2D graphite-or вЂњgrapheneвЂќ-was first isolated through mechanical exfoliation ( Novoselov et al., 2004, 2005). Manufacturing ProcessesДўD graphite was long believed to be relegated to the realm of theoreticians and condensed matter physicists, as the thermodynamic stability of such crystals was believed to be prohibitive for their existence ( Geim and Novoselov, 2007). Despite a sizable body of work, to date, there remain many unresolved questions as to cytotoxicity and the mechanisms underlying the Gr-cellular interaction that must be addressed moving forward. Finally, the interaction of Gr with murine neural systems, both in vivo and in vitro is examined. This is followed by an overview of work performed with non-murine models. We begin with an overview of Gr manufacturing advances, applications to hybrid materials systems as well as drug delivery strategies. This review is limited to preclinical applications, although Gr and Gr-based devices may someday advance to clinical implementation. We instead focus on new directions for application to the central nervous system. Gr-based materials for interfacing with the peripheral nervous system have been reviewed elsewhere ( DomГnguez-Bajo et al., 2017 Bramini et al., 2018). As the presence of Gr becomes more widespread and commonplace across the biomedical sciences, the relatively larger body of work detailing the biological effects of carbon nanotubes may serve as a template guiding the utility of Gr for biological applications ( Kostarelos et al., 2009). Gr may be poised for incorporation into such devices. Progress in brain-computer interfaces holds great promise for patients following stroke ( Ramos-Murguialday et al., 2013), to control prosthetic limbs ( Hochberg et al., 2006 Donoghue et al., 2007), with the motor degeneration characteristic of ParkinsonвЂ™s disease ( Little et al., 2013), and for a variety of other disorders and diseases ( Chaudhary et al., 2016). Although these ideas may create questions as to ethics for neuroscience in the future, the current state-of-the-art for implanted devices is far more limited in scope. From Michael ChrichtonвЂ™s tragic protagonist in The Terminal Man to the recent growth in start-up companies seeking to transfer consciousness, the fictive present and future call to mind visions of devices that enable neural interfacing and control. Graphene (Gr), the first true two-dimensional material to exist in isolation, is the type of new nanomaterial that results in interest for novel biomedical applications. The promises of nanomedicine are extensive. We discuss studies conducted in both non-murine and murine systems, and emphasize the preclinical aspect of grapheneвЂ™s potential without undermining its tangible clinical implementation. As the biological effects of graphene are still an area of active investigation, we discuss recent development, with special focus on how surface coatings and surface properties of graphene are relevant to its biological effects. We then highlight grapheneвЂ™s ever-widen utility and unique properties that may in the future be multiplexed for cross-modal modulation or interrogation of neuronal network. We further discuss how graphene may be composited with other bio-compatible materials of interest to make novel hybrid complexes with desired characteristics for bio-interfacing. In this review, we provide a primer for how manufacturing processes to produce graphene and graphene oxide result in materials properties that may be tailored for a variety of applications. Graphene, a two-dimensional carbon crystal, has emerged as a promising material for sensing and modulating neuronal activity in vitro and in vivo.

3The Brain Institute, Florida Atlantic University, Jupiter, FL, United States.2Department of Pharmacology, Vanderbilt University, Nashville, TN, United States.1Program in Interdisciplinary Materials Science, Vanderbilt University, Nashville, TN, United States.

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