How graphene is expected to impact neurotherapeutics in the near future

Abstract

The scientific research on graphene, a monolayer honeycomb lattice made of carbon atoms which was initially isolated in 2004, has grown exponentially in the last decade. The increasing amount of research funding directed to basic science studies on such revolutionary material promises to boost the scientific discoveries and technological developments in such field in an unprecedented way. Because its unique mechanical, optical, thermal, electronic and magnetic properties, graphene research is expected to foster new technological developments with significant applications to neurotherapeutics in several different fields in the near future. However, before the advances on graphene research may reach the clinical practice, future studies on the biocompatibility, neurotoxicity as well as long-term effects of distinct graphene forms (as well as graphene’s derivatives) upon different biological tissues are still required.

Keywords::

• functional neurosurgery
• graphene
• graphene oxide
• neuro-oncology
• neuroregeneration
• optogenetics
• photothermal therapies

Graphene, like carbon nanotubes and fullerenes, is a nanocarbon form. Nevertheless, because graphene is composed of only one layer of carbon atoms displayed in hexagonal honeycomb lattice, it exhibits unique mechanical, optical, thermal, electronic and magnetic properties. The research on graphene has grown exponentially since its initial isolation by Andre Geim and Kostya Novoselov in a laboratory at the University of Manchester in 2004. Due to its remarkable properties, the researchers responsible for such groundbreaking experiments were awarded the Noble Prize in physics in 2010. In 2013, the Graphene Flagship (a large international multi-institutional research initiative including more than 200 research institutes from 15 European countries) received a 1 billion euro grant from the European Union to foster the research and development of innovative graphene technology in the next 10 years. This was the largest amount of financial resources ever allocated to a single scientific endeavor and is expected to generate a major impact in biomaterial science in the near future. Such increased research efforts are expected to be translated into innumerable new technological developments, including, lightweight and malleable electronic devices, new optical modulators, ultracapacitors, molecular biodevices, organic photovoltaic cells and high-performance microbatteries, just to mention a few [1].

We have recently performed an extensive analysis on how the unique properties of graphene promise to open new frontline research avenues in neurotherapeutics in several fields including: neuro-oncology, neuroimaging, neuroregeneration, functional neurosurgery, neurointensive care, spine surgery and peripheral nerve surgery [2].

The high extent of aromatic structure in graphene with delocalized π orbitals allows free electron movement though its conjugated network. This yields graphene unique conductive properties. Unlike commonly used metallic electrical conductors (e.g., cooper and aluminum), the unique smooth surface of graphene present almost no electrical resistance at room temperature (less than 1 ohm/square), enabling surface electrons to experience exceptional ballistic transport for up to 16 microns without scattering [3]. Therefore, graphene has already been explored for design of several new high-efficiency electronic devices, such as new photovoltaic cells, lithium-ion microbatteries, modulators and ultracapacitors.

One special interest for neurotherapeutics is the development of a new generation of optimized intracranial monitoring devices. It has already been shown that close monitoring of critical intracranial parameters related to brain metabolism (such as intracranial pressure, cerebral blood flow, tissue oxygen and glucose levels) is able to lead to a significant improvement in the final clinical outcomes of patients with severe traumatic, ischemic or hemorrhagic brain lesions, as it enables the establishment of more targeted neurocritical care therapies [4]. Initial benchmark testings have already demonstrated that new biosensors based on graphene technology display improved accuracy in the detection of glucose levels, DNA, peptides as well as important enzymes involved in the synthesis of neurotransmitters (such as acetylcholinesterase) [5].

In recent years, several basic science and clinical studies have significantly expanded the possible applications of deep brain stimulation from classic indications (such as Parkinson’s disease) to other highly prevalent and challenging pathologies such as psychiatric disorders (obsessive-compulsive disorder, depression and addiction) [6] eating disorders (obesity and anorexia) [7] and minimally consciousness states [8], just to mention a few. Because of the unique optical, electronic and magnetic properties of graphene, the incorporation of such material to future deep brain stimulation technology is expected to open new avenues for neuromodulating strategies in functional neurosurgery.

Another important feature of graphene is that, although it presents the highest mechanical resistance ever measured in a material (with a Young’s modulus 10-times greater than titanium and 5-times greater than steel), it is very flexible and malleable. Because graphene arrays would display greater resistance to mechanical failure than currently available technology, a unique electrical conductivity profile as well as better adaptation to the cortical surface of the brain it seems to constitute the ideal material for the design of the next generation of electrocorticography monitoring arrays. Such type of devices have not only been extensively employed in the clinical practice for invasive monitoring of refractory epilepsy, but have also been demonstrated to have major applications in frontline research strategies in the field of brain–computer interface and robotic-based neurorehabilitation [9].

