Bioengineered sequential growth factor delivery stimulates brain tissue regeneration after stroke.
Stroke is a leading cause of disability with no effective regenerative treatment. One promising strategy for achieving tissue repair involves the stimulation of endogenous neural stem/progenitor cells through sequential delivery of epidermal growth factor (EGF) followed by erythropoietin (EPO). Yet currently available delivery strategies such as intracerebroventricular (ICV) infusion cause significant tissue damage. We designed a novel delivery system that circumvents the blood brain barrier and directly releases growth factors to the brain. Sequential release of the two growth factors is a key in eliciting tissue repair. To control release, we encapsulate pegylated EGF (EGF-PEG) in poly(lactic-co-glycolic acid) (PLGA) nanoparticles and EPO in biphasic microparticles comprised of a PLGA core and a poly(sebacic acid) coating. EGF-PEG and EPO polymeric particles are dispersed in a hyaluronan methylcellulose (HAMC) hydrogel which spatially confines the particles and attenuates the inflammatory response of brain tissue. Our composite-mediated, sequential delivery of EGF-PEG and EPO leads to tissue repair in a mouse stroke model and minimizes damage compared to ICV infusion.
Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON M5S 3E5, Canada; Institute of Biomaterials and Biomedical Engineering, 164 College Street, Room 407, Toronto, ON M5S 3G9, Canada.
Yuanfei
Y
Wang
Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON M5S 3E5, Canada; Institute of Biomaterials and Biomedical Engineering, 164 College Street, Room 407, Toronto, ON M5S 3G9, Canada.
Michael J
MJ
Cooke
Department of Surgery, University of Toronto, 160 College Street, Room 1006, Toronto, ON M5S 3E1, Canada.
Nadia
N
Sachewsky
Department of Surgery, University of Toronto, 160 College Street, Room 1006, Toronto, ON M5S 3E1, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada.
Cindi M
CM
Morshead
Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON M5S 3E5, Canada; Institute of Biomaterials and Biomedical Engineering, 164 College Street, Room 407, Toronto, ON M5S 3G9, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada. Electronic address: molly.shoichet@utoronto.ca.
Molly S
MS
Shoichet
D020341:Absorbable Implants; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D003692:Delayed-Action Preparations / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D004815:Epidermal Growth Factor / Q000008:administration & dosage* / Q000627:therapeutic use; D004921:Erythropoietin / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008747:Methylcellulose / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012038:Regeneration; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery
D003692:Delayed-Action Preparations; D011994:Recombinant Proteins; D004921:Erythropoietin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004815:Epidermal Growth Factor; D008747:Methylcellulose
Controlled delivery; Epidermal growth factor; Erythropoietin; Hydrogel composite; Stroke; Tissue regeneration