310 Chapter 13 see these microscopic signs of damage in all sections of animals with intestinal blood loss, we did see large lymph congestion in all hydrogel-treated animals. Additionally, the presence of a considerable volume of hydrogel in the peritoneal space may lead to a high intraabdominal pressure which contributes to this local thrust in the first hours after injection. Based on this hypothesis, we can assume that of the animals that were taken out of the experiment due to the blood loss, the anastomotic healing was influenced due to the impaired blood supply as they were not included in the data analysis. An important observation was the discomfort of the animals after the surgery. Our research team and the animal facility have ample experience with rat anastomosis research 22, 31 and with the intraperitoneal administration of the used hydrogel formulation 12, 13. During this experiment, five rats treated with unloaded hydrogel, one treated with MMC-loaded hydrogel and one saline-treated animal managed to open their laparotomy wound resulting all in re-interventions and the sacrifice of one of the animals, suggesting abdominal discomfort. Therefore, in all subsequently operated animals, the skin was closed with metal clips in addition to the sutures. In addition to this discomfort, control animals stabilized their weight from 3 days postoperatively, while hydrogel-treated animals kept on losing weight and almost all reached a HEP on day 7 based on the weight loss. The drop-out, general discomfort and decreased body weight were more prominent in hydrogel-treated animals, and more specific in the male animals compared to female animals, which was also reported in previous experiments 12. This is the first experiment to investigate the anastomotic safety of intraperitoneal administration of unloaded and MMC-loaded hydrogel (UPy–PEG). Outcomes of interest were compared with control animals receiving saline and undergoing identical study procedures and follow-up time. This study has some limitations. Due to the high number of dropouts, the sample size of animals that completed the experiment is small and lower than predefined in the power calculation. Given the small sample size, the study results should be interpreted with caution. Paradoxical to the observation that the MMC-loaded and unloaded hydrogel is not significantly causing more AL, we report unexpected signs of extensive intestinal blood loss in almost half of these animals in this model. As the cause of the intestinal blood loss at the anastomotic site after hydrogel injection is still hypothetical, further research to reveal this observation provides insight in anastomotic healing.
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