Engineering ROS-responsive double network hydrogel as bioactive barrier for postoperative abdominal adhesions prevention

Abstract

Postoperative adhesions are common and severe complications, which affect up to 90 % of patients undergoing abdominal surgery. Despite the application of various strategies to minimize adhesions, the clinical outcomes remain far from satisfactory. Herein, we engineered a ROS-responsive and scavenging double-network hydrogel (PD-OHN) with multiple biofunctions and good mechanical properties for effective PAA prevention. First, a novel ROS-cleavable dithiothreitol (DTT) crosslinking monomer (DPBA) was synthesized. Subsequently, PD-OHN hydrogel was fabricated within 5 s by forming phenylborate ester bond networks between DPBA and polyvinyl alcohol (PVA), and acylhydrazone bond networks between oxidized hyaluronic acid (OHA) and adipic acid dihydrazide-modified hyaluronic acid (HA-ADH). After spraying, it can form a uniform and stretchable hydrogel film. Results showed that PD-OHN had good mechanical properties with a storage modulus about 20 kPa, satisfactory tissue adhesion strength of approximately 8 kPa, and an appropriate in vivo cecum retention time of about 21 days with good biosafety. More importantly, DPBA in PD-OHN hydrogel scavenged ROS via phenylboronate bond cleavage and the subsequent release of DTT, which intelligently alleviated oxidative stress according to the ROS levels in wound sites and induced pro-inflammatory M1 macrophages to polarize into anti-inflammatory M2 phenotype to alleviate inflammation. Further, the fibrinolytic system balance was recovered and fibrosis was reduced. Consequently, PD-OHN hydrogel effectively prevented adhesion formation in a cecum-sidewall abrasion rat model, and provided a promising whole course care anti-adhesion barrier for effective PAA prevention.

Keywords

• Postoperative abdominal adhesions
• Double network hydrogels
• Reactive oxygen species (ROS)
• Bioactive barrier
• Dithiothreitol (DTT)