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The occurrence and development mechanisms of esophageal stricture: state of the art review

Journal of Translational Medicine volume 22, Article number: 123 (2024) Cite this article

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.

Introduction

The esophagus is a canal extending from the pharynx to the stomach and transporting food and water from mouth to stomach [1, 2]. Histologically, the esophagus can be divided into four architectural layers in cross-section; mucosal, submucosal, muscular, and extima. The mucosal layer is subdivided into the epithelium, composed of non-keratinized stratified squamous epithelial cells, the lamina propria, and the mucosal muscle. The esophagus muscle contains the inner circular and outer longitudinal muscular bilayers, consisting of skeletal muscle cells at the upper one-third and smooth muscle cells at the bottom one-third length with the mixture in the middle. The stability of the internal esophageal environment is crucial for the normal esophagus[3, 4].

With the development of contemporary endoscopic techniques, from ordinary endoscopic mucosal resection (EMR) to endoscopic submucosal dissection (ESD) [5], more and more esophageal diseases can be treated with endoscopic technology [6,7,8]. Figure 1 shows a typical clinical esophageal stricture case (provided by the Department of Gastroenterology of the Hospital Affiliated to School of Medicine, Ningbo University). The progression of postoperative esophageal strictures is torture for both patients and clinicians. The literature reports that resection of more than 3/4 circumference of the esophageal mucosa with ESD is a high-risk factor for esophageal stricture [9], with an incidence of 100% and 56–76% for esophagotomy and non-esophagotomy, respectively [10,11,12,13,14,15].

Fig. 1
figure 1

The stricture case after endoscopic submucosal dissection (ESD) surgery due to early-stage esophageal cancer. a Postoperative wound; b metal stents were placed towards preventing stricture; c the stent was removed after two months post-operation; d stricture recurred 20 days after stent removal; e completely blocked one and a half months after stent removal; f surgical stent placement again. The case was provided by the Department of Gastroenterology of Hospital Affiliated with Ningbo University School of Medicine

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In recent years, with the development of genomics and proteomics, the biological mechanisms leading to esophageal strictures are becoming more apparent. However, there are still many mysteries that remain to be solved. Some scholars believe that excessive tissue fibrosis is closely related to esophageal strictures and that the biological mechanisms leading to esophageal fibrosis may be an entry point for esophageal strictures. Topical use of Mitomycin C (MMC), a chemotherapeutic agent that inhibits fibrosis, at esophageal strictures can reduce the number of physical dilatations and give evidence of excessive fibrotic mechanisms leading to esophageal strictures [16].

Some scholars believe that esophageal stricture is associated with the excessive inflammatory response in the injured local tissues. A timely inflammatory response due to immune stress is beneficial for organism repair. Still, an excessive inflammatory response will be accompanied by a fractional secretion of inflammatory factors by immune cells and somatic cells, eventually leading to esophageal stricture. Steroids, clinically representative as anti-inflammatory therapy, are currently the main therapeutic agents for the prevention and treatment of esophageal strictures because oral administration with steroids before surgery and/or local injection in the postoperative region have some inhibitory effect on esophageal strictures [15, 17,18,19]. The usage of steroids gives supporting evidence that the inhibition of inflammatory response might be the mechanism of the occurrence of esophageal stricture. However, the efficiency of oral feeding or local injection is not the same for all esophageal patients; there are significant differences in patients with diverse disease seriousness or sensitivity to steroids.

Currently, some scholars focus on the loss of esophageal epithelial barrier function that ultimately leads to esophageal stricture [20,21,22,23]. The proposed mechanism gives a new direction to the mechanism of esophageal stricture. Under the influence of some microenvironments, the expression of genes and proteins of esophageal epithelial cells is altered, leading to the dysfunction of the esophageal epithelial barrier and eventually esophageal stricture [24,25,26,27,28,29,30,31]. With the progress of research in tissue engineering, the re-epithelialization of the esophagus is sought to be accomplished by biomaterial-assisted cells (e.g., cell patches, etc.) [32,33,34], thus treating esophageal strictures. The therapeutic approach of tissue engineering argues for the stricture's mechanism [35,36,37,38,39,40,41].

Until now, we have found that neither the hyper-fibrosis, the inflammatory response, nor even barrier damage can explain the mechanisms of esophageal strictures at a single level. In the clinic, neither treatments of repeat endoscopic dilation, steroid administration, etc. nor tissue engineering technologies like biological scaffolds can fundamentally solve the problem of esophageal stricture. The recurrence and repeated dilation are unavoidable. In recent years, the mechanism of esophageal stricture has been detected with the advances in molecular biology, genomics, and proteomics, though it is still unclear. Therefore, it is necessary to clarify the biological mechanisms of esophageal stricture so as to develop clinic therapies for this disease. This review aims to detect the possible molecular mechanisms and the key factors leading to esophageal stricture, further providing probable molecular targets or novel methods for treating the stricture.

Biological mechanisms of esophageal stricture

Inflammatory response

The inflammatory response is a typical defense of the human body against external stimuli such as bacteria, viruses, or other antigens. A timely and moderate inflammation can efficiently remove harmful antigens and allow the body to recover. However, incomplete removal of harmful antigens or the persistent inflammatory response will transform acute inflammation into chronic inflammation, inducing the secretion of many cytokines and profibrotic factors. In the case of esophageal disease, chronic inflammation will cause progressive or even excessive fibrosis, excessive deposition of extracellular matrix (ECM) [42,43,44], and eventually lead to the occurrence of stricture. The inflammatory response requires a high degree of cooperation among all systems in the body, of which the immune system takes the lead and plays a vital role inefficiently clearing harmful antigens.

The activation of the immune system often begins with phagocytosis of macrophages [45], stronger phagocytosis shorter duration of the disease [46]. The critical role of macrophages is to balance the inflammatory regression and fibrotic progress [47, 48]. Local stimulation or invasion of harmful antigens induces the migration of macrophages, which gradually move toward the center of inflammation occurrence. At the same time, myofibroblasts emerge, both generating complex-forming signaling and close intercellular communication [49,50,51]. Macrophages secrete a variety of cytokines, including pro-fibrotic cytokines like transforming growth factor (TGF-β), which in turn promote the occurrence of fibrosis [52, 53]. Effective inflammatory response, accompanied by rapidly recruiting macrophages that phagocytose pathogens and secrete cytokines to act on fibroblasts, promotes inflammatory healing and wound repair. In the esophagus as well, when inflammation is not healed in a timely manner, pro-inflammatory factors lead to over-differentiation of fibroblasts into myofibroblasts, which in turn results in an accumulation of ECM, leading to tissue fibrosis and ultimately esophageal stricture (Fig. 2).

Fig. 2
figure 2

Relationship between macrophages and fibroblasts in the inflammatory response during esophageal physiological healing and hyperfibrotic healing

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Macrophage acts as a “bridge” from inflammation to fibrosis-related diseases. They are involved in all phases of the fibrotic progress, with various roles and phenotypes as the fibrosis develops [54,55,56]. The phagocytosis of macrophages has an inhibitory effect on the fibrotic phenotype [57]. Several studies verified that macrophages can shift themselves into myofibroblasts directly, exacerbating the occurrence of fibrosis and accelerating fibrosis-related disease in some pathological cases, for example, renal fibrosis [58,59,60,61,62,63].

In esophagus-related diseases, the inflammatory bio-condition of the organ seems to be gradual and severe progress, from the beginning of gastroesophageal reflux where gastric acid or H+ions coming from foods constantly stimulate the mucosa tissue of the esophagus to produce damage and inflammatory stress response, to the pathological changes in the epithelium to cause diseases like Barrett's esophagus (BE) and even tumor occurrence. It can be found that the inflammatory response is in the progression of every stage of esophageal diseases. With inflammatory infiltration, the expression of critical genes about the activity and development of normal cells, such as BMP4 and PTGS2, etc., alters abnormally [64,65,66,67].

Esophagitis is the most common disease of esophagus in clinics. Eosinophilic esophagitis (EoE) is the relatively specific one among inflammatory-related diseases. The progression often varies with age, manifesting as an inflammatory response in children and as fibrosis or/and esophageal stricture in adults [68, 69]. Allergens, excess cytokines, or antigens leading to Eosinophilia in local tissues are the main pathways of EoE [70,71,72,73]. For example, Eosinophilia was developed in mice infected by Aspergillus fumigatus, which was verified that eosinophil accumulation and collagen deposition were mainly associated with interleukin-5 (IL-5) [74]. This allergic reaction produces various cytokines and mediators, causing diffuse esophagitis, esophageal hyperhidrosis, and eventually esophageal stricture. This may explain that EoE presents as inflammation in children but hyperfibrosis and esophageal stricture in adults with the disease progression.

