Evaluation of Thermoreversible Gelation Polymer for Regeneration of Focal Liver Injury

Abstract

Liver injuries are often associated with complications including infection of the dead space, bleeding, leakage of bile and so on. We have recently developed a thermoreversible gelation polymer (TGP) which provides a good healing environment for wounds and possibly reduces complications. The purpose of this study was to evaluate whether adequate regeneration occurred with a liver defect by using TGP. The sol-gel transition of TGP is reversibly controlled by temperature; TGP is soluble below a lower critical solution temperature (LCST) of 22°C, and becomes solid above the LCST. Soluble TGP can reach anywhere, and gelation of TGP occurs at the wound surface by body temperature to fill the wound/cavity. A section of median part of the left lobe comprising 3% (2 × 2 cm wide and 1 cm deep) of the liver was resected, and the Beagle dogs were assigned to three groups: ‘resection alone group’, ‘resection + fibrin glue (FG) group’ and ‘resection + TGP group’. The resection alone group and the resection + FG group showed severe fibrosis at week 12, and a scarring was clearly visible. The resection + TGP group showed almost complete healing by week 4, with no adhesion and recession of the wound; the resection site was completely filled with TGP, liver-like capsule organoids emerged to cover the wound and neovascularization was observed within the organoids. Furthermore, the resected liver regenerated completely by week 12, TGP was replaced by hepatocytes, and the presence of hepatic lobules confirmed structural reorganization. The number of RCA-1-positive macrophages accumulating around the wound was significantly reduced in the resection + TGP group compared to the other two groups. In the early stage of liver resection and regeneration, TGP seemed to suppress the accumulation of macrophages and stellate cells. In the late stage, when massive inflammatory cell accumulation had subsided, TGP was degraded, that may contribute to avoid unnecessary inhibition of the liver regeneration process. Collectively, TGP may induce efficient regeneration by reducing the fibrosis and enhancing proliferation, even with a minor liver defect. Because TGP has good biocompatibility, it may become useful as an ideal biomaterial for the treatment of liver injuries.