the initial weight on postoperative day 14 (POD14), and epithelialization on POD7 and 14 improved to almost 100%. Additionally, collagen accumulation and the number of α-SMA-positive cells decreased due to powder administration. Therefore, these findings indicate that the in situ cross-linkable powder can prevent esophageal stenosis after ESD.
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Affiliation(s)
- Qi Pan
- Center for Disease Biology and Integrative Medicine, School of Medicine, the University of Tokyo, Japan.
| | - Yosuke Tsuji
- Department of Gastroenterology, School of Medicine, the University of Tokyo, Japan
| | | | - Seiichi Ohta
- Center for Disease Biology and Integrative Medicine, School of Medicine, the University of Tokyo, Japan.
- Institute of Engineering Innovation, School of Engineering, the University of Tokyo, Japan
- Department of Bioengineering, School of Engineering, the University of Tokyo, Japan
| | - Ayano Fujisawa
- Department of Bioengineering, School of Engineering, the University of Tokyo, Japan
| | - Natsuko F Inagaki
- Center for Disease Biology and Integrative Medicine, School of Medicine, the University of Tokyo, Japan.
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, School of Medicine, the University of Tokyo, Japan
| | - Taichi Ito
- Center for Disease Biology and Integrative Medicine, School of Medicine, the University of Tokyo, Japan.
- Department of Chemical System Engineering, School of Engineering, the University of Tokyo, Japan
- Department of Bioengineering, School of Engineering, the University of Tokyo, Japan
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10
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Geng ZH, Zhu Y, Li QL, Fu PY, Xiang AY, Pan HT, Xu MD, Chen SY, Zhong YS, Zhang YQ, Ma LL, Hu JW, Cai MY, Qin WZ, Chen WF, Zhou PH. Muscular injury as an independent risk factor for esophageal stenosis after endoscopic submucosal dissection of esophageal squamous cell cancer. Gastrointest Endosc 2023; 98:534-542.e7. [PMID: 37207844 DOI: 10.1016/j.gie.2023.05.046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 05/01/2023] [Accepted: 05/04/2023] [Indexed: 05/21/2023]
Abstract
BACKGROUND AND AIMS Stenosis after esophageal endoscopic submucosal dissection (ESD) has a high incidence, and muscular injury is an important risk factor for esophageal stenosis. Hence, this study aimed to classify muscular injury degrees and investigate their association with postoperative stenosis. METHODS This retrospective study included 1033 patients with esophageal mucosal lesions treated with ESD between August 2015 and March 2021. Demographic and clinical parameters were analyzed, and stenosis risk factors were identified using multivariate logistic regression. A novel muscular injury classification system was proposed and used to investigate the association between different muscular injury degrees and postoperative stenosis. Finally, a scoring system was established to predict muscular injury. RESULTS Of 1033 patients, 118 (11.4%) had esophageal stenosis. The multivariate analysis demonstrated that the history of endoscopic esophageal treatment, circumferential range, and muscular injury were significant risk factors for esophageal stenosis. Patients with type II muscular injuries tended to develop complex stenosis (n = 13 [36.1%], P < .05), and type II muscular injuries were more likely to predispose patients to severe stenosis than type I (73.3% and 92.3%, respectively). The scoring system showed that patients with high scores (3-6) were more likely to have muscular injury. The score model presented good discriminatory power in the internal validation (area under the receiver-operating characteristic curve, .706; 95% confidence interval, .645-.767) and goodness-of-fit in the Hosmer-Lemeshow test (P = .865). CONCLUSIONS Muscular injury was an independent risk factor for esophageal stenosis. The scoring system demonstrated good performance in predicting muscular injury during ESD.
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Affiliation(s)
- Zi-Han Geng
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Yan Zhu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Quan-Lin Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Pei-Yao Fu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - An-Yi Xiang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Hai-Ting Pan
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Mei-Dong Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Shi-Yao Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Yun-Shi Zhong
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Yi-Qun Zhang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Li-Li Ma
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Jian-Wei Hu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Ming-Yan Cai
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Wen-Zheng Qin
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Wei-Feng Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Ping-Hong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
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11
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Wu R, Fu M, Tao HM, Dong T, Fan WT, Zhao LL, Fan ZN, Liu L. Benign esophageal stricture model construction and mechanism exploration. Sci Rep 2023; 13:11769. [PMID: 37474710 PMCID: PMC10359281 DOI: 10.1038/s41598-023-38575-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/11/2023] [Indexed: 07/22/2023] Open
Abstract
Esophageal stricture is a debilitating condition that negatively impacts patients' quality of life after undergoing endoscopic mucosal resection (EMR). Despite its significance, this disease remains underexplored due to the lack of a stable animal model. Under direct visualization with choledochoscopy, we retrogradely damaged the esophageal mucosal layer through the gastrostomy to create a rat model of esophageal stricture. The development of histological defects in the mucosal layer was assessed over a 2-week period after model induction. Then the models were evaluated using X-ray barium radiography, Hematoxylin-Eosin, Masson's trichrome, Sirius red, and Victoria blue staining, multiphoton microscopic imaging. Additionally, the molecular mechanisms of esophageal stricture were explored by conducting RNA transcriptome sequencing, PCR, immunohistochemistry, and immunofluorescence staining. We successfully established fifteen rat models of esophageal stricture by injuring the mucosal layer. In the model group, the mucosal defect initially occurs and subsequently repaired. The epithelium was absent and was plastically remodeled by collagen during the acute inflammatory phase (Day 1), proliferation phase (Day 7), anaphase of proliferation (Day 10), and plastic remodeling phase (Day 14). We observed increased expression of COL1A1, acta2, FGF, IL-1, and TGF-β1 pathway in the model group. We established a highly repeatable rat model of esophageal stricture, and our results suggest that the mucosal defect of the esophagus is a critical factor in esophageal stricture development, rather than damage to the muscularis layer. We identified Atp4b, cyp1a2, and gstk1 as potential targets for treating esophageal stricture, while the TGF-β pathway was found to play an important role in its development.
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Affiliation(s)
- Rui Wu
- Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, Jiangsu, China
- Department of Gastroenterology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210031, Jiangsu, China
- Department of Critical Care Medicine, Jinling Hospital of Nanjing Medical University, Nanjing, 210010, Jiangsu, China
| | - Min Fu
- Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Hui-Min Tao
- Department of Gynecology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Tao Dong
- Digestive Endoscopy Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210004, Jiangsu, China
| | - Wen-Tao Fan
- Department of Gastroenterology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210031, Jiangsu, China
| | - Li-Li Zhao
- Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
| | - Zhi-Ning Fan
- Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
- Department of Gastroenterology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210031, Jiangsu, China.
| | - Li Liu
- Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
- Department of Gastroenterology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210031, Jiangsu, China.
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12
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Chung H, An S, Han SY, Jeon J, Cho S, Lee YC. Endoscopically injectable and self-crosslinkable hydrogel-mediated stem cell transplantation for alleviating esophageal stricture after endoscopic submucosal dissection. Bioeng Transl Med 2023; 8:e10521. [PMID: 37206239 PMCID: PMC10189443 DOI: 10.1002/btm2.10521] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/17/2023] [Accepted: 03/29/2023] [Indexed: 05/21/2023] Open
Abstract
Esophageal stricture after extensive endoscopic submucosal dissection impairs the quality of life of patients with superficial esophageal carcinoma. Beyond the limitations of conventional treatments including endoscopic balloon dilatation and the application of oral/topical corticosteroids, several cell therapies have been recently attempted. However, such methods are still limited in clinical situations and existing setups, and the efficacies are less in some cases since the transplanted cells hardly remain at the resection site for a long time due to swallowing and peristalsis of the esophagus. Thus, a cell transplantation platform directly applicable with clinically established equipment and enabling stable retention of transplanted cells can be a promising therapeutic option for better clinical outcomes. Inspired by ascidians that rapidly self-regenerate, this study demonstrates endoscopically injectable and self-crosslinkable hyaluronate that allows both endoscopic injection in a liquid state and self-crosslinking as an in situ-forming scaffold for stem cell therapy. The pre-gel solution may compatibly be applied with endoscopic tubes and needles of small diameters, based on the improved injectability compared to the previously reported endoscopically injectable hydrogel system. The hydrogel can be formed via self-crosslinking under in vivo oxidative environment, while also exhibiting superior biocompatibility. Finally, the mixture containing adipose-derived stem cells and the hydrogel can significantly alleviate esophageal stricture after endoscopic submucosal dissection (75% of circumference, 5 cm in length) in a porcine model through paracrine effects of the stem cell in the hydrogel, which modulate regenerative processes. The stricture rates on Day 21 were 79.5% ± 2.0%, 62.8% ± 1.7%, and 37.9% ± 2.9% in the control, stem cell only, and stem cell-hydrogel groups, respectively (p < 0.05). Therefore, this endoscopically injectable hydrogel-based therapeutic cell delivery system can serve as a promising platform for cell therapies in various clinically relevant situations.
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Affiliation(s)
- Hyunsoo Chung
- Department of Internal Medicine and Liver Research InstituteSeoul National University College of MedicineSeoulRepublic of Korea
- Department of Medical Device DevelopmentSeoul National University College of MedicineSeoulRepublic of Korea
- Yonsei University Graduate School of MedicineSeoulRepublic of Korea
| | - Soohwan An
- Department of BiotechnologyYonsei UniversitySeoulRepublic of Korea
| | - Seung Yeop Han
- Department of BiotechnologyYonsei UniversitySeoulRepublic of Korea
| | - Jihoon Jeon
- Department of BiotechnologyYonsei UniversitySeoulRepublic of Korea
| | - Seung‐Woo Cho
- Department of BiotechnologyYonsei UniversitySeoulRepublic of Korea
- Center for Nanomedicine, Institute for Basic Science (IBS)SeoulRepublic of Korea
- Graduate Program of Nano Biomedical Engineering (NanoBME)Advanced Science Institute, Yonsei UniversitySeoulRepublic of Korea
| | - Yong Chan Lee
- Yonsei University Graduate School of MedicineSeoulRepublic of Korea
- Department of Internal MedicineYonsei University College of MedicineSeoulRepublic of Korea
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13
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Allogeneic transplantation of epidermal cell sheets followed by endoscopic submucosal dissection to prevent severe esophageal stricture in a porcine model. Regen Ther 2022; 21:157-165. [PMID: 35891710 PMCID: PMC9284451 DOI: 10.1016/j.reth.2022.06.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/12/2022] [Accepted: 06/23/2022] [Indexed: 12/03/2022] Open
Abstract
Introduction Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for early esophageal cancer. However, large mucosal defects after esophageal ESD result in refractory strictures. In the present study, we histologically evaluated the endoscopic transplantation of allogeneic epidermal cell sheets (ECSs) as a feasible therapy for preventing esophageal stricture after circumferential ESD in a porcine model. Methods Epidermal cells were isolated from the skin tissue of allogeneic pigs and cultured on temperature-responsive cell culture inserts for 2 weeks. Transplantable ECSs were harvested by reducing the temperature and endoscopically transplanting the sheets to ulcer sites immediately after esophageal ESD. The engraftment of transplanted ECSs was then evaluated in two pigs at 7 days after transplantation. Next, ten pigs were divided into two groups to evaluate the endoscopic transplantation of allogeneic ECSs for the prevention of esophageal strictures after ESD. Allogeneic ECSs were transplanted immediately after esophageal ESD in the transplantation group (n = 5), whereas the control group (n = 5) did not undergo transplantation. Results Most of the transplanted allogeneic ECSs were successfully engrafted at the ulcer sites in the early phase. Fluorescence in situ hybridization analysis revealed that several allogeneic cells were present in the transplanted area at 7 days after ESD. At 14 days after ESD, significant differences in body weight loss, dysphagia scores, and mucosal strictures were observed between the control and transplantation groups. Transplanting allogeneic ECSs after esophageal ESD promotes mucosal healing and angiogenesis and prevents excessive inflammation and granulation tissue formation. Conclusions Endoscopic and histological analyses revealed that allogeneic ECSs promoted artificial ulcer healing after ESD, preventing esophageal strictures after ESD.
