Evaluation of Safety and Efficacy of a Novel Alginate-Based Esophageal Mucosal Wound Protective Gel

Abstract

Background & Objective:

Endoscopic Submucosal Dissection (ESD) effectively treats early gastric cancer, but postoperative complications limit its clinical use. Therefore, this study examines how esophageal mucosal wound protective gels improve wound healing and reduce post-ESD complications.

Methods:

The gels were characterized for physical properties and stability using rheological behavior, injectability, swelling capacity, and enzymatic degradation resistance. Biocompatibility was assessed via hemolysis testing, cytotoxicity assays, and oral mucosal irritation tests. Furthermore, wound repair potential was evaluated through cell proliferation, migration, and cell cycle analysis in Het-1A cells. Finally, in vivo recovery experiments were conducted to assess post-ESD wound healing efficacy.

Results:

The gels exhibited favorable physical properties, chemical stability, and biocompatibility. Specifically, they maintained stability in the digestive tract, underwent rapid gelation at 37°C, and promoted cell proliferation. Post-ESD evaluation further revealed improved mucosal healing with no significant bleeding events.

Conclusion:

The developed esophageal mucosal wound-protective gels fulfill the requirements for submucosal interventions and show promising potential for ESD wound repair via rapid in situ gelation. This platform could be adapted for various endoscopic procedures and provides new insights for digestive tract tissue engineering applications.

Impact Statement

Endoscopic mucosal dissection (ESD) is recognized as an effective therapeutic modality for early digestive tract cancers; however, the postoperative complications associated with this procedure remain a significant clinical challenge. In this study, we systematically evaluated the application value of a novel esophageal mucosal wound protective gel in facilitating wound repair after ESD. Furthermore, we investigated potential novel application domains of alginate within this context. The results demonstrated that the assessed gel not only optimized the surgical procedure but also significantly enhanced patient outcomes, thus presenting a promising direction for regenerative medicine in the realm of digestive tract tissue engineering and wound repair.

Keywords

esophageal mucosal protective glue ESD surgery mucosal repair Het-1a cells sodium alginate

Introduction

According to the World Health Organization’s International Agency for Research on Cancer, lung, liver, gastric, breast, and colorectal cancers rank among the top five causes of cancer-related mortality worldwide.^1–6 In China, these malignancies—particularly lung, liver, gastric, esophageal, and colorectal cancers—are responsible for approximately 70% of all cancer deaths, with gastrointestinal cancers alone accounting for 45% of cancer mortality.^7–9 This mortality pattern shows significant geographical variation, with developed nations such as the United States and the United Kingdom reporting substantially lower rates.^7–9 The poor postoperative outcomes observed in Chinese patients are frequently attributed to late-stage diagnosis.^10–13

Early-stage digestive tract cancers typically manifest with nonspecific symptoms and are frequently confined to the mucosal and submucosal layers.^14–16 Conventional endoscopic examinations have demonstrated limited screening efficacy.¹⁷ Recent advances in endoscopic diagnostic techniques, however, have significantly improved early cancer detection. Endoscopic Submucosal Dissection (ESD) has emerged as the gold-standard treatment for early gastric cancer and precancerous lesions.^18–20 Originally developed in Japan in the mid-1990s as an evolution of endoscopic mucosal resection (EMR),²¹ ESD represents a specialized endoscopic resection technique primarily indicated for early-stage malignant gastric tumors. The technique’s applications have expanded to include various gastrointestinal lesions, particularly superficial colorectal neoplasms. In clinical practice, European centers routinely employ ESD for the management of early-stage and precancerous digestive tract lesions.²² Currently, ESD stands as the standard treatment for the complete removal of large early gastric epithelial lesions.²³

Compared with traditional EMR, ESD offers several clinical advantages.^24–27 This technique enables en bloc resection of superficial lesions regardless of their size, which facilitates complete tumor removal, lowers local recurrence rates, and allows for more accurate histopathological evaluation.²⁸ Nevertheless, ESD is associated with higher postoperative bleeding rates, particularly in gastric procedures (4.6 − 15.6%),^29–31 while perforation rates range from 6.1% to 9.6%.^32–35 These complications—including bleeding, ulcer formation, perforations, and mucosal hyperplasia—currently limit ESD’s widespread adoption. The procedure involves complete excision of the mucosal lesion, resulting in a substantial wound that extends to the submucosa or deeper muscularis propria, thereby creating what is clinically defined as an artificial ulcer.³⁶ Incomplete healing of these artificial ulcers combined with undetected surgical defects represents the main contributors to post-ESD complications.³³ Therapeutic biomaterials capable of adhering to wound beds, providing a protective barrier against digestive enzymes, and promoting ulcer healing could significantly reduce ESD-associated complications while broadening its clinical utility.^37–41

