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Background: Endoscopic closure techniques are effective and safe in the management of transmural gastrointestinal defects. However, there is a paucity of data regarding their comparative effectiveness. This study aimed to compare the efficacy and safety of several new-generation, endoscopic closure devices in a pre-clinical model. Methods: We evaluated five commercially available devices: a through-the-scope clip (TTSC), an anchor-pronged TTSC, a suturing device, helical tacking system, and over-the-scope clip. We tested closure strength using an ex-vivo porcine model. Next, live animals underwent 15 mm gastric and colonic perforations followed by immediate endoscopic closure with one of the devices. We assessed technical success, 7-day survival, time to complete closure, and National Aeronautical and Space Administration Task Load Index (NASA-TLX) task load index. Results: A total of 60 ex-vivo closures were conducted (12 per device). The suturing device achieved a higher closure strength than all other devices (P < 0.05 for all comparisons). Technical success was achieved in 80% of cases, and 9 of 10 animals (90%) survived to 7 days post-closure. The mean procedure time for the suturing device was longer than all other devices (P < 0.05 for all comparisons). The mean procedure time for the anchor-pronged TTSC was also faster than over-the-scope clip (P = 0.04). The total endoscopist NASA-TLX score for the suturing device and helical system were greater than all other devices (P < 0.05 for all comparisons). Conclusion: Each closure device varies significantly in closure strength, closure time, and ease of use. Optimal device selection will depend on defect size, anatomic location, the viability of the surrounding tissue, and endoscopist/technician expertise. [ABSTRACT FROM AUTHOR]