Tissue engineering-based strategies of prevention and treatment for esophageal stenosis after endoscopic submucosal dissection
Abstract
Due to lower trauma and higher resection rate, endoscopic submucosal dissection (ESD) has become the preferred therapy for early esophageal cancer. Esophageal stenosis is a common complication after ESD. A variety of methods are currently used to prevent and treat this complication, including oral administration or local injection of steroid hormones, balloon dilation, and stent implantation, but none are satisfactory when lesions exceed 3/4 of the esophageal circumference. With the development of tissue engineering and regenerative medicine, various biomaterials, including synthetic materials and natural materials, have been widely used and applied in wound healing and tissue regeneration. This review summarizes advancements in tissue engineering and regenerative medicine in wound repair, and focuses on the contribution of biomaterials in the prevention and treatment of esophageal stenosis after ESD to provide reference for exploring better strategies in clinical practice.
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References
1. He J, Chen WQ, Li ZS, et al. China guideline for the screening, early detection and early treatment of esophageal cancer (2022, Beijing). Zhonghua Zhong Liu Za Zhi. 2022; 44(6): 491-522.
2. Lorenzo D, Barret M, Leblanc S, et al. Outcomes of endoscopic submucosal dissection for early oesophageal squamous cell neoplasia at a Western centre. United European Gastroenterology Journal. 2019; 7(8): 1084-1092. doi: 10.1177/2050640619852260
3. Tomizawa Y, Friedland S, Hwang JH. Endoscopic submucosal dissection (ESD) for Barrett’s esophagus (BE)-related early neoplasia after standard endoscopic management is feasible and safe. Endoscopy International Open. 2020; 08(04): E498-E505. doi: 10.1055/a-0905-2465
4. Han C, Sun Y. Efficacy and safety of endoscopic submucosal dissection versus endoscopic mucosal resection for superficial esophageal carcinoma: a systematic review and meta-analysis. Diseases of the Esophagus. 2020; 34(4). doi: 10.1093/dote/doaa081
5. Park CH, Yang DH, Kim JW, et al. Clinical practice guideline for endoscopic resection of early gastrointestinal cancer. Intestinal Research. 2021; 19(2): 127-157. doi: 10.5217/ir.2020.00020
6. Minamide T, Kawata N, Maeda Y, et al. Clinical outcomes of endoscopic submucosal dissection for superficial circumferential esophageal squamous cell carcinoma. Gastrointestinal Endoscopy. 2023; 97(2): 232-240.e4. doi: 10.1016/j.gie.2022.09.027
7. Yu X, Liu Y, Xue L, et al. Risk factors for complications after endoscopic treatment in Chinese patients with early esophageal cancer and precancerous lesions. Surgical Endoscopy. 2020; 35(5): 2144-2153. doi: 10.1007/s00464-020-07619-z
8. Chen M, Dang Y, Ding C, et al. Lesion size and circumferential range identified as independent risk factors for esophageal stricture after endoscopic submucosal dissection. Surgical Endoscopy. 2020; 34(9): 4065-4071. doi: 10.1007/s00464-020-07368-z
9. Kim JS, Kim BW, Shin IS. Efficacy and Safety of Endoscopic Submucosal Dissection for Superficial Squamous Esophageal Neoplasia: A Meta-Analysis. Digestive Diseases and Sciences. 2014; 59(8): 1862-1869. doi: 10.1007/s10620-014-3098-2
10. Isomoto H, Yamaguchi N, Minami H, et al. Management of complications associated with endoscopic submucosal dissection/ endoscopic mucosal resection for esophageal cancer. Digestive Endoscopy. 2013; 25(S1): 29-38. doi: 10.1111/j.1443-1661.2012.01388.x
11. Zhang Y, Zhang B, Wang Y, et al. Advances in the prevention and treatment of esophageal stricture after endoscopic submucosal dissection of early esophageal cancer. Journal of Translational Internal Medicine. 2020; 8(3): 135-145. doi: 10.2478/jtim-2020-0022
12. DeNardi FG, Riddell RH. The Normal Esophagus. The American Journal of Surgical Pathology. 1991; 15(3): 296-309. doi: 10.1097/00000478-199103000-00010
13. Edwards DA. The oesophagus. Gut. 1971; 12(11): 948-956. doi: 10.1136/gut.12.11.948
14. Zhang Y, Bailey D, Yang P, et al. The development and stem cells of the esophagus. Development. 2021; 148(6). doi: 10.1242/dev.193839
15. Rosekrans SL, Baan B, Muncan V, et al. Esophageal development and epithelial homeostasis. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2015; 309(4): G216-G228. doi: 10.1152/ajpgi.00088.2015
16. Yang F, Hu Y, Shi Z, et al. The occurrence and development mechanisms of esophageal stricture: state of the art review. Journal of Translational Medicine. 2024; 22(1). doi: 10.1186/s12967-024-04932-2
