title: Injectable graphene oxide/hydrogel-based angiogenic gene delivery system for vasculogenesis and cardiac repair.
abstract: The objective of this study was to develop an injectable and biocompatible hydrogel which can efficiently deliver a nanocomplex of graphene oxide (GO) and vascular endothelial growth factor-165 (VEGF) pro-angiogenic gene for myocardial therapy. For the study, an efficient nonviral gene delivery system using polyethylenimine (PEI) functionalized GO nanosheets (fGO) complexed with DNAVEGF was formulated and incorporated in the low-modulus methacrylated gelatin (GelMA) hydrogel to promote controlled and localized gene therapy. It was hypothesized that the fGOVEGF/GelMA nanocomposite hydrogels can efficiently transfect myocardial tissues and induce favorable therapeutic effects without invoking cytotoxic effects. To evaluate this hypothesis, a rat model with acute myocardial infarction was used, and the therapeutic hydrogels were injected intramyocardially in the peri-infarct regions. The secreted VEGF from in vitro transfected cardiomyocytes demonstrated profound mitotic activities on endothelial cells. A significant increase in myocardial capillary density at the injected peri-infarct region and reduction in scar area were noted in the infarcted hearts with fGOVEGF/GelMA treatment compared to infarcted hearts treated with untreated sham, GelMA and DNAVEGF/GelMA groups. Furthermore, the fGOVEGF/GelMA group showed significantly higher (p < 0.05, n = 7) cardiac performance in echocardiography compared to other groups, 14 days postinjection. In addition, no significant differences were noticed between GO/GelMA and non-GO groups in the serum cytokine levels and quantitative PCR based inflammatory microRNA (miRNA) marker expressions at the injected sites. Collectively, the current findings suggest the feasibility of a combined hydrogel-based gene therapy system for ischemic heart diseases using nonviral hybrid complex of fGO and DNA.
authors.affiliation: Biomaterials Innovation Research Center, Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Arghya
authors.initials: A
authors.lastname: Paul
authors.forename: Anwarul
authors.initials: A
authors.lastname: Hasan
authors.forename: Hamood Al
authors.initials: HA
authors.lastname: Kindi
authors.forename: Akhilesh K
authors.initials: AK
authors.lastname: Gaharwar
authors.forename: Vijayaraghava T S
authors.initials: VT
authors.lastname: Rao
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nikkhah
authors.forename: Su Ryon
authors.initials: SR
authors.lastname: Shin
authors.forename: Dorothee
authors.initials: D
authors.lastname: Krafft
authors.forename: Mehmet R
authors.initials: MR
authors.lastname: Dokmeci
authors.forename: Dominique
authors.initials: D
authors.lastname: Shum-Tim
authors.forename: Ali
authors.initials: A
authors.lastname: Khademhosseini
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers / Q000737:chemistry*; D015316:Genetic Therapy; D006108:Graphite / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D007267:Injections; D009203:Myocardial Infarction / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010087:Oxides / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry; D051381:Rats; D012212:Rheology; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000235:genetics
chemical_list: D004337:Drug Carriers; D010087:Oxides; D042461:Vascular Endothelial Growth Factor A; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D006108:Graphite; D011094:Polyethyleneimine