Russell J. Andrews

Vertically Aligned Carbon Nanofiber Architecture as a Multifunctional 3-D Neural Electrical Interface

Developing biomaterial constructs that closely mimic the natural tissue microenvironment with its complex chemical and physical cues is essential for improving the function and reliability of implantable devices, especially those that require direct neural-electrical interfaces. Here we demonstrate that free-standing vertically aligned carbon nanofiber (VACNF) arrays can be used as a multifunctional 3-D brush-like nanoengineered matrix that interpenetrates the neuronal network of PC12 cells. We found that PC12 neuron cells cultured on VACNF substrates can form extended neural network upon proper chemical and biochemical modifications. The soft 3-D VACNF architecture provides a new platform to fine-tune the topographical, mechanical, chemical, and electrical cues at subcellular nanoscale. This new biomaterial platform can be used for both fundamental studies of material-cell interactions and the development of chronically stable implantable neural devices. Micropatterned multiplex VACNF arrays can be selectively controlled by electrical and electrochemical methods to provide localized stimulation with extraordinary spatiotemporal resolution. Further development of this technology may potentially result in a highly multiplex closed-loop system with multifunctions for neuromodulation and neuroprostheses

A carbon nanofiber based biosensor for simultaneous detection of dopamine and serotonin in the presence of ascorbic acid.

A biosensor based on an array of vertically aligned carbon nanofibers (CNFs) grown by plasma enhanced chemical vapor deposition is found to be effective for the simultaneous detection of dopamine (DA) and serotonin (5-HT) in the presence of excess ascorbic acid (AA). The CNF electrode outperforms the conventional glassy carbon electrode (GCE) for both selectivity and sensitivity. Using differential pulse voltammetry (DPV), three distinct peaks are seen for the CNF electrode at 0.13 V, 0.45 V, and 0.70 V for the ternary mixture of AA, DA, and 5-HT. In contrast, the analytes are indistinguishable in a mixture using a GCE. For the CNF electrode, the detection limits are 50 nM for DA and 250 nM for 5-HT.

Carbon nanofiber electrode array for electrochemical detection of dopamine using fast scan cyclic voltammetry

A carbon nanofiber (CNF) electrode array was integrated with the Wireless Instantaneous Neurotransmitter Concentration Sensor System (WINCS) for the detection of dopamine using fast scan cyclic voltammetry (FSCV). Dopamine detection performance by CNF arrays was comparable to that of traditional carbon fiber microelectrodes (CFMs), demonstrating that CNF arrays can be utilized as an alternative carbon electrode for neurochemical monitoring.

Neuroprotection Trek—The Next Generation

Abstract: Neuromodulation denotes controlled electrical stimulation of the central or peripheral nervous system. The three forms of neuromodulation described in this paper—deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation—were chosen primarily for their demonstrated or potential clinical usefulness. Deep brain stimulation is a completely implanted technique for improving movement disorders, such as Parkinsons disease, by very focal electrical stimulation of the brain—a technique that employs well‐established hardware (electrode and pulse generator/battery). Vagus nerve stimulation is similar to deep brain stimulation in being well‐established (for the treatment of refractory epilepsy), completely implanted, and having hardware that can be considered standard at the present time. Vagus nerve stimulation differs from deep brain stimulation, however, in that afferent stimulation of the vagus nerve results in diffuse effects on many regions throughout the brain. Although use of deep brain stimulation for applications beyond movement disorders will no doubt involve placing the stimulating electrode(s) in regions other than the thalamus, subthalamus, or globus pallidus, the use of vagus nerve stimulation for applications beyond epilepsy—for example, depression and eating disorders—is unlikely to require altering the hardware significantly (although stimulation protocols may differ). Transcranial magnetic stimulation is an example of an external or non‐implanted, intermittent (at least given the current state of the hardware) stimulation technique, the clinical value of which for neuromodulation and neuroprotection remains to be determined.