Graphene also displays unique thermal properties. Graphene’s thermal conductivity, which is among the highest of any known material (∼2000–4000 W m^–1K^–1), has already been exploited researchers in electronics for heat sink as well as thermal storage applications [10]. Therefore, the new graphene electronic technology is expected to couple high-efficiency with the capacity of long-term continuous operation without a meaningful temperature increase, a significant advantage when considering the development of implantable devices.

Besides traditional forms of modulating neuronal activity through electric or magnetic stimulation, new experimental strategies have focused on the use of optogenetic techniques to exert real-time, reversible external control of neurons that have been genetically modified to become sensitized to light [11]. Besides its already innumerable applications in the research area of photonics, graphene optical properties are also expected to lead to innovative developments in the field of optogenetics, such as the design of flexible and implantable light-emitting diodes [12]. Moreover, because graphene presents a property called saturable light absorption (i.e., it is able to absorb light until a certain threshold beyond which it emits heat), such material has been the focus of several research groups involved in the frontline field of molecular photothermal cancer therapy [13]. Such experimental therapeutic strategies are based on the targeted delivery of modified graphene derivatives (most commonly graphene oxide), which preferentially accumulate in cancer cells after intravenous injection, followed by irradiation of the tumor in the near-infrared spectrum, ultimately leading to selective photothermal ablation of the tumoral cells while sparing the normal surrounding tissue.

Graphene, similarly to other carbon nanoforms, presents increased chemical reactivity when compared with classic three-dimensional carbon structures (such as graphite or diamond), therefore, several graphene derivatives have already been produced, such as fluorographene and clorgraphene (halogenated graphene forms), as well as graphane (an hydrogenated graphene) [14]. Additionally, graphene can also be effectively conjugated with a variety of biomolecules, generating graphene-polymer composites that are able to induce specific biological responses. Due to excellent conductive properties of graphene, it can also be used to the development of new bioactive scaffolds, which have been shown to improve in benchmark basic science studies [15], providing new perspectives for future therapeutic strategies focused on enhancing neuronal regeneration in challenging pathologies such spinal cord injury and peripheral nerve transection [16].

Finally, graphene has been shown to exhibit unique magnetic properties (such as a unique quantum Hall effect) in magnetic fields above 10 T. Such features have generated increased attention from researchers in spintronics, an emerging research field that exploits both the intrinsic spin of the electrons and their associated magnetic moment in solid-state devices [17]. Of special interest to basic neuroscience research, the ongoing advances in spintronics are expected to lead to new powerful quantum information processing strategies, which may allow the integration of an exponentially greater amount of data. Such development would overcome some of the major challenges faced by neuroscientists involved in large brain mapping endeavors (such as the BRAIN Initiative/Brain Activity Map Project recently launched by the US government) [18], whose aspirations are frequently restricted by the limited processing and storage capacity of current computational technology. In relation to biomedical applications, the research endeavors in spintronics are expected to lead to the development of new molecular and magnetic-based imaging modalities.

Despite the significant amount of available data regarding the electrophysical properties of graphene, the investigations on its biological properties are still on a very early stage. Some preliminary data suggest that not only functional modifications of graphene may lead to major differences on its effects upon distinct biological tissues and the immune system [19], but also that differences in the morphology and dimensions of graphene presentations (such as graphene quantum dots, graphene sheets, graphene bilayers and graphene nanoribbons) [20] may also be crucial in determining their possible therapeutic as well as cytotoxic effects.

In summary, the ongoing research on the fundamental, thermal, mechanical, electronic, magnetic and optical properties of graphene promises to generate a major impact upon novel neurotherapeutic strategies in the next decades. The exponential growth in the research investments on such exquisite material will very likely lead to major technological developments that are expected to be soon incorporated not only in the basic science research scenario but also in the clinical practice in several medical specialties. Of special interest for neurotherapeutics, it is anticipated that graphene and its derivatives will have a major influence in numerous fields including brain–machine interface research, functional neurosurgery, neuro-oncology, neurointensive care and neuroregeneration research. However, before incorporation of such technological innovations to the clinical practice, more detailed studies on the biocompatibility as well as neurotoxicity of graphene in its various forms as well as its derivatives are warranted. Such rigorous safety requirements should not be seen as major barriers to future biotechnological developments involving graphene, but as necessary means in order to assure that the ‘graphene revolution’ may securely reach the clinical arena.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.