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Methods for recording and stimulating through implantable microtube arrays that may be of clinical use were developed. 3D assembly methods were designed. High reliability electrode arrays were fabricated with CMOS and implant compatible processing. Interconnect and percutaneous connectors were designed and implemented including an adapter that allows wire bonding of the silicon microelectrode arrays and soldering of interconnects to the percutaneous connectors. Initial approaches to production of microtubes on wafers or devices were unsuccessful. Alternative approaches were devised but most were: too expensive for commercial feasibility; involved materials of unknown biocompatibility; or were low yield in practice. Some approaches required relatively expensive capital equipment which could not be justified for prototypes. Recent efforts resulted in identification of commercial approaches that would likely be feasible if developed. A low cost, single device ?universal? casting method has recently shown promise and is currently being evaluated.

A regenerative microchannel scaffold capable of housing microelectrodes to form a high-throughput peripheral nerve interface is described. The regenerative microchannel scaffold was fabricated using polydimethylsiloxane (PDMS) and SU-8 as substrate and structural materials, respectively. This microchannel scaffold is capable of being integrated with a PDMS-based thin-film microelectrode array (MEA) to form a peripheral nerve interface. Preliminary in vitro characterization was performed using dorsal root ganglia cultures to evaluate biocompatibility and the ability of the microchannel design to direct and orient neurite outgrowth. Our findings provided evidence that the microchannel design will be effective in directing axon regeneration to the benefit of a neural interfacing device.

A high-resolution PDMS-based conformable microelectrode array (cMEA) with integrated electronics is implemented. The cMEA is incorporated into individual layers of a nanofiber-based nerve regeneration scaffold to create a novel regenerative electrode scaffold (RES) capable of establishing a stable, high-resolution peripheral nerve interface. The device features a compact size with an enhanced signal-to-noise ratio (SNR), as required by implantation applications. Preliminary characterizations of the device are performed using in vitro experimentations, including impedance spectroscopy and neural culturing.

Objectives The principle underlying this project is that, despite nervous reorganization following upper limb amputation, original pathways and CNS relays partially maintain their function and can be exploited for interfacing prostheses. Aim of this study is to evaluate a novel peripheral intraneural multielectrode for multi-movement prosthesis control and for sensory feed-back, while assessing cortical reorganization following the re-acquired stream of data. Methods Four intrafascicular longitudinal flexible multielectrodes (tf-LIFE4) were implanted in the median and ulnar nerves of an amputee; they reliably recorded output signals for 4 weeks. Artificial intelligence classifiers were used off-line to analyse LIFE signals recorded during three distinct hand movements under voluntary order. Results Real-time control of motor output was achieved for the three actions. When applied off-line artificial intelligence reached >85% real-time correct classification of trials. Moreover, different types of current stimulation were determined to allow reproducible and localized hand/fingers sensations. Cortical organization was observed via TMS in parallel with partial resolution of symptoms due to the phantom-limb syndrome (PLS). Conclusions tf-LIFE4s recorded output signals in human nerves for 4 weeks, though the efficacy of sensory stimulation decayed after 10 days. Recording from a number of fibres permitted a high percentage of distinct actions to be classified correctly. Reversal of plastic changes and alleviation of PLS represent corollary findings of potential therapeutic benefit. Significance This study represents a breakthrough in robotic hand use in amputees.

Many different concepts of peripheral nerve interfaces have been developed over the past few decades and transferred into neuroscientific or clinical applications with varying degrees of success. In this study, we present a novel electrode design that transversally penetrates the peripheral nerve and is intended to selectively activate subsets of axons in different fascicles within the nerve. The "transverse intrafascicular multichannel electrode" (TIME) has been designed and fabricated using the micromachining and patterning of a polyimide substrate and insulation material and platinum electrode sites. In vitro characterization of the electrodes were carried out to determine the electrochemical transfer characteristics during recording and stimulation. Acute implantations were performed in the sciatic nerves of rats and recruitment curves were determined. Results indicated selective stimulation of different fascicles with graded recruitment. Future studies will address chronic implantation to investigate the reactions on the material-tissue interface and the long-term behavior and recruitment properties of the TIMEs.

A methodology is investigated for determining the location of active pathways in a peripheral nerve using measurements from a multicontact cuff electrode. The problem is treated as an inverse problem of source localization and solved using the sLORETA algorithm, developed for the electroencephalogram/magnetoencephalogram source localization problem. Simulated measurements are generated corresponding to action potentials traveling along either one or three pathways in a rat sciatic nerve. The performance of the proposed methodology using these measurements is evaluated in terms of localization error, missed pathways, and spurious pathways. The source localization performance when assuming an idealized nerve anatomy is compared to that when the correct anatomy is known. The effect of a spatio-temporal constraint based on the nerve anatomy and electrophysiology is also investigated. The approach in its present form was not found to be sufficiently reliable for subfascicular localization in practice, due to mean localization errors in the 140-180 mum range, high numbers of spurious pathways, and low resolution. Nonetheless, the constraints were shown to produce a marked reduction in the number of spurious pathways. Conditions under which the source localization approach may be useful for peripheral nerves are discussed.

