Injectable Graphene Oxide/Hydrogel-Based Angiogenic Gene Delivery System for Vasculogenesis and Cardiac Repair

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 DNA(VEGF) was formulated and incorporated in the low modulus methacrylated gelatin (GeIMA) hydrogel to promote controlled and localized gene therapy. It was hypothesized that the fGO(VEGF)/Ge-IMA 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 pen-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 pen-infarct region and reduction in scar area were noted in the infarcted hearts with fGO(VEGF)/GeIMA treatment compared to infarcted hearts treated with untreated sham, GeIMA and DNA(VEGF)/GeIMA groups. Furthermore, the fGO(VEGF)/GeIMA 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/GeIMA 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 isdlemic heart diseases using nonviral hybrid complex of fGO and DNA.