Extensive research efforts currently focus on addressing postoperative ESD complications through medical devices, tissue adhesives, and biomaterials.^42–44 Conventional interventions such as hemostatic clips and surgical staplers carry inherent risks of secondary bleeding, incur substantial costs, and often require additional procedures that increase patient discomfort and healthcare burden. Recent breakthroughs in tissue engineering and materials science have facilitated biomedical material applications for digestive tract wound repair, particularly with various intraoperative wound protection materials, including fibrin-based adhesives, polylactic acid matrices, polyethylene glycol membranes, and fibrin glues. The primary limitation of these materials lies in their frequent requirement for suture fixation at the wound site, compromising their clinical practicality. Critical unmet needs persist in developing optimal post-ESD wound repair materials that must concurrently achieve effective sealing, biocompatibility, and ease of application.

The in situ forming depot (ISFD) system has emerged as an innovative controlled-release platform with broad applications in pharmaceutical and biomedical fields.⁴⁵ These systems consist of liquid formulations that undergo phase transition into solid or semisolid states upon injection, enabling controlled and sustained drug release through nongastrointestinal delivery.⁴⁶ These findings position ISFD systems as promising candidates for addressing current challenges in post-ESD wound management.

Based on these considerations, esophageal mucosal wound protective gel for post-ESD wound repair was developed. This gel comprises sodium alginate, β-glucan, hydroxypropyl methylcellulose, poloxamer, and other components. The formulation remains liquid at low temperatures while demonstrating excellent flowability. At physiological temperature (37°C), it undergoes rapid transformation into a semisolid gel state, thereby reducing secondary damage to the wound from digestive tract contents. When administered onto the wound through the endoscope tube at room temperature and subsequently treated with a fixing liquid, the gel quickly forms a protective film mediated by temperature and ionic interactions. This film covers the wound surface and protects against further stimulation by digestive tract contents. Our hydrogel not only simplifies the surgical procedure and lowers complication incidence but also effectively enhances wound healing, demonstrating potential as a medical material for treating internal mucosal injuries, particularly post-ESD wound damage.

Methods and Experiments

Materials

The esophageal mucosal wound protective gel (Patent No. 2023114491953, Hangzhou Yingjian Biotechnology Co., Ltd., Hangzhou, China) consists of two components: a gel-forming solution and a cross-linking solution. Physiological saline, dipotassium hydrogen phosphate, and sodium hydroxide were obtained from Sinopharm (Beijing, China). Trypsin was purchased from Biofroxx (Germany). The electrosurgical unit (VIO 200S) was from ERBE Elektromedizin GmbH (Tübingen, Germany). The gastroscope (VGT-Q30J) and colonoscope (VCC-Q30JI) were from AOHUA Endoscopy Co., Ltd. (Shanghai, China).

Methods

Initial gelation temperature

Rheological analysis was performed using an MCR92 rheometer (Anton Paar GmbH, Graz, Austria) in temperature sweep mode. The measurements were conducted at a constant frequency of 1 Hz with a strain amplitude of 1%. Temperature was increased from 0°C to 70°C at a rate of 2°C/min, and the elastic storage modulus (G′) and viscous loss modulus (G″) were recorded.

Mobility at different temperatures

The flow behavior of the hydrogel at different temperatures was evaluated by measuring the viscosity of the precursor solution using a rheometer. The sample was equilibrated at each test temperature (4, 15, 25, 37, and 50°C) before measurement. Viscosity measurements were conducted at a constant shear rate of 1 rad/s with three replicates at each temperature point.

Feasibility of injection

Injection force measurements were performed on an Instron 3382 universal testing machine using a 1 mL syringe fitted with a 25-gauge needle, at a crosshead speed of 30 mm/min with a 500 N load cell. Normal saline (0.9% NaCl) served as the control in all measurements. To evaluate clinical applicability, the solution was injected through a disposable endoscopic needle under both ambient (25°C) and physiological (37°C) conditions.