17. Honda M, Nakamura T, Hori Y, et al. Process of healing of mucosal defects in the esophagus after endoscopic mucosal resection: histological evaluation in a dog model. Endoscopy. 2010; 42(12): 1092-1095. doi: 10.1055/s-0030-1255741
18. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nature Reviews Molecular Cell Biology. 2005; 6(4): 328-340. doi: 10.1038/nrm1619
19. Akiyama M, Matsuo I, Shimizu H. Formation of cornified cell envelope in human hair follicle development. British Journal of Dermatology. 2002; 146(6): 968-976. doi: 10.1046/j.1365-2133.2002.04869.x
20. Bouwstra JA, Helder RWJ, El Ghalbzouri A. Human skin equivalents: Impaired barrier function in relation to the lipid and protein properties of the stratum corneum. Advanced Drug Delivery Reviews. 2021; 175: 113802. doi: 10.1016/j.addr.2021.05.012
21. Wang Z, Zhou H, Zheng H, et al. Autophagy-based unconventional secretion of HMGB1 by keratinocytes plays a pivotal role in psoriatic skin inflammation. Autophagy. 2020; 17(2): 529-552. doi: 10.1080/15548627.2020.1725381
22. Kim BE, Kim J, Goleva E, et al. Particulate matter causes skin barrier dysfunction. JCI Insight. 2021; 6(5). doi: 10.1172/jci.insight.145185
23. de Koning HD, van den Bogaard EH, Bergboer JGM, et al. Expression profile of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins during skin barrier repair. British Journal of Dermatology. 2012; 166(6): 1245-1254. doi: 10.1111/j.1365-2133.2012.10885.x
24. van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cellular and Molecular Life Sciences. 2008; 65(23): 3756-3788. doi: 10.1007/s00018-008-8281-1
25. Biswas KH. Molecular Mobility-Mediated Regulation of E-Cadherin Adhesion. Trends in Biochemical Sciences. 2020; 45(2): 163-173. doi: 10.1016/j.tibs.2019.10.012
26. Beutel O, Maraspini R, Pombo-García K, et al. Phase Separation of Zonula Occludens Proteins Drives Formation of Tight Junctions. Cell. 2019; 179(4): 923-936.e11. doi: 10.1016/j.cell.2019.10.011
27. Nishimura Y, Ono M, Okubo N, et al. Application of polyglycolic acid sheets and basic fibroblast growth factor to prevent esophageal stricture after endoscopic submucosal dissection in pigs. Journal of Gastroenterology. 2023; 58(11): 1094-1104. doi: 10.1007/s00535-023-02032-4
28. Siegel I. Phagocytosis: Macrophage-Lymphocyte Interactions. JAMA: The Journal of the American Medical Association. 1981; 246(10): 1127. doi: 10.1001/jama.1981.03320100063037
29. Lu P, Takai K, Weaver VM, et al. Extracellular Matrix Degradation and Remodeling in Development and Disease. Cold Spring Harbor Perspectives in Biology. 2011; 3(12): a005058-a005058. doi: 10.1101/cshperspect.a005058
30. Phan QM, Sinha S, Biernaskie J, et al. Single‐cell transcriptomic analysis of small and large wounds reveals the distinct spatial organization of regenerative fibroblasts. Experimental Dermatology. 2020; 30(1): 92-101. doi: 10.1111/exd.14244
31. Phan QM, Fine GM, Salz L, et al. Lef1 expression in fibroblasts maintains developmental potential in adult skin to regenerate wounds. eLife. 2020; 9. doi: 10.7554/elife.60066
32. Kumar V, Ali MJ, Ramachandran C. Effect of mitomycin-C on contraction and migration of human nasal mucosa fibroblasts: implications in dacryocystorhinostomy. British Journal of Ophthalmology. 2015; 99(9): 1295-1300. doi: 10.1136/bjophthalmol-2014-306516
33. Seo BR, Chen X, Ling L, et al. Collagen microarchitecture mechanically controls myofibroblast differentiation. Proceedings of the National Academy of Sciences. 2020; 117(21): 11387-11398. doi: 10.1073/pnas.1919394117
34. Shu DY, Lovicu FJ. Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis. Progress in Retinal and Eye Research. 2017; 60: 44-65. doi: 10.1016/j.preteyeres.2017.08.001
35. El-Asmar KM, Hassan MA, Abdelkader HM, et al. Topical mitomycin C application is effective in management of localized caustic esophageal stricture: A double-blinded, randomized, placebo-controlled trial. Journal of Pediatric Surgery. 2013; 48(7): 1621-1627. doi: 10.1016/j.jpedsurg.2013.04.014
36. Zhang Y, Wang X, LIU L, et al. Intramuscular injection of mitomycin C combined with endoscopic dilation for benign esophageal strictures. Journal of Digestive Diseases. 2015; 16(7): 370-376. doi: 10.1111/1751-2980.12255
37. Werner S, Grose R. Regulation of Wound Healing by Growth Factors and Cytokines. Physiological Reviews. 2003; 83(3): 835-870. doi: 10.1152/physrev.2003.83.3.835
38. Hosseini M, Shafiee A. Engineering Bioactive Scaffolds for Skin Regeneration. Small. 2021; 17(41). doi: 10.1002/smll.202101384
