Potential of temperature-response collagen-genipin sol as a novel submucosal injection agent for endoscopic resection: Acute and chronic phase study using living animals.

OBJECTIVES: We proposed a novel temperature-response collagen sol as a submucosal injection agent for endoscopic resection (ER) using pepsin-solubilized collagen (PSC) and genipin (Ge) in a prior study. This study aimed to evaluate the usefulness and safety of the sol (PSC/Ge) in acute and chronic phase experiments using living animals. METHODS: In experiment 1, we performed endoscopic submucosal dissection (ESD) for six pigs using normal saline (NS), sodium hyaluronate (SH), and PSC/Ge. We compared the required amount of each agent per unit area and procedure time. In experiment 2, we created artificial ulcers with endoscopic mucosal resection (EMR) for five pigs using NS and PSC sol. We compared the artificial ulcer residual rate at 7 and 14 days after EMR, and the scarring rate at 14 days after EMR. RESULTS: The required amount of agents per unit area for PSC/Ge (0.8 ± 0.8 mL/cm2 ) and SH (1.1 ± 0.8 mL/cm2 ) were significantly smaller than that for NS (1.8 ± 0.7 mL/cm2 ). The total procedure time did not have a statistical difference. The artificial ulcer residual rates were 47.3 ± 0.7% for NS and 40.3 ± 0.7% for PSC/Ge on day 7 (P = 0.51), and 15.0 ± 0.1% for NS and 10.2 ± 0.1% for PSC/Ge sol on day 14 (P = 0.35). The scarring rate on day 14 was 10% for NS and 20% for PSC/Ge. CONCLUSION: We demonstrated the feasibility of a novel temperature-response collagen gel as a submucosal injection agent for ER in the acute and chronic phase animal experiment.

Design and biopharmaceutical preclinical characterisation of a new thermosensitive hydrogel for the removal of gastric polyps.

BACKGROUND AND AIMS: Submucosal injection agents are widely used solutions in gastric polyp resection techniques. Currently, many different solutions are used in clinical practice, but most are not authorised for this use or are not biopharmaceutical characterised. The objective of this multidisciplinary work is to test the efficacy of a novel thermosensitive hydrogel designed specifically for this indication. METHODS: A mixture design of various components (Pluronic®, hyaluronic acid and sodium alginate) was carried out to select the combination with optimal properties for this use. Three final thermosensitive hydrogels were selected on which biopharmaceutical characterisation was performed and stability and biocompatibility were analysed. Efficacy in maintaining elevation was tested ex vivo on pig mucosa and in vivo in pigs RESULTS: The mixture design allowed selection of the ideal combinations of agents for the characteristics sought. The thermosensitive hydrogels studied showed high values of hardness and viscosity at 37 °C, maintaining good syringeability. One of them demonstrated superiority in maintaining polyp elevation in the ex vivo assay and non-inferiority in the in vivo assay. CONCLUSION: The thermosensitive hydrogel specifically designed for this use is promising both for its biopharmaceutical characteristics and for its demonstrated efficacy. This study lays the foundation for evaluating the hydrogel in humans.

Injectable Thermosensitive Chitosan Solution with ß-Glycerophosphate as an Optimal Submucosal Fluid Cushion for Endoscopic Submucosal Dissection.

Endoscopic submucosal dissection (ESD) is a surgical procedure to remove early neoplastic lesions in the gastrointestinal tract with the critical issue of perforation. A submucosal fluid cushion, such as normal saline, is used as a cushioning agent to prevent perforation; however, its cushioning maintenance is insufficient for surgery. In this study, we introduce an injectable thermosensitive chitosan solution (CS) with ß-glycerophosphate (ß-GP) as a submucosal injection agent for ESD. The CS/ß-GP system with optimal ß-GP concentration showed drastic viscosity change near body temperature while other commercial products did not. Additionally, the injectability of the solution was similar to or greater than other commercial products. The solution with low ß-GP concentration showed low cytotoxicity similar to other products. An in vivo preclinical study illustrated maintenance of the high cushioning of the thermosensitive solutions. These results indicate that a CS/ß-GP system with optimal ß-GP concentration might be used as a submucosal injection agent in ESD, and further studies are needed to validate the effectiveness of the solutions in vivo.

Safe and Efficient Colonic Endoscopic Submucosal Dissection Using an Injectable Hydrogel.

Endoscopic submucosal dissection (ESD) has not yet been widely adopted in the treatment of early colonic cancers due to the greater technical difficulty involved, longer procedure time, and the increased risk of perforation. Adequate mucosal elevation by submucosal injection is crucial for en bloc resection and prevention of perforation during colonic ESD. This study is aimed to evaluate the efficacy of an injectable thermoreversible hydrogel as the colonic submucosal agent for the first time. Triblock copolymer poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) was synthesized, and its concentrated aqueous solution was injected into the colonic submucosa of living minipig and spontaneously transformed into an in situ hydrogel with adequate mucosal elevation at body temperature. Such a mucosal lifting lasted for a longer time than that created by the control group, glycerol fructose. Colonic ESD was then performed with the administration of hydrogels at various polymer concentrations or glycerol fructose. All colonic lesions were successfully resected en bloc after one single injection of the hydrogel, and repeated injections were not needed. No evidence of major hemorrhage, perforation and tissue damage were observed. Considering the injection pressure, duration of mucosal elevation and efficacy of "autodissection", the hydrogel containing 15 wt % polymer was the optimized system for colonic ESD. Consequently, the thermoreversible hydrogel is an ideal submucosal fluid that provides a durable mucosal lifting and makes colonic ESD accessible to a large extent. In particular, the efficacy of "autodissection" after one single injection of the hydrogel simplifies significantly the procedures while minimizing the complications.