Blue Laser Triggered Hemostatic Peptide Hydrogel for Gastrointestinal Bleeding Treatment.

In an emergency, nonvariceal upper gastrointestinal bleeding (NVUGIB), endoscopic hemostasis is considered the gold standard intervention. However, current endoscopic hemostasis is very challenging to manage bleeding in large-diameter or deep lesions highly prone to rebleeding risk. Herein, a novel hemostatic peptide hydrogel (HPH) is reported, consisting of a self-assembly peptide sequence CFLIVIGSIIVPGDGVPGDG (PFV) and gelatin methacryloyl (GelMA), which can be triggered by blue laser endoscopy (BLE) for nonvariceal upper gastrointestinal bleeding treatment without recurring bleeding concerns. Upon contact with GelMA solution, PFV immediately fibrillates into ß-sheet nanofiber and solvent-induced self-assembly to form HPH gel. HPH nanofiber networks induced ultrafast coagulation by enveloping blood cells and activating platelets and coagulation factors even to the blood with coagulopathy. Besides its remarkable hemostatic performance in artery and liver injury models, HPH achieves instant bleeding management in porcine NVUGIB models within 60 s by preventing the rebleeding risk. This work demonstrates an extraordinary hemostatic agent for NVUGIB intervention by BLE for the first time, broadening potential application scenarios, including patients with coagulopathy and promising clinical prospects.

A new artificial intelligence system for both stomach and small-bowel capsule endoscopy.

BACKGROUND AND AIMS: Despite the benefits of artificial intelligence in small-bowel (SB) capsule endoscopy (CE) image reading, information on its application in the stomach and SB CE is lacking. METHODS: In this multicenter, retrospective diagnostic study, gastric imaging data were added to the deep learning-based SmartScan (SS), which has been described previously. A total of 1069 magnetically controlled GI CE examinations (comprising 2,672,542 gastric images) were used in the training phase for recognizing gastric pathologies, producing a new artificial intelligence algorithm named SS Plus. A total of 342 fully automated, magnetically controlled CE examinations were included in the validation phase. The performance of both senior and junior endoscopists with both the SS Plus-assisted reading (SSP-AR) and conventional reading (CR) modes was assessed. RESULTS: SS Plus was designed to recognize 5 types of gastric lesions and 17 types of SB lesions. SS Plus reduced the number of CE images required for review to 873.90 (median, 1000; interquartile range [IQR], 814.50-1000) versus 44,322.73 (median, 42,393; IQR, 31,722.75-54,971.25) for CR. Furthermore, with SSP-AR, endoscopists took 9.54 minutes (median, 8.51; IQR, 6.05-13.13) to complete the CE video reading. In the 342 CE videos, SS Plus identified 411 gastric and 422 SB lesions, whereas 400 gastric and 368 intestinal lesions were detected with CR. Moreover, junior endoscopists remarkably improved their CE image reading ability with SSP-AR. CONCLUSIONS: Our study shows that the newly upgraded deep learning-based algorithm SS Plus can detect GI lesions and help improve the diagnostic performance of junior endoscopists in interpreting CE videos.

Plant mucus-derived microgels: Blood-triggered gelation and strong hemostatic adhesion.

Arrest of bleeding usually applies clotting agents to trigger coagulation procedures or adhesives to interrupt blood flow through sealing the vessel; however, the efficiency is compromised. Here, we propose a concept of integration of hemostasis and adhesion via yam mucus's microgels. The mucus microgels exhibit attractive attributes of hydrogel with uniform size and shape. Their shear-thinning, self-healing and strong adhesion make them feasible as injectable bioadhesion. Exceptionally, the blood can trigger the microgels' gelation with the outcome of super extensibility, which leads to the microgels a strong hemostatic agent. We also found a tight gel adhesive layer formed upon microgels' contacting the blood on the tissue, where there is the coagulation factor XIII triggered to form a dense three-dimensional fibrin meshwork. The generated structures show that the microgels look like hard balls in the dispersed phase into the blood-produced fibrin mesh of a soft net phase. Both phases work together for a super-extension gel. We demonstrated the microgels' fast adhesion and hemostasis in the livers and hearts of rabbits and mini pigs. The microgels also promoted wound healing with good biocompatibility and biodegradability.