Swelling test

The swelling characteristics were evaluated as a key parameter for hydrogel performance. Preweighed dried hydrogel samples (W₀) were immersed in 2 mL of physiological saline at room temperature using a 24-well plate. At predetermined time intervals, the hydrogels were carefully removed, surface moisture was absorbed using filter article, and the mass (W) was recorded to calculate the swelling ratio.

SR % = (W - W_{0}) / W_{0} \times 100 %

Resistance to enzymatic hydrolysis test

The enzymatic degradation of hydrogels was evaluated by weight loss measurements. Hydrogel samples with known mass were immersed in artificial intestinal fluid (pH 6.8) at 37°C, and their mass changes were monitored daily for 7 days to assess the degradation behavior in the intestinal environment.

Biocompatibility evaluation tests

Cytotoxicity test

Mouse fibroblast L929 cells were seeded in 96-well plates (1 × 10⁵ cells/mL) and cultured at 37°C with 5% CO₂ for 24 h. Sample extracts (100 μL/well) were added at serial concentrations of 100%, 50%, 25%, and 12.5%, with positive, negative, and blank controls included (n = 6). Cell morphology was examined using an inverted fluorescence microscope (Olympus IX71, Japan) after 24 h incubation, followed by viability assessment using the CCK-8 assay (Dojindo Laboratories, Japan).

Hemolysis test

The hemolysis assay included three groups (n = 3): sample (hydrogel with 10 mL saline), negative control (10 mL saline), and positive control (10 mL distilled water) in 15 mL centrifuge tubes. After incubation at 37°C for 30 min, 0.2 mL diluted rabbit blood was added. The mixtures were gently mixed, incubated at 37°C for 60 min, and centrifuged at 358 g for 5 min. Supernatant absorbance was measured at 545 nm using a ultraviolet spectrophotometer (U-3310, Hitachi, Japan). The hemolysis rate was calculated based on the following formula:

Hemolysis Rate (%) = \frac{{OD}_{sample} - {OD}_{negative}}{{OD}_{positive} - {OD}_{negative}} \times 100 %

Oral mucosal irritation test

Animal experiments were approved by the Animal Ethics Committee of National Institutes for Food and Drug Control. Male golden hamsters (n = 12, 110 ± 10 g, specific pathogen free) were anesthetized with Sutex (45 mg/kg) and divided into two groups. Cotton balls (10 mm) with gel or saline were applied to the cheek pouch, with saline in the left pouch and gel in the right pouch. At 24 h, tissues were collected, fixed in 4% paraformaldehyde, and subjected to H&E histological examination.

Effectiveness of repair of esophageal intestinal epithelial cells

Toxic effects on Het-1a

Het-1a cells purchased from American Type Culture Collection were maintained in minimum essential medium (MEM, Corning) supplemented with 10% fetal bovine serum (FBS) and 1% Penicillin-Streptomycin (PS) at 37°C in 5% CO₂. The gel extract was prepared in medium for 24 h. Cells (2 × 10⁵/mL) were exposed to the extract for 24 h. Cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8) assay, with fresh medium as the blank control, 0.1% dimethyl sulfoxide (DMSO) in MEM as positive control, and polyethylene patch extract as negative control. Results were expressed as relative proliferation rate.

RGR (%) = \frac{A - A_{0}}{A_{0}} \times 100 %

A: Absorbance of the test group; A₀: Absorbance of the blank control group.

Effect on cell proliferation of Het-1a

The esophageal mucosal wound protective gel was incubated in culture medium at 37°C for 24 h to obtain the extract. Then, Het-1a cells (1 × 10⁵/mL) were cultured with the extract at different dilutions (1:1 ratio) in a humidified 5% CO₂ atmosphere at 37°C. Cell viability was assessed by CCK-8 assay at 24, 48, and 72 h, with fresh culture medium serving as control. Results were expressed as relative growth rate (RGR).

RGR (%) = \frac{A - A_{0}}{A_{0}} \times 100 %

A: Absorbance of the test group; A₀: Absorbance of the blank control group.

Effect on the cell cycle of Het-1a

Het-1a cells (1 × 10⁵/mL) were cultured with 100 μL of extracts at different dilutions in a humidified 5% CO₂ atmosphere for 24 h. The fluorescence signals were detected using a flow cytometer (BD CANTO II) with a 488 nm laser excitation. Appropriate gating strategy was applied to exclude cellular debris and aggregates. Data analysis was performed using FlowJo software.

