Abstract The ability to promote regeneration of the central nervous system remains elusive. Stroke is a leading cause of death and disability and creates immense burdens on stroke survivors, their caregivers, and society. Although acute stroke care has rapidly progressed over the past decades, only a small proportion of the patients qualify for these treatments. This leaves a majority of stroke patients without effective medical therapy to augment their stroke recovery. Biomaterials offer a unique avenue to interact with the nervous system. Stem cell treatments are another emerging stroke therapy that shows promise in both basic and clinical trials. However, the optimal method and environment for stem cell delivery remains unknown. We have developed a new stem cell delivery system (ElectricStem) that utilizes conductive polymer scaffolds to transplant neural stem cells into the stroked- brain. Because the polymers are conductive, electrical stimulation can be combined with the transplanted neural stem cells. We have demonstrated that electrical modulation of transplanted neural stem cells dramatically improves stroke recovery over traditional stem cell transplantation alone. In our preliminary studies, electrical modulation of neural stem cell transplants also increases the production of endogenous stem cells in the brain – suggesting a possible mechanism for this improved recovery. Further investigation about the role these endogenous stem cells play in stroke recovery will identify important stroke recovery mechanisms. By evaluating what proteins are upregulated in the transplanted neural stem cells that receive electrical modulation, we have identified stanniocalcin-2 (STC2) as an important pathway for improved recovery. STC2 is a glycoprotein with paracrine effects that plays a role in cell turnover and survival. If STC2 production is increased in transplanted neural stem cells, the animals have improved functional outcomes, and we see greater numbers of endogenous stem cells produced. If STC2 levels are decreased in the stem cells, the improvement in function and endogenous stem cell production is lost. Our proposed research investigates the ability of ElectricStem to recruit endogenous stem cells and alter their activity within the injured rodent brain tissue following stroke. The effects of electrical modulation on the transplanted neural stem cells and host brain will be evaluated in relation to the STC2 pathway. The project will also evaluate if STC2 is a potential therapy for stroke recovery. Finally, our ElectricStem system will be used in a translational aged rodent model to determine if the promising functional improvements seen in young adult animals are observed in older animals. Using these new techniques, we aim to test the hypothesis that augmentation of important endogenous recovery pathways via bioengineered systems will improve neural repair following stroke.