ROS-scavenging hybrid hydrogel for genetically engineered stem cell delivery and limb ischemia therapy

Abstract Stem cell therapy is a promising strategy for the treatment of ischemic diseases such as critical limb ischemia (CLI). The major obstacle is the poor survival rate and low efficiency of the implanted stem cells. Biomimetic scaffolds such as injectable hydrogels have shown the ability to promote cell retention and survival. However, the local ischemic microenvironment especially the high level of reactive oxygen species (ROS) usually induces cell loss and dysfunction, thereby leading to unsatisfactory therapeutic outcomes. Herein, we developed a new injectable hybrid hydrogel composed of natural type I collagen and melanin nanoparticles (MeNPs) for the delivery of Gremlin1 (Grem1)-overexpressed mesenchymal stem cells (Grem1-MSCs) and CLI therapy. After local injection of this cell delivery system into the ischemic limbs of mice, the thermal-triggered in situ gelation of collagen could maintain Grem1-MSCs at the injection site and MeNPs entrapped in the hydrogel framework could modulate the ischemic microenvironment via scavenging ROS to promote the survival of implanted stem cells. With this improved cell retention and survival, Grem1-MSCs could constantly secrete high concentration of Grem1, a newly discovered proangiogenic factor that can promote angiogenesis by activating the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, thereby leading to improved blood perfusion in the ischemic limbs and superior limb salvage. The strategy developed herein offers a promising therapeutic option for the effective cell-based treatment of ischemic diseases.