High efficient electrical stimulation of hippocampal slices with vertically aligned carbon nanofiber microbrush array.

Long-term neuroprostheses for functional electrical stimulation must efficiently stimulate tissue without electrolyzing water and raising the extracellular pH to toxic levels. Comparison of the stimulation efficiency of tungsten wire electrodes (W wires), platinum microelectrode arrays (PtMEA), as-grown vertically aligned carbon nanofiber microbrush arrays (VACNF MBAs), and polypyrrole coated (PPy-coated) VACNF MBAs in eliciting field potentials in the hippocampus slice indicates that, at low stimulating voltages that preclude the electrolysis of water, only the PPy-coated VACNF MBA is able to stimulate the CA3 to CA1 pathway. Unlike the W wires, PtMEA, as-grown VACNF MBA, and the PPy-coated VACNF MBA elicit only excitatory postsynaptic potentials (EPSPs). Furthermore, the PPy-coated VACNF MBA evokes somatic action potentials in addition to EPSPs. These results highlight the PPy-coated VACNF’s advantages in lower electrode impedance, ability to stimulate tissue through a biocompatible chloride flux, and stable vertical alignment in liquid that enables access to spatially confined regions of neuronal cells.

Trimodal nanoelectrode array for precise deep brain stimulation: prospects of a new technology based on carbon nanofiber arrays

Although deep brain stimulation (DBS) has recently been shown to be effective for neurological disorders such as Parkinsons disease, there are many limitations of the current technology: the large size of current microelectrodes (approximately 1 mm diameter); the lack of monitoring of local brain electrical activity and neurotransmitters (e.g. dopamine in Parkinsons disease); the open-loop nature of the stimulation (i.e. not guided by brain electrochemical activity). Reducing the size of the monitoring and stimulating electrodes by orders of magnitude (to the size of neural elements) allows remarkable improvements in both monitoring (spatial resolution, temporal resolution, and sensitivity) and stimulation. Carbon nanofiber nanoelectrode technology offers the possibility of trimodal arrays (monitoring electrical activity, monitoring neurotransmitter levels, precise stimulation). DBS can then be guided by changes in brain electrical activity and/or neurotransmitter levels (i.e. closed-loop DBS). Here, we describe the basic manufacture and electrical characteristics of a prototype nanoelectrode array for DBS, as well as preliminary studies with electroconductive polymers necessary to optimize DBS in vivo. An approach such as the nanoelectrode array described here may offer a generic electrical-neural interface for use in various neural prostheses.

Neuromodulation: advances in the next five years.

Neuromodulation (deep brain stimulation; DBS) has become an established treatment for movement disorders (e.g., Parkinsons disease), and is in trials for refractory epilepsy, headache, and certain mood disorders. Two main themes will advance DBS significantly in the next five years: closed‐loop DBS, that is, feedback from brain electrical activity to direct the stimulation; and computational analysis (CA)—electrophysiological modeling to enhance DBS. Closed‐loop DBS is currently in clinical trials for refractory epilepsy. New imaging techniques offer preoperative modeling for DBS surgery, including nerve fiber tracts (diffusion tensor imaging), and imaging of volume of tissue activated by a specific electrode. CA techniques for DBS include mathematical models of the abnormally synchronized electrical activity which underlies epilepsy, movement disorders, and likely many mood disorders as well. By incorporating feedback loops and multiple recording and/or stimulating sites, the abnormally synchronized brain electrical activity can be desynchronized, then “unlearned” (“unkindling” in epilepsy). Characteristics of DBS utilizing CA include low frequency rather than high frequency stimulation; multiple stimulation and/or recording sites; likely 10‐fold or more reduction in electrical current needs (much smaller “pulse generators”); more focused and less disruptive stimulation—fewer unwanted side effects; and potential to “cure” certain disorders by resetting abnormal firing patterns back to normal. These advantages of more sophisticated DBS techniques bring the following challenges, which may require a decade of research before reaching clinical practice because many brain disorders involve neurotransmitter abnormalities (e.g., dopamine in Parkinsons disease and certain mood disorders). Namely, how do we monitor and modulate neurotransmitters in addition to electrical activity? How do we get multiple microelectrodes into the brain in a minimally invasive manner? In the accompanying article, I address these two issues and offer some potential solutions.

