A new protective gel to facilitate ulcer healing in artificial ulcers following esophageal endoscopic submucosal dissection: A multicenter, randomized trial

doi:10.21203/rs.3.rs-2367201/v1

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A new protective gel to facilitate ulcer healing in artificial ulcers following esophageal endoscopic submucosal dissection: A multicenter, randomized trial

https://doi.org/10.21203/rs.3.rs-2367201/v1

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published 26 Apr, 2023

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There are significant risks of adverse events such as stricture, delayed bleeding and perforation following esophageal endoscopic submucosal dissection (ESD). So, it is necessary to protect the artificial ulcer and promote the healing process. This study was performed to investigate the protective role of a novel gel against esophageal ESD-associated wounds. It was a multicenter, randomized, single-blind, controlled trial, which recruited participants who underwent esophageal ESD in four hospitals in China. Participants were randomly assigned to the control or experimental group in a 1:1 ratio and the gel was used after ESD in the latter. Masking of the study group allocations was only attempted for participants. The participants were instructed to report any adverse events on post-ESD day 1, 14, and 30. Moreover, repeat endoscopy was performed at the two-week follow-up to confirm wound healing. Finally, of the 92 recruited patients, 81 completed the study. In the experimental group, the healing rates were significantly higher than the control group (83.89 ± 9.51% vs. 73.28 ± 17.81%, P = 0.0013). Participants reported no severe adverse events during the follow-up period. In conclusion, this novel gel could accelerate wound healing following esophageal ESD safely, effectively, and conveniently. Therefore, we recommend to apply this gel in daily clinical practice.

Health sciences/Gastroenterology/Gastrointestinal system

Health sciences/Gastroenterology/Oesophagogastroscopy

Endoscopic submucosal dissection

Ulcer healing

Protective gel

Randomized controlled trial

Poloxamers

Endoscopic submucosal dissection (ESD) is a popular intervention for digestive system neoplasms. Moreover, ESD is used to perform en bloc resection of entire esophageal neoplasms, contributing to a precise pathological assessment^1,2. The common adverse events related to esophageal ESD include delayed bleeding, perforation, and stricture³. Among them, stenosis is the main long-term complication of esophageal ESD, which occurs in 10–20% of patients undergoing ESD in the esophagus³. Furthermore, the risk of esophageal stricture could raise up to 90% when the ESD exceeds three-quarters of the esophageal circumference^4–6. Esophageal stricture can result in dysphagia, vomiting, weight loss, and a substantially reduced quality of life. Up to now, the circumferential extension of the artificial ulcer, longitudinal length of the mucosal defect, and histological depth have been reported to contribute to esophageal stricture after ESD^7–9. Endoscopic balloon dilatation, stent placement, oral steroids administration, and endoscopic steroid injection have been used prophylactically for stricture after ESD¹⁰. It is indicated that stricture prevention and resolution could impair esophageal motility, which may further cause dysphagia^11,12. Meanwhile, corticosteroids administration could cause severe infectious morbidity with a suboptimal efficacy^13–15. The exposure of the submucosal space to microbiological factors and chemical factors would induce an inflammatory and fibrogenic reaction leading to esophageal stricture^15,16. Meanwhile, the ulcer-healing process starts with local recruitment of inflammatory cells and fibroblasts, at the time when fibrous hyperplasia is evident¹⁷. Moreover, it was reported that larger mucosal defects are significantly associated with esophagus stricture after ESD². Therefore, it is necessary to protect the artificial ulcer and promote the healing process in order to prevent esophagus stricture after ESD. Currently, advanced strategies such as stimulating epithelial growth with growth factors, cell sheets, or covering the wound with mineral or organic sheets have been proposed to protect the wounds after ESD^18–21. However, some of them are time-consuming while others require high technical expertise²². It is necessary to develop new strategies to address these concerns.

