3D Printed Multifunctional Polysaccharide Scaffolds for Promoting Liver Tissue Regeneration and Inhibiting Hepatocellular Carcinoma Recurrence

Abstract

<p>Surgery is the most utilized treatment for hepatocellular carcinoma. But it may not provide 100% removal of carcinoma tissue and hence patients face a high risk of tumor recurrence. Residual cancerous cells are deeply and irregularly embedded among normal cells, which erects high barriers to effective clinical treatment. The remaining tumor cells have strong invasiveness and proliferation potential. It is thus necessary to kill the residual cancerous cells in postoperative treatment. Furthermore, the massive volume of tissue defects and tumor-associated inflammatory microenvironment generated by tumor resection makes liver tissue difficult to repair. In addition, systemic administration of chemotherapy agents is often accompanied by severe side effects. Therefore, there is an urgent need to develop a postoperative adjuvant therapy platform that can create an optimal microenvironment at tumor resection site to promote liver tissue regeneration and simultaneously prevent the recurrence of hepatocellular carcinoma. In this work, multifunctional scaffolds based on natural polysaccharides were fabricated by 3D printing for live tissue regeneration after surgery and to prevent postoperative recurrence of hepatocellular carcinoma. In the study, modified carboxymethyl chitosan and aldehyde-modified dextran were mixed and loaded with sorafenib-containing PLGA microspheres and hepatocyte growth factors (HGF) as the printing ink. When in use, the scaffold should release the loaded HGF first to promote vascularization and tissue repair. If and when cancer cells proliferate, they would stimulate the pH-sensitive hydrogel and promote the release of sorafenib from PLGA microspheres to kill the cancer cells. The rheological properties of hydrogels were assessed and their printability was investigated, and printed scaffolds were studied using various techniques. Culture experiments showed that hepatocytes had a high proliferation rate on the scaffolds. Sorafenib-containing PLGA microspheres enabled the functional scaffolds to provide local chemotherapy, killing cancer cells to prevent local recurrence of hepatocellular carcinoma.<br></p>