Large mucosal defects of the esophagus cause severe strictures. Allogeneic epidermal cell sheets promote esophageal mucosal healing. Allogeneic epidermal cell sheets induce angiogenesis in esophageal ulcers. Allogeneic epidermal cell sheets prevent excessive inflammation in esophageal ulcers.
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14
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Palam S, Mohorek M, Rizvi S, Dua K. Clinical outcomes on weekly endoscopic dilations as the initial approach to manage patients with complex benign esophageal strictures: report on 488 dilations. Surg Endosc 2022; 36:7056-7065. [PMID: 35477807 DOI: 10.1007/s00464-022-09248-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/07/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Success rate of endoscopic dilation (ED) of complex benign esophageal strictures (CBES) can be as low as 65%. Since EDs are usually performed at 2-4-week intervals, the aim of this study was to evaluate the clinical outcomes of EDs done initially at weekly intervals. METHODS A cohort of patients with CBES (luminal diameter < 10 mm) underwent ED at weekly intervals and subsequent dilation intervals adjusted based on response. Weekly EDs were also re-initiated in those requiring additional interventions (electro-cautery/stents). Group A patients: Failed prior EDs done at ≥ 2-week intervals. Group B: CBES with no prior dilations. Success was defined as achieving and maintaining a luminal diameter of ≥ 14 mm and patient remaining dysphagia-free with minimal re-interventions. RESULTS 488 EDs were performed on a cohort of 57 consecutive patients with CBES. Median follow-up was 4 years. Group A: 21 patients (mean age 65 ± 13 years; mean interval between prior failed dilations 17 ± 9 days). 57% of these patients achieved long-term success with weekly dilations (mean 8 ± 4.7 dilations/patient). Group B: 36 patients (mean age 61 ± 13 years, mean 6.5 ± 5.5 dilations/patient). Long-term success was 83.3% (P = 0.033). Despite weekly dilations, unable to achieve a diameter of 14 mm in 5 patients. AE: perforation 1 (0.2%), bleeding 1 (0.2%). CONCLUSION Significant proportion of patients with CBES who failed prior dilations done at ≥ 2-week intervals achieved dysphagia-free status by initiating weekly dilations. Hence, before considering other options (electro-cautery/stents), one can consider using this approach. This approach can also be used upfront in patients with newly diagnosed CBES.
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Affiliation(s)
- Sowmya Palam
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Mathew Mohorek
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Syed Rizvi
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Kulwinder Dua
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA.
- Graduate School of Biomedical Sciences, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
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15
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Human Mesenchymal Stem Cell Sheets Improve Uterine Incision Repair in a Rodent Hysterotomy Model. Am J Perinatol 2022; 39:1212-1222. [PMID: 33368093 DOI: 10.1055/s-0040-1721718] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVE The study aimed to assess the feasibility of creating and transplanting human umbilical cord mesenchymal stem cell sheets applied to a rat model of hysterotomy, and additionally to determine benefits of human umbilical cord mesenchymal stem cell sheet transplantation in reducing uterine fibrosis and scarring. STUDY DESIGN Human umbilical cord mesenchymal stem cell sheets are generated by culturing human umbilical cord mesenchymal stem cells on thermo-responsive cell culture plates. The temperature-sensitive property of these culture dishes facilitates normal cell culture in a thin contiguous layer and allows for reliable recovery of intact stem cell sheets without use of destructive proteolytic enzymes.We developed a rat hysterotomy model using nude rats. The rat uterus has two distinct horns: one horn provided a control/untreated scarring site, while the second horn was the cell sheet transplantation site.On day 14 following surgery, complete uteri were harvested and subjected to histologic evaluations of all hysterotomy sites. RESULTS The stem cell sheet culture process yielded human umbilical cord mesenchymal stem cell sheets with surface area of approximately 1 cm2.Mean myometrial thickness in the cell sheet-transplanted group was 274 μm compared with 191 μm in the control group (p = 0.02). Mean fibrotic surface area in the human umbilical cord mesenchymal stem cell sheet-transplanted group was 95,861 μm2 compared with 129,185 μm2 in the control group. Compared with control horn sites, cell sheet-transplanted horns exhibited significantly smaller fibrotic-to-normal myometrium ratios (0.18 vs. 0.27, respectively, p = 0.029). Mean number of fibroblasts in cell sheet-transplanted horns was significantly smaller than the control horns (483 vs. 716/mm2, respectively, p = 0.001). CONCLUSION Human umbilical cord mesenchymal stem cell sheet transplantation is feasible in a rat model of hysterotomy. Furthermore, use of stem cell sheets reduces fibroblast infiltration and uterine scar fibrotic tissue formation during hysterotomy healing, potentially mitigating risks of uterine scar formation. KEY POINTS · Stem cell sheet transplanted to hysterotomy promotes myometrial regeneration and reduced fibrotic tissue formation.. · This study demonstrates the feasibility of using human umbilical cord mesenchymal stem cell sheets..
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16
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Xu Y, Lin Z, Zhong S, Liang W. Muscular injury was identified the risk factor of post-operative stenosis after large area but non-circumferential esophageal endoscopic submucosal dissection. Scand J Gastroenterol 2022; 57:740-747. [PMID: 35148239 DOI: 10.1080/00365521.2022.2034939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 01/20/2022] [Accepted: 01/22/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND The incidence of post-operative stenosis after esophageal Endoscopic Submucosal Dissection (ESD) ranks high. This study aimed to investigate the association between the degree of muscular injury and the incidence of post-operative stenosis. RESEARCH DESIGN This was a retrospective study of 133 patients with superficial esophageal lesions treated by non-circumferential ESD enrolled between January 2016 and May 2021 at two endoscopy centers. Demographic and clinical parameters were analyzed. A novel muscular injury classification system was proposed. Stenosis risk factors were identified using multivariate logistic regression. The association between the different degrees of muscular injury and the incidence of post-operative stenosis was investigated further by propensity score matching (PSM). RESULTS There were 133 cases evaluated in this study, 33 of which developed stenosis. Multivariate analysis suggested lesions located in the upper 1/3 of the esophagus, resections >5/6 of the circumference, and muscular injury (Grade 3 or 4 according to our proposed classification) were risk factors for stenosis. Correlation analysis suggested a positive association between the degree of muscular injury and the incidence of post-operative stenosis (r = 0.408, p < .05). For PSM, 29 stenosis cases were matched and univariate analysis further corroborated that muscular injuries of grade 3 (OR = 6.429, 95%CI = 1.318-31.367, p = .021) or 4 (OR = 7, 95%CI = 1.068-45.901, p = .043) were risk factors for stenosis. CONCLUSION Grade 3-4 muscular injury was identified as a risk factor of post-operative stenosis.
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Affiliation(s)
- Yanqin Xu
- Department of Digestive Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Zhengrong Lin
- Department of Digestive Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Shishun Zhong
- Department of Digestive Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Wei Liang
- Department of Digestive Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian, China
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17
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Advances in the application of regenerative medicine in prevention of post-endoscopic submucosal dissection for esophageal stenosis. J Transl Int Med 2022; 10:28-35. [PMID: 35702182 PMCID: PMC8997800 DOI: 10.2478/jtim-2022-0011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Endoscopic submucosal dissection (ESD) is a curative treatment for superficial esophageal cancer with distinct advantages. However, esophageal stenosis after ESD remains a tough problem, especially after large circumferential proportion of esophageal mucosa is removed, which limits the wide use of ESD, especially in circumferential lesions. In this scenario, preventive procedures are highly recommended against post-ESD esophageal stenosis. However, the efficacy and safety of traditional prophylactic methods (steroids, metal and biodegradable stents, balloon dilation, radial incision, etc.) are not satisfactory and novel strategies need to be developed. Regenerative medicine has been showing enormous potential in the reconstruction of organs including the esophagus. In this review, we aimed to describe the current status of regenerative medicine in prevention of post-ESD esophageal stenosis. Cell injection, cell sheet transplantation, and extracellular matrix implantation have been proved effective. However, numerous obstacles still exist and further studies are necessary.
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Bao Y, Li Z, Li Y, Chen T, Cheng Y, Xu M. Recent Advances of Biomedical Materials for Prevention of Post-ESD Esophageal Stricture. Front Bioeng Biotechnol 2021; 9:792929. [PMID: 35004652 PMCID: PMC8727907 DOI: 10.3389/fbioe.2021.792929] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/22/2021] [Indexed: 11/13/2022] Open
Abstract
Esophageal stricture commonly occurs in patients that have suffered from endoscopic submucosal dissection (ESD), and it makes swallowing difficult for patients, significantly reducing their life qualities. So far, the prevention strategies applied in clinical practice for post-ESD esophageal stricture usually bring various inevitable complications, which drastically counteract their effectiveness. Nowadays, with the widespread investigation and application of biomedical materials, lots of novel approaches have been devised in terms of the prevention of esophageal stricture. Biomedical polymers and biomedical-derived materials are the most used biomedical materials to prevent esophageal stricture after ESD. Both of biomedical polymers and biomedical-derived materials possess great physicochemical properties such as biocompatibility and biodegradability. Moreover, some biomedical polymers can be used as scaffolds to promote cell growth, and biomedical-derived materials have biological functions similar to natural organisms, so they are important in tissue engineering. In this review, we have summarized the current approaches for preventing esophageal stricture and put emphasis on the discussion of the roles biomedical polymers and biomedical-derived materials acted in esophageal stricture prevention. Meanwhile, we proposed several potential methods that may be highly rational and feasible in esophageal stricture prevention based on other researches associated with biomedical materials. This review is expected to offer a significant inspiration from biomedical materials to explore more effective, safer, and more economical strategies to manage post-ESD esophageal stricture.