We designed a novel gel consists of a colloidal and a fixative solution, to protect artificial wounds after esophageal ESD. No previous randomized controlled trials have investigated this type of gel. The colloidal solution is composed of poloxamers and sodium alginate whereas the fixative solution contains calcium chloride. Poloxamers are synthetic non-ionic triblock co-polymers (PEO–PPO–PEO) of polyethylene oxide, and the most notable features of poloxamer include its temperature-dependent self-assembly and thermo-reversibility^23,24. The hydrogels keep a fluid state at room temperature, but become a semi-solid gel at body temperature, and when the temperature decreases, they return to fluid state²³. Poloxamers demonstrate strong water solubility, low biotoxicity, low stimulation for organisms, and versatile biocompatibility, which has allowed poloxamers to be used in forming micro/nanofibers, cell carrier constructs, and drug micro/nanocarriers in diverse applications²⁴. Recently, due to its versatility, biomaterials composed of poloxamer have been used in multiple areas of tissue engineering, such as neurogenesis, angiogenesis, and bone regeneration²⁴. Sodium alginate is a natural polymer that is non-toxic, biodegradable, and biocompatible; sodium alginate also contains polyelectrolytes that have amino and carboxyl groups, allowing it to form microparticles through electrostatic attraction²⁵. During the esophageal ESD process, soon after the mucosal resection, the colloidal solution is initially spread on the artificial ulcer, and the fixative solution is then sprayed on it. Calcium chloride can interact with sodium alginate quickly, resulting in molecular entanglements. Next, poloxamers would transform into a semisolid gel at body temperature, leading to further protection. Covering post-ESD wounds with this gel protects the artificial ulcer against digestive juices and accelerates mucosal regeneration.

In this multicenter, randomized, single-blind trial, we investigated the effectiveness and safety of a novel gel designed to protect esophageal wounds resulting from ESD.

Study design

This multicenter, randomized, single-blind trial performed in four hospitals in China which investigated the efficacy and safety of a novel protective gel applied after esophageal ESD. The study protocol was approved by the ethics committee of Zhejiang University School of Medicine First Affiliated Hospital (PRO20200140) and was executed in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local regulations. This trial was registered on http://www.chictr.org.cn/index.aspx (27/11/2021, ChiCTR2100053692).

Participants

The study included adults who underwent esophageal ESD between December 2020 and November 2021 across four participating hospitals. The inclusion criteria were as follows: (1) age 18–80 years, (2) underwent esophageal ESD successfully, (3) first time to resection in the same lesion and, (4) written consent provided for study participation. The exclusion criteria were as follows: (1) diagnosis of active infection or severe systemic diseases, (2) diagnosis of coagulative dysfunction, hepatic or renal failure, or cardiopulmonary dysfunction, (3) diagnosis of other tumors, (4) a history of esophageal surgery or radiotherapy, (5) inability to complete the ESD operation, (6) pregnancy, (7) underwent glucocorticoids therapy in the past six weeks and, (8) refusal to participate in the study.

Randomization and masking

Using a random number table, participants were randomly divided into the control and experimental group in a 1:1 ratio. Sequence generation, participant enrolment, and assignment were performed by three different individuals who were not involved in the rest of this clinical trial. And as a single blind trial, masking of the allocations was only attempted for participants in this study.

Procedures

In the control group, participants only underwent a standard esophageal ESD procedure, whereas those from the experimental group underwent application of this new gel after esophageal ESD. ESD was performed by experienced endoscopists at each participating institution. For ESD procedure, an upper gastrointestinal endoscope (GIF-Q260J Endoscope, Olympus, Tokyo, Japan) and a dual knife (Olympus, Tokyo, Japan) were used. The lesion was marked using dots, created by a dual knife. The lesion was lifted by injection into the submucosal layer by a solution stained using indigo carmine, and then submucosal dissection was performed.

Hangzhou Yingjian Bioscience & Technology Co.,Ltd provided the protective gel for free. This gel consists of colloidal and fixative solutions. The colloidal solution contains poloxamers, sodium alginate, and beta-glucan, whereas the fixative solution consists of calcium chloride. In the experimental group, after esophageal ESD, the colloidal solution is firstly spread onto the ulcer, followed by the fixative solution.