The present treatment in the clinic, oral medication or steroid injection, should support this inflammatory mechanism. Steroids are standard medicine adopted to moderate inflammation. Injection of steroid medicine like triamcinolone acetate into the focal infected area to be operated on [75]. This prophylactic steroid injection has been applied as one method to prevent esophageal stricture after the ESD surgery [13, 19]. Ramage et al. reported that steroid injection combined with balloon dilatation significantly reduced the dilatation frequency from 60 to 13% (p < 0.01) for recurrent dysphagia patients with esophageal stricture. The recurrence of esophageal stricture was delayed from 9 to 15 months(p < 0.01) [76]. In a randomized controlled trial (RCT), Takahashi et al. explored the therapeutic effects of steroid use for esophageal strictures. Thirty-two patients with mucosal defects involving ≥ 75% of the esophageal circumference were randomized to treatment with local injection of steroids (n = 16) and conventional treatment (n = 16). The results revealed a significant reduction in the number of re-dilatation procedures in the group treated with steroids, but a five-significant difference in the frequency of upper esophageal strictures. This reveals that prophylactic endoscopic steroid injection appears to be a safe means of relieving the severity of esophageal stricture following extensive ESD [14]. However, it is debatable till now whether it is necessary to administer a specific steroid dose, how often injections should be performed, and what’s the efficiency to prevent the stricture.

Undoubtedly, the inflammatory responses are incremental in the progression of esophageal disease. Once acute inflammation is not cured in time, it will turn into chronic inflammation. Chronic inflammation causes the mucosa tissue to fluctuate frequently between damage and repair, leading to hyperfibrosis occurrence; finally, esophageal stricture appears. The limited treatments against esophageal stricture, for example, local injection of steroids, take only partial effects, incompletely inhibiting inflammation and fibrosis. Thus, controlling the inflammatory response alone in response to hyperfibrosis is often insufficient and portends that intervening in the process of fibrosis progression is also particularly important, as discussed in the next section.

Excessive differentiation of fibroblasts

Fibroblast exists in most tissues and organs of the human body with a normal spindle shape. It plays an essential role in the secretion of ECM and the formation of granulation. When the tissue is injured, it takes part in wound healing through secreting ECM to give the body good "soil" and creating new connective tissue by depositing fibers, elastin, and laminin. In this case, the fibroblast undergoes a differentiation to become myofibroblast to promote organism repair when the homeostatic environment is disrupted, or the organism is under stressful situations [77,78,79]. The balance of matrix metalloproteinases (MMPs) and the inhibitors of MMPs in the microenvironment can remodel the structure of the ECM that is excessively secreted by myofibroblasts. Regular repair is accompanied by fibroblast differentiation and significant but not excessive ECM secretion, which play a critical role in the body during physiological healing (Fig. 3). Due to the altered microenvironment at the injury site, the emergence of various immune cells and the secretion of cytokines and ECM will promote fibroblasts to differentiate into myofibroblasts. Pakshiret al. found that myofibroblasts promote tissue repair by excessively expressing α-smooth muscle actin (α-SMA) to recruit myofibroblasts onto large amounts of ECM [80]. In research, the targeted transformation from fibroblasts to myofibroblasts is often determined by fluorescently labeling α- SMA [81].

Fig. 3
figure 3

Transformation of fibroblasts and extracellular matrix during esophageal physiological healing and hyperfibrotic healing

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Although myofibroblasts are particularly important in physiological repair, their roles are different at different periods in physiological healing. In chronic wound or chronic inflammation, the shift from fibroblast to myofibroblast can lead passively to excessive deposition of ECM and disorganized accumulation of cells, ultimately leading to hyperfibrotic healing, which manifests as esophageal stricture in the esophagus (Fig. 3) [16, 81,82,83]. According to epidemiological statistics, organ dysfunction due to fibrotic disease eventually leads to the death of about 45% of patients in the developed countries [84,85,86]. Hyperfibrosis in fibrotic disorders arises through the interplay of numerous biomarkers and molecular targets. These biomarkers (chemokines, pro-inflammatory factors, TGF-β superfamily, etc.) ultimately lead to organ or tissue hyperfibrosis by participating in different signaling pathways (Table 1). Specifically, the chemokine CCL2/MCP-1 is implicated in provoking an inflammatory response that leads to the over-differentiation of fibroblasts, a key event in the pathogenesis of fibrosis. Moreover, these biomarkers, which are instrumental in the progression of fibrosis, may also be exploited therapeutically to impede this process. For instance, Cenicriviroc, a selective inhibitor of CCL2/MCP-1, demonstrates anti-fibrotic properties by inhibiting the recruitment of macrophages into the local inflammatory environment [87, 88].

Table 1 Selected biomarkers of mechanisms leading to excessive fibrosis
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Histologically, the main layers of esophageal stricture caused by the esophageal disease are in the muscularis mucosa and submucosa, where the conversion of fibroblasts to myofibroblasts is undoubtedly essential in case of damage. It can contribute to the repair of damaged tissue. However, as mentioned above, persistent pathological activation of myofibroblast transformation will lead to the development of esophageal fibrosis and even tumorigenesis [70]. Fibroblast-to-myofibroblast shift is mainly mediated by activation of TGF-β pathway [89, 90], followed by activation of TGF-β receptor downstream molecules like Smads, JunD [91, 92], and other interconnected signaling pathways such as platelet-derived growth factor pathway (PDGF) and receptor tyrosine kinase pathways (RPTKs) [93,94,95,96]. These downstream receptors and signaling molecules eventually lead to fiber-derived cell proliferation, motility, secretion of ECM and cellular morphological transformation, and even cell mis-differentiation [97,98,99]. The esophageal fibrogenic cells (predominantly myofibroblasts) in the mucosal muscle and submucosa eventually lead to excessive fibrosis, stiffness, and finally stricture of the esophagus.

In the clinic, local injections of MMC are employed to treat recurrent esophageal strictures. MMC is a chemotherapeutic reagent applied topically to inhibit fibrosis towards curing post-surgical scarring [113,114,115,116]. In a rigorously designed double-blind trial, El-Asmar et al. explored the efficacy of MMC for esophageal stricture management. Forty patients from their medical center, spanning from January 2008 to October 2010, were randomly split into two groups: one receiving MMC and the other a placebo. Post six months of monitoring and assessment, the MMC group demonstrated an 80% success rate in stricture resolution, significantly surpassing the placebo group's 35% improvement. Additionally, the MMC group averaged fewer dilation procedures (n = 3.85 ± 2.08) compared to the placebo recipients (n = 6.9 ± 2.12), highlighting MMC's role in reducing the need for repetitive treatments for those suffering from esophageal strictures [16]. Findings from this clinical trial reveal that the local application of MMC, which inhibits the excessive differentiation of fibroblasts, can partly impede the progression of esophageal stricture. This indicates that the over-differentiation of fibroblasts contributes to esophageal stricture. Because the esophagus serves as an elongated passage to the external world, it is particularly critical to avert the excessive differentiation of fibroblasts by exogenous factors, a subject further explored in the next section on the EEB [20].

Damage of the esophageal epithelial barrier (EEB)

The epithelium of the esophagus consists of stratified nonkeratinized squamous epithelial cells. The cells synthesize keratinized envelope proteins to form the intact EEB structure, as shown in Fig. 4. This EEB can effectively block the attack of foreign antigens and allergens, H+ ions, etc., to protect the inner tissue [117,118,119]. Many kinds of esophageal diseases result from the damage of this EEB structure [120, 121]. However, few studies show how EEB damage leads to diseases. Simultaneously, the biological mechanisms of esophageal stricture related to EEB damage have been poorly investigated.

Fig. 4
figure 4

Schematic diagram of the Esophageal epithelial barrier (EEB) structure in the esophagus

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Keratin 14 (KRT 14) and filaggrin (FLG) are important proteins in the formation of the cornified envelope in the esophageal epithelial cells of the EEB structure. E-cadherin (E-cad) and Zonula Occludens (ZO-1) are important proteins for the esophageal epithelial cell–cell junctions in the EEB structure. They work together to maintain the normal function of the EEB [122,123,124,125,126,127]. A significant decrease of these proteins would result in spongy-like loosening among epithelial cells, increasing the intercellular gap and weakening the barrier function of EEB [128]. The enlarged gaps between epithelial cells in the patients with reflux esophagitis were once observed by laser confocal microscopy, which verified the theory about the relationship between EEB function and esophagitis [129]. Because the enlargement of the epithelial cell gaps will let H+ ions and other antigenic substances from diets or gastric reflux cross the EEB and invade the mucosa or/and submucosa, an allergic reaction or inflammatory response is triggered, ultimately leading to the occurrence of esophagitis [128] or BE [130,131,132]. These findings provide clues to the link between the damage of EEB structure and the occurrence of stricture diseases.