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Affiliation(s)
- Yuchen Bao
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Institute for Translational Nanomedicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhenguang Li
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Institute for Translational Nanomedicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yingze Li
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Institute for Translational Nanomedicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tao Chen
- Endoscopy Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yu Cheng
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Institute for Translational Nanomedicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Meidong Xu
- Endoscopy Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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19
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Jones BC, Shibuya S, Durkin N, De Coppi P. Regenerative medicine for childhood gastrointestinal diseases. Best Pract Res Clin Gastroenterol 2021; 56-57:101769. [PMID: 35331401 DOI: 10.1016/j.bpg.2021.101769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/30/2021] [Accepted: 10/08/2021] [Indexed: 01/31/2023]
Abstract
Several paediatric gastrointestinal diseases result in life-shortening organ failure. For many of these conditions, current therapeutic options are suboptimal and may not offer a cure. Regenerative medicine is an inter-disciplinary field involving biologists, engineers, and clinicians that aims to produce cell and tissue-based therapies to overcome organ failure. Exciting advances in stem cell biology, materials science, and bioengineering bring engineered gastrointestinal cell and tissue therapies to the verge of clinical trial. In this review, we summarise the requirements for bioengineered therapies, the possible sources of the various cellular and non-cellular components, and the progress towards clinical translation of oesophageal and intestinal tissue engineering to date.
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Affiliation(s)
- Brendan C Jones
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Specialist Neonatal and Paediatric Surgery Unit, Great Ormond Street Hospital, London, United Kingdom
| | - Soichi Shibuya
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Natalie Durkin
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Specialist Neonatal and Paediatric Surgery Unit, Great Ormond Street Hospital, London, United Kingdom
| | - Paolo De Coppi
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Specialist Neonatal and Paediatric Surgery Unit, Great Ormond Street Hospital, London, United Kingdom.
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20
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Nagase K. Thermoresponsive interfaces obtained using poly(N-isopropylacrylamide)-based copolymer for bioseparation and tissue engineering applications. Adv Colloid Interface Sci 2021; 295:102487. [PMID: 34314989 DOI: 10.1016/j.cis.2021.102487] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/09/2021] [Accepted: 07/10/2021] [Indexed: 12/11/2022]
Abstract
Poly(N-isopropylacrylamide) (PNIPAAm) is the most well-known and widely used stimuli-responsive polymer in the biomedical field owing to its ability to undergo temperature-dependent hydration and dehydration with temperature variations, causing hydrophilic and hydrophobic alterations. This temperature-dependent property of PNIPAAm provides functionality to interfaces containing PNIPAAm. Notably, the hydrophilic and hydrophobic alterations caused by the change in the temperature-responsive property of PNIPAAm-modified interfaces induce temperature-modulated interactions with biomolecules, proteins, and cells. This intrinsic property of PNIPAAm can be effectively used in various biomedical applications, particularly in bioseparation and tissue engineering applications, owing to the functionality of PNIPAAm-modified interfaces based on the temperature modulation of the interaction between PNIPAAm-modified interfaces and biomolecules and cells. This review focuses on PNIPAAm-modified interfaces in terms of preparation method, properties, and their applications. Advances in PNIPAAm-modified interfaces for existing and developing applications are also summarized.
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Affiliation(s)
- Kenichi Nagase
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato, Tokyo 105-8512, Japan.
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21
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Maeda H, Sasaki F, Morinaga Y, Kabayama M, Iwaya H, Komaki Y, Arima S, Nasu Y, Tanoue S, Hashimoto S, Kanmura S, Nishiguchi A, Taguchi T, Ido A. Covering Post-Endoscopic Submucosal Dissection Ulcers in Miniature Swine with Hexanoyl (Hx:C6) Group-Modified Alkaline-Treated Gelatin Porous Film (HAG) Induces Proper Healing by Decreasing Inflammation and Fibrosis. Digestion 2021; 102:415-427. [PMID: 32698185 DOI: 10.1159/000509056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 05/31/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Hexanoyl (Hx:C6) group-modified alkaline-treated gelatin porous film (HAG) is a newly developed degradable hydrogel characterized by strong adhesiveness and high affinity for vascular endothelial growth factor (VEGF). The aim of this study was to clarify the effect of HAG sheets on the healing process of post-endoscopic submucosal dissection (ESD) porcine gastric artificial ulcers. METHODS (1) To evaluate the adhesiveness of HAG sheets over time, we performed ESD to create 1 artificial ulcer and covered the lesion with 1 HAG sheet using 1 miniature swine. We observed 2 ulcers by endoscopic and microscopic examinations. (2) To examine the effect of HAG sheets on post-ESD ulcer healing, we performed ESD using 5 miniature swine. The artificial ulcers were covered with HAG sheets, or left uncovered after ESD (day 0), followed by macroscopic and microscopic examinations. On days 7 and 14, we observed 2 ulcers by endoscopic examinations. On day 14, the animals were sacrificed, and histological examination was performed on the 3 stomachs that could be extirpated. RESULTS (1) On day 7, adhesion of HAG sheets was observed. (2) Gastric ulcer area on day 7 was significantly larger in the covered ulcers than in the non-covered ulcers (p = 0.046). On day 14, although there was no significant difference in ulcer area irrespective of covering (p = 0.357), the covered ulcers tended to repair less fold convergence than non-covered ulcers. The covered ulcer sheets significantly decreased inflammatory cell infiltration (p = 0.011), but significantly increased the abundance of macrophages (p = 0.033), in submucosal layers. Also, the abundance of alpha-smooth muscle actin-positive cells in submucosal layers of the covered ulcers was significantly reduced (p = 0.044), leading to a decrease in collagen accumulation. In addition, fibrosis and atrophy of the muscularis propria were significantly lower for covered ulcers than for non-covered ulcers. Furthermore, microvessels and VEGF-positive cells were significantly more abundant in the submucosal layers of the covered ulcers (p < 0.001 and p = 0.024, respectively). CONCLUSIONS HAG sheets induced post-ESD ulcer healing with less submucosal inflammation and muscularis propria injury and have the potential to decrease excess scarring.
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Affiliation(s)
- Hidehito Maeda
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Fumisato Sasaki
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan,
| | - Yuko Morinaga
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Masayuki Kabayama
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Hiromichi Iwaya
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yuga Komaki
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Shiho Arima
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yuichiro Nasu
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Shiroh Tanoue
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Shinichi Hashimoto
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Shuji Kanmura
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Akihiro Nishiguchi
- Polymers and Biomaterials Field, Research Center for Functional Materials, National Institute for Materials Science, Ibaraki, Japan
| | - Tetsushi Taguchi
- Polymers and Biomaterials Field, Research Center for Functional Materials, National Institute for Materials Science, Ibaraki, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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22
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Zhou XB, Xu SW, Ye LP, Mao XL, Chen YH, Wu JF, Cai Y, Wang Y, Wang L, Li SW. Progress of esophageal stricture prevention after endoscopic submucosal dissection by regenerative medicine and tissue engineering. Regen Ther 2021; 17:51-60. [PMID: 33997185 PMCID: PMC8100352 DOI: 10.1016/j.reth.2021.01.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/17/2020] [Accepted: 01/11/2021] [Indexed: 01/10/2023] Open
Abstract
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.
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Key Words
- 5-FU, 5-Fluorouracil
- ADSC, Autologous adipose-derived stem cells
- ASGS, autologous skin graft surgery
- ChST15, carbohydrate sulfotransferase 15
- EBD, endoscopic balloon dilation
- ECM, extracellular matrix
- ESD, endoscopic submucosal dissection
- Endoscopic submucosal dissection
- Esophageal stricture
- FCMS, fully covered metal stent
- OMECs, oral mucosal epithelial cell sheets
- PGAs, polyglycolic acid sheet
- PIPAAm, poly(N-isopropylacrylamide)
- Regenerative medicine
- SESCNs, superficial esophageal squamous cell neoplasms
- SIS, small intestinal submucosa
- SeMS, self-expandable metal stents
- TA, triamcinolone acetonide
- TS-PGA, triamcinolone-soaked polyglycolic acid sheet
- Tissue engineering
- Tβ4, Thymosin β4
- ccESTD, complete circular endoscopic submucosal tunnel dissection
- siRNA, small interfering RNA
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Affiliation(s)
- Xian-bin Zhou
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, LinHai, Zhejiang, China
| | - Shi-wen Xu
- Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Li-ping Ye
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, LinHai, Zhejiang, China
| | - Xin-li Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, LinHai, Zhejiang, China
| | - Ya-hong Chen
- Health Management Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Jian-fen Wu
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, LinHai, Zhejiang, China
| | - Yue Cai
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, LinHai, Zhejiang, China
| | - Yi Wang
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, LinHai, Zhejiang, China
| | - Li Wang
- College of Basic Medicine, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Shao-wei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, LinHai, Zhejiang, China
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23
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Na HK, Lee JH, Shim IK, Jung HY, Kim DH, Kim CJ. Allogeneic epithelial cell sheet transplantation for preventing esophageal stricture after circumferential ESD in a porcine model: preliminary results. Scand J Gastroenterol 2021; 56:598-603. [PMID: 33764846 DOI: 10.1080/00365521.2021.1897669] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Circumferential endoscopic submucosal dissection (ESD) for large lesions induces severe stricture, requiring subsequent treatment. We aimed to evaluate the efficacy of allogeneic epithelial cell sheet transplantation in preventing esophageal stricture after circumferential ESD in a porcine model. MATERIALS AND METHODS A total of 15 conventional pigs underwent a 4 cm long circumferential ESD in the mid-esophagus. Out of these animals, 11 were immediately subjected to allogeneic oral mucosal cell sheet transplantation at the resection site, whereas four pigs underwent circumferential ESD only. We performed upper endoscopy 1 and 2 weeks after ESD and assessed the degree of esophageal stricture and histologic characteristics. RESULTS Dysphagia scores and weight change ratios recorded 1 and 2 weeks after ESD did not differ between the two groups. The stricture rate 2 weeks after ESD was 100% in the control group and 90.9% in the cell sheet group (p = 1.000). The median mucosal constriction rates of the control and cell sheet groups were 73.5% (range 63.0-80.0%) and 53.8% (37.5-73.3%, p = .018), respectively. With regard to microscopic measurements, the length of re-epithelialization was greater in the cell sheet group than in the control group (2,495 µm vs. 369 µm, p = .008). Median fibrosis thickness and degree of muscle damage were not significantly different between groups. CONCLUSIONS Although allogeneic epithelial cell sheet transplantation showed greater re-epithelialization and less mucosal constriction of post-ESD ulcers, it was not sufficiently effective in preventing post-ESD stricture.