Following the ESD, participants were instructed to report any discomfort, such as fever, chest pain, or dysphagia on post-ESD days 1, 14, and 30. A repeat endoscopy was performed, during the two-week follow-up, to confirm resection site healing, assess gel status, and detect any delayed bleeding, perforation, or dysphagia.

Outcomes

The primary outcome of this study, the healing rate, was calculated as follows: [(area of initial ulcer) - (ulcer area 14 days later)] / (area of initial ulcer) * 100%. And secondary endpoints included ulcer area 14 days later, absolute change of ulcer area, and the wound characteristics in endoscopic re-evaluation 14 days after ESD. The primary and secondary endpoints were centrally assessed among the participants completing the whole process. And safety outcomes were adverse events including fever, chest pain dysphagia, and so on, which was analyzed among all the participants who were randomly assigned and completed the esophageal ESD. Adverse events were coded by a coding specialist, and were tabulated by system organ class and preferred terms using the MedDRA dictionary, version 19.0.

Statistical analysis

The sample size was calculated based on the primary studies. The treatment difference assumption was mainly based on another study²⁶. A sample size of 46 patients per randomized group was required to achieve 90% power in our statistical analysis and show statistical significance at the one-sided α level of 0.025 (assuming a true difference of 25% and a dropout rate of 10%). The primary and secondary outcomes were assessed in the population completing the whole process. While the safety analyses were measured among all the patients who were randomly assigned and completed the esophageal ESD.

The ulcer area was measured using the same kind of reference through endoscopy initially after esophageal ESD and 14 days later, using the ImageJ 1.53 analysis system (National Institutes of Health, Bethesda, MD, USA) (Figure S1). Based on these statics, the absolute change of ulcer area was then calculated using the following formula: (area of initial ulcer) - (ulcer area 14 days later). The healing rate was calculated using the formula mentioned above. Adverse events were organized by our study group and presented as the number and proportion of patients. For other surgical information, the surgical time was defined as the interval between the start and completion of the esophageal ESD. The cutting time was the interval between the start of the resection and complete separation of the specimen. Moreover, the protective gel injection time and the wound coverage by gel were also calculated among the experimental group.

The results are presented as mean ± standard deviation or counts (percentages). The t-test was used for data analysis. All P values in this trial were two-sided, and P - values < 0.05 were considered to be statistically significant. All statistical analyses were performed using the SPSS software, version 25.0.0.0 for macOS, or Prism 8.4.0 for macOS.

Study flow

In this study, 92 patients were screened and considered eligible between December 2, 2020, and November 03, 2021. Among them, 46 individuals were randomly assigned to the control group, whereas other 46 individuals were assigned to the experimental group. Overall, 81 (88.0%) of 92 patients completed the whole process and were included in the efficacy analysis, while the remaining 11 (12.0%) patients were lost to follow-up and discontinued the study. All of these 92 individuals were included in the safety analysis (Fig. 1).

Baseline characteristics and wound characteristics

Baseline patient characteristics were similar between the groups (Table 1). Most patients in the control and experimental groups were male (33 [71.7%] and 32 [69.6%], respectively) and the mean age of patients in these groups were 65.8 ± 8.1 years and 66.0 ± 7.2 years, respectively (Table 1). Generally speaking, we observed no intergroup differences in mean age, height, weight, body mass index, and other baseline characteristics.