EEB dysfunction occurs in many pathologic conditions, including EoE, gastroesophageal reflux disease (GERD), and BE. The normal esophagus maintains proper spaces and junctions among epithelial cells. Proteins like ZO-3, ZO-1, and filaggrin are highly expressed [128]. However, in the diseased esophagus, dilatation of intercellular spaces is a prominent feature observed on light or under electron microscopy. The expressions of those proteins are reduced significantly. Using the transmission electron microscope (TEM), investigators have found the dilated intercellular space and thus documented it as a sensitive marker in patients with GERD and BE [131]. Once the GERD or the BE recurs, the eventual outcome is the esophageal stricture.

The mucosal ulcers cause EEB damage. Many specific cytokines, such as insulin growth factor-1 (IGF-1) and platelet-derived growth factor-C (PDGF-C) etc. will be produced [132]. These cytokines induce myofibroblasts to secrete large amounts of collagen to fill the tissue defect at the site of the ulcer and consequently lead to scar formation. Though the scar or/and ulcer have been considered positively correlated with esophageal stricture, there are limited studies to demonstrate that the damage of EEB is associated with the development of esophageal stricture disease. Still, the exact relationship between EEB structure, esophageal stricture formation, and the critical molecular mechanisms remain unclear.

We consider that the stability of EEB structure plays a vital barrier role in the esophagus. Genes like transglutaminase 1(TGM1), cystatin A(CSTA), transglutaminase 3(TGM3), involucrin(IVL), and loricrin (LOR) mediate the regular expression of proteins for the cornified envelope, thereby maintaining the EEB struction and function [117]. The abnormalities in genes will affect the normal synthesis of the cornified envelope proteins, further weakening the cell–cell junction. This pathology was discovered in the diseases like skin tissue [133,134,135,136,137,138]. However, these genes regulating barrier function have not been reported in the esophagus.

The clinical administrations, including steroid injections, stents, or dilators implantation, have had unsatisfactory efficiency for esophageal stricture. Tissue engineering techniques appear to be necessary for mucosal regeneration and EEB repairing. More importantly, the biological mechanism of the occurrence and treatment of esophageal stricture related to EEB damage and restore shall be clarified with more scientific evidence.

In recent years, more and more scholars have attempted to compensate for the re-epithelialization of mucosa with the injured EEB through tissue engineering technologies. For example, researchers injected the adipose mesenchymal stem cells (MSCs) into the post-ESD region of dogs, achieving45% of the mean degrees of mucosal constriction compared with 76% in the blank control (p < 0.008). The number of submucosal micro-vessels was also more than that in the blank control animals. Sure, a good blood supplement provides a suitable environment for epithelium repair [139]. Similar results were discovered in the porcine model using keratinocytes from the oral mucosa as the injected cells. The lesion in the keratinocyte implanted animal was covered by epithelial cells. The luminal surface was flat, with no ulceration taking place. Scarring and stricture were observed in the control group after two weeks post-EMR surgery [140].

The cell density and the exact location with cell injection are not able to be precisely control due to easily running off for the cell suspension. Some biological materials, such as amniotic membrane or decellularized matrix, etc., were studied as cell carriers. Cells were seeded on these materials to make cell patches. Nishida et al. reported that cell sheets could reconstruct the cornea, and the patients recovered their sight [141]. Ohki et al. fabricated the cell patches containing autologous oral mucosal cells cultured in temperature-responsive dishes. These patches were then transplanted onto mucosa wounds caused by ESD in the dog model. Complete healing of the mucosa was observed after the cell patches were placed for four weeks, whereas severe inflammation existed in blank control [142]. The same results were achieved in a porcine model, where endoscopic techniques placed the cell patches on the post-ESD area. Early re-epithelialization and moderate fibrosis in the muscle were observed in the transplanted animals, while all pigs in the blank control showed stricture occurrence [143]. Recently, a biosynthetic material with collagen vitrigel to make cellular patches (CVP) was studied by Aoki et al. They placed cellular sheets at the post-ESD site in pigs, inducing a re-epithelialization of the mucosa and reducing the hyperfibrosis, compared with a blank control group [144]. Research on animals has shown that mucosal re-epithelialization to improve EEB functionality aids in mitigating or forestalling pathological strictures. However, such animal trials, serving as anticipatory foundational studies, possess certain limitations, even as they endeavor to simulate actual clinical conditions. To further confirm these results, large-scale human clinical trials are necessary, considering the distinct differences in living conditions between animals and humans.

Correspondingly, clinical studies make less progress in this disease due to many ambiguities in the pathology and treatment mechanism. In a single-institute study, Ohki et al. investigated the potential of transplanting tissue-engineered cell sheets made from patients' own oral mucosal epithelial cells to avert post-ESD esophageal strictures. They gathered oral mucosal cells from 9 patients with non-deep esophageal cancers, cultivated them into cell sheets, and then transferred these sheets endoscopically to the surgical sites (Fig. 5). Monitoring through weekly endoscopies continued until the healing process was complete. The results showed a successful transplant and complete healing within an average timeframe of 3.5 weeks, with no subsequent complications like dysphagia or narrowing of the esophagus. This method, which involves no sutures and uses the patient's own cells, appears to safely and effectively promote healing after ESD, potentially preventing undesirable postoperative constriction and elevating patient quality of life. However, the study suggests that further investigation is needed to confirm its preventive capabilities against stricture formation [145]. Recently, researchers transplanted epithelial cell sheets to the post-operation area of patients who had congenital esophageal atresia. Six months later, the patient was aware of a reduction in dysphagia. And the intervals between endoscopic balloon dilatation were extended twice as much as the blank control group [146].

Fig. 5
figure 5

Treatment of the artificial ulceration after esophageal ESD by transplantation of autologous oral mucosal epithelial cell sheets fabricated on temperature-responsive culture inserts. a Biopsy specimens were taken from the patient’s own oral, buccal mucosal tissue. Oral epithelial cells were isolated from the tissue by dispase I and trypsin. b The epithelial cells were seeded onto temperature-responsive culture inserts without a 3T3 feeder layer and cultured with autologous serum for 16 days at 37 °C. c Oral mucosal epithelial cell sheets were harvested by reducing the culture temperature to 20 °C. d, e Autologous oral mucosal epithelial cell sheets on a support membrane were transplanted with endoscopic forceps onto the bed of the esophageal ulceration immediately after ESD (diagrammatically displayed by us according to the work of literature [119])

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The efficacy of cellular patches in warding off esophageal strictures clarifies the connection between EEB deficits and the development of these strictures, providing a glimmer of hope for affected patients. However, the application of cellular patches as a treatment is still contested. Moreover, the small sample sizes in these clinical trials do not provide enough evidence to assert that cellular patches are suitable for widespread mucosal debridement in ESD or for patients with esophageal stricture.

Cross-talking of multiple mechanisms

Esophageal stricture is often a parallel or cross-cascade result from multiple biologic mechanisms. The studies above suggest that fibrosis, inflammation, or EEB damage is not the independent individual etiology to induce esophageal stricture [147,148,149,150,151,152]. Kasagi et al. and Rochmanet al. observed that some genes involved in barrier function are lost in EoE, triggering the inflammation progress. The abnormalities in gene or gene transcription/translation might delay EEB repair, contributing to wrong esophageal cell differentiation and even disease induction [149, 153]. Those with long-standing inflammation develop fibrosis in the esophagus at the mucosa and submucosa site. As a result, the esophagus becomes stiff, and hence the stricture develops [154, 155].

Histologically, it can be found that there is a mechanism for each link from the surface to the deeper layers, i.e., damage to the barrier—persistent inflammatory stress—excessive fibrosis. Harmful substances from digested food or the sick tissue weakened junction between mucosal epithelial cells, abnormally enlarged cell–cell gap, and disturbed translation of cornified envelope proteins. Consequently, the normal EEB is impaired to let those harmful substances attack deeper tissues.

Many diseases in the esophagus, such as EoE, GERD, and BE, start from the impaired EEB structure [130, 156,157,158,159]. As harmful substances attack the deeper tissue, the esophageal epithelium becomes severely damaged, thereby the body begins to initiate the inflammatory response. Macrophages start to work, and with the recruitment of macrophages, the aggregated macrophages begin to engulf harmful substances and release a large number of inflammatory factors and cytokines, which continuously stimulate fibroblasts to differentiate into myofibroblasts to repair damaged tissues. The duration of the inflammation is significantly essential, as the inflammatory response plays an active role in tissue repair. Once the inflammation progresses into chronic inflammation, the excessive differentiation of fibroblasts into myofibroblasts will lead to excessive secretion of cytokines and finally lead to the occurrence of severe fibrosis. As a result, the esophagus becomes stiff, and the stricture is eventually induced. These crossed multi-mechanisms by which the esophageal stricture takes place were schematically drawn in Fig. 6. We believe that any medicines or biomaterials which can interfere with these mechanisms will be the therapies for esophageal stricture.