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Affiliation(s)
- Hee Kyong Na
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong Hoon Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In Kyong Shim
- Department of Biomedical Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hwoon-Yong Jung
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Do Hoon Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chong Jai Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Ni W, Lin S, Bian S, Xiao M, Wang Y, Yang Y, Lu C, Zheng W, Zhou P. Biological testing of chitosan-collagen-based porous scaffolds loaded with PLGA/Triamcinolone microspheres for ameliorating endoscopic dissection-related stenosis in oesophagus. Cell Prolif 2021; 54:e13004. [PMID: 33543561 PMCID: PMC7941226 DOI: 10.1111/cpr.13004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/05/2021] [Accepted: 01/22/2021] [Indexed: 12/11/2022] Open
Abstract
Objectives Endoscopic submucosal dissection (ESD), a preferential approach for early oesophageal neoplasms, inevitably results in oesophageal strictures in patients. Clinical use of glucocorticoids through submucosal injection is beneficial for inhibiting oesophageal stricture following injury; however, it also has limitations, such as dose loss and perforation. Hence, alternatives to glucocorticoid therapy should be developed. Methods A novel porous composite scaffold, ChCo‐TAMS, composed of chitosan, collagen‐I and triamcinolone acetonide (TA) loaded into poly (lactic‐co‐glycolic) acid (PLGA) microspheres (TAMS), was successfully constructed and subjected to biological testing to ameliorate oesophageal ESD‐related stenosis. Results The synthesized biomaterials displayed unique properties in inhibiting the activation of macrophages, chemokine‐mediated cell recruitment and fibrogenesis of fibroblasts. Further application of the scaffolds in the rat dermal defect and porcine oesophageal ESD model showed that these novel scaffolds played a robust role in inhibiting wound contracture and oesophageal ESD strictures. Conclusions The developed composite scaffolds provide a promising clinical medical device for the prevention of post‐operative oesophageal stricture.
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Affiliation(s)
- Wenkai Ni
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Shengli Lin
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Saiyan Bian
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China.,Medical College, Nantong University, Nantong, China
| | - Mingbing Xiao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yongjun Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Yumin Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Cuihua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Pinghong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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Hikichi T, Nakamura J, Takasumi M, Hashimoto M, Kato T, Kobashi R, Takagi T, Suzuki R, Sugimoto M, Sato Y, Irie H, Okubo Y, Kobayakawa M, Ohira H. Prevention of Stricture after Endoscopic Submucosal Dissection for Superficial Esophageal Cancer: A Review of the Literature. J Clin Med 2020; 10:20. [PMID: 33374780 PMCID: PMC7796365 DOI: 10.3390/jcm10010020] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/18/2020] [Accepted: 12/20/2020] [Indexed: 12/14/2022] Open
Abstract
Endoscopic resection has been the standard treatment for intramucosal esophageal cancers (ECs) because of the low risk of lymph node metastases in the lesions. In recent years, endoscopic submucosal dissection (ESD), which can resect large ECs, has been performed. However, the risk of esophageal stricture after ESD is high when the mucosal defect caused by the treatment exceeds 3/4 of the circumference of the lumen. Despite the subsequent high risk of luminal stricture, ESD has been performed even in cases of circumferential EC. In such cases, it is necessary to take measures to prevent stricture. Therefore, in this review, we aimed to clarify the current status of stricture prevention methods after esophageal ESD based on previous literature. Although various prophylactic methods have been reported to have stricture-preventing effects, steroid injection therapy and oral steroid administration are mainstream. However, in cases of circumferential EC, both steroid injection therapy and oral steroid administration cannot effectively prevent luminal stricture. To solve this issue, clinical applications, such as tissue shielding methods with polyglycolic acid sheet, autologous oral mucosal epithelial sheet transplantation, and stent placement, have been developed. However, effective prophylaxis of post-ESD mucosal defects of the esophagus is still unclear. Therefore, further studies in this research field are needed.
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Affiliation(s)
- Takuto Hikichi
- Department of Endoscopy, Fukushima Medical University Hospital, Fukushima-City 960-1295, Fukushima, Japan; (J.N.); (M.H.); (T.K.); (Y.O.); (M.K.)
| | - Jun Nakamura
- Department of Endoscopy, Fukushima Medical University Hospital, Fukushima-City 960-1295, Fukushima, Japan; (J.N.); (M.H.); (T.K.); (Y.O.); (M.K.)
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
| | - Mika Takasumi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
| | - Minami Hashimoto
- Department of Endoscopy, Fukushima Medical University Hospital, Fukushima-City 960-1295, Fukushima, Japan; (J.N.); (M.H.); (T.K.); (Y.O.); (M.K.)
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
| | - Tsunetaka Kato
- Department of Endoscopy, Fukushima Medical University Hospital, Fukushima-City 960-1295, Fukushima, Japan; (J.N.); (M.H.); (T.K.); (Y.O.); (M.K.)
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
| | - Ryoichiro Kobashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
| | - Tadayuki Takagi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
| | - Rei Suzuki
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
| | - Mitsuru Sugimoto
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
| | - Yuki Sato
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
| | - Hiroki Irie
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
| | - Yoshinori Okubo
- Department of Endoscopy, Fukushima Medical University Hospital, Fukushima-City 960-1295, Fukushima, Japan; (J.N.); (M.H.); (T.K.); (Y.O.); (M.K.)
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
| | - Masao Kobayakawa
- Department of Endoscopy, Fukushima Medical University Hospital, Fukushima-City 960-1295, Fukushima, Japan; (J.N.); (M.H.); (T.K.); (Y.O.); (M.K.)
- Department of Medical Research Center, Fukushima Medical University, Fukushima-City 960-1295, Fukushima, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima-City 960-1295, Fukushima, Japan; (M.T.); (R.K.); (T.T.); (R.S.); (M.S.); (Y.S.); (H.I.); (H.O.)
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Kawai Y, Takagi R, Ohki T, Yamamoto M, Yamato M. Evaluation of human keratinocyte sheets transplanted onto porcine excised esophagus after submucosal dissection in an ex vivo model. Regen Ther 2020; 15:323-331. [PMID: 33426235 PMCID: PMC7770430 DOI: 10.1016/j.reth.2020.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 11/18/2020] [Indexed: 10/26/2022] Open
Abstract
BACKGROUND The utility of endoscopic transplantation of epithelial cell sheets to ulcer sites after endoscopic submucosal dissection (ESD) has been shown to prevent scar stenosis after ESD of early esophageal cancer. Previously, our group reported use of an endoscopic transplantation device fabricated with a 3-dimensional printer. Cell sheets are transplanted to the esophageal wound site with the following procedure: first, a cell sheet harvested from temperature-responsive culture dishes is placed on the device's deflated balloon surface and transported to the wound site with endoscopic forceps; second, by applying pressure from inflating the balloon locally at the wound site, the cell sheet is successfully transferred and adhered to the wound tissue; third, the balloon is deflated, and the device is removed. By repeating the procedure, several cell sheets can be safely transplanted to a wider ESD area. Nonetheless, possible damage to cell sheets using this procedure has not yet been assessed. OBJECTIVE Effects of endoscopic transplantation balloon inflation on cell viability and damage of normal human epidermal keratinocyte sheets resident on the device's balloon surface were evaluated by histology after sheet placement onto lumenal surfaces in the ex vivo porcine submucosal dissection esophagus model. Endoscopic transplantation of these same cell sheets with conventional methods using a polyvinylidene fluoride (PVDF) cell sheet support membrane, balloon device transfer, and also using a novel modified balloon transfer procedure was also examined. Cell sheet transfer results obtained with these three procedures were compared. METHOD Normal human epidermal keratinocyte sheets were fabricated on temperature-responsive culture inserts. By temperature reduction to 20 °C, all cells were harvested as a single contiguous cell sheet. Freshly excised porcine esophagi purchased in a slaughter house were turned inside-out, and the exposed lumenal mucosa and submucosal layers were removed by Cooper scissors. This luminal surface was then utilized as a transplantation bed in ex vivo cell sheet experiments. Cell sheets were adhered to the endoscopic transfer device balloon, expanded by balloon inflation and resulting cell viability was evaluated by trypan blue exclusion test after cell sheet trypsinization and dispersion. Cell sheets were transferred onto the esophagus lumen ex vivo using forceps and the balloon device, and also using a modified balloon transfer method. The obtained results were compared with those without balloon expansion, and evaluated for sheet thickness and lumenal histology. Finally, TUNEL staining was performed to examine cell apoptosis. RESULT Cell sheets thinned after cell sheet balloon expansion, but no apoptosis was observed after these procedures. CONCLUSION Expanding keratinocyte cell sheets on a balloon endoscopic transfer device did not damage the cell sheets. This sheet transplantation method using the endoscopic balloon transfer device may be considered as a future standard cell sheet endoscopic transplantation procedure for repairing the esophagus.
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Affiliation(s)
- Yosuke Kawai
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Japan
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Japan
| | - Ryo Takagi
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Japan
| | - Takeshi Ohki
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Japan
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Japan
| | - Masakazu Yamamoto
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Japan
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Japan
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27
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Gao Y, Jin SZ. Strategies for treating oesophageal diseases with stem cells. World J Stem Cells 2020; 12:488-499. [PMID: 32742566 PMCID: PMC7360987 DOI: 10.4252/wjsc.v12.i6.488] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 05/02/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023] Open
Abstract
There is a wide range of oesophageal diseases, the most general of which are inflammation, injury and tumours, and treatment methods are constantly being developed and updated. With an increasingly comprehensive understanding of stem cells and their characteristics of multilineage differentiation, self-renewal and homing as well as the combination of stem cells with regenerative medicine, tissue engineering and gene therapy, stem cells are playing an important role in the treatment of a variety of diseases. Mesenchymal stem cells have many advantages and are most commonly applied; however, most of these applications have been in experimental studies, with few related clinical trials for comparison. Therefore, the methods, positive significance and limitations of stem cells in the treatment of oesophageal diseases remain incompletely understood. Thus, the purpose of this paper is to review the current literature and summarize the efficacy of stem cells in the treatment of oesophageal diseases, including oesophageal ulceration, acute radiation-induced oesophageal injury, corrosive oesophageal injury, oesophageal stricture formation after endoscopic submucosal dissection and oesophageal reconstruction, as well as gene therapy for oesophageal cancer.
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Affiliation(s)
- Yang Gao
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
| | - Shi-Zhu Jin
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
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Kasai Y, Takagi R, Kobayashi S, Owaki T, Yamaguchi N, Fukuda H, Sakai Y, Sumita Y, Kanai N, Isomoto H, Kanetaka K, Ohki T, Asahina I, Nagai K, Nakao K, Takeda N, Okano T, Eguchi S, Yamato M. A stable protocol for the fabrication of transplantable human oral mucosal epithelial cell sheets for clinical application. Regen Ther 2020; 14:87-94. [PMID: 31988998 PMCID: PMC6970131 DOI: 10.1016/j.reth.2019.11.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/08/2019] [Accepted: 11/30/2019] [Indexed: 01/16/2023] Open
Abstract
INTRODUCTION Cultured stratified epithelial cell sheets have been clinically utilized as transplantable grafts for the regeneration of epithelial tissues, such as the esophagus, cornea, skin, and intraoral cavity. These cell sheets are expected to gain widespread use as regenerative medicine products and save many patients. For this purpose, establishing and disseminating the stale protocol of fabricating the cell sheet is crucial. The fabrication of cultured stratified epithelial cell sheets consists of many important steps, and since the patients' epithelial cell conditions vary widely and are sometimes unstable, the qualities of the epithelial cell grafts are likewise potentially unstable. Therefore, in this paper, we report the stable protocol for fabrication of the transplantable cell sheet particularly from patient-derived oral mucosal tissues. METHODS Serum extracted from blood and buccal mucosal tissue were collected in Nagasaki University and transported to Tokyo Women's Medical University. Oral mucosal epithelial cells were collected by minimum trypsin method, and this treatment was studied whether to be a critical procedure. After 14 days cultivation, cultured cells were examined whether to be transplantable as cell sheets. RESULTS We successfully transported buccal mucosal tissue and serum without damage and contamination. Oral mucosal epithelial cells were collected with high viability by minimum trypsin method. Finally, we succeeded to stably fabricate oral mucosal epithelial cell sheets in all 10 patients. CONCLUSIONS We established a stable protocol for the fabrication of human oral mucosal epithelial cell sheets and their transportation in clinical settings in this study. These methodologies could also be basis for transplantation therapy using cultured cell sheets of various types other than oral mucosal epithelial cell and will contribute largely to the future development of regenerative medicine.