Table 1

Patients’ baseline characteristics^†. ^†There were no significant differences (P < 0.05) between the study groups. Data are n (%) or mean (SD). BMI, Body-mass index.
Characteristic	Control group (n = 46)	Experimental group (n = 46)
Sex, n (%)
Male	33 (71.7%)	32 (69.6%)
Female	13 (28.3%)	14 (30.4%)
Mean age (SD), y	65.8 (8.1)	66.0 (7.2)
Mean height (SD), cm	163.2 (6.6)	163.7 (6.3)
Mean weight (SD), kg	59.8 (10.5)	63.1 (8.6)
BMI (SD), kg/m²	22.5 (4.1)	23.6 (2.9)
Systolic blood pressure (SD), mmHg	128.7 (14.0)	132.3 (17.6)
Diastolic blood pressure (SD), mmHg	73.3 (9.1)	76.2 (9.9)
Temperature (SD), ^oC	36.7 (0.3)	36.7 (0.4)
Pulse (SD), /min	76.3 (10.8)	77.9 (12.2)
Respiration (SD), /min	18.0 (0.8)	18.2 (0.9)

Altogether 92 individuals completed the esophageal ESD successfully and the procedure time was similar between two groups (53.0 ± 21.3 minutes vs. 52.9 ± 19.0 minutes, P = 0.984) (Table 2). Similarly, there was also no significant difference in cutting time between the control and experimental group (35.1 ± 17.5 minutes vs. 33.4 ± 16.6 minutes, P = 0.638) (Table 2). In this study, this protective gel can successfully cover approximately 91.1 ± 3.6% of the area of the artificial ulcer in 2.1 ± 2.7 minutes. And the endoscopically measured initial ulcer area was approximately 7.7 ± 4.1 cm² in the control group and 9.3 ± 5.1 cm² in the experimental group without significantly difference (Fig. 2a).

Table 2

Details of the endoscopic submucosal dissection procedures. Data are mean (SD) unless otherwise stated.
	Control group (n = 46)	Experimental group (n = 46)	P value
Procedure time (SD), min	53.0 (21.3)	52.9 (19.0)	0.984
Injection time (SD), min	-	2.1 (2.7)	-
Cutting time (SD), min	35.1 (17.5)	33.4 (16.6)	0.638
Covering range (SD), %	-	91.1 (3.6)	-

Evaluation of ulcer healing

Assessed from the endoscopic re-evaluation two weeks after esophageal ESD, the remaining ulcer area was much larger in control group than in the experimental group (1.80 ± 1.32 cm² vs. 1.26 ± 0.67 cm², P = 0.0224) (Fig. 2b). Meanwhile, the calculated absolute ulcer area changes and healing rates in the control group and experimental group were 5.95 ± 3.90 cm² vs. 8.07 ± 4.97 cm² (P = 0.0352) (Fig. 2c) and 73.28 ± 17.81% vs. 83.89 ± 9.51% (P = 0.0013) (Fig. 2d), which made it more convincing that this kind of protective gel could speeding up ulcer healing. Furthermore, when detected by endoscopy two weeks later, wounds in the control group showed greater severity, accompanied by severe necrosis and edema compared with the experimental group. And we did not detect any residual gel over the ulcer bed in endoscopic re-evaluation (Fig. 3).

Adverse events

On the first day after esophageal ESD, 11 (23.9%) patients in the control group, and 19 (41.3%) patients in the experimental group, showed signs of adverse events, most of which were fever, chest pain, or abdominal pain (Table 3). However, these participants recovered without any additional medical treatment. Further evaluation indicated that these adverse events were related to the ESD procedure itself rather than protective gel application. There were no other adverse events such as delayed bleeding, delated perforation, or dysphagia reported in the two-week and one-month follow-ups (Table 3).

Table 3

Adverse events.
Time	Adverse events	Control group	Experimental group
1 day
	Fever, n/N (%)	6/46 (13.0%)	12/46 (26.1%)
	Chest pain, n/N (%)	2/46 (4.3%)	5/46 (10.9%)
	Abdominal pain, n/N (%)	3/46 (6.5%)	0
	Dizziness, n/N (%)	0	1/46 (2.2%)
	Cough, n/N (%)	0	1/46 (2.2%)
14 days
	Adverse events	0	0
30 days
	Adverse events	0	0
Data are n/N (%). The adverse events of the day after endoscopy were measured among all the patients who were randomly assigned and completed the endoscopic submucosal dissection. And the follow-up 14 days later or 30 days later only measured the participants that continued the study.

