(84e) Hydrogels for Controlling Neural Stem Cell Fate through Intracellular Redox State

Neurological injuries and diseases often result in an inflammatory environment hostile toward regeneration. This causes an acute release of reactive oxygen species (ROS) that can result in a secondary insult and toxicity for transplanted cells. Even at sub-lethal levels, an increase in extracellular ROS can change the intracellular redox state and affect key intracellular pathways. Here we focus on the redox capacity of the hydrolytically degradable poly(lactic acid)-b-PEG-b-poly(lactic acid) dimethacrylate block copolymer (PEG-PLA) to influence encapsulated NSC survival and function.

As PEG-PLA hydrogels degrade they release lactic acid, which we have previously shown to scavenge free radicals and rescues NSCs from free radical-induced death in a concentration dependent manner. We systematically synthesized a family of PEG-PLA hydrogels ranging from 0-100% degradable content to quantify the release of lactic acid into the medium and its neuroprotective capabilities. While keeping the initial (< 24 hours) mechanical properties constant, the degradable macromer content had an immediate (30 minutes) and prolonged (7 days) effect on intracellular redox state indicating fewer intracellular ROS. Cells encapsulated in hydrogels with increasing degradable content were more viable and more proliferative, with the 100% degradable material supporting a three-fold increase in metabolic ATP content and a more than two-fold increase in DNA content compared to the 0% degradable material after 7 days. In these highly degradable 3D hydrogels, we further showed that NSCs had greater concentrations of total glutathione. Our current work extends these findings to create permissive microenvironments for oligodendrocyte precursor cell proliferation and differentiation to facilitate function myelination of regrowing axons. These hydrogels may be beneficial for cell transplantation therapy, where injured host cells as well as transplanted cells may be stimulated to survive via ROS-scavenging properties of the hydrogel.