Novel silk protein/hyaluronic acid hydrogel loaded with azithromycin as an immunomodulatory barrier to prevent postoperative adhesions

Peritoneal adhesions, a common postoperative complication of laparotomy, are still treated with physical bar-riers, but their efficacy and ease of use are controversial. In this paper, we developed a wound microenvironment-responsive hydrogel composed of Antheraea pernyi silk protein (ASF) from wild cocoons and tyramine-modified hyaluronic acid (HA-Ph) loaded with azithromycin (AZI), glucose oxidase (GOX), and horseradish peroxidase (HRP). In addition, GOX-catalyzed oxygen production enhanced the antibacterial ability of the hydrogel. Moreover, the drug-loaded hydrogel increased macrophage CD206 expression while decreasing IL-6 and TNF-alpha expression. More importantly, the retarding effect of this novel hydrogel system on AZI almost eliminated the appearance of postoperative adhesions in rats. It was also found that the novel hydrogel enhanced the modulation of the TLR-4/Myd88/NF-kappa B pathway and TGF-beta/Smad2/3 pathway by azithromycin in the locally damaged peritoneum of rats, which accelerated the remodeling of damaged tissues and dramatically reduced the deposition of collagen. Therefore, spraying the novel drug-loaded hydrogel on postoperative abdominal wounds can effectively inhibit the formation of postoperative adhesions.