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Affiliation(s)
- Yoshiyuki Kasai
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University (TWIns), 2-2 Wakamatsu-Cho, Shinjuku-ku, Tokyo, 162-8480, Japan
| | - Ryo Takagi
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Shinichiro Kobayashi
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki-Shi, Nagasaki, 852-8501, Japan
| | - Toshiyuki Owaki
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Naoyuki Yamaguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki-Shi, Nagasaki, 852-8501, Japan
| | - Hiroko Fukuda
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki-Shi, Nagasaki, 852-8501, Japan
| | - Yusuke Sakai
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki-Shi, Nagasaki, 852-8501, Japan
| | - Yoshinori Sumita
- Department of Regenerative Oral Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki-Shi, Nagasaki, 852-8501, Japan
| | - Nobuo Kanai
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Hajime Isomoto
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki-Shi, Nagasaki, 852-8501, Japan
| | - Kengo Kanetaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki-Shi, Nagasaki, 852-8501, Japan
| | - Takeshi Ohki
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Izumi Asahina
- Department of Regenerative Oral Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki-Shi, Nagasaki, 852-8501, Japan
| | - Kazuhiro Nagai
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki-Shi, Nagasaki, 852-8501, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki-Shi, Nagasaki, 852-8501, Japan
| | - Naoya Takeda
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University (TWIns), 2-2 Wakamatsu-Cho, Shinjuku-ku, Tokyo, 162-8480, Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki-Shi, Nagasaki, 852-8501, Japan
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University (TWIns), 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
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Lesion size and circumferential range identified as independent risk factors for esophageal stricture after endoscopic submucosal dissection. Surg Endosc 2020; 34:4065-4071. [PMID: 31953729 PMCID: PMC7395023 DOI: 10.1007/s00464-020-07368-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 01/04/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Endoscopic submucosal dissection (ESD) is used to treat early esophageal cancer and precancerous lesions. Patients undergoing ESD are prone to esophageal stenosis, which impairs therapeutic efficacy and quality of life. This retrospective study aimed to investigate the potential association between patient demographics and esophageal lesion characteristics with the risk of esophageal stenosis following ESD. METHODS For this retrospective study 190 consecutive patients who underwent ESD between January 2013 and January 2015 were recruited. Data on patient demographics, esophageal lesion-related factors, operation details, esophageal stenosis occurrence and measures taken to prevent or treat stricture were collected, and the normality of distribution of each indicator was assessed with a Kolmogorov-Smirnov test. Stenosis risk factors were then identified using univariate and multivariate logistic regression. RESULTS Post-ESD esophageal stenosis occurred in 51 cases. Multivariate logistic regression analysis was performed to identify independent risk factors. A history of EMR/ESD (OR = 4.185, 95% CI: 1.511-11.589), resection circumferential diameter (OR = 1.721, 95% CI: 1.135-2.610), non-en bloc resection (OR = 7.413, 95% CI: 2.398-22.921), submucosal infiltration (OR = 3.449, 95% CI: 1.014-11.734) and circumferential resection range (OR = 57.493, 95% CI: 17.236-191.782) were identified as independent risk factors for post-ESD esophageal stenosis. Spraying porcine fibrin adhesive on the resection bed reduced neither the incidence of postoperative stenosis nor the extent of postoperative dilation. CONCLUSION Post-ESD esophageal stenosis is significantly related to size and circumferential range of lesion resection. EMR/ESD history, non-en bloc resection and submucosal infiltration may be additional risk factors.
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Doberenz F, Zeng K, Willems C, Zhang K, Groth T. Thermoresponsive polymers and their biomedical application in tissue engineering - a review. J Mater Chem B 2020; 8:607-628. [PMID: 31939978 DOI: 10.1039/c9tb02052g] [Citation(s) in RCA: 195] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Thermoresponsive polymers hold great potential in the biomedical field, since they enable the fabrication of cell sheets, in situ drug delivery and 3D-printing under physiological conditions. In this review we provide an overview of several thermoresponsive polymers and their application, with focus on poly(N-isopropylacrylamide)-surfaces for cell sheet engineering. Basic knowledge of important processes like protein adsorption on surfaces and cell adhesion is provided. For different thermoresponsive polymers, namely PNIPAm, Pluronics, elastin-like polypeptides (ELP) and poly(N-vinylcaprolactam) (PNVCL), synthesis and basic chemical and physical properties have been described and the mechanism of their thermoresponsive behavior highlighted. Fabrication methods of thermoresponsive surfaces have been discussed, focusing on PNIPAm, and describing several methods in detail. The latter part of this review is dedicated to the application of the thermoresponsive polymers and with regard to cell sheet engineering, the process of temperature-dependent cell sheet detachment is explained. We provide insight into several applications of PNIPAm surfaces in cell sheet engineering. For Pluronics, ELP and PNVCL we show their application in the field of drug delivery and tissue engineering. We conclude, that research of thermoresponsive polymers has made big progress in recent years, especially for PNIPAm since the 1990s. However, manifold research possibilities, e.g. in surface fabrication and 3D-printing and further translational applications are conceivable in near future.
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Affiliation(s)
- Falko Doberenz
- Department Biomedical Materials, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 4, 06120 Halle (Saale), Germany.
| | - Kui Zeng
- Wood Technology and Wood Chemistry, University of Goettingen, Büsgenweg 4, D-37077 Göttingen, Germany
| | - Christian Willems
- Department Biomedical Materials, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 4, 06120 Halle (Saale), Germany.
| | - Kai Zhang
- Wood Technology and Wood Chemistry, University of Goettingen, Büsgenweg 4, D-37077 Göttingen, Germany
| | - Thomas Groth
- Department Biomedical Materials, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 4, 06120 Halle (Saale), Germany. and Interdisciplinary Center of Material Science, Martin Luther University, Halle-Wittenberg, 06099 Halle (Saale), Germany and Institute for Bionic Technologies and Engineering, I.M. Sechenov First Moscow State Medical University, 1, 19991, Trubetskaya st. 8, Moscow, Russian Federation
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Yu M, Tan Y, Liu D. Strategies to prevent stricture after esophageal endoscopic submucosal dissection. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:271. [PMID: 31355238 PMCID: PMC6614329 DOI: 10.21037/atm.2019.05.45] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 05/10/2019] [Indexed: 12/12/2022]
Abstract
Endoscopic submucosal dissection (ESD) has been widely applied as a less invasive and more effective method for treating early esophageal cancers such as squamous cell carcinoma and dysplasia of Barrett's esophagus. However, post-ESD esophageal stricture often occurs if patients suffer circumferential mucosal defects of more than three-quarters of the circumference of the esophagus, which makes it difficult for patients to swallow and greatly reduces their quality of life. Moreover, there is currently no standard method to treat post-ESD esophageal stricture, even though it is extraordinarily important to prevent its formation. In recent years, several strategies to prevent esophageal stricture have emerged. These strategies can be classified into pharmacological, mechanical, tissue engineering, and other novel strategies, with each strategy having its own strengths and weaknesses. Although the pharmacological prophylaxis and mechanical strategies are relatively mature, they still have their drawbacks like high time-consumption, the occurrence of re-stricture, and significant side effects. Tissue engineering strategies and other novel strategies have shown promising preliminary results, but more clinical trials are needed. In this review, we discuss these strategies, with a particular focus on tissue engineering strategies and other novel strategies. It is hoped that this discussion will aid in finding more effective and safer strategies to prevent esophageal stricture.
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Affiliation(s)
- Meihong Yu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yuyong Tan
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Deliang Liu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
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Liu BR, Liu D, Yang W, Ullah S, Cao Z, He D, Zhang X, Shi Y, Zhou Y, Chen Y, He D, Zhao L, Yuan Y, Li D. Mucosal loss as a critical factor in esophageal stricture formation after mucosal resection: a pilot experiment in a porcine model. Surg Endosc 2019; 34:551-556. [PMID: 30980136 DOI: 10.1007/s00464-019-06793-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 04/09/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND AIM Esophageal stricture is a major complication of large areas endoscopic submucosal dissection (ESD). Until now, the critical mechanism of esophageal stricture remains unclear. We examined the role of mucosal loss versus submucosal damage in esophageal stricture formation after mucosal resection using a porcine model. MATERIALS AND METHODS Twelve swine were randomly divided into two groups, each of 6. In each group, two 5-cm-long submucosal tunnels were made to involve 1/3rd of the widths of the anterior and posterior esophageal circumference. The entire mucosal roofs of both tunnels were resected in group A. In group B, the tunnel roof mucosa was incised longitudinally along the length of the tunnel, but without excision of any mucosa. Stricture formation was evaluated by endoscopy after 1, 2, and 4 weeks, respectively. Anatomical and histological examinations were performed after euthanasia. RESULTS Healing observed on endoscopy in both groups after 1 week. Group A (mucosa resected) developed mild-to-severe esophageal stricture, dysphagia, and weight loss. In contrast, no esophageal stricture was evident in group B (mucosa incisions without resection) after 2 and 4 weeks, respectively. Macroscopic examination showed severe esophageal stricture and shortening of esophagus in only group A. Inflammation and fibrous hyperplasia of the submucosal layer was observed on histological examination in both groups. CONCLUSION The extent of loss of esophageal mucosa appears to be a critical factor for esophageal stricture. Inflammation followed by fibrosis may contribute to alteration in compliance of the esophagus but is not the main mechanism of postresection stricture.
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Affiliation(s)
- Bing-Rong Liu
- Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052, China.
| | - Dan Liu
- Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052, China
| | - Wenyi Yang
- Department of Gastroenterology, First Affiliated Hospital of Henan University, Kaifeng, Henan, China
| | - Saif Ullah
- Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052, China
| | - Zhen Cao
- Department of Gastroenterology, First Affiliated Hospital of Henan University, Kaifeng, Henan, China
| | - Dezhi He
- Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052, China
| | - Xuehui Zhang
- Department of Gastroenterology, First Affiliated Hospital of Henan University, Kaifeng, Henan, China
| | - Yang Shi
- Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052, China
| | - Yangyang Zhou
- Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052, China
| | - Yong Chen
- Department of Gastroenterology, First Affiliated Hospital of Henan University, Kaifeng, Henan, China
| | - Donghai He
- Department of Gastroenterology, First Affiliated Hospital of Henan University, Kaifeng, Henan, China
| | - Lixia Zhao
- Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052, China
| | - Yulian Yuan
- Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052, China
| | - Deliang Li
- Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052, China
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Epidermal Cell Sheet Transplantation on an Anastomotic Site of the Small Intestine in an Experimental Animal Model. Int Surg 2018. [DOI: 10.9738/intsurg-d-18-00008.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective:
The present study was performed to examine the effects of anastomotic site tissue reconstruction by transplantation of epidermal cell sheets onto the small intestine in an animal model. Cell sheet engineering using cell sheets are used to construct monolayers and bilayers, which are then transplanted into organs. Clinical trials of the application of cell sheets to the cornea, esophagus, lung, and heart muscle are currently underway.
