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Neurosurgery:
doi: 10.1227/NEU.0000000000000302
Review

Technological Developments and Future Perspectives on Graphene-Based Metamaterials: A Primer for Neurosurgeons

Mattei, Tobias A. MD*; Rehman, Azeem A. BS

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Author Information

*Invision Health Brain and Spine Center, Williamsville, New York;

University of Illinois College of Medicine at Peoria, Peoria, Illinois

Correspondence: Tobias A. Mattei, MD, Invision Health Brain and Spine Center, 400 International Drive, Williamsville, NY 14421. E-mail: tobias.mattei@osumc.edu

Received October 01, 2013

Accepted January 13, 2014

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Abstract

Graphene, a monolayer atomic-scale honeycomb lattice of carbon atoms, has been considered the greatest revolution in metamaterials research in the past 5 years. Its developers were awarded the Nobel Prize in Physics in 2010, and massive funding has been directed to graphene-based experimental research in the last years. For instance, an international scientific collaboration has recently received a €1 billion grant from the European Flagship Initiative, the largest amount of financial resources ever granted for a single research project in the history of modern science. Because of graphene's unique optical, thermal, mechanical, electronic, and quantum properties, the incorporation of graphene-based metamaterials to biomedical applications is expected to lead to major technological breakthroughs in the next few decades. Current frontline research in graphene technology includes the development of high-performance, lightweight, and malleable electronic devices, new optical modulators, ultracapacitors, molecular biodevices, organic photovoltaic cells, lithium-ion microbatteries, frequency multipliers, quantum dots, and integrated circuits, just to mention a few. With such advances, graphene technology is expected to significantly impact several areas of neurosurgery, including neuro-oncology, neurointensive care, neuroregeneration research, peripheral nerve surgery, functional neurosurgery, and spine surgery. In this topic review, the authors provide a basic introduction to the main electrophysical properties of graphene. Additionally, future perspectives of ongoing frontline investigations on this new metamaterial are discussed, with special emphasis on those research fields that are expected to most substantially impact experimental and clinical neurosurgery in the near future.

ABBREVIATIONS: BCI, brain-computer interface

CNS, central nervous system

FRET, fluorescence resonance energy transfer

GO, graphene oxide

MEMS, microelectromechanical system

NEMS, nanoelectromechanical system

NIR, near-infrared region; rGO, reduced graphene oxide

Initially derived from graphite, graphene is a metamaterial (ie, a material artificially engineered to have unique properties not commonly found in nature) composed of a single layer of carbon atoms arranged in a 2-dimensional, regular hexagonal (honeycomb) lattice (Figure 1).1 Alongside diamond, graphite, carbon nanotubes, and fullerenes, graphene constitutes one of the crystalline forms of carbon (Figure 2). Although the Canadian physicist Philip Wallace had already described graphene's chemical structure in 1947,2 this metamaterial was not successfully isolated until 2004. In that year, using a quite simple and ingenious process, the physicists Andre Geim and Konstantin Novoselov from the University of Manchester artificially synthesized graphene sheets by using adhesive tape. The process consisted of a repeated splitting of graphite crystals into increasingly thinner pieces until achieving the thickness of 0.01 thousandth of an inch (Figure 3).3 Scientists had previously predicted that free-standing 2-dimensional atomic crystals would be thermodynamically unstable, with a tendency to scroll and buckle if unsupported.4 Therefore, the synthesis of graphene was quite unexpected by the specialized scientific community, ultimately leading the 2 researchers to be awarded the Noble Prize in Physics in 2010.

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Figure 2
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These initial groundbreaking experiments prompted several research groups around the world to start massive research endeavors to investigate graphene's unique optical, electronic, and quantum properties that were theoretically predicted many years earlier.5,6 Such widespread initiatives led to a recent boom in the number of peer-reviewed publications on graphene research as well as graphene-related industrial patent requests (Figure 4). In 2012, graphene was 1 of the 2 projects awarded the Future and Emerging Technologies Flagship Initiative, a multibillion dollar competition organized by the European Commission (the legislative and executive body of the European Union) as part of a decade funding program for innovative research.7 This grant (which was the largest financial incentive to a single research project in the history of modern science) is expected to lead to an exponential growth in the amount of research on graphene in the near future. As a result, graphene-related technological applications are expected to ultimately impact several branches of applied research, including biotechnology and biomedical fields.

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Graphene is considered a semimetal or a zero band-gap semiconductor (ie, a semiconductor that requires no electrical potential to become conductive). Conversely, air, for example, is considered a high band-gap material because a high voltage is necessary to generate electron flow and enable electrical conductivity. Graphene, therefore, exhibits unique electronic properties that differ from most conventional 3-dimensional materials. Because each carbon atom is entirely exposed on graphene's surface, this metamaterial displays a very high surface area (approximately 2630 m2/g), leading to a remarkably high electrical conductivity, which is nearly independent of temperature between 10 Kelvin (K) and 100 K. Among other applications, the high conductivity of graphene has been extensively explored for its potential in the development of high-performance energy storage devices that would by far outrange even the best currently available electrochemical capacitors.8

Additionally, the high surface area of graphene displays an optimal biochemical arrangement for efficient bioconjugation. For example, it has already been demonstrated that graphene sheets can be successfully conjugated with a variety of commonly used biomolecules, such as poly(ethylene oxide), poly(vinyl alcohol), polyurethane, and poly(methyl methacrylate), generating graphene-polymer composites with specific biological properties.9 Because graphene is also gas impermeable, such new graphene-polymer composites also demonstrate a significant potential for improving the barrier properties of currently available polymers.