39. Hutmacher DW. Scaffolds in tissue engineering bone and cartilage. Biomaterials. 2000; 21(24): 2529-2543.
40. Li X, You R, Luo Z, et al. Silk fibroin scaffolds with a micro-/nano-fibrous architecture for dermal regeneration. Journal of Materials Chemistry B. 2016; 4(17): 2903-2912. doi: 10.1039/c6tb00213g
41. Chouhan D, Chakraborty B, Nandi SK, et al. Role of non-mulberry silk fibroin in deposition and regulation of extracellular matrix towards accelerated wound healing. Acta Biomaterialia. 2017; 48: 157-174. doi: 10.1016/j.actbio.2016.10.019
42. Ju YM, Yu B, West L, et al. A novel porous collagen scaffold around an implantable biosensor for improving biocompatibility. II. Long‐term in vitro/in vivo sensitivity characteristics of sensors with NDGA‐ or GA‐crosslinked collagen scaffolds. Journal of Biomedical Materials Research Part A. 2009; 92A(2): 650-658. doi: 10.1002/jbm.a.32400
43. Kundu B, Rajkhowa R, Kundu SC, et al. Silk fibroin biomaterials for tissue regenerations. Advanced Drug Delivery Reviews. 2013; 65(4): 457-470. doi: 10.1016/j.addr.2012.09.043
44. Suntornnond R, Tan EYS, An J, et al. A highly printable and biocompatible hydrogel composite for direct printing of soft and perfusable vasculature-like structures. Scientific Reports. 2017; 7(1). doi: 10.1038/s41598-017-17198-0
45. Houshyar S, Kumar GS, Rifai A, et al. Nanodiamond/poly-ε-caprolactone nanofibrous scaffold for wound management. Materials Science and Engineering: C. 2019; 100: 378-387. doi: 10.1016/j.msec.2019.02.110
46. Stratton S, Shelke NB, Hoshino K, et al. Bioactive polymeric scaffolds for tissue engineering. Bioactive Materials. 2016; 1(2): 93-108. doi: 10.1016/j.bioactmat.2016.11.001
47. Han Y, Li Y, Zeng Q, et al. Injectable bioactive akermanite/alginate composite hydrogels for in situ skin tissue engineering. Journal of Materials Chemistry B. 2017; 5(18): 3315-3326. doi: 10.1039/c7tb00571g
48. Li Y, Han Y, Wang X, et al. Multifunctional Hydrogels Prepared by Dual Ion Cross-Linking for Chronic Wound Healing. ACS Applied Materials & Interfaces. 2017; 9(19): 16054-16062. doi: 10.1021/acsami.7b04801
49. Zhou Y, Gao L, Peng J, et al. Bioglass Activated Albumin Hydrogels for Wound Healing. Advanced Healthcare Materials. 2018; 7(16). doi: 10.1002/adhm.201800144
50. Mikos AG, McIntire LV, Anderson JM, Babensee JE. Host response to tissue engineered devices. Adv Drug Deliv Rev. 1998; 33(1-2): 111-139.