Fig. 6
figure 6

Schematic diagram of multiple crossed mechanisms by which the stricture in the esophagus takes place. The three stages of damage to the barrier—persistence of the inflammatory stress response—excessive fibrosis

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In recent years, more and more scholars in the area of tissue engineering are trying to find a kind of biocompatible biomaterial that can not only inhibit inflammation and fibrosis but also facilitate epithelium regeneration. Some researchers have found that decellularized human amniotic membranes had all three functions: anti-inflammation, anti-fibrosis, and promotion of epithelialization. For example, Chen et al. found that decellularized human amniotic membranes could achieve an anti-fibrosis effect by inhibiting MMP-2 [160]. Oba et al. attached decellularized human amniotic membranes to the wound area of burn patients and found that it had anti-inflammatory and antibacterial effects, measured by immunohistochemical staining and corresponding protein detection [161]. These studies give supports of our hypothesis that esophageal strictures are caused by a disease in which multiple mechanisms exist in parallel and interact with each other.

Conclusion

The burden of esophageal stricture, whether from disease or treatment like ESD/EMR, is becoming more manageable as we unravel its complex mechanisms. We see it as a dynamic process involving multiple stages: initial EEB damage, inflammatory escalation, and final fibrotic closure.

Therapeutically, we have pinpointed interventions including steroids, MMC, and cell sheet technology for the distinct pathogenic mechanisms of esophageal stricture. However, these studies stand to gain from the expansion into larger multicenter clinical trials to thoroughly ascertain their therapeutic value in practice. Our findings suggest that the condition of esophageal narrowing is due to intertwined mechanisms, and new treatment avenues like tissue engineering could offer a more comprehensive approach. The full promise of blending such regenerative approaches with gene editing remains an exciting prospect for future observation.

Nevertheless, the full effectiveness of these therapies and their applicability to extensive tissue damage have yet to be determined. As our understanding grows, especially in the fields of genetics and proteomics, we anticipate the identification of key genes and regulatory elements crucial for epithelial protection and recovery. This knowledge is expected to lead to new treatments that better alleviate patient suffering.

Availability of data and materials

All data generated or analysed during this study are included in this published article [and its additional information files].

References

  1. DeNardi FG, Riddell RH. The normal esophagus. Am J Surg Pathol. 1991;15:296–309.

    Article  CAS  PubMed  Google Scholar 

  2. Edwards DA. The oesophagus. Gut. 1971;12:948–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rosekrans SL, Baan B, Muncan V, van den Brink GR. Esophageal development and epithelial homeostasis. Am J Physiol Gastrointest Liver Physiol. 2015;309:G216-228.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang Y, Bailey D, Yang P, Kim E, Que J. The development and stem cells of the esophagus. Dev Camb Engl. 2021;148:dev193839.

    CAS  Google Scholar 

  5. Oyama T, Tomori A, Hotta K, Morita S, Kominato K, Tanaka M, et al. Endoscopic submucosal dissection of early esophageal cancer. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2005;3:S67-70.

    Google Scholar 

  6. Wang KK. Endoscopic submucosal dissection and potential cancer dissemination. Gut. 2022;71:236–7.

    Article  PubMed  Google Scholar 

  7. Landin MD, Guerrón AD. Endoscopic mucosal resection and endoscopic submucosal dissection. Surg Clin North Am. 2020;100:1069–78.

    Article  PubMed  Google Scholar 

  8. Draganov PV, Wang AY, Othman MO, Fukami N. AGA institute clinical practice update: endoscopic submucosal dissection in the United States. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2019;17:16-25.e1.

    Google Scholar 

  9. Wang Y, Xia W, Tian L, Zhu B, Chen M, Si X, et al. Comparison of statins with steroids and botulinum toxin A in the prevention of benign strictures after esophageal endoscopic submucosal dissection: a retrospective cohort study. Surg Endosc. 2023;37:4328–37.

    Article  PubMed  Google Scholar 

  10. Katada C, Muto M, Manabe T, Boku N, Ohtsu A, Yoshida S. Esophageal stenosis after endoscopic mucosal resection of superficial esophageal lesions. Gastrointest Endosc. 2003;57:165–9.

    Article  PubMed  Google Scholar 

  11. Ono S, Fujishiro M, Niimi K, Goto O, Kodashima S, Yamamichi N, et al. Long-term outcomes of endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms. Gastrointest Endosc. 2009;70:860–6.

    Article  PubMed  Google Scholar 

  12. Shi Q, Ju H, Yao L-Q, Zhou P-H, Xu M-D, Chen T, et al. Risk factors for postoperative stricture after endoscopic submucosal dissection for superficial esophageal carcinoma. Endoscopy. 2014;46:640–4.

    Article  PubMed  Google Scholar 

  13. Kadota T, Yano T, Kato T, Imajoh M, Noguchi M, Morimoto H, et al. Prophylactic steroid administration for strictures after endoscopic resection of large superficial esophageal squamous cell carcinoma. Endosc Int Open. 2016;4:E1267–74.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Takahashi H, Arimura Y, Okahara S, Kodaira J, Hokari K, Tsukagoshi H, et al. A randomized controlled trial of endoscopic steroid injection for prophylaxis of esophageal stenoses after extensive endoscopic submucosal dissection. BMC Gastroenterol. 2015;15:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yamaguchi N, Isomoto H, Nakayama T, Hayashi T, Nishiyama H, Ohnita K, et al. Usefulness of oral prednisolone in the treatment of esophageal stricture after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma. Gastrointest Endosc. 2011;73:1115–21.

    Article  PubMed  Google Scholar 

  16. El-Asmar KM, Hassan MA, Abdelkader HM, Hamza AF. Topical mitomycin C application is effective in management of localized caustic esophageal stricture: a double-blinded, randomized, placebo-controlled trial. J Pediatr Surg. 2013;48:1621–7.

    Article  PubMed  Google Scholar 

  17. Kataoka M, Anzai S, Shirasaki T, Ikemiyagi H, Fujii T, Mabuchi K, et al. Efficacy of short period, low dose oral prednisolone for the prevention of stricture after circumferential endoscopic submucosal dissection (ESD) for esophageal cancer. Endosc Int Open. 2015;3:E113-117.

    PubMed  Google Scholar 

  18. Hashimoto S, Kobayashi M, Takeuchi M, Sato Y, Narisawa R, Aoyagi Y. The efficacy of endoscopic triamcinolone injection for the prevention of esophageal stricture after endoscopic submucosal dissection. Gastrointest Endosc. 2011;74:1389–93.

    Article  PubMed  Google Scholar 

  19. Nagami Y, Ominami M, Shiba M, Sakai T, Fukunaga S, Sugimori S, et al. Prediction of esophageal stricture in patients given locoregional triamcinolone injections immediately after endoscopic submucosal dissection. Dig Endosc Off J Jpn Gastroenterol Endosc Soc. 2018;30:198–205.

    Google Scholar 

  20. Kleuskens MTA, Haasnoot ML, Herpers BM, van Ampting MTJ, Bredenoord AJ, Garssen J, et al. Butyrate and propionate restore interleukin 13-compromised esophageal epithelial barrier function. Allergy. 2022;77:1510–21.

    Article  CAS  PubMed  Google Scholar 

  21. Doyle AD, Masuda MY, Pyon GC, Luo H, Putikova A, LeSuer WE, et al. Detergent exposure induces epithelial barrier dysfunction and eosinophilic inflammation in the esophagus. Allergy. 2023;78:192–201.

    Article  CAS  PubMed  Google Scholar 

  22. Nguyen N, Fernando SD, Biette KA, Hammer JA, Capocelli KE, Kitzenberg DA, et al. TGF-β1 alters esophageal epithelial barrier function by attenuation of claudin-7 in eosinophilic esophagitis. Mucosal Immunol. 2018;11:415–26.

    Article  CAS  PubMed  Google Scholar 

  23. Kaymak T, Kaya B, Wuggenig P, Nuciforo S, Göldi A, Swiss EoE Cohort Study Group (SEECS), et al. IL-20 subfamily cytokines impair the oesophageal epithelial barrier by diminishing filaggrin in eosinophilic oesophagitis. Gut. 2023;72:821–33.