Previously we reported a finite-element model that predicted that microchannels could be sensitive recording devices, amplifying the extracellular signal as action potentials pass through them, and making recording independent of node of Ranvier location. Here, we present an in vitro experimental study that validates these predictions and also demonstrates that microchannel electrodes can be highly efficient stimulators. Several aspects of whole-nerve cuff technology, including noise-reduction techniques and unidirectional stimulation methods, are readily transferable to this small scale. If axons can be persuaded to regenerate in large numbers through narrow channels, the results presented here suggest that a regenerative microchannel array could be used to produce an in vivo peripheral nerve interface with a high-resolution for both recording and stimulation.

A computational model linking stochastic neural innervation processes and functional neuromuscular excitation is developed to investigate peripheral nerve interface based limb prostheses. A means of classifying the virtual nerve data is presented by using both a time domain feature set and a spike detection algorithm. Some intrinsic parameters in recording and classification, such as brachial fiber activation, analysis window length and feature selection, are discussed to achieve good neural signal recognition. Recommendations for optimal performance are made, with regard to information content and window length.

Electrical stimulation of nerve tissue and recording of neural electrical activity are the basis of emerging prostheses and treatments for spinal cord injury, stroke, sensory deficits, and neurological disorders. An understanding of the electrochemical mechanisms underlying the behavior of neural stimulation and recording electrodes is important for the development of chronically implanted devices, particularly those employing large numbers of microelectrodes. For stimulation, materials that support charge injection by capacitive and faradaic mechanisms are available. These include titanium nitride, platinum, and iridium oxide, each with certain advantages and limitations. The use of charge-balanced waveforms and maximum electrochemical potential excursions as criteria for reversible charge injection with these electrode materials are described and critiqued. Techniques for characterizing electrochemical properties relevant to stimulation and recording are described with examples of differences in the in vitro and in vivo response of electrodes.

Microchannels containing electrodes have a number of favourable properties that make them potentially suitable as the basis of a peripheral nerve interface design. In this study we have evaluated microchannel recording in vitro in the presence of a realistic simulation of electrical interference from musculature adjacent to an implanted interface. Tripolar recording and high-pass filtration both help improve signal discrimination. At high noise levels designed to replicate the effects of intense muscular activity, a combination of both these techniques is required, and only signals in larger axons can be recovered. © 2008 IEEE.

In this study, sputtered iridium oxide films were subjected to a long-term stimulation and accelerated soak procedure to determine the ability of these electrodes to maintain high level of charge injection in an in vitro environment without delaminating. Scanning electron microscopy was used after the procedure to examine the electrodes for delamination. Characterization of the electrochemical properties of reactively sputtered iridium oxide films on LCP was also performed.

An elegant solution to the problem of instrumenting paralyzed limbs with artificial sensors for use with closed-loop FES systems is to use natural sensors, such as muscle afferent activity as feedback for the artificial controller. Longitudinal intra-fascicular electrodes (LIFEs) are electrodes that have shown promise in this application. As a peripheral nerve interface, they are designed to be placed inside the peripheral nerve, but near potentially active muscles and the stimulating electrode. Artefacts from EMG and stimulation remain limiting factors in signal acquisition. Here, we present a technique for improving the signal-to-noise ratio which consists of wrapping a shield around the implant site of the recording electrode. Preliminary results obtained during in-vivo experiments suggest that the shielding increases the level of the neural signal in the recordings.

This paper presents our experience evaluating a multi-channel peripheral nerve interface, the thin-film longitudinal intra-fascicular electrode (tfLIFE). One application for the tfLIFE is their potential use as a means to detect independent channels of volitional commands from the amputee. The neural interface would be required to be sufficiently selective to detect the activity of single motor nerve fibres within the nerve stump. Experiments were conducted in the acute rabbit model evaluate the recording characteristics of the tfLIFE array. Multiunit activity was recorded in response to mechanical stimulation of peripheral mechanoreceptors. In some channels in all experiments, large single unit spikes were clearly visible. These data were then processed to determine whether an artificial discriminator could be trained to detect and track activity from the multi unit recordings. We also tested whether inclusion of multi channel information could be used to improve the performance of the discriminator. Our preliminary results indicate the inclusion of multiple channels significantly improves the performance.