51. Tabata Y. Biomaterial technology for tissue engineering applications. Journal of The Royal Society Interface. 2009; 6(suppl_3). doi: 10.1098/rsif.2008.0448.focus
52. Nam K, Kimura T, Funamoto S, et al. Preparation of a collagen/polymer hybrid gel designed for tissue membranes. Part I: Controlling the polymer–collagen cross-linking process using an ethanol/water co-solvent. Acta Biomaterialia. 2010; 6(2): 403-408. doi: 10.1016/j.actbio.2009.06.021
53. Zuercher BF, George M, Escher A, et al. Stricture prevention after extended circumferential endoscopic mucosal resection by injecting autologous keratinocytes in the sheep esophagus. Surgical Endoscopy. 2012; 27(3): 1022-1028. doi: 10.1007/s00464-012-2509-8
54. Honda M, Hori Y, Nakada A, et al. Use of adipose tissue-derived stromal cells for prevention of esophageal stricture after circumferential EMR in a canine model. Gastrointestinal Endoscopy. 2011; 73(4): 777-784. doi: 10.1016/j.gie.2010.11.008
55. Mizushima T, Ohnishi S, Hosono H, et al. Oral administration of conditioned medium obtained from mesenchymal stem cell culture prevents subsequent stricture formation after esophageal submucosal dissection in pigs. Gastrointestinal Endoscopy. 2017; 86(3): 542-552.e1. doi: 10.1016/j.gie.2017.01.024
56. Su S, Pang T, Wang Y, et al. Prevention of Esophageal Stricture after Endoscopic Submucosal Dissection with an Autologous Esophageal Epithelial Cell Suspension: An Animal Study. Discovery Medicine. 2023; 35(179): 1026. doi: 10.24976/discov.med.202335179.98
57. Abbas O, Mahalingam M. Epidermal stem cells: practical perspectives and potential uses. British Journal of Dermatology. 2009; 161(2): 228-236. doi: 10.1111/j.1365-2133.2009.09250.x
58. Kopp J, Jeschke MG, Bach AD, et al. Applied tissue engineering in the closure of severe burns and chronic wounds using cultured human autologous keratinocytes in a natural fibrin matrix. Cell Tissue Bank. 2004; 5(2): 89-96.
59. El-Ghalbzouri A, Gibbs S, Lamme E, et al. Effect of fibroblasts on epidermal regeneration. British Journal of Dermatology. 2002; 147(2): 230-243. doi: 10.1046/j.1365-2133.2002.04871.x
60. Wang JHC, Thampatty BP, Lin JS, et al. Mechanoregulation of gene expression in fibroblasts. Gene. 2007; 391(1-2): 1-15. doi: 10.1016/j.gene.2007.01.014
61. Plikus MV, Gay DL, Treffeisen E, et al. Epithelial stem cells and implications for wound repair. Seminars in Cell & Developmental Biology. 2012; 23(9): 946-953. doi: 10.1016/j.semcdb.2012.10.001
62. Phinney DG. Functional heterogeneity of mesenchymal stem cells: Implications for cell therapy. Journal of Cellular Biochemistry. 2012; 113(9): 2806-2812. doi: 10.1002/jcb.24166
63. Takagi R, Yamato M, Murakami D, et al. Fabrication and Validation of Autologous Human Oral Mucosal Epithelial Cell Sheets to Prevent Stenosis after Esophageal Endoscopic Submucosal Dissection. Pathobiology. 2011; 78(6): 311-319. doi: 10.1159/000322575
64. Ohki T, Yamato M, Ota M, et al. Prevention of Esophageal Stricture After Endoscopic Submucosal Dissection Using Tissue-Engineered Cell Sheets. Gastroenterology. 2012; 143(3): 582-588.e2. doi: 10.1053/j.gastro.2012.04.050
65. Jonas E, Sjöqvist S, Elbe P, et al. Transplantation of tissue‐engineered cell sheets for stricture prevention after endoscopic submucosal dissection of the oesophagus. United European Gastroenterology Journal. 2016; 4(6): 741-753. doi: 10.1177/2050640616631205
66. Kanai N, Yamato M, Ohki T, et al. Fabricated autologous epidermal cell sheets for the prevention of esophageal stricture after circumferential ESD in a porcine model. Gastrointestinal Endoscopy. 2012; 76(4): 873-881. doi: 10.1016/j.gie.2012.06.017
67. Kobayashi S, Kanai N, Tanaka N, et al. Transplantation of epidermal cell sheets by endoscopic balloon dilatation to avoid esophageal re-strictures: initial experience in a porcine model. Endoscopy International Open. 2016; 04(11): E1116-E1123. doi: 10.1055/s-0042-116145
68. Liu X, Inda ME, Lai Y, et al. Engineered Living Hydrogels. Advanced Materials. 2022; 34(26). doi: 10.1002/adma.202201326