Analyzing Mushroom Structural Patterns of a Highly Compressible and Expandable Hemostatic Foam for Gastric Perforation Repair.

Nature presents the most beautiful patterns through evolving. Here, a layered porous pattern in golden ratio (0.618) is reported from a type of mushroom -Dictyophora Rubrovalvata stipe (DRS). The hierarchical structure shows a mathematical correlation with the golden ratio. This unique structure leads to superior mechanical properties. The gradient porous structure from outside to innermost endows it with asymmetrical hydrophilicity. A mathematical model is then developed to predict and apply to 3D printed structures. The mushroom is then explored to repair gastric perforation because the stomach is a continuous peristaltic organ, and the perforated site is subject to repeated mechanical movements and pressure changes. At present, endoscopic clipping is ineffective in treating ulcerative perforation with fragile surrounding tissues. Although endoscopic implant occlusion provides a new direction for the treatment of gastric ulcers, but the metal or plastic occluder needs to be removed, requiring a second intervention. Decellularized DRS (DDRS) is found with asymmetric water absorption rate, super-compressive elasticity, shape memory, and biocompatibility, making it a suitable occluder for the gastric perforation. The efficacy in blocking gastric perforation and promoting healing is confirmed by endoscopic observation and tissue analysis during a 2-month study.

Efficacy and safety of piecemeal submucosal tunneling endoscopic resection for giant esophageal leiomyoma.

BACKGROUND AND AIMS: Giant esophageal leiomyoma usually requires a thoracotomy or thoracoscopic surgery, which is more invasive than an endoscopic treatment. The purpose of this study is to evaluate the efficacy and safety of piecemeal submucosal tunneling endoscopic resection (P-STER) for giant leiomyoma originating from the muscularis propria (MP) layer of the esophagus. METHODS: This is a retrospective study. Patients with giant esophageal leiomyoma (transverse diameter ≥ 3 cm) who underwent P-STER were enrolled from November 2012 to May 2023. Clinical data and results were investigated. RESULTS: A total of 16 patients were enrolled for analysis. The lesion mean transverse diameter and longitudinal diameter were 4.22 ± 1.20 cm and 6.20 ± 1.57 cm, respectively. Our mean operation time was 195.38 ± 84.99 min. The mean number of piecemeal resected was 4.31 ± 2.36. An adverse event noted was an esophageal fistula that occurred in one case (6.25%) and was treated conservatively. The mean length of hospital stay was around 11.81 ± 7.30 days. The mean total hospitalization cost was U.S. dollars (USD) $5976.50 ± 2866.39. No recurrence or metastasis was found during the follow-up period. CONCLUSIONS: P-STER can be an effective and safe treatment for giant leiomyoma originating from the MP layer of the esophagus.

Biosynthetic Plastics as Tunable Elastic and Visible Stent with Shape-Memory to Treat Biliary Stricture.

Common biliary tract is ≈4 mm in diameter to deliver bile from liver to small intestine to help digestion. The abnormal narrowing leads to severe symptoms such as pain and nausea. Stents are an effective treatment. Compared with non-degradable stents which require repeated removal, biodegradable stents have the advantage of reducing secondary injury related to endoscopic operation and patient burden. However, current biodegradable materials may cause tissue hyperplasia and the treatment method does not target etiology of stricture. So recurrence rates after biodegradable stent implantation are still high. Here, a biodegradable helical stent fabricated from biosynthetic P(3HB-co-4HB) is reported. Tunable properties can be acquired through altering culture substrates. Stent shows shape memory in various solvents. The stent has an optimized design with helical structure and outer track. The self-expanding of helical structure and double drainage realized by outer track greatly improve drainage of bile. Importantly, stent-loading triamcinolone acetonide can inhibit proliferation of fibroblasts and reduce incidence of restricture. Therapeutic effect is also demonstrated in minipigs with biliary stricture. The results of minipig experiments show that biliary duct in treatment group is unobstructed and tissue hyperplasia is effectively inhibited.

