309 Intraperitoneal cytostatic-loaded supramolecular hydrogel and intestinal anastomotic healing location of the anastomosis and dose of MMC, histological examination of the anastomoses in rats given an intraperitoneal bolus of 2 mg/kg MMC showed significantly slower anastomotic healing, with an incidence of AL of 52.8% after 7 days. An investigated explanation for this impaired anastomotic healing is the affected collagen synthesis, as this is an essential feature of anastomotic healing in the intestine 16. The strength of anastomosis is influenced by the interplay between newly-synthesized and deposited collagen, as well as the degradation of preformed collagen 17. In the initial post-operative phase (3–5 days after surgery), there is a notable decrease of up to 40% in collagen concentration near the anastomosis site, primarily attributed to increased collagenase activity at the anastomosis site 16, 17. However, starting from day 5 onwards, there is a gradual rise in collagen synthesis, leading to a progressive increase in the strength of the anastomosis. By the 7th day after surgery, the anastomosis achieves approximately 50% of its measured strength 16, 30. MMC halts the proliferation of fibroblasts, which play vital roles in several crucial aspects of the previous wound-healing process 17. Previous experiments showed that intraperitoneal MMC administered on or after the 5th day after anastomosis creation had no significant effect on the anastomotic healing anymore 17. As the injectable hydrogel used in our study forms an intraperitoneal depot of slow-releasing MMC, we hypothesized less impaired anastomotic healing due to the slowreleasing characteristics. This was confirmed by the finding that we did not observe any rats suffering from AL as reported in other studies 16, 17. No significant differences could be observed between the two experimental groups (unloaded hydrogel vs. MMC-loaded hydrogel) suggesting that slow-releasing but prolonged exposure of the chemotherapeutic does not impair wound healing, nor does the hydrogel. However, our results do show, although not significant, reduced fibroblast activity in unloaded hydrogel and MMC-loaded hydrogel treated animals. Despite the reduction in AL incidence in our study, we did not gain a clinical improvement due to the drop-out of almost half of the animals. Active hemorrhage was only seen intraluminal at the site of the anastomosis and not in the abdominal cavity. Our previous study, in which this hydrogel was applied in a rat PM model, did not demonstrate intraluminal, extensive blood loss. The main reasons for intraluminal blood loss in animal experiments are (1) a Clostridium piliforme or Clostridium perfrigens entertoxin infection, (2) intestinal ulcer formation and (3) a systemic coagulation problem. In rats suffering from intestinal hemorrhage in the current experiment, these potential causes were all excluded by follow-up analysis of feces, tissue and blood samples. After ruling out several probable causes of blood loss in animal experiments, we propose an explanation based on microscopic findings. We observed lymphangiectasia, edema in the muscularis propria and vacuolated macrophages around the anastomotic site and in the surrounding peritoneal fat that contained foreign material, also reported by Wintjens et al. 12. We hypothesize that the hydrogel is partly absorbed by the intestinal lymph system and macrophages, causing local congestion, which causes blood vessel damage around the anastomosis. The degree of damage ranged from larger necrotic blood vessels to hemorrhagic spots in different layers (serosa, muscularis mucosa and the mucosa). Although we did not 13
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