In addition to the classical method of graphene synthesis through direct exfoliation from graphite, numerous alternative isolation methods have been investigated to improve the scalability and quality of its production.10 These alternative methods include top-down fabrication techniques, such as reduction from graphite oxide or graphite fluoride (one of the most promising techniques for large-scale graphene production; Figure 5), as well as several bottom-up techniques, such as chemical vapor deposition, arc discharge epitaxial growth on silicon carbide, reduction of carbon monoxide, and self-assembly of surfactants.9 Moreover, such new methods of graphene production have led to the possibility of synthesizing several graphene derivatives, such as graphene fluoride, graphene oxide (GO), and reduced graphene oxide (rGO), each of which has unique material properties that can be explored for specific purposes. Finally, such optimized techniques for graphene synthesis prompted the industrial production of graphene to be significantly scaled upward, causing its overall costs to dramatically drop. For the sake of comparison, in 2008, graphene was one of the most expensive materials on earth, costing about $100 000 000/cm2 or around $1000 for a sample with the cross-section of a human hair. At the present time, it is possible to buy rGO for approximately $270/g and a 10 × 10 mm monolayer of graphene on a silicon dioxide on silicon substrate (SiO2/Si) for about $83.

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In order to enhance the awareness of the neurosurgical community about the special properties of this groundbreaking metamaterial, a comprehensive review of the unique mechanical, optical, photothermal, electronic, and quantum properties of graphene is provided. Additionally, a critical appraisal of current frontline experimental research involving graphene in neurosurgical-related fields is presented, highlighting the future developments in graphene-based technology that are expected to cause major impacts in clinical and experimental neurosurgery in the next decades. In order to facilitate the introduction of some technical concepts of material science and physics to the general neurosurgeon, a glossary containing basic definitions of the most important technical terminology used throughout the article is also provided (Table).

TABLE Glossary of Te...
TABLE Glossary of Te...
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UNIQUE PHYSICAL PROPERTIES OF GRAPHENE

Mechanical Properties

Although composed of a single layer of atoms, the intrinsic strength of graphene is extremely remarkable. Early in the 20th century, it was demonstrated that the actual breaking strength of a brittle material is governed by the sizes of the defects and flaws within the material (which often initiate fracture in its 3-dimensional structure), rather than by the intrinsic strength of the atomic bonds among its molecules.11 This is one of the reasons a metamaterial such as graphene, whose structure presents no defects or grain boundaries within its composition, displays such an exceptional intrinsic strength while being composed of only a single layer of atoms.

In fact, by using a technique called atomic force microscope nanoindentation, a recent study has shown that graphene exhibits the greatest mechanical strength ever measured in a natural or artificial material.12 According to this study, graphene demonstrates a Young modulus of 1000 gigapascals (GPa)—the standard unit measure of stiffness or tensile strength of materials—which is equivalent to 106 N/mm2, and an ultimate strength of approximately 145 000 000 pound-force per square inch (psi)—the standard unit measure of pressure or stress. As an illustrative comparison, titanium displays a Young modulus of 110.3 GPa (almost 10 times less than graphene's), whereas steel presents a Young modulus of 200 GPa.12 Additionally, it has also been shown that graphene's intrinsic strength is only minimally reduced when it is produced as a large-area film.13

Despite its impressive mechanical resistance, graphene is also very light, weighing only 0.77 mg/m2. At the 2010 Nobel Prize ceremony, the event in which the graphene developers were awarded the annual prize in physics, the official announcement emphasized such unique mechanical properties by stating that “a 1 m2 of graphene hammock would support a 4 kg cat but would weigh only as much as one of the cat's whiskers, at 0.77 mg” (about 0.001% of the weight of a 1 m2 paper).14

Furthermore, in contrast to its significant mechanical strength, graphene displays a surprising elasticity that can be attributed to its carbon-carbon bonds displayed in a hexagonal arrangement.15,16 Owing to such unprecedented mechanical strength and concomitant elasticity, lightweight graphene has been suggested to be the ideal candidate for fabrication of solid structures that are required to both support weight and resist tension and stretch. Finally, it has already been demonstrated that variable amounts of graphene and its derivatives can be successfully combined with other metals, such as copper or nickel, in order to increase the tensile strength of such widely used materials.17

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Optical and Photothermal Properties

Despite being nearly transparent, the 1-atom-thick graphene layer can still be seen by the naked eye because of its excellent white light absorbance (2.3% visible light absorbance in just 3.3 Å thickness [1 Å = 1 × 10−10 m]).18 Moreover, unlike most other metamaterials, graphene displays an inherent absorbance of light in both the ultraviolet and the near-infrared spectrum.19 These unique optical properties have generated great interest from researchers because of the possibility of using graphene layers in the development of new solar cells with a better performance than conventional silicon photovoltaic cells.20

Graphene also displays an interesting nonlinear optical behavior called “saturable absorption,” in which its molecules become saturated when the optical intensity of the light input surpasses a certain threshold value. Consequently, after saturation is reached, graphene is capable of releasing energy in the form of heat. This special property has attracted the attention of researchers in experimental neuro-oncology,21 because nanoparticle-mediated thermal therapy has already been shown to constitute a promising therapeutic modality in animal models of several types of cancer,22 including high-grade gliomas.23 In comparison with carbon nanotubes, another metamaterial that has also been investigated in anticancer nanoparticle thermal therapies, graphene displays a significantly higher thermal conductivity, up to around 5300 watts per meter kelvin, W/(mK).24 This value corresponds to the upper bound for the class of single-walled carbon nanotubes, rendering graphene-based nanoparticles as ideal tools for heat conduction in thermal-based anticancer therapies.

