Hydrogel delivery of erythropoietin to the brain for endogenous stem cell stimulation after stroke injury.
Drug delivery to the brain is challenging because systemic delivery requires high doses to achieve diffusion across the blood-brain barrier and often results in systemic toxicity. Intracerebroventricular implantation of a minipump/catheter system provides local delivery, yet results in brain tissue damage and can be prone to infection. An alternate local delivery strategy, epi-cortical delivery, releases the biomolecule directly to the brain while causing minimal tissue disruption. We pursued this strategy with a hyaluronan/methyl cellulose (HAMC) hydrogel for the local release of erythropoietin to induce endogenous neural stem and progenitor cells of the subventricular zone to promote repair after stroke injury in the mouse brain. Erythropoeitin promotes neurogenesis when delivered intraventricularly, thereby making it an ideal biomolecule with which to test this new epi-cortical delivery strategy. We investigated HAMC in terms of the host tissue response and the diffusion of erythropoeitin therefrom in the stroke-injured brain for neural repair. Erythropoietin delivered from HAMC at 4 and 11 days post-stroke resulted in attenuated inflammatory response, reduced stroke cavity size, increased number of both neurons in the peri-infarct region and migratory neuroblasts in the subventricular zone, and decreased apoptosis in both the subventricular zone and the injured cortex. We demonstrate that HAMC-mediated epi-cortical administration is promising for minimally invasive delivery of erythropoeitin to the brain.
Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, Canada M5S 3E5.
Yuanfei
Y
Wang
Michael J
MJ
Cooke
Cindi M
CM
Morshead
Molly S
MS
Shoichet
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002452:Cell Count; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D004268:DNA-Binding Proteins; D000089622:Doublecortin Domain Proteins; D004333:Drug Administration Routes; D016503:Drug Delivery Systems / Q000379:methods*; D004921:Erythropoietin / Q000008:administration & dosage* / Q000494:pharmacology*; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D008747:Methylcellulose / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
D004268:DNA-Binding Proteins; D000089622:Doublecortin Domain Proteins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009479:Neuropeptides; D009687:Nuclear Proteins; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D006820:Hyaluronic Acid; D008747:Methylcellulose