    Article  CAS  PubMed  Google Scholar 

  24. Chummun I, Gimié F, Goonoo N, Arsa IA, Cordonin C, Jhurry D, et al. Polysucrose hydrogel and nanofiber scaffolds for skin tissue regeneration: architecture and cell response. Mater Sci Eng C. 2022;135:112694.

    Google Scholar 

  25. Goonoo N. Tunable biomaterials for myocardial tissue regeneration: promising new strategies for advanced biointerface control and improved therapeutic outcomes. Biomater Sci. 2022;10:1626–46.

    Article  CAS  PubMed  Google Scholar 

  26. Yang M, Zhang Y, Fang C, Song L, Wang Y, Lu L, et al. Urine-microenvironment-initiated composite hydrogel patch reconfiguration propels scarless memory repair and reinvigoration of the urethra. Adv Mater. 2022;34: e2109522.

    Article  PubMed  Google Scholar 

  27. Yang Y, Shi K, Yu K, Xing F, Lai H, Zhou Y, et al. Degradable hydrogel adhesives with enhanced tissue adhesion, superior self-healing, cytocompatibility, and antibacterial property. Adv Healthc Mater. 2022;11: e2101504.

    Article  PubMed  Google Scholar 

  28. Zhang Y, Zheng Y, Shu F, Zhou R, Bao B, Xiao S, et al. In situ-formed adhesive hyaluronic acid hydrogel with prolonged amnion-derived conditioned medium release for diabetic wound repair. Carbohydr Polym. 2022;276:118752.

    Article  CAS  PubMed  Google Scholar 

  29. Mohammadi S, Ravanbakhsh H, Taheri S, Bao G, Mongeau L. Immunomodulatory microgels support proregenerative macrophage activation and attenuate fibroblast collagen synthesis. Adv Healthc Mater. 2022;11: e2102366.

    Article  PubMed  Google Scholar 

  30. Coron AE, Kjesbu JS, Kjærnsmo F, Oberholzer J, Rokstad AMA, Strand BL. Pericapsular fibrotic overgrowth mitigated in immunocompetent mice through microbead formulations based on sulfated or intermediate G alginates. Acta Biomater. 2022;137:172–85.

    Article  CAS  PubMed  Google Scholar 

  31. Qin X, Xu Y, Zhou X, Gong T, Zhang Z-R, Fu Y. An injectable micelle-hydrogel hybrid for localized and prolonged drug delivery in the management of renal fibrosis. Acta Pharm Sin B. 2021;11:835–47.

    Article  CAS  PubMed  Google Scholar 

  32. Honda M, Nakamura T, Hori Y, Shionoya Y, Nakada A, Sato T, et al. Process of healing of mucosal defects in the esophagus after endoscopic mucosal resection: histological evaluation in a dog model. Endoscopy. 2010;42:1092–5.

    Article  CAS  PubMed  Google Scholar 

  33. Chung A, Bourke MJ, Hourigan LF, Lim G, Moss A, Williams SJ, et al. Complete Barrett’s excision by stepwise endoscopic resection in short-segment disease: long term outcomes and predictors of stricture. Endoscopy. 2011;43:1025–32.

    Article  CAS  PubMed  Google Scholar 

  34. Iizuka T, Kikuchi D, Hoteya S, Kaise M. Effectiveness of modified oral steroid administration for preventing esophageal stricture after entire circumferential endoscopic submucosal dissection. Dis Esophagus Off J Int Soc Dis Esophagus. 2018;31:dox140.

    Google Scholar 

  35. Jia Y, Wang Y, Niu L, Zhang H, Tian J, Gao D, et al. The plasticity of nanofibrous matrix regulates fibroblast activation in fibrosis. Adv Healthc Mater. 2021;10:2001856.

    Article  CAS  Google Scholar 

  36. Ni W, Lin S, Bian S, Xiao M, Wang Y, Yang Y, et al. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Luc G, Charles G, Gronnier C, Cabau M, Kalisky C, Meulle M, et al. Decellularized and matured esophageal scaffold for circumferential esophagus replacement: proof of concept in a pig model. Biomaterials. 2018;175:1–18.

    Article  CAS  PubMed  Google Scholar 

  38. Poghosyan T, Gaujoux S, Vanneaux V, Bruneval P, Domet T, Lecourt S, et al. In vitro development and characterization of a tissue-engineered conduit resembling esophageal wall using human and pig skeletal myoblast, oral epithelial cells, and biologic scaffolds. Tissue Eng Part A. 2013;19:2242–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jensen T, Blanchette A, Vadasz S, Dave A, Canfarotta M, Sayej WN, et al. Biomimetic and synthetic esophageal tissue engineering. Biomaterials. 2015;57:133–41.

    Article  CAS  PubMed  Google Scholar 

  40. Keane TJ, Londono R, Carey RM, Carruthers CA, Reing JE, Dearth CL, et al. Preparation and characterization of a biologic scaffold from esophageal mucosa. Biomaterials. 2013;34:6729–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rafaeva M, Horton ER, Jensen ARD, Madsen CD, Reuten R, Willacy O, et al. Modeling metastatic colonization in a decellularized organ scaffold-based perfusion bioreactor. Adv Healthc Mater. 2022;11:2100684.

    Article  CAS  Google Scholar 

  42. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454:428–35.

    Article  CAS  PubMed  Google Scholar 

  43. Raschi E, Chighizola CB, Cesana L, Privitera D, Ingegnoli F, Mastaglio C, et al. Immune complexes containing scleroderma-specific autoantibodies induce a profibrotic and proinflammatory phenotype in skin fibroblasts. Arthritis Res Ther. 2018;20:187.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Scrivo R, Vasile M, Bartosiewicz I, Valesini G. Inflammation as “common soil” of the multifactorial diseases. Autoimmun Rev. 2011;10:369–74.

    Article  PubMed  Google Scholar 

  45. Siegel I, Gleicher N. Phagocytosis: macrophage-lymphocyte interactions. JAMA. 1981;246:1127.

    Article  CAS  PubMed  Google Scholar 

  46. Hu W, Gu Z, Zhao L, Zhang Y, Yu C. Vertical orientation probability matters for enhancing nanoparticle-macrophage interaction and efficient phagocytosis. Small Methods. 2022;6: e2101601.

    Article  PubMed  Google Scholar 

  47. Wasmuth HE, Tacke F, Trautwein C. Chemokines in liver inflammation and fibrosis. Semin Liver Dis. 2010;30:215–25.

    Article  CAS  PubMed  Google Scholar 

  48. Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis. 2010;30:245–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Huang E, Peng N, Xiao F, Hu D, Wang X, Lu L. The roles of immune cells in the pathogenesis of fibrosis. Int J Mol Sci. 2020;21:E5203.

    Article  Google Scholar 

  50. Lupher ML, Gallatin WM. Regulation of fibrosis by the immune system. Adv Immunol. 2006;89:245–88.

    Article  CAS  PubMed  Google Scholar 

  51. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Meng X-M, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12:325–38.

    Article  CAS  PubMed  Google Scholar 

  53. Muñoz-Félix JM, González-Núñez M, Martínez-Salgado C, López-Novoa JM. TGF-β/BMP proteins as therapeutic targets in renal fibrosis: where have we arrived after 25 years of trials and tribulations? Pharmacol Ther. 2015;156:44–58.

    Article  PubMed  Google Scholar 

  54. Hesketh M, Sahin KB, West ZE, Murray RZ. Macrophage phenotypes regulate scar formation and chronic wound healing. Int J Mol Sci. 2017;18:E1545.

    Article  Google Scholar 

  55. Novak ML, Koh TJ. Phenotypic transitions of macrophages orchestrate tissue repair. Am J Pathol. 2013;183:1352–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Smigiel KS, Parks WC. Macrophages, wound healing, and fibrosis: recent insights. Curr Rheumatol Rep. 2018;20:17.

    Article  PubMed  Google Scholar 

  57. Jeljeli M, Riccio LGC, Doridot L, Chêne C, Nicco C, Chouzenoux S, et al. Trained immunity modulates inflammation-induced fibrosis. Nat Commun. 2019;10:5670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wang Y-Y, Jiang H, Pan J, Huang X-R, Wang Y-C, Huang H-F, et al. Macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. J Am Soc Nephrol JASN. 2017;28:2053–67.

    Article  CAS  PubMed  Google Scholar 

  59. Tang PM-K, Zhou S, Li C-J, Liao J, Xiao J, Wang Q-M, et al. The proto-oncogene tyrosine protein kinase Src is essential for macrophage-myofibroblast transition during renal scarring. Kidney Int. 2018;93:173–87.