In this multicenter, randomized, single-blind, efficacy and safety trial, we validated the potential of our novel protective gel as an effective and safe therapeutic agent for artificial wounds after esophageal ESD. This gel could be applied to cover more than 90% of the ulcer area within approximately two minutes. And the healing rates of ulcers treated with this protective gel were much higher than that observed in the control group. Patients treated with the gel also had less severe wounds as determined by repeat endoscopy. Therefore, our findings suggest that this kind of protective gel should be assessed as a potential treatment for patients receiving esophageal ESD. Additionally, we observed no severe adverse events related to gel application that were reported during the one-month follow-up.

ESD has enabled the en bloc resection of large-sized superficial esophageal neoplasms, but it carries the risk of causing esophageal stricture, bleeding, and perforation⁹. Among them, stenosis is the main long-term complication of esophageal ESD which can substantially impair the patient’s quality of life. Currently, there are many prophylactic options to prevent esophagus stricture after ESD, including corticosteroids administration, polyglycolic acids (PGA) sheets, endoscopic balloon dilation (EBD), and autologous cell sheet transplantation²⁷. But this kind of protective gel that consists of colloidal and fixative solutions has never been reported in current literature. The interaction between calcium chloride and sodium alginate results in molecular entanglements. Then, poloxamers transform into a semisolid gel at body temperature, which can further protect the wound. During the wound healing process, the infiltration of inflammatory cells, excessive collagen formation, and disorganized fibrosis might play a role in stricture formation¹². Therefore, reducing the inflammatory reaction, promoting rapid re-epithelialization, and minimizing the damage will prevent esophagus stricture after ESD²⁸. In this study, the healing rate in the experimental group was significantly higher than the control group, which indicates that this kind of protective gel could strongly accelerate the re-epithelialization process after esophagus ESD. The protective effects of the gel can be attributed to the following underlying mechanisms. First of all, this protective gel could cover the artificial ulcer and protect it from harmful microbiological factors and chemical factors in the gastrointestinal tract. Secondly, poloxamers have been demonstrated to encompass the healing characteristics. Poloxamers could stimulate the expression of vascular endothelial growth factor (VEGF) as well as transforming growth factor-β (TGF-β), which could strengthen the wound healing process. They could enhance the tissue granulation along with fibroblast proliferation²⁹. Thirdly, the emergence of bacterial biofilm in most of the chronic wounds could hinder the wound healing since they could endure many antibiotic and antimicrobial treatments. It was reported that poloxamers could improve the biofilm removal³⁰. Lastly, it was known that poloxamers could increase the performance of matrix metalloproteinase 2 and 9 gelatinases, while simultaneously inhibiting matrix metalloproteinase-8 collagenase. And it is expected to accelerate autolytic debridement by degrading the damaged collagen and protecting the untouched collagen³¹. And most of the mechanism has been confirmed in our in vitro experiments. We confirmed that this novel protective gel could not only protect the epithelial cells from digestive juices but also promote epithelial cells proliferation, migration and angiogenesis, all of which were essential for wound healing.

In our study, the protective gel could be applied to cover more than 90% of the ulcer area within approximately three minutes. Recently, other novel techniques such as tissue engineering, autologous tissue transplantation, and polyglycolic acid (PGA) sheets have been proposed as options to improve wound healing. Tissue engineering and autologous tissue transplantation are potential preventive methods and are currently used in animal experiments. However, compared to protective gel application, tissue engineering and autologous tissue transplantation require high technical surgeon expertise and a much longer fixation time³². A PGA sheet can promote cell migration during the healing process, thereby reducing the risk of esophagus stricture. Nevertheless, the delivery and fixation of PGA sheets are time consuming and the PGA sheets could easily be disturbed by food³³. Above all, our gel provides the efficacy, safety, and convenience that collectively make it a viable option for preventing esophageal strictures after ESD.