Endoscopy Deliverable and Mushroom-Cap-Inspired Hyperboloid-Shaped Drug-Laden Bioadhesive Hydrogel for Stomach Perforation Repair.

Gastrointestinal tract perforation is a full-thickness injury that causes bleeding and fatal infection of the peritoneum. This condition worsens in an acidic gastric environment which interferes with the normal coagulation cascade. Current endoscopic clips to repair gastric perforations are ineffective, and metal or plastic occluders need secondary surgery to remove them. Herein, we report a self-expandable, endoscopy deliverable, adhesive hydrogel to block gastric perforation. We found the nanosilica coating significantly enhanced the adhesive strength even under a simulated strong acidic stomach environment. The developed device was disulfide cross-linked for the reducible degraded gel. By loading with vonoprazan fumarate (VF) and acidic fibroblast growth factor (AFGF), the hyperboloid-shaped device can have a sustained drug release to regulate intragastric pH and promote wound healing. The gel device can be compressed and then expanded like a mushroom when applied in an acute gastric perforation model in both rabbits and minipigs. By utilizing a stomach capsule robot for remotely monitoring the pH and by immunohistochemical analysis, we demonstrated that the compressible hyperboloid-shaped gel could stably block the perforation and promoted wound healing during the 28 days of observation. The real-time pH meter demonstrated that the gel could control intragastric pH above 4 for nearly 60 h to prevent bleeding.

In Vivo Anchoring Bis-Pyrene Probe for Molecular Imaging of Early Gastric Cancer by Endoscopic Techniques.

With the development of blue laser endoscopy (BLE) technique, it's often used to diagnose early gastric cancer (EGC) by the morphological changes of blood vessels through BLE. However, EGC is still not obvious to identify, resulting in a high rate of missed diagnosis. Molecular imaging can show the changes in early tumors at molecular level, which provides a possibility for diagnosing EGC. Therefore, developing a probe that visually monitors blood vessels of EGC under BLE is particularly necessary. Herein, a bis-pyrene (BP) based nanoprobe (BP-FFVLK-(PEG)-RGD, M1 ) is designed, which can target angiogenesis and self-assemble into fibers in situ, resulting in stable and long-term retention in tumor. Moreover, M1 probe can emit yellow-green fluorescence for imaging under BLE. M1 probe is confirmed to steadily remain in tumor for up to 96 hours in mice transplanted subcutaneously. In addition, the M1 probe is able to target angiogenesis for molecular imaging of isolated human gastric cancer tissue under BLE. Finally, M1 probe i.v. injected into primary gastric cancer model rabbits successfully highlighted the tumor site under BLE, which is confirmed by pathological analysis. It's the first time to develop a probe for diagnosing EGC by visualizing angiogenesis under BLE, showing great clinical significance.

Aligned nanofibrous collagen membranes from fish swim bladder as a tough and acid-resistant suture for pH-regulated stomach perforation and tendon rupture.

BACKGROUND: Wound closure in the complex body environment places higher requirements on suture's mechanical and biological performance. In the scenario of frequent mechanical gastric motility and extremely low pH, single functional sutures have limitations in dealing with stomach bleeding trauma where the normal healing will get deteriorated in acid. It necessitates to advance suture, which can regulate wounds, resist acid and intelligently sense stomach pH. METHODS: Based on fish swim bladder, a double-stranded drug-loaded suture was fabricated. Its cytotoxicity, histocompatibility, mechanical properties, acid resistance and multiple functions were verified. Also, suture's performance suturing gastric wounds and Achilles tendon was verified in an in vivo model. RESULTS: By investigating the swim bladder's multi-scale structure, the aligned tough collagen fibrous membrane can resist high hydrostatic pressure. We report that the multi-functional sutures on the twisted and aligned collagen fibers have acid resistance and low tissue reaction. Working with an implantable "capsule robot", the smart suture can inhibit gastric acid secretion, curb the prolonged stomach bleeding and monitor real-time pH changes in rabbits and pigs. The suture can promote stomach healing and is strong enough to stitch the fractured Achilles tendon. CONCLUSIONS: As a drug-loaded absorbable suture, the suture shows excellent performance and good application prospect in clinical work.

