title: Controlled epi-cortical delivery of epidermal growth factor for the stimulation of endogenous neural stem cell proliferation in stroke-injured brain.
abstract: One of the challenges in treating central nervous system (CNS) disorders with biomolecules is achieving local delivery while minimizing invasiveness. For the treatment of stroke, stimulation of endogenous neural stem/progenitor cells (NSPCs) by growth factors is a promising strategy for tissue regeneration. Epidermal growth factor (EGF) enhances proliferation of endogenous NSPCs in the subventricular zone (SVZ) when delivered directly to the ventricles of the brain; however, this strategy is highly invasive. We designed a biomaterials-based strategy to deliver molecules directly to the brain without tissue damage. EGF or poly(ethylene glycol)-modified EGF (PEG-EGF) was dispersed in a hyaluronan and methylcellulose (HAMC) hydrogel and placed epi-cortically on both uninjured and stroke-injured mouse brains. PEG-modification decreased the rate of EGF degradation by proteases, leading to a significant increase in protein accumulation at greater tissue depths than previously shown. Consequently, EGF and PEG-EGF increased NSPC proliferation in uninjured and stroke-injured brains; and in stroke-injured brains, PEG-EGF significantly increased NSPC stimulation. Our epi-cortical delivery system is a minimally-invasive method for local delivery to the brain, providing a new paradigm for local delivery to the brain.
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, Canada M5S 3E5.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cooke
authors.forename: Yuanfei
authors.initials: Y
authors.lastname: Wang
authors.forename: Cindi M
authors.initials: CM
authors.lastname: Morshead
authors.forename: Molly S
authors.initials: MS
authors.lastname: Shoichet
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D006820:Hyaluronic Acid / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy*
chemical_list: D011092:Polyethylene Glycols; D004815:Epidermal Growth Factor; D006820:Hyaluronic Acid; D010447:Peptide Hydrolases