Graphene also demonstrates unique electronic properties when interacting with light on its surface, so that the molecules at its metal-dielectric surface are able to give rise to coherent electron oscillations called surface plasmon polaritons, or simply, surface plasmons.25 Surface plasmons can be understood as quasiparticles (quantum packages) of rapid oscillations of the electron density in conducting media such as plasmas or metals, in the same way photons and phonons are quantizations of electromagnetic and mechanical vibrations, respectively. Surface plasmons are coherent electron oscillations that emerge at the interface between any 2 materials presenting with opposite dielectric properties (ie, an insulator and a conductor), such as a metal sheet in the air.26 The importance of surface plasmons is that they can be excited by light, generating surface electromagnetic waves that propagate in a direction parallel to the metal/dielectric interface (Figure 6). The properties of such light-generated infrared or visible-frequency electromagnetic waves have been extensively investigated for their possible applications in molecular biology. For example, it has already been shown that surface plasmon polariton technology can be used to create new optical devices that are able to perform several important tasks such as sensing spectral analysis, biomolecular imaging, manipulation and heating of biomolecules, as well as high-performance data processing in nanodevices.27

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It has also been postulated that under intensive laser illumination, graphene may display a nonlinear optical Kerr effect,28 a behavior typical of materials that generate surface plasmons. The occurrence of the nonlinear optical Kerr effect led researchers to investigate graphene as the basis for new photonic systems operating with a basis on solitons (a self-reinforcing solitary wave that maintains its shape while traveling at a constant speed due to the absence of cancellation of nonlinear and dispersive effects in the medium).29 The technological developments in such a field are expected to enable long-distance light transmission without the use of repeaters and with an estimated capacity that is approximately twice that of the systems currently used in telecommunications.

Finally, because of a special property related to the delocalized pi electrons on its surface, which enable easy energy exchange with neighboring biomolecules, graphene has been shown to be an effective quencher of fluorescent dyes.30,31 Such a characteristic has special interest for neurosurgery, especially taking into account the emergent role of real-time intraoperative fluorescent imaging in oncological32 and vascular neurosurgery.33

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Electronic and Quantum Properties

Similarly to other materials, the electronic properties of graphene are derived from its basic chemical composition and the essential molecular arrangement of its atoms. One essential chemical characteristic of graphene is that its surface electrons are not associated with a single atom or 1 covalent bond and, therefore, are said to be “delocalized.” In graphene, such electrons inhabiting the pi bonds between the carbon atoms (ie, the second carbon bond in a C=C double bond) exhibit very high electrical mobility due to graphene's lattice structure. Therefore, such electrons are able to travel at an effective speed of light, behaving as massless particles.34 Consequently, the corresponding resistivity of graphene is extremely low, being estimated to be around 10−6 Ω·cm (ohm centimeter), which is less than that of silver, the substance with the lowest resistivity at room temperature previously known.35

These special forms of electrons that occur on graphene's surface are called relativistic Dirac fermions, in contrast to the nonrelativistic fermions that follow the standard Schrödinger equation and that appear in other condensed matter states.36 The quantum properties of relativistic Dirac fermions present in graphene lead to several unique electron transport properties, including the so-called anomalous integer quantum Hall effect37,38 and the Klein tunneling effect.39

Finally, because of its 2-dimensional property, it is possible to obtain a charge fractionalization in graphene surface molecules (where the apparent charge of individual pseudoparticles is less than a single quantum),40 making graphene an ideal candidate for future quantum computing strategies.41

The emergence of quantum computing strategies has given rise to a new paradigm of information processing in which quantum phenomena (such as superposition, entanglement, and quantum coherence) are used to perform multiple parallel data operations with the use of quantum bits (commonly called qubits).42 Such qubits differ from the conventional bits used in classic transistor-based digital computers because, owing to the phenomenon of quantum superposition, they may hold exponentially more information than their binary counterparts. Although the technology of quantum computing is still relatively far from commercial applications, the scientific community has witnessed an exponential growth in the amount of experimental research involving several distinct quantum computing strategies. Some examples of these new quantum computing strategies are trapped ion quantum computers,43 optical lattice quantum computers,44 quantum dot computers45 and nuclear magnetic resonance quantum computers,46 just to mention a few.

Of special interest to neurosurgery, the future incorporation of quantum computing strategies into our specialty creates the possibility of designing new high-performance implantable monitoring devices (especially for functional neurosurgery and epilepsy applications). Because of the inherent processing power of quantum computation, such optimized devices would be able to decode and process neural data in a much larger scale without the current limitations imposed by size, power, and single function of conventional monitoring devices.47 Similarly, the incorporation of quantum computing algorithms in the research arena would enable faster and more efficient processing of exponentially larger data sets.48 It is also expected that quantum computing strategies will have a profound impact in new imaging technologies (with special attention to the possibility of combining several different imaging modalities). Finally, quantum computers will likely lead to faster and more efficient processing and integration of large amounts of physiological data, such as those obtained through different monitoring strategies routinely used in neurosurgical acute critical care (such as intracranial pressure, partial pressure of oxygen in brain tissue, and relative cerebral blood volume).

Another important quantum phenomenon in graphene is the already-mentioned quantum anomalous Hall effect. The Hall effect (which has been called in lay terms “pressing electricity”) can be defined as the production of a voltage difference (the Hall voltage) across an electrical conductor, transverse to an electric current in the conductor and a magnetic field perpendicular to the current. In ferromagnetic materials, the final resistivity includes an additional contribution from the so-called anomalous Hall effect, which depends directly on the magnetization of the material, and which is often much larger than the ordinary intrinsic Hall effect.49 The key element for the appearance of an anomalous Hall effect in graphene has been suggested to be the massless Dirac type of its low-energy electron excitations. Because of graphene's strong magnetoelectric coupling, researchers believe that it may be possible to generate an electrically tunable quantum anomalous Hall effect in graphene through the application of moderate electric fields, inducing graphene's molecules to switch their spontaneous magnetization direction.50 Such an achievement would enable the development of low-power consumption and high-efficiency electronic devices in the near future.