Development and Validation of an Artificial Intelligence Model for Small Bowel Capsule Endoscopy Video Review.

Importance: Reading small bowel capsule endoscopy (SBCE) videos is a tedious task for clinicians, and a new method should be applied to solve the situation. Objectives: To develop and evaluate the performance of a convolutional neural network algorithm for SBCE video review in real-life clinical care. Design, Setting, and Participants: In this multicenter, retrospective diagnostic study, a deep learning neural network (SmartScan) was trained and validated for the SBCE video review. A total of 2927 SBCE examinations from 29 medical centers were used to train SmartScan to detect 17 types of CE structured terminology (CEST) findings from January 1, 2019, to June 30, 2020. SmartScan was later validated with conventional reading (CR) and SmartScan-assisted reading (SSAR) in 2898 SBCE examinations collected from 22 medical centers. Data analysis was performed from January 25 to December 31, 2021. Exposure: An artificial intelligence-based tool for interpreting clinical images of SBCE. Main Outcomes and Measures: The detection rate and efficiency of CEST findings detected by SSAR and CR were compared. Results: A total of 5825 SBCE examinations were retrospectively collected; 2898 examinations (1765 male participants [60.9%]; mean [SD] age, 49.8 [15.5] years) were included in the validation phase. From a total of 6084 CEST-classified SB findings, SSAR detected 5834 findings (95.9%; 95% CI, 95.4%-96.4%), significantly higher than CR, which detected 4630 findings (76.1%; 95% CI, 75.0%-77.2%). SmartScan-assisted reading achieved a higher per-patient detection rate (79.3% [2298 of 2898]) for CEST findings compared with CR (70.7% [2048 of 2298]; 95% CI, 69.0%-72.3%). With SSAR, the mean (SD) number of images (per SBCE video) requiring review was reduced to 779.2 (337.2) compared with 27 910.8 (12 882.9) with CR, for a mean (SD) reduction rate of 96.1% (4.3%). The mean (SD) reading time with SSAR was shortened to 5.4 (1.5) minutes compared with CR (51.4 [11.6] minutes), for a mean (SD) reduction rate of 89.3% (3.1%). Conclusions and Relevance: This study suggests that a convolutional neural network-based algorithm is associated with an increased detection rate of SBCE findings and reduced SBCE video reading time.

Nature-Derived Okra Gel as Strong Hemostatic Bioadhesive in Human Blood, Liver, and Heart Trauma of Rabbits and Dogs.

Bioadhesive performance can be compromised due to bleeding. Bleeding increases mortality. Adhesives with hemostatic function are of great significance. A sustainable and robust hemostatic bioadhesive from okra is reported. The adhesive strength reaches around three and six-fold higher than commercial fibrin on pigskin and glass, respectively. The okra gel presents high-pressure resistance and great underwater adhesive strength. In human blood experiments, the okra gel can activate platelets, enhance the adhesion of activated platelets, and release coagulation factors XI and XII. By forming a fast gel layer and closely adhering to the wound, it can quickly stop bleeding in the liver and heart of rabbits and dogs. Meanwhile, okra gel can cause platelet activation at the wound site and further strengthen its hemostatic performance. It is biocompatible, biodegradable, and can promote wound healing and shows potential as a sustainable bioadhesive, especially in the scenario of significant hemorrhage.

Endoscopic features of esophageal high-grade intraepithelial neoplasia dominated by cytological atypia.

