Carboxymethyl chitosan/oxidized hyaluronic acid hydrogel-encapsulated hucMSC-derived exosomes for enhanced hepatic regeneration and post-hepatectomy applications

Hepatectomy is the primary therapeutic intervention for liver disorders. Nonetheless, an increased risk of liver failure and postoperative mortality exists due to the rapid reduction in liver size after surgery. Human umbilical cord mesenchymal stem cell (hucMSC) exosomes (Exos) have been recognized in the promotion of liver regeneration. However, intravenous administration of Exos faces several challenges including poor targeting and rapid clearance. Herein, we employed CMCS/OHA/LA-loaded hucMSCs derived Exos (hydrogel-Exos) to address liver regeneration after hepatectomy. Release and uptake studies showed hydrogel-Exos enables localized release of Exos, prolonging their presence and concentration in liver tissue. Meanwhile, the hydrogel-Exos exhibited good characteristics in injectability, self-healing, biocompatibility, liver adhesion, swelling performance, postoperative hemostasis and minimization of peritoneal adhesions post-resection. Moreover, proliferation and scratch wound healing assays demonstrated the ability of hydrogel-Exos to promote liver cell proliferation and migration. During in vivo studies, the Exos-containing hydrogel was injected into the resected surface of a 70 % hepatectomy rat model. The result indicated Exos was released into the liver tissue through the hydrogel to promote angiogenesis and liver regeneration. Bioinformatics analysis revealed liver regeneration mechanisms involve cell cycle-related pathways. As such, hydrogel-encapsulated Exos appeared promising to be employed following hepatectomy.