Methods:
The small intestine in female pig (20 kg) was cut 1.5 cm vertically at 6 points at 10-cm intervals, and Gambee sutures were applied at 5-mm intervals. The suture line was covered by epidermal cell sheets. Resection was performed 1 week after the operation.
Results:
Cell sheets applied to sutures in the small intestine survived and differentiated 1 week after transplantation. The small intestine showed marked thickening in the region of cell sheet transplantation, and the amount of connective tissue in the transplanted specimens was 2.54 times that in controls.
Conclusions:
Further studies are necessary to identify the strength of anastomosis and substances that may enhance collagen synthesis and healing at sites of anastomosis.
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Dua KS, Sasikala M. Repairing the human esophagus with tissue engineering. Gastrointest Endosc 2018; 88:579-588. [PMID: 30220298 DOI: 10.1016/j.gie.2018.06.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 06/29/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Kulwinder S Dua
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A
| | - Mitnala Sasikala
- Institute of Basic Sciences and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
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Chai NL, Feng J, Li LS, Liu SZ, Du C, Zhang Q, Linghu EQ. Effect of polyglycolic acid sheet plus esophageal stent placement in preventing esophageal stricture after endoscopic submucosal dissection in patients with early-stage esophageal cancer: A randomized, controlled trial. World J Gastroenterol 2018; 24:1046-1055. [PMID: 29531468 PMCID: PMC5840469 DOI: 10.3748/wjg.v24.i9.1046] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 01/02/2018] [Accepted: 01/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the effect of polyglycolic acid (PGA) plus stent placement compared with stent placement alone in the prevention of post-endoscopic submucosal dissection (ESD) esophageal stricture in early-stage esophageal cancer (EC) patients. METHODS Seventy EC patients undergoing ESD were enrolled in this randomized, controlled study. Patients were allocated randomly at a 1:1 ratio into two groups as follows: (1) PGA plus stent group (PGA sheet-coated stent placement was performed); and (2) Stent group (only stent placement was performed). This study was registered on http://www.chictr.org.cn (No. chictr-inr-16008709). RESULTS The occurrence rate of esophageal stricture in the PGA plus stent group was 20.5% (n = 7), which was lower than that in the stent group (46.9%, n = 15) (P = 0.024). The mean value of esophageal stricture time was 59.6 ± 16.1 d and 70.7 ± 28.6 d in the PGA plus stent group and stent group (P = 0.174), respectively. Times of balloon dilatation in the PGA plus stent group were less than those in the stent group [4 (2-5) vs 6 (1-14), P = 0.007]. The length (P = 0.080) and diameter (P = 0.061) of esophageal strictures were numerically decreased in the PGA plus stent group, whereas no difference in location (P = 0.232) between the two groups was found. Multivariate logistic analysis suggested that PGA plus stent placement (P = 0.026) was an independent predictive factor for a lower risk of esophageal stricture, while location in the middle third (P = 0.034) and circumferential range = 1/1 (P = 0.028) could independently predict a higher risk of esophageal stricture in EC patients after ESD. CONCLUSION PGA plus stent placement is more effective in preventing post-ESD esophageal stricture compared with stent placement alone in EC patients with early-stage disease.
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Affiliation(s)
- Ning-Li Chai
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - Jia Feng
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - Long-Song Li
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - Sheng-Zhen Liu
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - Chen Du
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - Qi Zhang
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - En-Qiang Linghu
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
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Progress on the Prevention of Esophageal Stricture after Endoscopic Submucosal Dissection. Gastroenterol Res Pract 2018; 2018:1696849. [PMID: 29686699 PMCID: PMC5857296 DOI: 10.1155/2018/1696849] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Accepted: 01/28/2018] [Indexed: 12/13/2022] Open
Abstract
Endoscopic submucosal dissection (ESD) has been widely accepted as an effective, minimally invasive treatment for superficial esophageal cancers. However, esophageal stricture often occurs in patients with large mucosal defects after ESD. In this review, we discuss various approaches recently researched to prevent esophageal strictures after ESD. These approaches can be classified as pharmacological treatments, esophageal stent treatments, and tissue engineering approaches. Most of the preventive approaches still have their limitations and require further research. With the improvement of current therapies, ESD can be more widely utilized as a minimally invasive treatment with minimal complications.
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Shibagaki K, Ishimura N, Oshima N, Mishiro T, Fukuba N, Tamagawa Y, Yamashita N, Mikami H, Izumi D, Taniguchi H, Sato S, Ishihara S, Kinoshita Y. Esophageal triamcinolone acetonide-filling method: a novel procedure to prevent stenosis after extensive esophageal endoscopic submucosal dissection (with videos). Gastrointest Endosc 2018; 87:380-389. [PMID: 28843584 DOI: 10.1016/j.gie.2017.08.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 08/06/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Endoscopic submucosal dissection (ESD) for extensive esophageal carcinomas may cause severe stenosis requiring endoscopic balloon dilations (EBDs). A standard prevention method has not been established. We propose the esophageal triamcinolone acetonide (TA)-filling method as a novel local steroid administration procedure. METHODS We enrolled 22 consecutive patients with early esophageal cancer who were treated using either subcircumferential or circumferential ESD (15 and 7 procedures, respectively) in this case series. Esophageal TA filling was performed on the day after ESD and 1 week later and was performed again if mild stenosis was found on follow-up. EBD with TA filling was performed only for severe stenosis that prevented endoscope passage. The primary endpoint was the incidence of severe stenosis. Secondary endpoints were the total number of EBDs and additional TA filling, dysphagia score, time to stenosis and to complete re-epithelialization, and any adverse events. RESULTS The incidence of severe stenosis was 4.5% (1/22; confidence interval, .1%-22.8%), and EBD was performed 2 times in 1 patient. Mild stenosis was found in 9 patients. Additional TA filling was performed in 45.5% of patients (10/22; median, 5 times; range, 1-13). The dysphagia score deteriorated to 1 to 2 in 31.8% (7/22) but showed a final score of 0 after complete re-epithelialization in 90.9% (20/22). The median time to stenosis was 3 weeks (range, 3-4) and that to complete re-epithelialization was 7 weeks (range, 4-36). No severe adverse events occurred. CONCLUSIONS The esophageal TA-filling method is highly effective for preventing severe stenosis after extensive esophageal ESD.
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Affiliation(s)
- Kotaro Shibagaki
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Norihisa Ishimura
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Naoki Oshima
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Tsuyoshi Mishiro
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Nobuhiko Fukuba
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Yuji Tamagawa
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Noritsugu Yamashita
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Hironobu Mikami
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Daisuke Izumi
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Hideaki Taniguchi
- Department of Gastroenterology, Tottori Municipal Hospital, Tottori, Japan
| | - Shuichi Sato
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Shunji Ishihara
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Yoshikazu Kinoshita
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
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38
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Chung EJ. Bioartificial Esophagus: Where Are We Now? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1064:313-332. [DOI: 10.1007/978-981-13-0445-3_19] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Oral epithelial cell sheets engraftment for esophageal strictures after endoscopic submucosal dissection of squamous cell carcinoma and airplane transportation. Sci Rep 2017; 7:17460. [PMID: 29234120 PMCID: PMC5727129 DOI: 10.1038/s41598-017-17663-w] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 11/29/2017] [Indexed: 12/20/2022] Open
Abstract
Endoscopic submucosal dissection (ESD) permits en bloc removal of superficial oesophageal squamous cell carcinoma (ESCC). However, post-procedure stricture is common after ESD for widespread tumours, and multiple endoscopic balloon dilation (EBD) procedures are required. We aimed to evaluate the safety and effectiveness of endoscopic transplantation of tissue-engineered autologous oral mucosal epithelial cell sheets that had been transported by air over a distance of 1200 km in controlling postprocedural oesophageal stricture. Ten patients who underwent complete circular or semicircular ESD for ESCC were transplanted with cell sheets. The safety of the entire process including cell sheet preparation, transport, ESD and cell sheet transplantation was assessed. The incidence of oesophageal stricture, number of EBD sessions, and time until epithelialization were investigated. Each ESD was successfully performed, with subsequent cell sheet engrafting carried out safely. Following cell sheet transplantation, the luminal stenosis rate was 40%, while the median number of EBD sessions was 0. The median post-ESD ulcer healing period was rather short at 36 days. There were no significant complications at any stage of the process. Cell sheet transplantation and preparation at distant sites and transportation by air could be a safe and promising regenerative medicine technology.
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40
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Abe S, Iyer PG, Oda I, Kanai N, Saito Y. Approaches for stricture prevention after esophageal endoscopic resection. Gastrointest Endosc 2017; 86:779-791. [PMID: 28713066 DOI: 10.1016/j.gie.2017.06.025] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 06/23/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Endoscopic resection of extensive esophageal lesions has become more common as endoscopic resection techniques and equipment have developed. However, extensive esophageal endoscopic resections can cause postoperative esophageal strictures, which have a negative impact on the quality of life of patients. We aimed to review current treatments and innovative approaches to prevent esophageal strictures after widespread endoscopic resection of esophageal lesions. METHODS We performed a comprehensive literature search from 2000 to 2016 using predetermined search terms to identify relevant articles and summarized their results as a narrative review. RESULTS A total of 21 original articles and case series were identified. A circumferential mucosal defect involving more than three fourths of the esophageal luminal circumference was the primary risk factor for developing an esophageal stricture after endoscopic resection. Oral and injectable steroid therapy demonstrated promise in preventing post-endoscopic submucosal dissection esophageal strictures, with both strategies significantly reducing the number of required endoscopic balloon dilations. More data are needed on prophylactic self-expandable metal stents, local botulinum toxin injection, and oral tranilast as a strategy to prevent post-endoscopic submucosal dissection esophageal strictures. Although preliminary studies of tissue-shielding resection sites with polyglycolic acid sheets and fibrin glue and autologous cell sheet transplantation have demonstrated promising results, additional larger validation studies are needed. CONCLUSIONS Oral and locally injected/administered steroids are first-line options for the prevention of esophageal strictures, but additional innovative solutions are being developed.