69. Wang C, Varshney RR, Wang DA. Therapeutic cell delivery and fate control in hydrogels and hydrogel hybrids. Advanced Drug Delivery Reviews. 2010; 62(7-8): 699-710. doi: 10.1016/j.addr.2010.02.001
70. Griffin DR, Archang MM, Kuan CH, et al. Activating an adaptive immune response from a hydrogel scaffold imparts regenerative wound healing. Nature Materials. 2020; 20(4): 560-569. doi: 10.1038/s41563-020-00844-w
71. Peura M, Kaartinen I, Suomela S, et al. Improved skin wound epithelialization by topical delivery of soluble factors from fibroblast aggregates. Burns. 2012; 38(4): 541-550. doi: 10.1016/j.burns.2011.10.016
72. Iizuka T, Kikuchi D, Yamada A, et al. Polyglycolic acid sheet application to prevent esophageal stricture after endoscopic submucosal dissection for esophageal squamous cell carcinoma. Endoscopy. 2014; 47(04): 341-344. doi: 10.1055/s-0034-1390770
73. Sakaguchi Y, Tsuji Y, Ono S, et al. Polyglycolic acid sheets with fibrin glue can prevent esophageal stricture after endoscopic submucosal dissection. Endoscopy. 2014; 47(04): 336-340. doi: 10.1055/s-0034-1390787
74. Chai NL, Feng J, Li LS, et al. 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 Journal of Gastroenterology. 2018; 24(9): 1046-1055. doi: 10.3748/wjg.v24.i9.1046
75. Sakaguchi Y, Tsuji Y, Sato J, et al. Repeated steroid injection and polyglycolic acid shielding for prevention of refractory esophageal stricture. Surgical Endoscopy. 2023; 37(8): 6267-6277. doi: 10.1007/s00464-023-10111-z
76. Tang J, Ye S, Ji X, et al. Deployment of carboxymethyl cellulose sheets to prevent esophageal stricture after full circumferential endoscopic submucosal dissection: A porcine model. Digestive Endoscopy. 2018; 30(5): 608-615. doi: 10.1111/den.13070
77. Silva OA, Pellá MG, Sabino RM, et al. Carboxymethylcellulose hydrogels crosslinked with keratin nanoparticles for efficient prednisolone delivery. International Journal of Biological Macromolecules. 2023; 241: 124497. doi: 10.1016/j.ijbiomac.2023.124497
78. Zhang Y, Mao XL, Zhu W, et al. Esophageal Mucosal Autograft for Preventing Stricture After Widespread Endoscopic Submucosal Dissection of Superficial Esophageal Lesions. Turkish Journal of Gastroenterology. 2022; 33(4): 312-319. doi: 10.5152/tjg.2021.201032
79. Liu Y, Li Z, Dou L, et al. Autologous esophageal mucosa with polyglycolic acid transplantation and temporary stent implantation can prevent stenosis after circumferential endoscopic submucosal dissection. Annals of Translational Medicine. 2021; 9(7): 546-546. doi: 10.21037/atm-20-6987
80. Hochberger J, Koehler P, Wedi E, et al. Transplantation of Mucosa From Stomach to Esophagus to Prevent Stricture After Circumferential Endoscopic Submucosal Dissection of Early Squamous Cell. Gastroenterology. 2014; 146(4): 906-909. doi: 10.1053/j.gastro.2014.01.063
81. Liu Y, Dou L, Song T, et al. Successful prevention of post-endoscopic submucosal dissection esophageal stenosis by using autologous buccal mucosa with polyglycolic acid and self-help inflatable balloon. Gastrointest Endosc. 2023.
82. Zou J, Chai N, Linghu E, et al. Autologous skin-grafting surgery to prevent esophageal stenosis after complete circular endoscopic submucosal tunnel dissection: a case-matched controlled study. Surgical Endoscopy. 2020; 35(11): 5962-5970. doi: 10.1007/s00464-020-08081-7
83. Nieponice A, McGrath K, Qureshi I, et al. An extracellular matrix scaffold for esophageal stricture prevention after circumferential EMR. Gastrointestinal Endoscopy. 2009; 69(2): 289-296. doi: 10.1016/j.gie.2008.04.022
84. Schomisch S, Yu L, Wu Y, et al. Commercially available biological mesh does not prevent stricture after esophageal mucosectomy. Endoscopy. 2013; 46(02): 144-148. doi: 10.1055/s-0033-1344997
85. Zhou X bin, Li S wei, He S qin, et al. Transplantation of acellularized dermis matrix (ADM) plus fully covered metal stent to prevent stricture after circumferential endoscopic submucosal dissection of early esophageal cancer (with video). Regenerative Therapy. 2021; 18: 441-446. doi: 10.1016/j.reth.2021.10.002