title: Hydrogel-delivered brain-derived neurotrophic factor promotes tissue repair and recovery after stroke.
abstract: Stroke is the leading cause of adult disability. Systemic delivery of candidate neural repair therapies is limited by the blood-brain barrier and off-target effects. We tested a bioengineering approach for local depot release of BDNF from the infarct cavity for neural repair in chronic periods after stroke. The brain release levels of a hyaluronic acid hydrogel + BDNF were tested in several stroke models in mouse (strains C57Bl/6, DBA) and non-human primate ( Macaca fascicularis) and tracked with MRI. The behavioral recovery effects of hydrogel + BDNF and the effects on tissue repair outcomes were determined. Hydrogel-delivered BDNF diffuses from the stroke cavity into peri-infarct tissue over 3 weeks in two mouse stroke models, compared with 1 week for direct BDNF injection. Hydrogel delivery of BDNF promotes recovery of motor function. Mapping of motor system connections indicates that hydrogel-BDNF induces axonal sprouting within existing cortical and cortico-striatal systems. Pharmacogenetic studies show that hydrogel-BDNF induces the initial migration of immature neurons into the peri-infarct cortex and their long-term survival. In chronic stroke in the non-human primate, hydrogel-released BDNF can be detected up to 2 cm from the infarct, a distance relevant to human functional recovery in stroke. The hydrogel can be tracked by MRI in mouse and primate.
authors.affiliation: 1 Department of Surgery, Division of Neurosurgery, Kingston General Hospital, Kingston, Canada.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Cook
authors.affiliation: 2 Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: 2 Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, USA.
authors.forename: Hyun N
authors.initials: HN
authors.lastname: Chun
authors.affiliation: 2 Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: L Llorente
authors.affiliation: 2 Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, USA.
authors.forename: Abraham S
authors.initials: AS
authors.lastname: Chiu
authors.affiliation: 2 Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Machnicki
authors.affiliation: 3 BioTime, Inc., Alameda, USA.
authors.forename: Thomas I
authors.initials: TI
authors.lastname: Zarembinski
authors.affiliation: 2 Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, USA.
authors.forename: S Thomas
authors.initials: ST
authors.lastname: Carmichael
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008279:Magnetic Resonance Imaging; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects*; D020127:Recovery of Function / Q000187:drug effects*; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; C579455:BDNF protein, human
keywords: Axonal sprouting; bioengineering; hyaluronan; neural repair; neurogenesis