Finally, because of the small spin-orbit interaction of its electrons and the near absence of nuclear magnetic moments in its carbon atoms, graphene also figures as a promising material for future investigations in Spintronics (an abbreviation for “spin transport electronics”).51 Spintronics (also known as magnetoelectronics) is an emerging research field that, by taking into account both the intrinsic spin and the associated magnetic moment of electrons (in addition to their fundamental electronic charge), promises to generate several improvements in the technology of semiconductor lasers and magnetically sensitive transistors.52 As is well known, magnetism is the main repository of information in computer hardware. At the atomic level, it is the electron spin (the elementary nanomagnet) that actually carries information. Owing to its possible applications for future magnetic information storage technologies, several studies have investigated the unique electronic properties of 2-dimensional53 and 3-dimensional topological insulators based on graphene derivatives.54 The main property explored by spintronics is the weak spin-orbit coupling in conductors, in which the electron spin (ie, the angular momentum intrinsic to the electron) is separated from the angular momentum generated by its orbital motion. The fact that graphene semiconductors present a long spin lifetime, combined with a large electron velocity in its surface, renders such devices excellent candidates for spintronic applications. Graphene semiconductors would, therefore, be able to transport spin information efficiently over long distances, enabling the creation of complex devices in which information is coded by pure spin current circuits and processed through a series of logic gates acting on spin polarization. According to theoretical predictions, the spin diffusion distances of graphene are above the 100-μm range, much higher than those of conventional metals and semiconductors (whose maximal reported spin diffusion length is 4 μm).55

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FUTURE APPLICATIONS OF GRAPHENE TECHNOLOGY TO NEUROSURGERY

Because of its unique mechanical, optical, photothermal, electronic, and quantum properties, graphene-based research is expected to give rise to several technological applications in the near future. Among them, the most important are lightweight, thin, and flexible liquid crystal displays, flexible electronic devices, integrated electric circuits, new high-efficiency transistors, organic photovoltaic cells, single-molecule gas detectors, optical modulators, organic light-emitting diodes, frequency multipliers, coolant additives, ultracapacitors, and better electrodes for lithium-ion microbatteries.56

Additionally, graphene has been demonstrated to be a promising material for the design of several types of future biomedical devices (especially in the field of nanotechnology), such as nanopore-based electronic DNA-sequencing devices, nanoparticles for molecular imaging and targeted drug delivery, and biocompatible scaffolds for cell culture.57

Because many of these applications are expected to generate a significant impact in various neurosurgical subspecialties, the authors present a comprehensive analysis of the major recent developments in graphene biomedical technology.21 Such basic review dedicates special attention to the specific benefits that the incorporation of new graphene-based technology in the future neurosurgical armamentarium may bring. Finally, a critical appraisal of the current evidence regarding the biocompatibility of graphene interface with neuronal tissues is provided.

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NEURO-ONCOLOGY

Because of its unique electronic and magnetic properties, the possibility of using graphene-based materials for the design of new nanotechnology devices promises to generate a major impact in experimental and clinical research in neuro-oncology.

Undoubtedly, neurosurgery has always been a specialty that heavily relies on accurate brain and spinal cord imaging, not only for diagnostic purposes, but also for effective therapeutic targeting. In addition to incorporating high-resolution systems, modern neuroimaging strongly depends on the differential uptake of contrast agents by normal and tumoral tissues.58 Because of their unique fluorescent, photoacoustic, and magnetic resonance profile, several studies have explored the possibility of incorporating graphene-based nanoparticles to enhance the in vivo visualization of brain tumors and improve tumor targeting of molecular anticancer strategies.59-61

In the experimental setting, it has already been demonstrated that graphene is able to provide high-resolution, real-time imaging of the cellular environment.60 In a recent study, for example, it has been shown that an aptamer-carboxyfluorescein/GO nanosheet can be successfully used for intracellular monitoring and in situ molecular probing of specific clusters of living cells, such as tumors artificially implanted in mice.61 Following the same strategy, GO nanosheets have also been used as platforms for in vivo imaging of the intracranial vasculature by using multiphoton-induced luminescence (Figure 7).62 The investigations on the safety profile of contrast agents using GO for cellular MRI have demonstrated enhanced imaging quality with high stability and low cytotoxicity.63 Finally, recent studies have also shown that graphene-derived materials may be successfully used in photoacoustic imaging strategies that rely on the acoustic response to heat expansion following optical energy absorption.64

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Besides its diagnostic applications, graphene has also been investigated in many experimental therapeutic strategies in neuro-oncology. One important focus in current neuro-oncology research is the development of nanoparticles for effective drug targeting and gene therapy delivery.65 Because of their large surface area, as well as the possibility of conjugating different biomolecules upon their surface, graphene nanoparticles have been considered a very promising scaffold that allows conjugation with several pharmacologically active molecules such as drugs, monoclonal antibodies, as well as proteins,66,67 carbohydrates,68 polymers,69 DNAs,70 and small-interfering RNAs.71

Likewise, it has already been shown that the incorporation of specific functional chemical groups onto graphene derivatives may help to render solubility to previously insoluble drugs, while retaining their anticancer properties.72 In a recent study, for example, the authors demonstrated that adding a branched polyethylene glycol (PEG) chain to nanographene oxide particles allows further noncovalent attachment of hydrophobic aromatic drug molecules to such conjugate via pi-pi stacking.73

Such experimental developments are of special interest to new drug therapies targeting the central nervous system (CNS), because they may help overcome the limitations imposed by the blood-brain barrier, one of the primary causes of failure of past chemotherapy regimens.74 Moreover, it has already been shown that graphene nanoparticles are capable of carrying multiple drugs simultaneously, potentially enhancing their cytotoxicity to CNS cancer cells.72 Such a type of multimodal drug therapy has been considered very promising, especially taking into account aggressive and resistant tumors such as glioblastoma, in which the blockage of only 1 type of cell receptor (or the inhibition of a single intracellular pathway) has already been shown to lead to complex intracellular feedback effects that may ultimately dampen the intended antitumor effects.75