Among the one-month follow-up, we observed adverse events, such as fever, chest pain, or abdominal pain on the day after esophageal ESD in 30 patients in our study. The symptoms of these patients were mild and these individuals recovered soon without additional medical treatment. Further analyses showed that these adverse events were more likely a result of the esophagus ESD itself rather than the protective gel application. No delayed bleeding or delayed perforation were reported during the follow-up period. Nowadays, steroid administration and repeated endoscopic balloon dilatation are the common interventions for preventing esophagus strictures. However, it was reported that intralesional steroid injections could inhibit the healing process and cause esophageal perforation and gastrointestinal bleeding, whereas systemic administration increases the risk of immunosuppression and osteoporosis². Similarly, the effect of endoscopic balloon dilatation is temporary, which could decrease the patients’ quality of life and increase the medical costs. Repeated esophageal dilatation has been reported to carry a risk of perforation (0.4–1.1% per procedure, and up to 9% per patient) ^6,34,35. The results of our study demonstrated that this kind of protective gel could be safely applied to the artificial ulcer protection after esophageal ESD.

Admittedly, there are some limitations in this study. First of all, most of the former studies have indicated that postoperative stricture formed after 14 days^2,15,28,36. And we performed the repeated endoscopy 14 days after esophageal ESD and did not perform a third endoscopy at the one-month follow-up. However, there are some patients that don’t experience dysphagia until one month later or even much longer. Therefore, a long-term study is needed in future research. Secondly, 11 patients were lost to follow-up and discontinued the study. These may cause some bias in this randomized controlled trial. Finally, the potential for observation bias could not be avoided because it was impossible to blind the endoscopists during the esophageal ESD process.

Generally speaking, this multicenter, randomized, single-blind trial emphasizes the effectiveness, convenience, and safety of our novel protective gel when applied over the wounds following the esophageal ESD. It could be applied to cover more than 90% of the ulcer area within approximately three minutes. More importantly, no severe relative adverse events were reported during the one-month follow-up. Therefore, we recommend using this protective gel as a prophylactic intervention to promote ulcer healing and protect the ulcer bed after esophageal ESD.

Acknowledgements

We would like to thank all the investigators who cooperated in recruiting patients at participating institutions. We would like to thank Hangzhou Yingjian Bioscience & Technology Co.,Ltd that provided the protective gel for free.

Author contributions

T.Z., X.M. and L.X. contributed equally to this article. Z.S. acted as guarantors of the article. Z.S. and C.Y. conceived and designed the study. T.Z. and L.C. collected and analyzed the data. T.Z. wrote the manuscript. C.D. generated the random allocation sequence. L.X. enrolled participants. X.M., L.X., H.J., J.W., W.L., F.J. and B.L. performed the endoscopy. T.Z., X.M., L.X., H.J., L.C., C.D., L.X., J.W., W.L., B.L., F.J., C.Y. and Z.S. had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Data availability statement

All the related data is available on reasonable request. The data that support the findings of this study have been deposited in http://60.191.20.66/wy_sgcd, and the data is available from the corresponding author, Zhe Shen, on reasonable request.

Funding

This work was supported by the Science Technology Department of Zhejiang Province (No 2021C03115 to Z.S., 2019C03040 to X.M.). The funders did not play any role in the study design, data collection and analysis, decisions regarding data release or manuscript preparation.

Declaration of Competing Interest

The authors disclose no conflicts. The authors alone are responsible for the content and writing of the paper.

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No competing interests reported.

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A new protective gel to facilitate ulcer healing in artificial ulcers following esophageal endoscopic submucosal dissection: A multicenter, randomized trial

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Abstract

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Introduction

Methods

Study design

Participants

Randomization and masking

Procedures

Outcomes

Statistical analysis

Results

Study flow

Baseline characteristics and wound characteristics

Evaluation of ulcer healing

Adverse events

Discussion

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References

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