We investigated the potential of collagen–genipin sols as biomaterials for treating artificial ulcers following endoscopic submucosal dissection. Collagen sol viscosity increased with condensation, allowing retention on tilted ulcers before gelation and resulting in collagen gel deposition on whole ulcers. The 1.44% collagen sols containing genipin as a crosslinker retained sol fluidity at 23°C for >20 min, facilitating endoscopic use. Collagen sols formed gel depositions on artificial ulcers in response to body temperature, and high temperature responsiveness of gelation because of increased neutral phosphate buffer concentration allowed for thick gel deposition on tilted ulcers. Finally, histological observations showed infiltration of gels into submucosal layers. Taken together, the present data show that genipin-induced crosslinking significantly improves the mechanical properties of collagen gels even at low genipin concentrations of 0.2–1 mM, warranting the use of in situ gelling collagen–genipin sols for endoscopic treatments of gastrointestinal ulcers.

Background and study aims We developed a novel submucosal (SM) injection material that contained pepsin-solubilized collagen (PSC), genipin (Ge) and phosphate buffer (PB). The aim of this study was to validate safety and usability of it for endoscopic resection (ER). Materials and methods In preliminary studies, 1) appropriate warming time and concentration of Ge, and concentration of NaCl in PB, 2) storage modulus of PSC, Ge, and PB mixture (PSC/Ge), and PSC as a mechanical property, 3) histological finding after injection, and histological toxicity of PSC/Ge was evaluated. We injected PSC/Ge, PSC, sodium hyaluronate (SH), dextrose (DW), and normal saline (NS) into SM of resected porcine stomach. We compared mean height of mucosal elevation after immediate injection (MH) and mean retaining rate at 60 minutes (MR) as ex vivo study. Results Optimal condition of PSC/Ge was Ge 5.5 mMol with 24 hours worming time and NaCl 280 mMol. PSC/Ge had better mechanical property than PSC. It was efficiently integrated and confined to the SM with acceptable toxicity. MH of PSC/Ge (5.1 ± 0.74 mm) and PSC (4.8 ± 0.84 mm) were significantly higher than NS (3.2 ± 0.84 mm). MR of PSC/Ge (100 ± 0.0%) was significantly higher than NS (61.7 ± 11.2%), DW (58.3 ± 11.8%) and SH (61.8 ± 8.6%). Conclusion PSC/Ge and PSC has potential to be safe and usable for ER. PSC/Ge was better than PSC because of better mechanical property than PSC.

Objective: A prior study using porcine colon demonstrated the feasibility of a novel injectable, temperature-responsive, and biodegradable collagen sol (ICS) that transforms from a liquid to a gel state in response to body temperature for endoscopic closure of perforation during endoscopic resection (ER). This study aims to report the acute and survival outcomes of ICS for gastric perforations during ER. Methods:In two experiments using nine live pigs under general anesthesia, four and six perforations (3-5 mm) were created using an electrosurgical knife in acute and survival experiments, respectively. ICS was delivered to the perforations using an endoscopic catheter. In Experiment 1, a leak test and histopathology were performed on all explanted stomachs after euthanization. In Experiment 2, perforation sites were assessed by gastroscopy and histopathology 7, 14 and 28 days post-procedure. Results:In Experiment 1, gastroscopy confirmed complete closure of the perforations with ICS and no evidence of leak. Subsequent histopathology revealed a fixation of collagen gel (CG) as a sealant agent at the perforation sites. There were no adverse effects related with ESD or the use of ICS. In Experiment 2, histopathology revealed a fixation of CG as a sealant agent, replacement with granulation tissue and no CG; and fibrotic tissue at 7, 14 and 28 days, respectively.Conclusions: This study presents a novel method using ICS, demonstrating promising efficacy and safety profile for endoscopic closure of perforations during ER. Further studies are necessary before translating to clinical use.

Objectives: Endoscopic submucosal dissection (ESD) poses a risk of intraprocedural perforation. We have developed a biodegradable injectable collagen sol that undergoes a liquidto-gel formation in response to body temperature. Here, we investigated the feasibility of this novel collagen sol for the endoscopic closure of iatrogenic perforation holes. Methods:In two experiments, 12 and 5 colonic perforation holes (3-5 mm) were made using an ESD knife in four and three live pigs under general anesthesia, respectively. In Experiment 1, collagen sol was delivered to the perforation holes using an endoscopic catheter. When the colon was expanded by CO 2 insufflation, endoclips were applied to the perforation holes. For Experiment 2, Collagen sol adjusted based on the Experiment 1 results was delivered to the perforation holes in the same manner. A leak test was performed for every colon after the pigs were killed, and the histology of the perforation sites was evaluated. Results:In both experiments, collagen sol was smoothly delivered to the target area and fixed as a gel on the perforation holes. Experiment 1, 83% (10/12) of the perforation holes were completely closed, and all endo-clips were placed with composure. Experiment 2, all perforation holes were completely closed with collagen gel. There was no leak from the perforation holes. Histology revealed a fixation of the collagen gel as an embolus agent in the perforation holes.Conclusions: This novel collagen sol may be used for the endoscopic closure of intraprocedural perforation. Further studies will determine this collagen sol's clinical feasibility and safety.

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