Metformin-loaded Citric Acid Cross-linked Agarose Films in the Prevention of Postoperative Abdominal Adhesion

Postoperative abdominal adhesion (PAA) causes significant long-term postoperative morbidity. Although numerous physical anti-adhesion barriers (AAB) are used as therapeutical interventions, none of them has achieved sustained success. As a potential strategy to overcome the limitations, drug-eluting AAB have attracted scientific attention. Here, we produced agar films (AF) chemically cross-linked with different concentrations of citric acid (CA) and we measured the physicochemical properties such as crosslinking strength, swelling ratio, hydrophilicity, and biodegradability of the yielded CA-AFs. Next, Metformin (MET), an antidiabetic drug with anti-proliferative and anti-inflammatory properties, was loaded in the CA-AFs yielding the MET-loaded CA-AF (MET@CA-AF) and the time-dependent MET release was monitored. Based on their physicochemical properties, MET@CA-AF containing 20% CA appeared a promising AAB candidate and was further used in an in vivo study. Mouse models of PAA were established with cecum abrasion and the MET@CAAF and CA-AF were applied between the injured interfaces. At postoperative day 14, the therapeutic efficacies were analyzed by using clinical adhesion scoring and quantification of collagen-I and fibroblasts in adhesion interfaces. The results showed that applications of MET@CA-AF or CA-AF for 14 days significantly attenuated the clinical adhesion score and thickness of adhesion interface. Furthermore, when compared with the group with operation, the groups with MET@CA-AF or CA-AF exhibited the significant attenuation in PAA-associated myofibroblast activation in adhesion interface. Importantly, these attenuations were significantly more intensified in the group with MET@CA-AF than in the group with CA-AF. Based on our data, we anticipate that MET@CAAF, a novel synthesized drug-eluting AAB, can protect against PAA by exerting the dual role of physical barrier and MET-based pharmaceutic.