Effect on cell migration of Het-1a

The cell migration capacity was evaluated using a scratch assay. Het-1a cells were seeded into 24-well plates at a density of 1 × 10⁵ cells per well. When the cells reached approximately 90% confluence, a scratch was made with a pipette tip perpendicular to the plate surface. The scratch width was observed under microscope at 0, 12, 24, and 36 h timepoints, and the results were analyzed.

In vivo evaluation of Post-ESD wound protection and healing

The Ethics Committee of Zhejiang Chinese Medical University approved this prospective randomized controlled animal study at the Laboratory Animal Center between March and June 2023. Ten healthy Bama miniature pigs weighing 20–25 kg were selected as experimental subjects. A standard endoscope (Olympus, Tokyo, Japan) was used to create four artificial wounds in the esophagus of each pig through ESD, generating 40 experimental wounds randomly distributed into treatment and control groups (1:1). In the treatment group, 2.5 mL of colloidal solution was sprayed evenly onto the wound surface through the endoscope working channel, followed by an equal volume of fixing solution. The protective membrane formed on the wound surface within 3–5 min. Wound assessment was performed at two time points: immediately after ESD and 14 days postprocedure. Each wound was photographed during endoscopic examination using biopsy forceps or circular pads as size references and analyzed with ImageJ 1.47 system (National Institutes of Health, Bethesda, MD, USA).

Statistical analysis

All experiments were independently repeated at least three times (n ≥3) and presented as mean ± standard deviation. Statistical significance between the results was determined by one-way analysis of variance (ANOVA) and Student’s t-test. p < 0.05 was considered to be statistically significant (*p < 0.05, **p < 0.01, and ***p < 0.001).

Results

Physical and chemical properties test

Rheological measurements revealed the relationship between storage modulus (G′) and loss modulus (G″) in the gel system (Fig. 1A). The storage modulus (G′) reflects the elastic component of the material, while the loss modulus (G″) characterizes the viscous behavior. At low temperatures (4–15°C), the G″/G′ ratio demonstrated a liquid state of the esophageal mucosal wound protective gel, with low viscosity values (Fig. 1B). Upon temperature increase, G′ increased gradually along with gel viscosity. The system reached a critical point at 35°C where G′ equaled G″, marking the sol-gel transition and network formation. At physiological temperature (37°C), the material formed a complete gel state with significantly increased viscosity compared with lower temperatures. This temperature-dependent behavior arises from the thermal response of the colloidal system, promoting hydrogel network formation at the critical temperature. Further heating enhanced the gel structure, as evidenced by the higher viscosity measurements, indicating increased network density throughout the matrix.

FIG. 1.

(A) Rheological diagram of thermo-sensitive gel at different temperatures. (B) Viscosity of the gel at different temperatures. (C) Injection force of the gel precursor solution. (D) Smooth injection of the gel precursor solution with an injection needle through a disposable endoscope. (a, the fixative solution was injected through an endoscopic needle at 37°C; b, colloid solution was injected through an endoscopic needle at 37°C; c, the fixative solution was injected through an endoscopic needle at room temperature; d, colloid solution was injected through an endoscopic needle at room temperature.). (E) Swelling of gel at different times.

Feasibility of injection

The viscosity of precursor solutions is crucial for endoscopic delivery performance, as appropriate viscosity ensures successful administration through endoscopic needles to wound sites. Injection force measurements (Fig. 1C) showed that both the colloidal and crosslinking components flowed adequately at room temperature through standard disposable endoscopic needles (Fig. 1D). At physiological temperature (37°C), the system maintained good injectability, supporting its potential for clinical application with minimal procedural complications.

Swelling test

The swelling ratio is a key parameter in hydrogel characterization, primarily determined by the network crosslinking density. Time-dependent swelling measurements of the hydrogel were conducted at predetermined intervals (Fig. 1E). The sample exhibited initial swelling progression with a maximum ratio of 238% at 24 h, followed by a gradual decline to 180% at 60 h, reaching equilibrium after 48 h. In the initial phase, the rate of water uptake exceeded degradation, leading to progressive swelling of the network. As degradation became predominant in later stages, the swelling ratio decreased accordingly. These findings indicate that the sample possesses considerable water retention capacity and creates suitable conditions for cellular growth, demonstrating promise for wound repair applications.