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Affiliation(s)
- Seiichiro Abe
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Prasad G Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ichiro Oda
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Nobuo Kanai
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
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Nagase K, Yamato M, Kanazawa H, Okano T. Poly(N-isopropylacrylamide)-based thermoresponsive surfaces provide new types of biomedical applications. Biomaterials 2017; 153:27-48. [PMID: 29096399 DOI: 10.1016/j.biomaterials.2017.10.026] [Citation(s) in RCA: 257] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 10/12/2017] [Accepted: 10/15/2017] [Indexed: 02/06/2023]
Abstract
Thermoresponsive surfaces, prepared by grafting of poly(N-isopropylacrylamide) (PIPAAm) or its copolymers, have been investigated for biomedical applications. Thermoresponsive cell culture dishes that show controlled cell adhesion and detachment following external temperature changes, represent a promising application of thermoresponsive surfaces. These dishes can be used to fabricate cell sheets, which are currently used as effective therapies for patients. Thermoresponsive microcarriers for large-scale cell cultivation have also been developed by taking advantage of the thermally modulated cell adhesion and detachment properties of thermoresponsive surfaces. Furthermore, thermoresponsive bioseparation systems using thermoresponsive surfaces for separating and purifying pharmaceutical proteins and therapeutic cells have been developed, with the separation systems able to maintain their activity and biological potency throughout the procedure. These applications of thermoresponsive surfaces have been improved with progress in preparation techniques of thermoresponsive surfaces, such as polymerization methods, and surface modification techniques. In the present review, the various types of PIPAAm-based thermoresponsive surfaces are summarized by describing their preparation methods, properties, and successful biomedical applications.
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Affiliation(s)
- Kenichi Nagase
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato, Tokyo 105-8512, Japan; Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan.
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan
| | - Hideko Kanazawa
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato, Tokyo 105-8512, Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan; Cell Sheet Tissue Engineering Center (CSTEC) and Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 30 South 2000 East, Salt Lake City, Utah 84112, USA.
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42
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Mizushima T, Ohnishi S, Hosono H, Yamahara K, Tsuda M, Shimizu Y, Kato M, Asaka M, Sakamoto N. Oral administration of conditioned medium obtained from mesenchymal stem cell culture prevents subsequent stricture formation after esophageal submucosal dissection in pigs. Gastrointest Endosc 2017; 86:542-552.e1. [PMID: 28153569 DOI: 10.1016/j.gie.2017.01.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 01/16/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Endoscopic submucosal dissection (ESD) for esophageal cancer often causes postoperative stricture when more than three fourths of the circumference of the esophagus is dissected. Mesenchymal stem cells are a valuable cell source in regenerative medicine, and conditioned medium (CM) obtained from mesenchymal stem cells reportedly inhibits inflammation. In this study we evaluated whether CM could prevent esophageal stricture after ESD. METHODS We resected a semi-circumference of pig esophagus by ESD. We prepared CM gel by mixing with 5% carboxymethyl cellulose and endoscopically applied it onto the wound bed immediately after ESD and on days 8 and 15 (weekly CM group) or administered it orally from days 1 to 4 (daily CM group). We also injected triamcinolone acetonide into the remaining submucosa immediately after ESD (steroid group). We killed the pigs on day 8 or day 22 to measure the stricture rate and to perform histologic analysis. RESULTS Stricture rate in weekly and daily CM groups and steroid groups were significantly lower than in the control group on day 22. Moreover, CM significantly attenuated the number of activated myofibroblasts and fiber thickness on day 22. CM also significantly decreased the infiltration of neutrophils and macrophages compared with the control group on day 8. CONCLUSIONS CM gel prevents esophageal stricture formation by suppressing myofibroblast activation and fibrosis after the infiltration of neutrophils and macrophages. Oral administration of CM gel is a promising treatment for the prevention of post-ESD stricture.
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Affiliation(s)
- Takeshi Mizushima
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shunsuke Ohnishi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hidetaka Hosono
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Kenichi Yamahara
- Department of Transfusion Medicine and Cell Therapy, Hyogo College of Medicine, Nishinomiya, Japan
| | - Momoko Tsuda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Yuichi Shimizu
- Division of Endoscopy, Hokkaido University Hospital, Sapporo, Japan
| | - Mototsugu Kato
- Division of Endoscopy, Hokkaido University Hospital, Sapporo, Japan
| | - Masahiro Asaka
- Department of Cancer Preventive Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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43
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WEO Newsletter. Dig Endosc 2017. [DOI: 10.1111/den.12889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
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44
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Barret M, Bordaçahar B, Beuvon F, Terris B, Camus M, Coriat R, Chaussade S, Batteux F, Prat F. Self-assembling peptide matrix for the prevention of esophageal stricture after endoscopic resection: a randomized controlled trial in a porcine model. Dis Esophagus 2017; 30:1-7. [PMID: 28375444 DOI: 10.1093/dote/dow015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 11/09/2016] [Indexed: 02/07/2023]
Abstract
Esophageal stricture formation after extensive endoscopic resection remains a major limitation of endoscopic therapy for early esophageal neoplasia. This study assessed a recently developed self-assembling peptide (SAP) matrix as a wound dressing after endoscopic resection for the prevention of esophageal stricture. Ten pigs were randomly assigned to the SAP or the control group after undergoing a 5-cm-long circumferential endoscopic submucosal dissection of the lower esophagus. Esophageal diameter on endoscopy and esophagogram, weight variation, and histological measurements of fibrosis, granulation tissue, and neoepithelium were assessed in each animal. The rate of esophageal stricture at day 14 was 40% in the SAP-treated group versus 100% in the control group (P = 0.2). Median interquartile range (IQR) esophageal diameter at day 14 was 8 mm (2.5-9) in the SAP-treated group versus 4 mm (3-4) in the control group (P = 0.13). The median (IQR) stricture indexes on esophagograms at day 14 were 0.32 (0.14-0.48) and 0.26 (0.14-0.33) in the SAP-treated and control groups, respectively (P = 0.42). Median (IQR) weight variation during the study was +0.2 (-7.4; +1.8) and -3.8 (-5.4; +0.6) in the SAP-treated and control groups, respectively (P = 0.9). Fibrosis, granulation tissue, and neoepithelium were not significantly different between the groups. The application of SAP matrix on esophageal wounds after a circumferential endoscopic submucosal dissection delayed the onset of esophageal stricture in a porcine model.
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Affiliation(s)
- M Barret
- Department of Gastroenterology, Cochin Hospital, Paris, France.,Faculté Paris Descartes, Paris, France.,Inserm Unit 1016, Paris, France
| | - B Bordaçahar
- Faculté Paris Descartes, Paris, France.,Inserm Unit 1016, Paris, France
| | - F Beuvon
- Faculté Paris Descartes, Paris, France.,Department of Pathology, Cochin Hospital, Paris, France
| | - B Terris
- Faculté Paris Descartes, Paris, France.,Department of Pathology, Cochin Hospital, Paris, France
| | - M Camus
- Department of Gastroenterology, Cochin Hospital, Paris, France.,Faculté Paris Descartes, Paris, France.,Inserm Unit 1016, Paris, France
| | - R Coriat
- Department of Gastroenterology, Cochin Hospital, Paris, France.,Faculté Paris Descartes, Paris, France.,Inserm Unit 1016, Paris, France
| | - S Chaussade
- Department of Gastroenterology, Cochin Hospital, Paris, France.,Faculté Paris Descartes, Paris, France
| | - F Batteux
- Faculté Paris Descartes, Paris, France.,Inserm Unit 1016, Paris, France.,Department of Immunology, Cochin Hospital, Paris, France
| | - F Prat
- Department of Gastroenterology, Cochin Hospital, Paris, France.,Faculté Paris Descartes, Paris, France.,Inserm Unit 1016, Paris, France
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Kasai Y, Takeda N, Kobayashi S, Takagi R, Yamato M. Cellular events and behaviors after grafting of stratified squamous epithelial cell sheet onto a hydrated collagen gel. FEBS Open Bio 2017; 7:691-704. [PMID: 28469981 PMCID: PMC5407900 DOI: 10.1002/2211-5463.12213] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 01/25/2017] [Accepted: 02/21/2017] [Indexed: 11/10/2022] Open
Abstract
Autologous stratified squamous epithelial cell sheets have been successfully used to treat epithelial defects in tissues such as the cornea and the esophagus. However, the regenerative cellular events occurring in the grafted epithelial cells are unclear in the early stages of wound healing. In this study, we created an in vitro grafting model using cultured normal human epidermal keratinocyte (NHEK) sheets and a type I collagen gel to investigate the cellular processes that occur within the grafted cell sheet. Cultured NHEK cells successfully became a stratified squamous cell sheet resembling epithelial tissue, retained expression of cellular integrins and adhesion proteins, and adhered successfully to a type I collagen gel. After culture on the collagen gel, expression of E‐cadherin, and β‐catenin decreased in the cells of the basal layer of the grafted cell sheet, resembling events characteristic of a partial epithelial–mesenchymal transition (EMT). These basal cells also induced migration of the cell sheet. Those phenomena are consistent with the essential events that occur in the wound‐healing process observed previously in cell studies. Therefore, the epithelial cell sheet grafted onto a type I collagen gel is a suitable model in vitro to study cellular events and behaviors. Furthermore, we also addressed the therapeutic mechanisms by which the epithelial cell sheet promotes wound healing.
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Affiliation(s)
- Yoshiyuki Kasai
- Department of Life Science and Medical Bioscience Graduate School of Advanced Science and Engineering Waseda University (TWIns) Shinjuku-ku Tokyo Japan.,Institute of Advanced Biomedical Engineering and Science Tokyo Women's Medical University (TWIns) Shinjuku-ku Tokyo Japan
| | - Naoya Takeda
- Department of Life Science and Medical Bioscience Graduate School of Advanced Science and Engineering Waseda University (TWIns) Shinjuku-ku Tokyo Japan
| | - Shinichiro Kobayashi
- Institute of Advanced Biomedical Engineering and Science Tokyo Women's Medical University (TWIns) Shinjuku-ku Tokyo Japan.,Department of Surgery Nagasaki University Graduate School of Biomedical Sciences Nagasaki-shi Nagasaki Japan
| | - Ryo Takagi
- Institute of Advanced Biomedical Engineering and Science Tokyo Women's Medical University (TWIns) Shinjuku-ku Tokyo Japan
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science Tokyo Women's Medical University (TWIns) Shinjuku-ku Tokyo Japan
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46
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Perrod G, Pidial L, Camilleri S, Bellucci A, Casanova A, Viel T, Tavitian B, Cellier C, Clément O, Rahmi G. ADSC-sheet Transplantation to Prevent Stricture after Extended Esophageal Endoscopic Submucosal Dissection. J Vis Exp 2017. [PMID: 28287510 DOI: 10.3791/55018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
In past years, the cell-sheet construct has spurred wide interest in regenerative medicine, especially for reconstructive surgery procedures. The development of diversified technologies combining adipose tissue-derived stromal cells (ADSCs) with various biomaterials has led to the construction of numerous types of tissue-engineered substitutes, such as bone, cartilage, and adipose tissues from rodent, porcine, or human ADSCs. Extended esophageal endoscopic submucosal dissection (ESD) is responsible for esophageal stricture formation. Stricture prevention remains challenging, with no efficient treatments available. Previous studies reported the effectiveness of mucosal cell-sheet transplantation in a canine model and in humans. ADSCs are attributed anti-inflammatory properties, local immune modulating effects, neovascularization induction, and differentiation abilities into mesenchymal and non-mesenchymal lineages. This original study describes the endoscopic transplantation of an ADSC tissue-engineered construct to prevent esophageal stricture in a swine model. The ADSC construct was composed of two allogenic ADSC sheets layered upon each other on a paper support membrane. The ADSCs were labeled with the PKH67 fluorophore to allow probe-based confocal laser endomicroscopy (pCLE) monitoring. On the day of transplantation, a 5-cm and hemi-circumferential ESD known to induce esophageal stricture was performed. Animals were immediately endoscopically transplanted with 4 ADSC constructs. The complete adhesion of the ADSC constructs was obtained after 10 min of gentle application. Animals were sacrificed on day 28. All animals were successfully transplanted. Transplantation was confirmed on day 3 with a positive pCLE evaluation. Compared to transplanted animals, control animals developed severe strictures, with major fibrotic tissue development, more frequent alimentary trouble, and reduced weight gain. In our model, the transplantation of allogenic ADSCs, organized in double cell sheets, after extended ESD was successful and strongly associated with a lower esophageal stricture rate.
