Abstract
Poly(ethylene glycol) (PEG) hydrogels crosslinked with enzyme-cleavable peptides are promising biodegradable vehicles for therapeutic cell delivery. However, peptide synthesis at the level required for bulk biomaterial manufacturing is costly, and fabrication of hydrogels from scalable, low-cost synthetic precursors while supporting cell-specific degradation remains a challenge. Reactive oxygen species (ROS) are cell-generated signaling molecules that can also be used as a trigger to mediate specific in vivo degradation of biomaterials. Here, PEG-based hydrogels crosslinked with ROS-degradable poly(thioketal) (PTK) polymers were successfully synthesized via thiol-maleimide chemistry and employed as a cell-degradable, antioxidative stem cell delivery platform. PTK hydrogels were mechanically robust and underwent ROS-mediated, dose-dependent degradation in vitro, while promoting robust cellular infiltration, tissue regeneration, and bioresorption in vivo. Moreover, these ROS-sensitive materials successfully encapsulated mesenchymal stem cells (MSCs) and maintained over 40% more viable cells than gold-standard hydrogels crosslinked with enzymatically-degradable peptides. The higher cellular survival in PTK-based gels was associated with the antioxidative function of the ROS-sensitive crosslinker, which scavenged free radicals and protected encapsulated MSCs from cytotoxic doses of ROS. Improved MSC viability was also observed in vivo as MSCs delivered within injectable PTK hydrogels maintained significantly more viability over 11 days compared against cells delivered within gels crosslinked with either a PEG-only control polymer or a gold-standard enzymatically-degradable peptide. Together, this study establishes a new paradigm for scalable creation and application of cell-degradable hydrogels, particularly for cell delivery applications.