Finally, because of the previously discussed special photothermal properties of graphene, several groups began to explore graphene nanoparticles as potential tools for anticancer photothermal therapies (Figure 8).59,76 This application basically relies on the substantial optical absorbance of graphene in the near-infrared region (NIR), which enables the production of heat when using NIR-targeting lasers on tumors accumulating graphene deposits. For example, in a recent laboratory investigation with U251 glioma cells, graphene nanoparticles displayed significantly greater photothermal anticancer properties than carbon nanotubes after NIR excitation.77 According to this study, under the same conditions, graphene nanoparticles generated heat more efficiently (ΔT ≈ 35°C in 5 min at a 10 μg/mL concentration) than carbon nanotubes (ΔT ≈ 18°C-19°C in 5 min at a 10 μg/mL concentration). Similarly, graphene nanoparticles performed significantly better than carbon nanotubes in inducing photothermal death of U251 human glioma cells, when cell viability after both treatments was compared by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and through measures of cell numbers and mitochondrial dehydrogenase activity.

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NEUROMONITORING

The majority of recent therapeutic improvements in the neurointensive care for acute brain injuries (ischemic, hemorrhagic, or traumatic) rely on new technological devices for continuous monitoring of physiological changes in the brain microenvironment in response to medical and surgical therapies devised to reduce intracranial pressure and to improve brain oxygenation and perfusion.78

In past years, multimodal monitoring strategies (including microdialysis, jugular venous oxygen saturation, regional oxygen saturation, and partial pressure of oxygen in brain tissue) has been extensively studied as powerful bedside tools that are able to provide an on-line analysis of both the regional and global cerebral oxygenation and metabolism status.79-82 Despite the fact that precise monitoring of the cellular microenvironment would probably enable a better overview of the evolution of acute brain injuries, at the present moment, few biosensors exhibit the high sensitivity and specificity necessary to provide an accurate, fast, reliable, and noise-free panorama of the actual state of the cellular microenvironment in the brain.

Certain unique properties of graphene have directed the attention of researchers to explore the incorporation of graphene in the development of new electrochemical sensors.21,83-85 Some of these special properties are a high electrocatalytic activity (ie, its capacity to increase the rate of electrochemical reactions without being consumed), a broad electrochemical field response, a high charge transfer capability, a robust stability, a high flexibility, a low electrical resistance, and a high mechanical flexibility and strength. In a recent report, for example, it has been demonstrated that a graphene-based amperometric biosensor (ie, a sensor that operates by the measurement of changes in electric currents) can be successfully used as a very reproducible method for the detection of extracellular concentrations of glucose. This development has a significant implication to neurointensive care monitoring, because glucose is one of the most important biochemical parameters taken into account during conventional techniques of brain microdialysis.86 According to the results reported in this study, the new graphene biosensor proved to be very sensitive when applied for the in vivo detection of the glucose levels in the striatum of rats after intraperitoneal administration of a 30-μL injection of insulin, which, as expected, resulted in a major decrease in the extracellular concentration of glucose within 30 minutes.

Additionally, it is important to highlight that it is possible to modify the chemical structure of graphene through the attachment of reactive functional groups (such an amino, carboxyl, hydroxyl, alkyl halogen, or azide group).87 Such modifications enable researchers to change the basic electrical and optical properties of graphene. These modifications also allow the conjugation of a spectrum of contrast agents, antibodies, peptides, ligands, drugs, and genes to the surface of graphene nanoparticles. These biochemical additions may provide the means for further customization of biosensors so that they may be used to detect other important physiological variables related to the brain metabolism.88

Besides these cellular biosensing strategies, it has also been demonstrated that graphene technology may be used for the development of therapeutic tools aiming to restore or improve intracranial physiological parameters. For example, an international research group in nanostructure physics has recently developed a graphene-based electrical field stimulator. This noncontact external device has been shown to effectively increase the cerebral blood flow in the intracranial arteries under the stimulated field.89 The enhanced blood flow was detected after a flexible and transparent graphene membrane was directly placed onto the cortical surface of mice and used to generate a noncontact electric field to specific blood vessels distant from the stimulation site. Although still in the experimental phase, this type of nonpharmaceutical and indirect strategy for blood flow restoration may have a substantial impact in future therapeutic strategies for treating brain hypoperfusion in several neurosurgical pathologies, such as moyamoya disease, chronic ischemic failure, and maybe even acute ischemic stroke and traumatic brain injuries.

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MOLECULAR DIAGNOSIS

Genetic and biochemical analyses have been increasingly used in both neurology and neurosurgery as noninvasive methods for detecting surrogate markers of neurological diseases and better establish their prognosis.90

One of the major developments in molecular biology in the past years has been the development of biomimetic nanopores that can be used as biosensors for detecting the presence of specific molecules, such as single-stranded DNA, RNA, or proteins.91 Recent studies have demonstrated that biomimetic nanopores can also be successfully used for optimizing DNA sequencing. This advantage relies on the fact that biomimetic nanopores seem to be capable of combining the potential for long read lengths with high speed without the necessity of amplification methods, such as the standard polymerase chain reaction (PCR).92

Several recent studies have investigated the use of graphene-based technologies for molecular diagnostic purposes. Because of the high electron mobility present at graphene's surface, it has been demonstrated that graphene-based electrodes can accurately detect DNA strands93,94 and single-nucleotide polymorphisms, providing optimized tools for experimental research in molecular biology.95 Additionally, it has also been shown that such graphene-based electrodes may be able to accurately detect other important molecules in the brain microenvironment, such as dopamine.96 Such new molecular detecting tools have special importance for experimental neuroscience research, because dopamine and its metabolites have been extensively investigated in microdialysis studies as surrogate markers of neuronal metabolism in specific brain regions that may become affected by neurological pathologies (such as Parkinson disease) as well as by drugs and anesthetics.97,98