    Article  CAS  PubMed  Google Scholar 

  60. Meng X-M, Wang S, Huang X-R, Yang C, Xiao J, Zhang Y, et al. Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis. Cell Death Dis. 2016;7: e2495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Little K, Llorián-Salvador M, Tang M, Du X, Marry S, Chen M, et al. Macrophage to myofibroblast transition contributes to subretinal fibrosis secondary to neovascular age-related macular degeneration. J Neuroinflammation. 2020;17:355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tang PM-K, Zhang Y-Y, Xiao J, Tang PC-T, Chung JY-F, Li J, et al. Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition. Proc Natl Acad Sci USA. 2020;117:20741–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Feng Y, Guo F, Mai H, Liu J, Xia Z, Zhu G, et al. Pterostilbene, a bioactive component of blueberries, alleviates renal interstitial fibrosis by inhibiting macrophage-myofibroblast transition. Am J Chin Med. 2020;48:1715–29.

    Article  CAS  PubMed  Google Scholar 

  64. Jiang M, Li H, Zhang Y, Yang Y, Lu R, Liu K, et al. Transitional basal cells at the squamous-columnar junction generate Barrett’s oesophagus. Nature. 2017;550:529–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mari L, Milano F, Parikh K, Straub D, Everts V, Hoeben KK, et al. A pSMAD/CDX2 complex is essential for the intestinalization of epithelial metaplasia. Cell Rep. 2014;7:1197–210.

    Article  CAS  PubMed  Google Scholar 

  66. Peters Y, Al-Kaabi A, Shaheen NJ, Chak A, Blum A, Souza RF, et al. Barrett oesophagus. Nat Rev Dis Primer. 2019;5:35.

    Article  Google Scholar 

  67. Vega ME, Giroux V, Natsuizaka M, Liu M, Klein-Szanto AJ, Stairs DB, et al. Inhibition of Notch signaling enhances transdifferentiation of the esophageal squamous epithelium towards a Barrett’s-like metaplasia via KLF4. Cell Cycle Georget Tex. 2014;13:3857–66.

    Article  CAS  Google Scholar 

  68. Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133:1342–63.

    Article  CAS  PubMed  Google Scholar 

  69. Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med. 2004;351:940–1.

    Article  CAS  PubMed  Google Scholar 

  70. Gonsalves NP, Aceves SS. Diagnosis and treatment of eosinophilic esophagitis. J Allergy Clin Immunol. 2020;145:1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Akei HS, Mishra A, Blanchard C, Rothenberg ME. Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice. Gastroenterology. 2005;129:985–94.

    Article  CAS  PubMed  Google Scholar 

  72. Atkins D, Kramer R, Capocelli K, Lovell M, Furuta GT. Eosinophilic esophagitis: the newest esophageal inflammatory disease. Nat Rev Gastroenterol Hepatol. 2009;6:267–78.

    Article  PubMed  Google Scholar 

  73. Mishra A, Hogan SP, Brandt EB, Rothenberg ME. IL-5 promotes eosinophil trafficking to the esophagus. J Immunol Baltim Md. 1950;2002(168):2464–9.

    Google Scholar 

  74. Mishra A, Wang M, Pemmaraju VR, Collins MH, Fulkerson PC, Abonia JP, et al. Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia. Gastroenterology. 2008;134:204–14.

    Article  PubMed  Google Scholar 

  75. Kochhar R, Poornachandra KS. Intralesional steroid injection therapy in the management of resistant gastrointestinal strictures. World J Gastrointest Endosc. 2010;2:61–8.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Ramage JI, Rumalla A, Baron TH, Pochron NL, Zinsmeister AR, Murray JA, et al. A prospective, randomized, double-blind, placebo-controlled trial of endoscopic steroid injection therapy for recalcitrant esophageal peptic strictures. Am J Gastroenterol. 2005;100:2419–25.

    Article  CAS  PubMed  Google Scholar 

  77. Lu P, Takai K, Weaver VM, Werb Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol. 2011;3: a005058.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Phan QM, Sinha S, Biernaskie J, Driskell RR. Single-cell transcriptomic analysis of small and large wounds reveals the distinct spatial organization of regenerative fibroblasts. Exp Dermatol. 2021;30:92–101.

    Article  CAS  PubMed  Google Scholar 

  79. Phan QM, Fine GM, Salz L, Herrera GG, Wildman B, Driskell IM, et al. Lef1 expression in fibroblasts maintains developmental potential in adult skin to regenerate wounds. eLife. 2020;9: e60066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Pakshir P, Alizadehgiashi M, Wong B, Coelho NM, Chen X, Gong Z, et al. Dynamic fibroblast contractions attract remote macrophages in fibrillar collagen matrix. Nat Commun. 2019;10:1850.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Kumar V, Ali MJ, Ramachandran C. Effect of mitomycin-C on contraction and migration of human nasal mucosa fibroblasts: implications in dacryocystorhinostomy. Br J Ophthalmol. 2015;99:1295–300.

    Article  PubMed  Google Scholar 

  82. Seo BR, Chen X, Ling L, Song YH, Shimpi AA, Choi S, et al. Collagen microarchitecture mechanically controls myofibroblast differentiation. Proc Natl Acad Sci USA. 2020;117:11387–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Shu DY, Lovicu FJ. Myofibroblast transdifferentiation: the dark force in ocular wound healing and fibrosis. Prog Retin Eye Res. 2017;60:44–65.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature. 2020;587:555–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cannito S, Novo E, Parola M. Therapeutic pro-fibrogenic signaling pathways in fibroblasts. Adv Drug Deliv Rev. 2017;121:57–84.

    Article  CAS  PubMed  Google Scholar 

  86. Ramming A, Dees C, Distler JHW. From pathogenesis to therapy–Perspective on treatment strategies in fibrotic diseases. Pharmacol Res. 2015;100:93–100.

    Article  PubMed  Google Scholar 

  87. Tacke F. Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis. Expert Opin Investig Drugs. 2018;27:301–11.

    Article  CAS  PubMed  Google Scholar 

  88. O’Halloran JA, Ko ER, Anstrom KJ, Kedar E, McCarthy MW, Panettieri RA, et al. Abatacept, cenicriviroc, or infliximab for treatment of adults hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA. 2023;330:328–39.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Massagué J. TGFβ signalling in context. Nat Rev Mol Cell Biol. 2012;13:616–30.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Morikawa M, Derynck R, Miyazono K. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol. 2016;8: a021873.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Jin Y, Ratnam K, Chuang PY, Fan Y, Zhong Y, Dai Y, et al. A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat Med. 2012;18:580–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Palumbo K, Zerr P, Tomcik M, Vollath S, Dees C, Akhmetshina A, et al. The transcription factor JunD mediates transforming growth factor {beta}-induced fibroblast activation and fibrosis in systemic sclerosis. Ann Rheum Dis. 2011;70:1320–6.

    Article  CAS  PubMed  Google Scholar 

  93. Distler JHW, Distler O. Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies. Ann Rheum Dis. 2010;69(Suppl 1):i48-51.

    Article  CAS  PubMed  Google Scholar 

  94. Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer. 2018;17:58.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134:1655–69.

    Article  CAS  PubMed  Google Scholar 

  96. Papadopoulos N, Lennartsson J. The PDGF/PDGFR pathway as a drug target. Mol Aspects Med. 2018;62:75–88.

    Article  CAS  PubMed  Google Scholar 

  97. Casaletto JB, McClatchey AI. Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer. 2012;12:387–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Fan Y, Bazai SK, Daian F, Arechederra M, Richelme S, Temiz NA, et al. Evaluating the landscape of gene cooperativity with receptor tyrosine kinases in liver tumorigenesis using transposon-mediated mutagenesis. J Hepatol. 2019;70:470–82.

    Article  CAS  PubMed  Google Scholar 

  99. McDonell LM, Kernohan KD, Boycott KM, Sawyer SL. Receptor tyrosine kinase mutations in developmental syndromes and cancer: two sides of the same coin. Hum Mol Genet. 2015;24:R60-66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Puthumana J, Thiessen-Philbrook H, Xu L, Coca SG, Garg AX, Himmelfarb J, et al. Biomarkers of inflammation and repair in kidney disease progression. J Clin Invest. 2021;131: e139927, 139927.

    Article  PubMed  Google Scholar 

  101. Ou L, Zhang P, Huang Z, Cheng Y, Miao Q, Niu R, et al. Targeting STING-mediated pro-inflammatory and pro-fibrotic effects of alveolar macrophages and fibroblasts blunts silicosis caused by silica particles. J Hazard Mater. 2023;458:131907.