Resistance to enzymatic hydrolysis test

The stability of the esophageal mucosal wound protective gels was evaluated in artificial intestinal fluid containing trypsin, demonstrating excellent structural integrity and resistance to enzymatic degradation (Table 1 and Fig. 2A). The gels, composed of polyoxyethylene-polyoxypropylene block copolymer, sodium alginate, hydroxypropyl methylcellulose, and calcium chloride, form through physical cross-linking at physiological temperature (37°C) when calcium ions interact with the colloidal components. This cross-linked network creates a stable physical barrier that prevents digestive fluid contact with the wound surface, while the primary components remain resistant to intestinal digestion due to the absence of specific degradative enzymes. These properties ensure that the gel components maintain their structural integrity without being absorbed in the digestive tract, making them suitable for esophageal wound protection.

FIG. 2.

(A) Hydrogel changes in artificial intestinal fluid containing trypsin. (B) Toxicity evaluation of gel extract on L929 cells. (C) Hemolysis in each group after centrifugation. (D) Hemolysis experiments of the hydrogel. (E) Pathological map of oral mucosa of golden hamster.

Table 1.

Quality of Hydrogels at Different Times (X ± s, n = 3)

Days	Gel mass (g)	Rate of degradation
0	5.2504 ± 0.0118	—
1	5.2506 ± 0.0121	0%
2	5.2506 ± 0.0115	0%
3	5.2507 ± 0.0117	0%
4	5.2502 ± 0.0118	0%
5	5.2504 ± 0.0117	0%
6	5.2507 ± 0.0119	0%
7	5.2506 ± 0.0117	0%

Biocompatibility evaluation tests

The biocompatibility of the esophageal mucosal wound protective gels was evaluated through multiple tests. The cytotoxicity test showed high L929 cell viability after 24 h coculture, with survival rates of 100.85% to 112.62% (Fig. 2B), confirming excellent cellular biocompatibility. In the hemolysis test, the sample group showed clear supernatant with blood cell precipitation (Fig. 2C), and the measured hemolysis rate of 0.68% (Fig. 2D) was well below the 5% threshold, demonstrating good blood compatibility. Oral mucosal irritation testing revealed no adverse reactions in golden hamsters during both 1 h and 4 h exposure periods. Histological examination (Fig. 2E) showed intact mucosal epithelium with normal cell arrangement and stratification, while the connective tissue maintained its typical structure without inflammatory infiltration or edema. These results collectively demonstrate the excellent biocompatibility of the esophageal mucosal wound protective gels for clinical applications.

Repair efficacy on esophageal epithelial cells

The therapeutic potential of the esophageal mucosal wound gel was systematically evaluated using Het-1a cells. Cytotoxicity assays confirmed excellent biocompatibility, with cell viability consistently exceeding 70% at all tested concentrations (Fig. 3A). Proliferation assays revealed a time-dependent response, peaking at 24 h before gradually declining (Fig. 3B). Notably, all gel extract concentrations significantly enhanced proliferation compared with controls (p < 0.001), with the 100% concentration exhibiting the most pronounced effect (Fig. 3C). Flow cytometry analysis demonstrated an increased proportion of cells in S phase after treatment (Fig. 4), suggesting cell cycle modulation as a potential mechanism for the observed proliferative effects. In wound healing assays (Figs. 3D and 5), a distinct concentration-dependent pattern emerged, with lower concentrations (particularly 12.5%) showing greater efficacy in promoting cell migration. Collectively, these data indicate that the gel not only maintains Het-1a cell viability but also stimulates proliferation, modulates cell cycle progression, and facilitates migration—key processes in esophageal mucosal repair. These findings support its potential clinical application for enhancing mucosal regeneration.

FIG. 3.

(A) Results of Het-1a cytotoxicity assay. (B) The effect of extraction time on the proliferation of Het-1a cells. (C) The effect of concentration on the proliferation of Het-1a cells. (D) Effect of sample extract on the migration of Het-1a cells. (*p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.001 compared with the control group; data without asterisks indicate no significant difference).

FIG. 4.

Flow cytometry of Het-1a cells. (A–E) The cell cycle distribution after the cells were treated with the control, 100%, 50%, 25%, and 12.5% concentration groups, respectively. (F) Het-1a cell cycle distribution (n = 3).