Finally, because initial experimental studies have shown that graphene is able to strongly quench fluorescent molecules,30,31 there has been increasing interest in exploring the field of graphene biosensors based on fluorescence resonance energy transfer (FRET). Essentially, these FRET devices are able to provide quantitative descriptions and real-time imaging of the molecular environment based on transfers of energy between fluorophores (ie, fluorescent chemical compounds that can reemit light upon an initial light excitation) located nanometers apart.99,100 These types of graphene-derived biosensors utilizing FRET technology have already been shown to be able to accurately detect DNA101,102 and microRNA,103 constituting, therefore, a promising investigative tool in molecular biology and neuroscience research. In addition to its possible function as a fluorophore quencher, graphene has also been successfully used as a nanoscaffold for devices that improve the sensitivity and specificity of current biosensors.

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SPINAL INSTRUMENTATION

Construct failure and pseudarthrosis are major concerns in current spine surgery practice.104 Therefore, several technological efforts, including new material technology as well as biological strategies for stimulating bone growth, have been proposed to improve the rates of fusion as well as to avoid the problems related to hardware/bone interface and infection.

At present, titanium is the most widespread alloy used in spinal hardware, providing several advantages over older stainless steel rods, such as lower rates of infection105 and fewer MRI and CT scan artifacts.106 Nevertheless, the failure of titanium spinal constructs is still a major concern, especially in complex spinal surgery, with reported rates of symptomatic rod fracture occurring in approximately 6.8% of adult spinal deformity cases and in up to 15.8% in patients submitted to pedicle subtraction osteotomies.107 In fact, instrumentation failure has been reported to be the major cause of reoperation in the first year (with rates up to 17%) in patients undergoing complex deformity surgery.108

The fact that graphene monolayer sheets have been demonstrated to have the highest strength and resistance of any artificial material ever tested raises the possibility of increasing the resistance of current spinal hardware by either mixing graphene with other alloys or by coating them with layers of graphene. Additionally, it has been recently demonstrated that graphene sheets may have a significant antibacterial effect.109 Therefore, the incorporation of graphene to spinal hardware might possibly significantly reduce the rates of infection after fusions, a major concern in spinal surgery.

However, owing to graphene's unique electronic and magnetic properties, future studies are required to investigate the compatibility of graphene-based instrumentation with MRI. In fact, because graphene demonstrates a saturable photothermal absorption, further safety studies exploring the behavior of graphene-based hardware under several magnetic fields would be necessary to rule out any abnormal heating.

In addition to spinal instrumentation, another promising application of graphene technology to spine surgery is the development of new micro/nano-electromechanical systems (MEMS and NEMS).110 It has already been demonstrated that MEMS and NEMS sensing devices coupled to surgical spinal implants may play an important role in future in vivo biomechanical investigations. This new type of dynamic analysis would enable real-time evaluation of the biomechanics of a specific individual under different real-life situations after being submitted to placement of a spinal implant (such as an artificial disc or an interbody cage).111 As demonstrated by recent studies, several different types of NEMS (including gigahertz oscillators, nanorelays, and nanoresonators) can be developed based on the relative motion (or small relative vibrations) of graphene layers.112

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NEUROREGENERATION

The development of biomaterials that can improve neuronal growth is expected to have a major impact in future neuroregenerative therapeutic strategies after both CNS and peripheral nerve lesions. In the past years, significant efforts have been dedicated to the incorporation of biomolecules in artificial scaffolds designed to foster neural regeneration.113,114

Several experimental studies on animal models of peripheral nerve transection have demonstrated that electrical stimulation (especially in lower frequencies, ie, about 2 Hz)115 has a positive effect on neural growth.116,117 For example, in a study in which the sciatic nerves of rats were transected and the stumps were further sutured in silicon stumps (leaving a 10-mm gap between them), it was demonstrated that percutaneous electrical stimulation of 1 mA at 2 Hz every other day for 6 weeks has a positive effect on neuronal regrowth. At the histological analysis, the animals that received the percutaneous electrical stimulation demonstrated more myelinated fibers, higher axon density, and a higher ratio of blood vessel to total nerve area in comparison with the control group. During electrophysiological studies, the group that received the 2-Hz electrical stimulation demonstrated significantly shorter latency, longer duration, and faster conduction velocity in the regenerated nerves.

Additionally, although regeneration of axons in the CNS has classically been considered to be very poor, some studies have demonstrated that brief electrical stimulation may also promote sensory axon regeneration in the CNS.118

Because of the unique electroconductive properties of graphene, there has been great interest in the use of such metamaterial for the design of electroactive scaffolds that may be able to transmit externally applied electrical stimuli and, therefore, to enhance neuroregeneration.119 Furthermore, a recent study suggested that 3-dimensional porous graphene scaffolds may offer a unique environment for future neuroregenerative therapies involving neural stem cells.120 Such scaffolds have been demonstrated to enhance the differentiation of neural stem cells toward electrically active and functional neurons.