    Article  CAS  PubMed  Google Scholar 

  102. Zhao M, Wang L, Wang M, Zhou S, Lu Y, Cui H, et al. Targeting fibrosis: mechanisms and clinical trials. Signal Transduct Target Ther. 2022;7:1–21.

    Google Scholar 

  103. She YX, Yu QY, Tang XX. Role of interleukins in the pathogenesis of pulmonary fibrosis. Cell Death Discov. 2021;7:1–10.

    Article  Google Scholar 

  104. Lancaster LH, de Andrade JA, Zibrak JD, Padilla ML, Albera C, Nathan SD, et al. Pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis. Eur Respir Rev Off J Eur Respir Soc. 2017;26:170057.

    Article  Google Scholar 

  105. Ruwanpura SM, Thomas BJ, Bardin PG. Pirfenidone: molecular mechanisms and potential clinical applications in lung disease. Am J Respir Cell Mol Biol. 2020;62:413–22.

    Article  CAS  PubMed  Google Scholar 

  106. Frangogiannis NG. Transforming growth factor-β in myocardial disease. Nat Rev Cardiol. 2022;19:435–55.

    Article  CAS  PubMed  Google Scholar 

  107. Lamb YN. Nintedanib: a review in fibrotic interstitial lung diseases. Drugs. 2021;81:575–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381:1718–27.

    Article  CAS  PubMed  Google Scholar 

  109. Wang XX, Xie C, Libby AE, Ranjit S, Levi J, Myakala K, et al. The role of FXR and TGR5 in reversing and preventing progression of Western diet-induced hepatic steatosis, inflammation, and fibrosis in mice. J Biol Chem. 2022;298:102530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tian S-Y, Chen S-M, Pan C-X, Li Y. FXR: structures, biology, and drug development for NASH and fibrosis diseases. Acta Pharmacol Sin. 2022;43:1120–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Czigany Z, Lurje I, Schmelzle M, Schöning W, Öllinger R, Raschzok N, et al. Ischemia-reperfusion injury in marginal liver grafts and the role of hypothermic machine perfusion: molecular mechanisms and clinical implications. J Clin Med. 2020;9:846.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Latella G. Redox imbalance in intestinal fibrosis: beware of the TGFβ-1, ROS, and Nrf2 connection. Dig Dis Sci. 2018;63:312–20.

    Article  CAS  PubMed  Google Scholar 

  113. Gillespie MB, Day TA, Sharma AK, Brodsky MB, Martin-Harris B. Role of mitomycin in upper digestive tract stricture. Head Neck. 2007;29:12–7.

    Article  PubMed  Google Scholar 

  114. Zhang Y, Wang Q, Xu Y, Sun J, Ding Y, Wang L, et al. Mitomycin c inhibits esophageal fibrosis by regulating cell apoptosis and autophagy via lncRNA-ATB and miR-200b. Front Mol Biosci. 2021;8:675757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Xu F, Shen X, Sun C, Xu X, Wang W, Zheng J. The effect of mitomycin C on reducing endometrial fibrosis for intrauterine adhesion. Med Sci Monit Int Med J Exp Clin Res. 2020;26: e920670.

    CAS  Google Scholar 

  116. Sultana T, Van Hai H, Park M, Lee S-Y, Lee B-T. Controlled release of Mitomycin C from modified cellulose based thermo-gel prevents post-operative de novo peritoneal adhesion. Carbohydr Polym. 2020;229:115552.

    Article  CAS  PubMed  Google Scholar 

  117. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 2005;6:328–40.

    Article  CAS  PubMed  Google Scholar 

  118. Akiyama M, Matsuo I, Shimizu H. Formation of cornified cell envelope in human hair follicle development. Br J Dermatol. 2002;146:968–76.

    Article  CAS  PubMed  Google Scholar 

  119. 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. Adv Drug Deliv Rev. 2021;175:113802.

    Article  CAS  PubMed  Google Scholar 

  120. Blevins CH, Iyer PG, Vela MF, Katzka DA. The esophageal epithelial barrier in health and disease. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2018;16:608–17.

    CAS  Google Scholar 

  121. Lottrup C, Khan A, Rangan V, Clarke JO. Esophageal physiology-an overview of esophageal disorders from a pathophysiological point of view. Ann N Y Acad Sci. 2020;1481:182–97.

    Article  PubMed  Google Scholar 

  122. Wang Z, Zhou H, Zheng H, Zhou X, Shen G, Teng X, et al. Autophagy-based unconventional secretion of HMGB1 by keratinocytes plays a pivotal role in psoriatic skin inflammation. Autophagy. 2021;17:529–52.

    Article  PubMed  Google Scholar 

  123. Kim BE, Kim J, Goleva E, Berdyshev E, Lee J, Vang KA, et al. Particulate matter causes skin barrier dysfunction. JCI Insight. 2021;6: e145185, 145185.

    Article  PubMed  Google Scholar 

  124. de Koning HD, van den Bogaard EH, Bergboer JGM, Kamsteeg M, van Vlijmen-Willems IMJJ, Hitomi K, et al. Expression profile of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins during skin barrier repair. Br J Dermatol. 2012;166:1245–54.

    Article  PubMed  Google Scholar 

  125. van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci CMLS. 2008;65:3756–88.

    Article  CAS  PubMed  Google Scholar 

  126. Biswas KH. Molecular mobility-mediated regulation of E-cadherin adhesion. Trends Biochem Sci. 2020;45:163–73.

    Article  CAS  PubMed  Google Scholar 

  127. Beutel O, Maraspini R, Pombo-García K, Martin-Lemaitre C, Honigmann A. Phase separation of zonula occludens proteins drives formation of tight junctions. Cell. 2019;179:923-936.e11.

    Article  CAS  PubMed  Google Scholar 

  128. Katzka DA, Tadi R, Smyrk TC, Katarya E, Sharma A, Geno DM, et al. Effects of topical steroids on tight junction proteins and spongiosis in esophageal epithelia of patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2014;12:1824-1829.e1.

    CAS  Google Scholar 

  129. Chu C-L, Zhen Y-B, Lv G-P, Li C-Q, Li Z, Qi Q-Q, et al. Microalterations of esophagus in patients with non-erosive reflux disease: in-vivo diagnosis by confocal laser endomicroscopy and its relationship with gastroesophageal reflux. Am J Gastroenterol. 2012;107:864–74.

    Article  PubMed  Google Scholar 

  130. Alvaro-Villegas JC, Sobrino-Cossío S, Hernández-Guerrero A, Alonso-Lárraga JO, de-la-Mora-Levy JG, Molina-Cruz A, et al. Dilated intercellular spaces in subtypes of gastroesophagic reflux disease. Rev Esp Enferm Dig Organo Of Soc Espanola Patol Dig. 2010;102:302–7.

    CAS  Google Scholar 

  131. Gibbens YY, Lansing R, Johnson ML, Blevins CH, Katzka DA, Iyer PG. Effects of central obesity on esophageal epithelial barrier function. Am J Gastroenterol. 2021;116:1537–41.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Shook BA, Wasko RR, Rivera-Gonzalez GC, Salazar-Gatzimas E, López-Giráldez F, Dash BC, et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science. 2018;362:eaar2971.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Catunda R, Rekhi U, Clark D, Levin L, Febbraio M. Loricrin downregulation and epithelial-related disorders: a systematic review. J Dtsch Dermatol Ges J Ger Soc Dermatol JDDG. 2019;17:1227–38.

    Google Scholar 

  134. Moosbrugger-Martinz V, Jalili A, Schossig AS, Jahn-Bassler K, Zschocke J, Schmuth M, et al. Epidermal barrier abnormalities in exfoliative ichthyosis with a novel homozygous loss-of-function mutation in CSTA. Br J Dermatol. 2015;172:1628–32.

    Article  CAS  PubMed  Google Scholar 

  135. Rice RH, Green H. The cornified envelope of terminally differentiated human epidermal keratinocytes consists of cross-linked protein. Cell. 1977;11:417–22.

    Article  CAS  PubMed  Google Scholar 

  136. Cheng T, van Vlijmen-Willems IMJJ, Hitomi K, Pasch MC, van Erp PEJ, Schalkwijk J, et al. Colocalization of cystatin M/E and its target proteases suggests a role in terminal differentiation of human hair follicle and nail. J Invest Dermatol. 2009;129:1232–42.

    Article  CAS  PubMed  Google Scholar 

  137. Ishitsuka Y, Roop DR. Loricrin: past, present, and future. Int J Mol Sci. 2020;21:E2271.

    Article  Google Scholar 

  138. Eckert RL, Crish JF, Efimova T, Dashti SR, Deucher A, Bone F, et al. Regulation of involucrin gene expression. J Invest Dermatol. 2004;123:13–22.