Little is known about esophageal high-grade intraepithelial neoplasia dominated by cytological atypia (HGINc). We aimed to elucidate the endoscopic features of HGINc compared with esophageal high-grade intraepithelial neoplasia dominated by architectural atypia (HGINa). All patients pathologically diagnosed as esophageal high-grade intraepithelial neoplasia after endoscopic submucosal dissection at our center between January 2018 and December 2019 were included in this study. According to the pathological diagnosis, the patients were divided into two groups: HGINa group and HGINc group. Basic characteristics and endoscopic information were collected in detail. Data were analyzed statistically. Binary logistic regression was performed and a predictive model for HGINc was established. Then we evaluated its predictive value and built a nomogram for clinical application. A total of 175 patients were included in this study (126 with HGINa and 49 with HGINc). Among 228 lesions found in all patients, there were 148 HGINa and 80 HGINc. The independent relevant factors for HGINc were tobacco and alcohol usage, color, and gross type. To predict risk of HGINc, a three-factor model (TFM) was established with a highest area under curve (AUC) as 0.869 (95% CI, 0.852, 0.939). When the cut-off value was set as 0.3569184, the diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for HGINc was 81.14%, 88.75%, 77.03%, 67.62%, and 92.68%, respectively. HGINc differs greatly in endoscopic features from HGINa in our study. It's important to reduce misdiagnosis that our model was established with good predictive value for clinical application.

In vitro and in vivo evaluation of DC-targeting PLGA nanoparticles encapsulating heparanase CD4+ and CD8+ T-cell epitopes for cancer immunotherapy.

Heparanase has been identified as a universal tumor-associated antigen, but heparanase epitope peptides are difficult to recognize. Therefore, it is necessary to explore novel strategies to ensure efficient delivery to antigen-presenting cells. Here, we established a novel immunotherapy model targeting antigens to dendritic cell (DC) receptors using a combination of heparanase CD4+ and CD8+ T-cell epitope peptides to achieve an efficient cytotoxic T-cell response, which was associated with strong activation of DCs. First, pegylated poly(lactic-coglycolic acid) (PLGA) nanoparticles (NPs) were used to encapsulate a combined heparanase CD4+ and CD8+ T-cell epitope alone or in combination with Toll-like receptor 3 and 7 ligands as a model antigen to enhance immunogenicity. The ligands were then targeted to DC cell-surface molecules using a DEC-205 antibody. The binding and internalization of these PLGA NPs and the activation of DCs, the T-cell response and the tumor-killing effect were assessed. The results showed that PLGA NPs encapsulating epitope peptides (mHpa399 + mHpa519) could be targeted to and internalized by DCs more efficiently, stimulating higher levels of IL-12 production, T-cell proliferation and IFN-γ production by T cells in vitro. Moreover, vaccination with DEC-205-targeted PLGA NPs encapsulating combined epitope peptides exhibited higher tumor-killing efficacy both in vitro and in vivo. In conclusion, delivery of PLGA NP vaccines targeting DEC-205 based on heparanase CD4+ and CD8+ T-cell epitopes are suitable immunogens for antitumor immunotherapy and have promising potential for clinical applications.

Effectiveness of Vitamin C Solution in Reducing Adverse Reactions Caused by Painless Lugol Chromoendoscopy: A Multicenter Randomized Controlled Trial.

