Postoperative Adhesion Prevention Using a Biodegradable Temperature-Responsive Injectable Polymer System and Concomitant Effects of the Chymase Inhibitor

Postoperative adhesion remains a problem in surgery and causes postoperative complications. Laparoscopic surgery is now common, making it increasingly important to develop injectable formulations of adhesion barriers that can be applied during such surgeries. Temperature-responsive injectable polymer (IP) systems exhibiting a sol-to-gel transition in response to temperature are promising candidates as effective adhesion barriers that can be applied conveniently during laparoscopic surgery. We previously developed IP systems exhibiting temperature-responsive irreversible gelation based on a triblock copolymer of poly(ϵ-caprolactone-co-glycolic acid) (PCGA) and poly(ethylene glycol) (PEG) (PCGA-b-PEG-b-PCGA: tri-PCG) and a tri-PCG derivative with acrylate groups at the termini (tri-PCG-acryl). A mixture of tri-PCG-acryl micelle solution and tri-PCG micelle solution containing polythiol exhibited an irreversible sol-to-gel transition in response to a temperature increase. The gel contains partial covalent cross-linking, and the degradation and physical properties of these IP hydrogels can easily be controlled by changing the mixing ratio of tri-PCG-acryl in the formulation. In this study, we investigated the effect of physical properties of the IP hydrogel on the efficacy of adhesion prevention using our IP system containing various amounts of tri-PCG-acryl. Our results show that an IP system with lower physical strength and rapid degradation reduces adhesion more effectively. Chymase plays a crucial role in exacerbating adhesion formation, and a peptide derivative-type chymase inhibitor (CI), Suc-Val-Pro-PheP(OPh)2, was previously reported to prevent adhesion. We thus investigated the concomitant use of this CI with our IP system using two methods: separate administration of the CI and IP and entrapping the CI in the IP hydrogel. IP systems with separately administrated CI provided better results than the administration of an IP system entrapping the CI or sole IP systems. These findings suggest that the pharmacological effect of the CI and a physical barrier generated by our IP system effectively prevents adhesion.