Project Summary Reactive oxygen species (ROS) are a major factor in the pathogenesis of ischemic stroke and subsequent inflammation and neurodegeneration. Our long term goal is to develop biomaterial strategies to attenuate ROS-mediated damage such as inflammation and preserve sensitive cells, such as those within the brain. Antioxidant delivery is therapeutically relevant in oxidant-stressed systems and has been shown to markedly restore myelin in rats after hypoxic-ischemic insult. Delivering such molecules with temporal control is a critical step in rescuing tissue and promoting regeneration after inflammatory processes mediated by ROS. Poly(lactic-co-glycolic acid) (PLGA) microparticles can provide a localized, controlled release of encapsulated drugs. However to date, combining features that support a high loading capacity of small molecule neurotherapeutics and release greater than a few hours with a delivery strategy that allows a minimally invasive injection has not been achieved. We have previously encapsulated high loads of the small-molecule antioxidant drug N-acetylcysteine (NAC) within PLGA microparticles and shown ability of these NAC-loaded microparticles to protect and rescue oligodendrocyte progenitor cells from hydrogen peroxide-mediated damage. We now aim to: 1) Modify the encapsulation of drug NAC to achieve high loadings and extended release profiles of at least 7 days, 2) Protect stem/progenitor cells and primary neurons from oxidative stress using super-loaded antioxidant particles, and 3) Reduce stroke lesion volumes by injecting our drug delivery system after temporary ischemia. We hypothesize that controlled release of NAC for 1 week after cerebral ischemic injury will reduce overall lesion volume and spare neural tissue. These microparticles could be an off- the-shelf product that prevents further ROS-mediated damage after ischemia and reperfusion. This platform will yield important insights regarding drug delivery design, such as the loading of small molecule antioxidants during microparticle formulation, and characterize the specific effects on cells in vitro and in vivo.