Injectable In Situ Forming Double-Network Hydrogel To Enhance Transplanted Cell Viability and Retention

Cell transplantation by injection has emerged as a promising strategy for the treatment of several diseases and injuries throughout the body. However, the therapeutic efficacy is hampered by the inevitable cell death during mechanical injection, low cell retention at the injection site, and lack of structural support for long-term survival and functioning of the transplanted cells. Till date, no hydrogel formulation exists that can address all of these issues accompanying cell transplantation. Herein, an injectable in situ forming double-network (DN-I) hydrogel has been developed that can provide mechanical cell protection during injection, support long-term retention postinjection, and be degraded rapidly to allow space for encapsulated cell growth. The hydrogel was cross-linked via a reversible dynamic covalent C=C double bond produced via a Knoevenagel condensation reaction and was further reinforced by in situ UV-induced secondary cross-linking. The dynamic exchange of cross-links in the first network of DN-I hydrogel was significantly enhanced using a biocompatible catalyst, histidine. The large dynamic network of the DN-I hydrogel allowed injection of prefabricated hydrogels with encapsulated cells using less force and provided mechanical protection from the injection forces. The secondary cross-linking network improved the retention of the transplanted cells postinjection and subsequently provided support for cell proliferation and differentiation. The as-developed injectable in situ forming double-network hydrogel can be used as an effective carrier for stem cell transplantation and tissue regeneration applications.