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Affiliation(s)
- Guillaume Perrod
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; Department of Gastroenterology, Hôpital Européen Georges Pompidou; UMR-S970, Université Paris Descartes Sorbonne Paris Cité
| | | | - Sophie Camilleri
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; Department of Pathology, Hôpital Européen Georges Pompidou
| | - Alexandre Bellucci
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; UMR-S970, Université Paris Descartes Sorbonne Paris Cité; Department of Radiology, Hôpital Européen Georges Pompidou
| | | | - Thomas Viel
- UMR-S970, Université Paris Descartes Sorbonne Paris Cité
| | - Bertrand Tavitian
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; UMR-S970, Université Paris Descartes Sorbonne Paris Cité; Department of Radiology, Hôpital Européen Georges Pompidou
| | - Chirstophe Cellier
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; Department of Gastroenterology, Hôpital Européen Georges Pompidou
| | - Olivier Clément
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; UMR-S970, Université Paris Descartes Sorbonne Paris Cité; Department of Radiology, Hôpital Européen Georges Pompidou
| | - Gabriel Rahmi
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; Department of Gastroenterology, Hôpital Européen Georges Pompidou; UMR-S970, Université Paris Descartes Sorbonne Paris Cité;
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Narita T, Yunoki S, Ohyabu Y, Yahagi N, Uraoka T. In situ gelation properties of a collagen-genipin sol with a potential for the treatment of gastrointestinal ulcers. MEDICAL DEVICES-EVIDENCE AND RESEARCH 2016; 9:429-439. [PMID: 28008290 PMCID: PMC5170602 DOI: 10.2147/mder.s116633] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
We investigated the potential of collagen-genipin sols as biomaterials for treating artificial ulcers following endoscopic submucosal dissection. Collagen sol viscosity increased with condensation, allowing retention on tilted ulcers before gelation and resulting in collagen gel deposition on whole ulcers. The 1.44% collagen sols containing genipin as a crosslinker retained sol fluidity at 23°C for >20 min, facilitating endoscopic use. Collagen sols formed gel depositions on artificial ulcers in response to body temperature, and high temperature responsiveness of gelation because of increased neutral phosphate buffer concentration allowed for thick gel deposition on tilted ulcers. Finally, histological observations showed infiltration of gels into submucosal layers. Taken together, the present data show that genipin-induced crosslinking significantly improves the mechanical properties of collagen gels even at low genipin concentrations of 0.2-1 mM, warranting the use of in situ gelling collagen-genipin sols for endoscopic treatments of gastrointestinal ulcers.
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Affiliation(s)
- Takefumi Narita
- Biotechnology Group, Tokyo Metropolitan Industrial Technology Research Institute, Koto-ku
| | - Shunji Yunoki
- Biotechnology Group, Tokyo Metropolitan Industrial Technology Research Institute, Koto-ku
| | - Yoshimi Ohyabu
- Biotechnology Group, Tokyo Metropolitan Industrial Technology Research Institute, Koto-ku
| | - Naohisa Yahagi
- Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Shinjuku-ku
| | - Toshio Uraoka
- Department of Gastroenterology, National Hospital Organization Tokyo Medical Center, Meguro-ku, Tokyo, Japan
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48
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Lee DY, Kim HB, Shim IK, Kanai N, Okano T, Kwon SK. Treatment of chemically induced oral ulcer using adipose-derived mesenchymal stem cell sheet. J Oral Pathol Med 2016; 46:520-527. [PMID: 27805722 DOI: 10.1111/jop.12517] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND This study investigated the effects of mesenchymal stem cell (MSC) sheet transplantation on healing of chemically induced oral ulceration in a rabbit animal model. METHODS Oral mucosal ulcers were induced by topical application of filter paper soaked with 70% acetic acid to the anterior gingiva and buccal mucosa of 12 New Zealand white rabbits. The animals were randomly assigned to two groups: with (treatment group, n = 6) or without (control group, n = 6) cell sheets applied to ulcers. Gross findings were sequentially evaluated, and histologic examination was performed on day 7. RESULTS Based on gross inspection, ulceration resolved before day 5 in the treatment group; however, in the control group, healing was incomplete on day 7. In the treatment group, the total area of the ulcer decreased significantly from day 2 to day 5 (P < 0.001) and from day 5 to day 7 (P = 0.020), whereas the area decreased significantly from day 5 to day 7 in the control group (P < 0.001). Histologic and immunofluorescence examination revealed full-thickness mucosa healing and complete basal cell coverage in the treatment group; in contrast, only partial healing was observed on day 7 in the control group. CONCLUSIONS Cell sheet technology using MSC can be an alternative treatment for oral ulcerations in that it can decrease healing time without invasive properties.
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Affiliation(s)
- Doh Young Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Anam Hospital, Korea University Medical Center, Seoul, Korea
| | - Hee-Bok Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Dongguk University Ilsan Hospital, Goyang, Korea
| | - In Kyoung Shim
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Nobuo Kanai
- Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, Tokyo, Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, Tokyo, Japan
| | - Seong Keun Kwon
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea.,Cancer Research Institute, Seoul National University Hospital, Seoul, Korea.,Medical Research Center, Seoul National University Hospital, Seoul, Korea
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Kobayashi S, Kanai N, Tanaka N, Maeda M, Hosoi T, Fukai F, Eguchi S, Yamato M. Transplantation of epidermal cell sheets by endoscopic balloon dilatation to avoid esophageal re-strictures: initial experience in a porcine model. Endosc Int Open 2016; 4:E1116-E1123. [PMID: 27853736 PMCID: PMC5110348 DOI: 10.1055/s-0042-116145] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 08/01/2016] [Indexed: 01/06/2023] Open
Abstract
Background and study aims: Epidermal cell sheet (ECS) transplantation immediately after aggressive endoscopic submucosal dissection (ESD) has been shown to be safe and effective in the prevention of esophageal strictures. This study evaluated the feasibility of ECS transplantation after endoscopic balloon dilation (EBD) in a porcine model. Methods: Six pigs underwent circumferential esophageal ESD under general anesthesia. Two weeks later, two pigs underwent EBD and transplantation of an autologous ECS, two underwent EBD alone, and two underwent endoscopic observation only (control). Results: The two pigs in the transplantation group underwent six ECS transplants after EBD with five of the six (83 %) being successful, as shown by engraftment of transplanted ECSs after 7 days. No adverse events were observed. Stricture rates were lower in the two transplanted pigs (55 % and 60 %) than in the control (92.2 % and 87.7 %) and EBD-treated (71.7 % and 78.2 %) pigs. Infiltration of inflammatory cells was significantly lower in the transplanted pigs than in the control and EBD-treated pigs. Conclusion: Preliminary results indicate the stability of the ECS transplantation procedure and the engraftment of transplanted ECS in the tears after EBD. This proof-of-concept study suggests that covering tears with ECSs after EBD may avoid re-strictures.
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Affiliation(s)
- Shinichiro Kobayashi
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan,Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan
| | - Nobuo Kanai
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan,Corresponding author Nobuo Kanai, MD PhD Institute of Advanced Biomedical Engineering and ScienceTokyo Women’s Medical University8-1 Kawada-choShinjuku-kuTokyo 162-8666Japan+81-3-33596046
| | - Nobuyuki Tanaka
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan,Laboratory for Integrated Biodevice, Quantitative Biology Center – RIKEN, Fukita, Japan
| | - Masanori Maeda
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan
| | - Takahiro Hosoi
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan,Department of Pharmaceutical Sciences, Graduate School of Pharmaceutical Science, Tokyo University of Science, Noda, Japan
| | - Fumio Fukai
- Department of Pharmaceutical Sciences, Graduate School of Pharmaceutical Science, Tokyo University of Science, Noda, Japan
| | - Susumu Eguchi
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan
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50
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Dua KS, Hogan WJ, Aadam AA, Gasparri M. In-vivo oesophageal regeneration in a human being by use of a non-biological scaffold and extracellular matrix. Lancet 2016; 388:55-61. [PMID: 27068836 DOI: 10.1016/s0140-6736(15)01036-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Tissue-engineered extracellular matrix populated with autologous pluripotent cells can result in de-novo organogenesis, but the technique is complex, not widely available, and has not yet been used to repair large oesophageal defects in human beings. We aimed to use readily available stents and extracellular matrix to regenerate the oesophagus in vivo in a human being to re-establish swallowing function. METHODS In a patient aged 24 years, we endoscopically placed a readily available, fully covered, self-expanding, metal stent (diameter 18 mm, length 120 mm) to bridge a 5 cm full-thickness oesophageal segment destroyed by a mediastinal abscess and leading to direct communication between the hypopharynx and the mediastinum. A commercially available extracellular matrix was used to cover the stent and was sprayed with autologous platelet-rich plasma adhesive gel. The sternocleidomastoid muscle was placed over the matrix. After 4 weeks, stent removal was needed due to stent migration, and was replaced with three stents telescopically aligned to improve anchoring. The stents were removed after 3·5 years and the oesophagus was assessed by endoscopy, biopsy, endoscopic ultrasonography, and high-resolution impedance manometry. FINDINGS After stent removal we saw full-thickness regeneration of the oesophagus with stratified squamous epithelium, a normal five-layer wall, and peristaltic motility with bolus transit. 4 years after stent removal, the patient was eating a normal diet and maintaining a steady weight. INTERPRETATION Maintenance of the structural morphology of the oesophagus with off-the-shelf non-biological scaffold and stimulation of regeneration with commercially available extracellular matrix led to de-novo structural and functional regeneration of the oesophagus. FUNDING None.
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Affiliation(s)
- Kulwinder S Dua
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
| | - Walter J Hogan
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Abdul A Aadam
- Division of Gastroenterology and Hepatology, Northwestern University, Evanston, IL, USA
| | - Mario Gasparri
- Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
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