    Article  CAS  PubMed  Google Scholar 

  139. Honda M, Hori Y, Nakada A, Uji M, Nishizawa Y, Yamamoto K, et al. Use of adipose tissue-derived stromal cells for prevention of esophageal stricture after circumferential EMR in a canine model. Gastrointest Endosc. 2011;73:777–84.

    Article  PubMed  Google Scholar 

  140. Sakurai T, Miyazaki S, Miyata G, Satomi S, Hori Y. Autologous buccal keratinocyte implantation for the prevention of stenosis after EMR of the esophagus. Gastrointest Endosc. 2007;66:167–73.

    Article  PubMed  Google Scholar 

  141. Nishida K, Yamato M, Hayashida Y, Watanabe K, Yamamoto K, Adachi E, et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med. 2004;351:1187–96.

    Article  CAS  PubMed  Google Scholar 

  142. Ohki T, Yamato M, Murakami D, Takagi R, Yang J, Namiki H, et al. Treatment of oesophageal ulcerations using endoscopic transplantation of tissue-engineered autologous oral mucosal epithelial cell sheets in a canine model. Gut. 2006;55:1704–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kanai N, Yamato M, Ohki T, Yamamoto M, Okano T. Fabricated autologous epidermal cell sheets for the prevention of esophageal stricture after circumferential ESD in a porcine model. Gastrointest Endosc. 2012;76:873–81.

    Article  PubMed  Google Scholar 

  144. Aoki S, Sakata Y, Shimoda R, Takezawa T, Oshikata-Miyazaki A, Kimura H, et al. High-density collagen patch prevents stricture after endoscopic circumferential submucosal dissection of the esophagus: a porcine model. Gastrointest Endosc. 2017;85:1076–85.

    Article  PubMed  Google Scholar 

  145. Ohki T, Yamato M, Ota M, Takagi R, Murakami D, Kondo M, et al. Prevention of esophageal stricture after endoscopic submucosal dissection using tissue-engineered cell sheets. Gastroenterology. 2012;143:582-588.e2.

    Article  PubMed  Google Scholar 

  146. Fujino A, Fuchimoto Y, Baba Y, Isogawa N, Iwata T, Arai K, et al. First-in-human autologous oral mucosal epithelial sheet transplantation to prevent anastomotic re-stenosis in congenital esophageal atresia. Stem Cell Res Ther. 2022;13:35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Muir AB, Wang JX, Nakagawa H. Epithelial-stromal crosstalk and fibrosis in eosinophilic esophagitis. J Gastroenterol. 2019;54:10–8.

    Article  CAS  PubMed  Google Scholar 

  148. Doyle AD, Masuda MY, Kita H, Wright BL. Eosinophils in eosinophilic esophagitis: the road to fibrostenosis is paved with good intentions. Front Immunol. 2020;11:603295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Rochman M, Azouz NP, Rothenberg ME. Epithelial origin of eosinophilic esophagitis. J Allergy Clin Immunol. 2018;142:10–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Dunn JLM, Caldwell JM, Ballaban A, Ben-Baruch Morgenstern N, Rochman M, Rothenberg ME. Bidirectional crosstalk between eosinophils and esophageal epithelial cells regulates inflammatory and remodeling processes. Mucosal Immunol. 2021;14:1133–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Rochman M, Travers J, Abonia JP, Caldwell JM, Rothenberg ME. Synaptopodin is upregulated by IL-13 in eosinophilic esophagitis and regulates esophageal epithelial cell motility and barrier integrity. JCI Insight. 2017;2:96789.

    Article  PubMed  Google Scholar 

  152. Yin X-L, Zhong L, Lin C-Y, Shi X-S, Zhang J, Chen Z-Y, et al. Tojapride reverses esophageal epithelial inflammatory responses on reflux esophagitis model rats. Chin J Integr Med. 2021;27:604–12.

    Article  CAS  PubMed  Google Scholar 

  153. Kasagi Y, Dods K, Wang JX, Chandramouleeswaran PM, Benitez AJ, Gambanga F, et al. Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α. J Allergy Clin Immunol. 2019;144:171–82.

    Article  CAS  PubMed  Google Scholar 

  154. Hiremath G, Choksi YA, Acra S, Correa H, Dellon ES. Factors associated with adequate lamina propria sampling and presence of lamina propria fibrosis in children with eosinophilic esophagitis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2021;19:1814-1823.e1.

    Google Scholar 

  155. Hirano I. Clinical relevance of esophageal subepithelial activity in eosinophilic esophagitis. J Gastroenterol. 2020;55:249–60.

    Article  CAS  PubMed  Google Scholar 

  156. Blevins CH, Sharma AN, Johnson ML, Geno D, Gupta M, Bharucha AE, et al. Influence of reflux and central obesity on intercellular space diameter of esophageal squamous epithelium. United Eur Gastroenterol J. 2016;4:177–83.

    Article  CAS  Google Scholar 

  157. Caviglia R, Ribolsi M, Maggiano N, Gabbrielli AM, Emerenziani S, Guarino MPL, et al. Dilated intercellular spaces of esophageal epithelium in nonerosive reflux disease patients with physiological esophageal acid exposure. Am J Gastroenterol. 2005;100:543–8.

    Article  PubMed  Google Scholar 

  158. Capaldo CT, Farkas AE, Hilgarth RS, Krug SM, Wolf MF, Benedik JK, et al. Proinflammatory cytokine-induced tight junction remodeling through dynamic self-assembly of claudins. Mol Biol Cell. 2014;25:2710–9.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Blanchard C, Stucke EM, Burwinkel K, Caldwell JM, Collins MH, Ahrens A, et al. Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis. J Immunol Baltim Md. 1950;2010(184):4033–41.

    Google Scholar 

  160. Chen X, Zhou Y, Sun Y, Ji T, Dai H. Transplantation of decellularized and lyophilized amniotic membrane inhibits endometrial fibrosis by regulating connective tissue growth factor and tissue inhibitor of matrix metalloproteinase-2. Exp Ther Med. 2021;22:968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Oba J, Okabe M, Yoshida T, Soko C, Fathy M, Amano K, et al. Hyperdry human amniotic membrane application as a wound dressing for a full-thickness skin excision after a third-degree burn injury. Burns Trauma. 2020;8:tkaa014.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge the financial support from the National Natural Science Foundation of China U20A20121 (KQT), One Health Interdisciplinary Research Project of Ningbo University HY202210 (YBZ), Major Project of 2025 Sci & Tech Innovation of Ningbo 2020Z096 (ZWS). This study was also sponsored by K.C.Wang Magna/Education Fund of Ningbo University.

Funding

National Natural Science Foundation of China U20A20121 (KQT). One Health Interdisciplinary Research Project of Ningbo University HY202210 (YBZ). Major Project of 2025 Sci & Tech Innovation of Ningbo 2020Z096 (ZWS).

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Authors and Affiliations

  1. Health Science Center, Ningbo University, Ningbo, 315211, People’s Republic of China

    Fang Yang, Yiwei Hu, Zewen Shi, Mujie Liu, Qian Pang, Ruixia Hou & Yabin Zhu

  2. The First Affiliated Hospital of Ningbo University, Ningbo, 315000, People’s Republic of China

    Kefeng Hu & Guoliang Ye

  3. Institute of Mass Spectrometry, School of Material Science and Chemical Engineering, Ningbo University, Ningbo, 315211, People’s Republic of China

    Keqi Tang

  4. Ningbo No.2 Hospital, Ningbo, 315001, People’s Republic of China

    Zewen Shi

Authors
  1. Fang Yang
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  2. Yiwei Hu
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  3. Zewen Shi
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  4. Mujie Liu
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  5. Kefeng Hu
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  9. Keqi Tang
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  10. Yabin Zhu
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Contributions

Conceptualization: YBZ, KQT. Methodology: FY, YWH, KFH, GLY, MJL. Investigation: ZWS, QP, RXH. Visualization: FY, MJL. Supervision: YBZ, KQT. Writing—original draft: FY, YWH. Writing—review & editing: FY, YWH, ZWS

Corresponding authors

Correspondence to Keqi Tang or Yabin Zhu.

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Ethics approval and consent to participate

The study protocol was approved by the ethical committee of the Hospital Affiliated to the School of Medicine of Ningbo University (Ethics approval code: KY20190101). All participants were provided with the subject information sheet and gave written informed consent to the study.

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The authors declare that they have no competing interests.

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Yang, F., Hu, Y., Shi, Z. et al. The occurrence and development mechanisms of esophageal stricture: state of the art review. J Transl Med 22, 123 (2024). https://doi.org/10.1186/s12967-024-04932-2

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Journal of Translational Medicine

ISSN: 1479-5876

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