Injectable VEGF Hydrogels Produce Near Complete Neurological and Anatomical Protection Following Cerebral Ischemia in Rats

*InCytu, Inc., Lincoln, RI, USA†Wyss Institute for Biologically Inspired Engineering, Cambridge, MA, USA‡School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA§Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL, USAVascular endothelial growth factor (VEGF) is a potent proangiogenic peptide and its administration has beenconsidered as a potential neuroprotective strategy following cerebral stroke. Because VEGF has a short half-life and limited access to the brain parenchyma following systemic administration, approaches are beingdeveloped to deliver it directly to the site of infarction. In the present study, VEGF was incorporated into asustained release hydrogel delivery system to examine its potential benefits in a rat model of cerebral ische-mia. The hydrogel loaded with VEGF (1 µg) was stereotaxically injected into the striatum of adult rats 15min prior to a 1-h occlusion of the middle cerebral artery. Two days after surgery, animals were tested formotor function using the elevated bias swing test (EBST) and Bederson neurological battery. Control animalsreceived either stroke alone, stroke plus injections of a blank gel, or a single bolus injection of VEGF (1µg). Behavioral testing confirmed that the MCA occlusion resulted in significant deficits in the the EBSTand Bederson tests. In contrast, the performance of animals receiving VEGF gels was significantly improvedrelative to controls, with only modest impairments observed. Cerebral infarction analyzed using 2,3,5-triphe-nyl-tetrazolium chloride staining confirmed that the VEGF gels significantly and potently reduced the lesionvolume. No neurological or histological benefits were conferred by either blank gel or bolus VEGF injec-tions. These data demonstrate that VEGF, delivered from a hydrogel directly to the brain, can induce signifi-cant functional and structural protection from ischemic damage in a rat model of stroke.Key words: Alginate; Stroke; Vascular endothelial growth factor (VEGF); Hydrogel; Neuroprotection;Transplantation