Regarding the response of neuronal cells to graphene, it has already been demonstrated that immobilized graphene surfaces exhibit a very satisfactory biocompatibility profile.121 Such graphene surfaces were superior to uncoated poly(D-lysine) surfaces (the synthetic polymer most commonly used in culture microplates), with minimal neuronal cytotoxicity as measured by lactate dehydrogenase, a surrogate marker of neuronal death. In another study, it was shown that graphene scaffolds are not only biocompatible with neural interface, but may actually increase neuronal sprouting and outgrowth in comparison with conventional strategies. For example, in a mouse hippocampal culture model, graphene scaffolds have been shown to increase the numbers of neurites as well as the average neurite length 7 days after cell seeding when compared with neuronal culture on polystyrene substrates. Besides, the graphene group demonstrated higher levels of growth-associate protein-43 (a surrogate marker of neuronal growth), as demonstrated by Western blot analysis.122

Although such studies have suggested that graphene scaffolds present an acceptable profile in relation to its interaction with neuronal interface, some specific biocompatibility issues (especially with the use of granulated GO or graphene-based nanoparticles) still need to be addressed. For example, a recent study proved that, although lower doses (0.10-0.25 mg) of soluble GO did not exhibit any obvious toxicity to mice, higher doses (around 0.40 mg) may lead to chronic toxicity due to granuloma formation in the lung, liver, spleen, and kidneys.123 Similarly, when fibroblast cells were cultured in doses of more than 50 μg/mL graphene, there was obvious cytotoxicity, with graphene particles penetrating into lysosomes, mitochondrion, endoplasm, and cell nuclei, and causing decreased cell adhesion and apoptosis. Likewise, another study suggested that the irregular edges and protrusions commonly present in graphene microsheets may lead to spontaneous penetration of cells.124 This feature of graphene sheets generates some safety concerns regarding the incorporation of graphene sheets to future biological applications, because their sharp corners may potentially cause cytoskeletal disruption, impaired cell motility, compromised epithelial barrier function, and other geometric and steric effects.124 Nevertheless, this high-penetration capacity of graphene layers, if carefully explored in the experimental scenario, may actually lead to specific developments in devices for cell manipulation (such as nanoknives, which may be used for carefully planned incisions at the cellular level).125

Another frontline research area that may significantly benefit from graphene-based technologies is the field of brain-computer interface (BCI), also known as brain-machine interface or neuroprosthetics. The research endeavors in such a research field attempt to combine modern strategies of neural signal processing with advanced robotic engineering technology to enable patients who experienced some type of neural injury (such as stroke, spinal cord injury, or limb loss, for example) to regain function through the use of artificial patient-controlled prosthetic devices or through artificial stimulation of the CNS (such as in the case of cochlear implants, retinal prosthesis, and deep brain stimulators).126

One important topic in BCI research is signal processing. In fact, the acquisition of pure, strong, and reliable neural signals (especially single-neuron action potentials and local field potentials) without the use of deep invasive implants connected by wires to the brain surface is still a technical challenge. However, recent experimental advances have demonstrated the feasibility of using low-power, wireless, miniaturized BCIs that, by using frequency multipliers, may be wirelessly connected to outside decoders.127 Such frequency multipliers operate as electronic circuits that are able to transform very low-frequency signals (for example, those of single-cell action potentials) in output signals at higher frequencies that can be more easily detected by distant decoders. In relation to such technology, recent experimental studies have suggested that, owing to its high electron mobility, graphene seems to be a very promising material for the design of the next generation of frequency multipliers.128

Another major challenge in BCI research is the mismatch between the hard and stiff planar surfaces of conventional electronics (which display an elastic modulus usually greater than 1 × 1011 pascals, Pa or N/m2) and the irregular and soft brain surface (which possesses an elastic modulus of less than 500 Pa).129 Because it has already been demonstrated that graphene sheets can be submitted to an elastic deformation of up 20% without any perturbation in its electrical properties,36 such metamaterial has been considered as an ideal candidate for future generations of cortical surface electrodes.

Finally, it has already been shown that graphene films can be successfully used to build low-weight energy storage devices (lithium-ion microbatteries) with very high reported capacities (up to 13 263 milliamp hours per gram [mAh/g] for a monolayer of graphene) (Figure 9).130 As a comparative illustration, the specific capacity of a lead acid battery (the most commonly used rechargeable battery that is commercially available) is around 83 mAh/g (Figure 7).131 Among several other challenges in BCI research,132 the necessity of compact and efficient energy sources that may enable continuous wireless recordings of deep neural signals is 1 important requirement for such technologies to reach widespread clinical applications in the near future. In relation to this issue, the incorporation of high-energy graphene-based microbatteries to wirelessly powered signal detectors constitutes a promising strategy for future signaling and monitoring strategies.

Figure 9
Figure 9
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FUNCTIONAL NEUROSURGERY

There has been intense research in functional neurosurgery to widen the application of neurostimulation beyond its standard indications in movement disorders to possibly include, for example, several psychiatric diseases (such as obsessive-compulsive disorder and depression) and even minimal consciousness states and refractory obesity.133,134 Nevertheless, the current hardware technology used in deep brain stimulation still requires improvements to overcome common hardware problems, such as lead fracture, connector erosion, cranial lead migration, infection requiring removal of the system, and loss of clinical efficacy associated with electrode impedance increment due to gliosis around the electrode tip.135

Besides their classical role in deep brain stimulation, electric fields may have a potential therapeutic role in regenerative therapies involving central and peripheral nerve lesions. In fact, in the experimental setting, it has already been shown that electrical stimulation may increase neuronal growth rates,136 guide migration,137 direct appropriate alignment of astrocytes,138,139 initiate myelin repair,140 and improve functional outcomes following spinal cord injury.141 Additionally, alternating electrical fields have also been explored as possible tools for arresting cell proliferation in several tumor types, including gliomas (Figure 10).142,143 This new therapeutic strategy relies on the capacity of low-intensity and intermediate-frequency electric fields to inhibit cancerous cell growth by disrupting the physiological dynamics of microtubules during cell replication. In 2011, after an extensive investigation in animal models and clinical trials (which demonstrated reasonable results), a new therapeutic modality called Novo Tumor Treatment Fields (TTF-100A System) was approved by the US Food and Drug Administration for the treatment of adult patients with confirmed diagnosis of recurrent supratentorial glioblastoma after all surgical, radiation, and chemotherapy options have been exhausted.144

Figure 10
Figure 10
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Because of its high electronic conductivity, surface-to-area ratio, and atomic-level thickness, graphene has been considered to have promising applications for noncontact electric stimulation. More importantly, experimental studies have already demonstrated that graphene-based noncontact electrical stimulation has enough field strength to successfully control cell-to-cell interaction.145

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CONCLUSION

Since graphene's synthetic isolation in 2004, there has been an exponential rise in the amount of scientific research on the unique physical properties of graphene. Experts from several disciplines (including electronics,146 quantum physics,101 computation,41 energy management,146 molecular biology,95 nanotechnology,123 and biomedicine65) have already carefully evaluated the possible applications of this revolutionary metamaterial to their respective research fields.