FIG. 5.

(A–E): Flow cytometry of Het-1a cells. (A–E show the cell cycle distribution after the cells were treated with the control, 100%, 50%, 25%, and 12.5% concentration groups, respectively). (F) Het-1a cell cycle distribution (n = 3).

In vivo evaluation of Post-ESD wound protection and healing

Endoscopic evaluation at 14 days post-ESD showed improved wound healing in the gel-treated group compared with controls. As illustrated in Figure 6B, wounds treated with the esophageal mucosal wound protective gel showed favorable healing with smooth, pink regenerated mucosa, whereas control wounds displayed irregular surface patterns. As shown in Figure 7 and Table 2, the experimental group demonstrated significantly higher healing rates (91.6 ± 6.0%) compared with controls (66.6 ± 19.2%; p < 0.0001), suggesting the gel enhances mucosal repair. No major bleeding events occurred during the study period, confirming the safety and tolerability of the gel application.

FIG. 6.

(A) ESD procedure in the esophagus. (a) Resection margin marking; (b) Injection of submucosal lifting solution; (c) Mucosal dissection; (d) Coagulation for hemostasis; (e) Wound surface treatment with esophageal mucosal protective gel and staining. (B) Endoscopic findings at 14-day follow-up. (a) Post-ESD ulcer in control group; (b) Post-ESD ulcer in treatment group.

FIG. 7.

(A) Remaining pore size at day 14. (B) Wound healing rate at day 14. (*p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.001 compared with the control group; data without asterisks indicate no significant difference).

Table 2.

Comparison of Pore Size and Healing Rate 14 Days after ESD (X ± s, n = 20)

Group	Nc			Gel
Group	InitialPore Size	RemainingPore Size	HealingRate (%)	InitialPore Size	RemainingPore Size	HealingRate (%)
Mean ± SD	4.673 ± 2.437	1.533 ± 1.401	66.59 ± 19.17	5.748 ± 2.498	0.4440 ± 0.3467	91.64 ± 6.040

The esophageal mucosal wound protective gel formed a stable barrier over the exposed surface, preventing direct contact between the wound and esophageal contents, including gastric reflux and food debris. The gel remained adherent throughout the observation period, accompanied by uniform mucosal regeneration and accelerated healing rates. Post-ESD monitoring confirmed that the gel reduced ulcer formation and associated complications.

In addition, its application simplified the surgical process and enhanced wound healing. These findings suggest that the hydrogel is an effective treatment for post-ESD wounds, supporting its potential clinical use for internal mucosal injuries.

Discussion

This study evaluated an esophageal mucosal wound protective gel for post-ESD wound repair. The dual-component gel system showed excellent biocompatibility, with appropriate fluidity for precise delivery and rapid crosslinking to form a stable protective barrier under physiological conditions. The gel promoted wound healing by stimulating Het-1A cell proliferation, increasing S phase population, and enhancing cellular migration, particularly at lower concentrations. In vivo studies using the ESD model showed substantial improvement in wound healing, with treated areas exhibiting smooth, pink regenerated mucosa by 14 days postprocedure. The gel maintained structural integrity throughout the healing process and prevented postoperative complications through sustained wound coverage.

This protective gel system advances post-ESD wound management with potential applications in digestive tract endoscopic procedures. Initial results suggest applications beyond ESD, including EMR, peroral endoscopic myotomy, and management of digestive tract fistulas. Its injectable delivery, rapid in situ gelation, and demonstrated wound healing properties support potential clinical translation. Integration with current endoscopic techniques could improve minimally invasive digestive tract interventions by optimizing procedural efficiencies and patient outcomes. This protective gel platform offers new possibilities for regenerative medicine applications in digestive tract tissue engineering and wound repair.

Authors’ Contributions

Conceptualization, Q.H. and H.W.; methodology, H.W., M.Y., and J.L.; data curation, J.L. and M.Y.; writing—original draft preparation, J.L., M.Y., X.S., and F.Q.; writing—review and editing, Q.H. and H.W. All authors have read and agreed to the published version of the article.

Footnotes

Author Disclosure Statement

The authors declare no conflicts of interest.

Funding Information

This research was funded by NATIONAL KEY R&D PROGRAM OF CHINA, grant number 2022YFC2401802.

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