Injectable OPF/graphene oxide hydrogels provide mechanical support and enhance cell electrical signaling after implantation into myocardial infarct

Abstract

After myocardial infarction (MI), the scar tissue contributes to ventricular dysfunction by electrically uncoupling viable cardiomyocytes in the infarct region. Injection of a conductive hydrogel could not only provide mechanical support to the infarcted region, but also synchronize contraction and restore ventricular function by electrically connecting isolated cardiomyocytes to intact tissue.Methods: We created a conductive hydrogel by introducing graphene oxide (GO) nanoparticles into oligo(poly(ethylene glycol) fumarate) (OPF) hydrogels. The hydrogels were characterized by AFM and electrochemistry workstation. A rat model of myocardial infarction was used to investigate the ability of OPF/GO to improve cardiac electrical propagation in the injured heart in vivo. Echocardiography (ECHO) was used to evaluate heart function 4 weeks after MI. Ca2+ imaging was used to visualize beating cardiomyocytes (CMs). Immunofluorescence staining was used to visualize the expression of cardiac-specific markers.Results: OPF/GO hydrogels had semiconductive properties that were lacking in pure OPF. In addition, the incorporation of GO into OPF hydrogels could improve cell attachment in vitro. Injection of OPF/GO 4 weeks after myocardial infarction in rats enhanced the Ca2+ signal conduction of cardiomyocytes in the infarcted region in comparison with PBS or OPF alone. Moreover, the injection of OPF/GO hydrogel into the infarct region enhanced the generation of cytoskeletal structure and intercalated disc assembly. Echocardiography analysis showed improvement in load-dependent ejection fraction/fractional shortening of heart function 4 weeks after injection.Conclusions: We prepared a conductive hydrogel (OPF/GO) that provide mechanical support and biological conduction in vitro and in vivo. We found that injected OPF/GO hydrogels can provide mechanical support and electric connection between healthy myocardium and the cardiomyocytes in the scar via activating the canonical Wnt signal pathway, thus upregulating the generation of Cx43 and gap junction associated proteins. Injection of OPF/GO hydrogel maintained better heart function after myocardial infarction than the injection of a nonconductive polymer.

3D Graphene Scaffolds for Skeletal Muscle Regeneration: Future Perspectives

“…Additionally, GBM has been also used as a platform for neural cell growth, osteogenic differentiation, and chondrogenic differentiation, the major components of the musculoskeletal system. Besides being electrically activable, GBM have the intrinsic capability of (i) improve the viability of myoblasts (Ciriza et al, 2015) [and more generally of cells attached on surface, thanks to the adsorption of biomolecules and surface roughness (Zhou et al, 2018)] and (ii) induce myogenic differentiation probably facilitating the communication between cells (Jo et al, 2017). GBM have also been used in 2D films for muscle cell growth (Zhang et al, 2018), but we focused on 3D structures since these kinds of architectures recapitulate the native tissue inducing the expression of key myogenic modulators, parallel growth of muscle fibers and a correct organization of cytoskeleton and cell junctions increasing the community effect (Shin et al, 2018a;Naik et al, 2019).…”

“…Graphene can modify micro and nano-features of 3D scaffolds. For example, the introduction of GO in hydrogel is used to increase the surface roughness (Zhou et al, 2018). Further, compressive strain-induced deformation of graphene substrates has been employed to form crumpled folds and cause the alignment and elongation of myoblasts (Kim et al, 2019).…”

N-acetyl cysteine-loaded graphene oxide-collagen hybrid membrane for scarless wound healing

“…Graphene oxide (GO) is a derivative of graphene, and functionalization of graphene sp 2 -bonded carbon to produce 2D nanomaterials has shown high potential as nanocarriers for biological molecules and therapeutic drug delivery 24-26. Due to its numerous -COOH and -OH groups and unique lamellar structure, GO can promote the mechanical properties and biological interactions when functionalized with collagen by providing more binding sites for bioactive growth factors or specific drugs 27, 28. Thus, GO may play an essential role in skin regeneration by combining with other biomaterials and drugs.…”

Nanoparticle-Mediated Drug Delivery for Treatment of Ischemic Heart Disease

“…Selective studies using inorganic nanoparticles for the delivery of therapeutics to repair infarcted myocardial tissue were listed as Table 2 . Unlike the organic nanoparticles, the inorganic nanomaterials alone (without therapeutic agents loaded) could provide mechanical support even enhance cell electrical signaling in some conducting nanomaterials ( Zhou J. et al, 2018 ). Zhou et al, created a conductive hydrogel by introducing graphene oxide (GO) nanoparticles into oligo(poly(ethylene glycol) fumarate) (OPF) hydrogels and delivered to the Sprague Dawley rats’ acute MI heart by peri-infarct intramyocardial injection.…”

“…Zhou et al, created a conductive hydrogel by introducing graphene oxide (GO) nanoparticles into oligo(poly(ethylene glycol) fumarate) (OPF) hydrogels and delivered to the Sprague Dawley rats’ acute MI heart by peri-infarct intramyocardial injection. They found that injected OPF/GO hydrogels can not only provide mechanical support but also electric connection between normal cardiomyocytes and the myocardium in the scar via activating the canonical Wnt signaling pathway, thus upregulating the generation of Cx43 and gap junction-associated proteins ( Zhou J. et al, 2018 ). However, inorganic nanoparticles loaded with potential therapeutic agents have been widely studied.…”