GOAL: The purpose of this study was to evaluate the effectiveness of vitamin C solution (VCS) in reducing adverse reactions caused by painless Lugol chromoendoscopy. BACKGROUND: Lugol chromoendoscopy is an effective method for screening superficial esophageal squamous cell carcinoma, although Lugol iodine solution (LIS) causes mucosal irritation. STUDY: In 4 hospitals in China, patients were randomized and divided into a distilled water (DW) group, an sodium thiosulfate solution (STS) group and a VCS group. Patients' esophageal mucosal surfaces were stained with either 1.2% or 0.5% LIS and then sprayed with DW, STS, or VCS at various concentrations. For the current randomized study, 1610 patients were enrolled in the 1.2% LIS group and 1355 patients were enrolled in the 0.5% LIS group. In addition, 150 patients were enrolled to assess the discoloration effect. The primary outcome for evaluation was the incidence of acute or late adverse reactions after Lugol iodine staining. The secondary outcome for evaluation was the discoloration effect on esophageal iodine-stained mucosa. RESULTS: VCS significantly reduced the occurrence of acute adverse reactions due to staining from 1.2% LIS. The effect of VCS was similar to that of STS but better than that of DW ( P <0.05). Regarding 0.5% LIS staining, VCS reduced the incidence of acute adverse reactions and heartburn within 1 week ( P <0.05). Both VCS and STS had similar effects. In addition, compared with spraying NS, VCS caused rapid decolorization of iodine-stained esophageal mucosa. After 120 seconds of deiodination, the color of the esophageal mucosa faded by 90%, which is similar to the results seen in the STS group. This contrasts with the results seen in the DW group, which showed fading by only 50.97% ( P <0.05). CONCLUSION: VCS can effectively reduce adverse reactions caused by different concentrations of LIS, indicating its important clinical application in the screening of superficial esophageal squamous cell carcinoma.

Fully automated magnetically controlled capsule endoscopy for examination of the stomach and small bowel: a prospective, feasibility, two-centre study.

BACKGROUND: The use of magnetically controlled capsules for gastroscopy is in the early stages of clinical adoption. We aimed to evaluate the safety and efficacy of a fully automated magnetically controlled capsule endoscopy (FAMCE) system in clinical practice for gastroscopy and small bowel examination. METHODS: We did a prospective, comparative study to evaluate the safety and efficacy of FAMCE. Patients from two hospitals in Chongqing, China were consecutively enrolled. Eligible participants were aged 18-80 years with suspected gastric pathology and no previous surgery. Participants underwent FAMCE for screening of gastric lesions, then conventional transoral gastroscopy 2 h later, and stomach examination results were compared. The primary outcome was the rate of complete detection of gastric anatomy landmarks (cardia, fundus, body, angulus, antrum, and pylorus) by FAMCE. Secondary outcomes were the time required for gastric completion by FAMCE, the rate of detection of gastric lesions by FAMCE compared with conventional transoral gastroscopy, and the rate of complete small bowel examination. Adverse events were also evaluated. The study was registered in the Chinese Clinical Trial Registry, ChiCTR2000040507. FINDINGS: Between May 12 and Aug 17, 2020, 114 patients (mean age 44·0 years [IQR 34·0-55·0]; 63 [55%] female) were enrolled. The rate of complete detection of gastric anatomical structures by FAMCE was 100% (95% CI 99·3-100·0). The concordance between FAMCE and conventional transoral gastroscopy was 99·61% (99·45-99·78). The mean completion time of a gastroscopy with FAMCE was 19·17 min (SD 1·43; median 19·00, IQR 19·00-20·00), compared with 5·21 min (2·00; 5·18, 3·68-6·45) for conventional transoral gastroscopy. In 114 enrolled patients, 214 lesions were detected by FAMCE and conventional transoral gastroscopy. Of those, 193 were detected by both modalities. FAMCE missed five pathologies (four cases of gastritis and one polyp), whereas conventional transoral gastroscopy missed 16 pathologies (12 cases of gastritis, one polyp, one fundal xanthoma, and two antral erosions). FAMCE was able to provide a complete small bowel examination for all 114 patients and detected intestinal lesions in 50 (44%) patients. During the study, two (2%) patients experienced adverse events. No serious adverse events were recorded, and there was no evidence of capsule retention. INTERPRETATION: The performance of FAMCE is similar to conventional transoral gastroscopy in completion of gastric examination and lesion detection. Furthermore, it can provide a complete small bowel examination. Therefore, FAMCE could be effective method for examination of the gastrointestinal tract. FUNDING: Chinese National Key Research and Development Program.