As a surgical specialty that heavily relies on technological innovations, it is expected that neurosurgery will significantly benefit from several graphene-based technological developments in the next decades. Neuro-oncology may profit from the evolving technology of graphene nanoparticles for tumor-targeted imaging, selective photothermal therapies, and anticancer electrical field stimulation. Neurointensive care may gain from the development of new electrical and optical biosensors for neuromonitoring. Neuroregeneration research is expected to develop novel brain-machine interface devices with a basis on graphene metamaterials and also benefit from the development of strategies to control and enhance neuroregeneration with basis in electric field stimulation. Peripheral nerve surgery is expected to benefit with the development of electroactive graphene-coated scaffolds for stimulating neuronal growth. Functional neurosurgery may benefit with the improvement of current electrophysiological monitoring systems in epilepsy and movement disorders. Finally, a new generation of spinal instrumentation may emerge with the development of high-resistance graphene-based hardware.

However, despite the fact that initial studies have already demonstrated the biocompatibility of graphene with neuronal tissue, future studies are still required to investigate the long-term biological effects of graphene implants, the behavior of graphene under electromagnetic fields commonly used in neuroimaging, as well as the issues related to the reported cytotoxicity of graphene derivatives as well as cellular damage caused by edge irregularities on graphene nanomaterials.124 Ultimately, a better understanding of how the different methods for graphene synthesis influence its unique material properties as well as its biocompatibility profile are still necessary before graphene technology may be successfully incorporated into clinical applications.

Finally, it is expected that an increased awareness of the ongoing frontline research on graphene may enable the neurosurgical community to properly take advantage of the technological applications such a new metamaterial may offer to experimental and clinical neurosurgery in the near future.

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Disclosure

The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

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COMMENT

Neurosurgeons are masters at technology transfer; like the house sparrow they often raise new ideas in the nests of others. Biomedical engineering has been a critical component of neurosurgical advance, and biomaterials have been of great interest since the earliest days of implantable devices and integrated circuits. You cannot imagine my excitement on reading this excellent review of graphene-based technology, beginning with the most remarkable abstract I have read in years; the potential implications are enormous, but some issues were strangely familiar and took me back to earlier experiences. Derived from graphite, graphene consists of a single 2-D layer of carbon atoms arranged in a hexagonal lattice and belongs to the category of gapless semiconductors in which no threshold energy is required to move electrons from occupied states in the valence band to empty states in the conduction band. This property, in combination with the large surface area of graphene films, allows for extreme electrical conductivity and extreme sensitivity to external influences such as pressure fluctuations or magnetic fields. As the authors indicate, a large number of methods exist for the synthesis of graphene, including chemical vapor deposition, a method similar to sputtering, a technique my colleagues and I used in the early 1970s to deposit thin films of Parylene-C, a biocompatible insulator, on the surface of chronic recording intracortical microelectrodes.1,2 Since then parylene-C has become a leading packaging material for implanted devices, but graphene can potentially record physiological parameters, produce hyperthermia3 (a valuable approach, currently stalled), and release chemo-active agents in addition to acting as a passive surface coating for other materials! Although there are many exciting possibilities here for the future of neuro-oncology and deep brain stimulation, many of the usual clinical conundrums also remain. Using graphene-based nanoparticles for interstitial hyperthermia sounds relatively noninvasive until one recalls the necessity for bringing laser light sources into the tumor and into the brain. In the era of true multimodality therapy, the introduction of a new biocompatible material for after-loading catheters, as we found with alumina ceramic,4 might facilitate 1 type of treatment (eg, hyperthermia) while simultaneously degrading another (eg, interstitial radiation). We will need to learn how graphene, a stronger and more flexible material, behaves in this regard and whether it is truly nontoxic during prolonged implantation (see the warning examples provided by the authors). Increased capabilities for brain monitoring in academic intensive care units is certain to be of value to investigators, but the clinical benefits of such monitoring in head injury patients have been difficult to demonstrate in the past. Nevertheless, these are all lovely challenges to have; I can already imagine graphene transistors in the heads of microelectrodes and neural prostheses serving as almost noiseless signal amplifiers.

Michael Salcman

Baltimore, Maryland

1. Salcman M, Bak MJ. Thumbtack microelectrode and method of making same. U.S. Patent No. 3,826,244, 1974. Cited Here...

2. Loeb GE, Bak MJ, Salcman M, Schmidt EM. Parylene as a chronically stable, biocompatible microelectrode insulator. IEEE Trans Biomed Eng. 1977;24(2):121–128. PubMed | CrossRef Cited Here... |

3. Salcman M, Samaras GM. Hyperthermia for brain tumors: biophysical rationale. Neurosurg 1981;9(3):327–335. Cited Here...

4. Ferraro FT, Salcman M, Broadwell RD, Sewchand W, Neuberth G. Alumina ceramic as a biomaterial for use in after loading radiation catheters for hyperthermia. Neurosurgery. 1989;25(2):209–213. View Full Text | PubMed | CrossRef Cited Here... |

Keywords:

Biomedical devices; Graphene; Metamaterials; Plasmonics; Translational research

Copyright © by the Congress of Neurological Surgeons

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