Neuroprotection at the Nanolevel-Part II Nanodevices for Neuromodulation-Deep Brain Stimulation and Spinal Cord Injury

Nanotechniques presented in this articles companion report are being multiplexed into nanodevices that promise to greatly advance our understanding and treatment of many nervous system disorders. Current neuromodulation techniques for deep brain stimulation have major drawbacks, such as large size (in comparison with ideal of small neuron group stimulation), lack of feedback monitoring of brain electrical activity, and high electrical current needs. Carbon nanotube nanoelectrode arrays address these drawbacks and offer the possibility of monitoring neurotransmitter levels at the synapse/neuronal level in real time. Such arrays can monitor and modulate electrochemical events occurring among neural networks, which should add greatly to our understanding of neuronal communication. A multiplex nanodevice for studying (and enhancing) axonal regeneration after spinal cord injury is also being developed. The nanotechniques described in the companion piece are combined in a micron‐sized neural growth tube lined with nanodevices through which the regenerating axon extends—allowing continuous monitoring and modulation of the axons electrochemical environment plus directional guidance with a biodegradable nanoscaffold. Multifunction nanodevices provide opportunities for neuronal (and subneuronal) monitoring and modulation that will enhance neuroprotection and neurorepair far beyond the micro‐ and macrolevel techniques used heretofore.

Neuroprotection at the nanolevel--Part I: Introduction to nanoneurosurgery.

Nanoneurosurgery demands a departure from the traditional “excise what you can see and touch” role of neurosurgeons. Moreover, there is a conceptual leap necessary for neuroscientists as well as neurosurgeons in developing and applying nanotechniques to neurosurgery at the nanolevel. After introducing the realm of nanotechnology and some unique properties of nanomaterials, I review several of the nanotechniques in development that are most likely to affect neuroprotection at the nanolevel. These techniques include quantum dot “nanobarcode” labeling of cellular and subcellular entities, as well as nanotechniques for following enzymatic reactions in real time. Nanoscaffolds offer mechanical enhancement of neurorepair; carbon nanotube electrode arrays can provide nanolevel electrical and chemical enhancement. Even traditional “cut and sew” surgery is being taken down to the micron, if not nano, level for single axon repair, and the technology can use capillaries to deliver therapeutics to virtually any portion of the nervous system with greater than pinpoint accuracy. In this report, I use these nanotechniques to introduce the multiplex nanodevices under development.

Neuromodulation: selected approaches and challenges

The brain operates through complex interactions in the flow of information and signal processing within neural networks. The ‘wiring’ of such networks, being neuronal or glial, can physically and/or functionally go rogue in various pathological states. Neuromodulation, as a multidisciplinary venture, attempts to correct such faulty nets. In this review, selected approaches and challenges in neuromodulation are discussed. The use of water‐dispersible carbon nanotubes has been proven effective in the modulation of neurite outgrowth in culture and in aiding regeneration after spinal cord injury in vivo. Studying neural circuits using computational biology and analytical engineering approaches brings to light geometrical mapping of dynamics within neural networks, much needed information for stimulation interventions in medical practice. Indeed, sophisticated desynchronization approaches used for brain stimulation have been successful in coaxing ‘misfiring’ neuronal circuits to resume productive firing patterns in various human disorders. Devices have been developed for the real‐time measurement of various neurotransmitters as well as electrical activity in the human brain during electrical deep brain stimulation. Such devices can establish the dynamics of electrochemical changes in the brain during stimulation. With increasing application of nanomaterials in devices for electrical and chemical recording and stimulating in the brain, the era of cellular, and even intracellular, precision neuromodulation will soon be upon us.