Longitudinal intrafascicular electrodes (LIFEs) designed to be placed inside a peripheral nerve seem adequate devices for constituting a nerve-prosthesis interface. In this study we evaluated the functional and morphological effects of newly designed polyimide-based thin-film (tf-)LIFEs implanted in the rat sciatic nerve for 3 months. The tf-LIFEs used are highly flexible, and have 8 regularly spaced contacts, 4 at each side of the folded structure. Functional results at 1 month showed a mild decline in nerve conduction velocity and amplitude of muscle responses, which recovered during the following 2 months. Histological results showed a mild scar response around the intraneural electrode, but no signs of axonal loss and degeneration. Longitudinally implanted LIFEs behaved slightly better than transversally inserted LIFEs. Acute experiments proved that selective neural signal recording and nerve stimulation could be achieved from the different active sites in one tf-LIFE.

Evidence indicates that user acceptance of modern artificial limbs by amputees would be significantly enhanced by a system that provides appropriate, graded, distally referred sensations of touch and joint movement, and that the functionality of limb prostheses would be improved by a more natural control mechanism. We have recently demonstrated that it is possible to implant electrodes within individual fascicles of peripheral nerve stumps in amputees, that stimulation through these electrodes can produce graded, discrete sensations of touch or movement referred to the amputee's phantom hand, and that recordings of motor neuron activity associated with attempted movements of the phantom limb through these electrodes can be used as graded control signals. We report here that this approach allows amputees to both judge and set grip force and joint position in an artificial arm, in the absence of visual input, thus providing a substrate for better integration of the artificial limb into the amputee's body image. We believe this to be the first demonstration of direct neural feedback from and direct neural control of an artificial arm in amputees.

A thin-film microfabricated multisite longitudinal intra-fascicular electrode (LIFE) array was realized as a patterned thin film on polyimide structure. These electrodes were tested in the acute rabbit animal preparation to determine their recording characteristics for comparison to standard metal wire LIFEs and the cuff electrode. It was found that the tfLIFE provided nearly as high signal amplitudes as the metal electrodes, with greater recording selectivity, making them a promising peripheral nerve interface for advanced FNS and neuroprosthetic applications

Parylene C is a biocompatible polymer that has been investigated as an encapsulation material for implantable microsystems. Since parylene C is deposited directly on the substrate from the vapor phase it can conform to a wide range of geometries. However, the thickness of the deposited layer tends to decrease in microscale gaps, which might lead to an insulation failure. To ensure more robustness of the coating, the changes in parylene C coating thickness have been investigated experimentally using simple gaps of known dimensions. In an attempt to better understand these experimental findings, two theoretical models have been developed. The first one, which is based on a diffusion approximation, is able to reproduce and extrapolate the experimental results, leading to a useful design rule for practical applications involving parylene C coating. As an example, we present the substrate design of a flexible sieve electrode for a peripheral nerve interface. The second model aims at an appropriate microscopic description of the coating process in terms of kinetic theory of gases.

Considerable scientific and technological efforts have been devoted to develop neuroprostheses and hybrid bionic systems that link the human nervous system with electronic or robotic prostheses, with the main aim of restoring motor and sensory functions in disabled patients. A number of neuroprostheses use interfaces with peripheral nerves or muscles for neuromuscular stimulation and signal recording. Herein, we provide a critical overview of the peripheral interfaces available and trace their use from research to clinical application in controlling artificial and robotic prostheses. The first section reviews the different types of non-invasive and invasive electrodes, which include surface and muscular electrodes that can record EMG signals from and stimulate the underlying or implanted muscles. Extraneural electrodes, such as cuff and epineurial electrodes, provide simultaneous interface with many axons in the nerve, whereas intrafascicular, penetrating, and regenerative electrodes may contact small groups of axons within a nerve fascicle. Biological, technological, and material science issues are also reviewed relative to the problems of electrode design and tissue injury. The last section reviews different strate- gies for the use of information recorded from peripheral interfaces and the current state of control neuroprostheses and hybrid bionic systems.

Polyimide sieve electrodes were implanted between the severed ends of the sciatic nerve in rats. The degree of axonal regeneration through the electrode was examined by physiological and histological methods from 2 to 12 months post implantation. Regeneration was successful in the 30 animals implanted. Functional reinnervation of hindlimb targets progressed to reach maximal levels at 6 months. Comparatively, the reinnervation of distal plantar muscles was lower than that of proximal muscles and of digital nerves. The number of regenerated myelinated fibers increased from 2 to 6 months. when it was similar to control values. The Majority of myelinated fibers crossing the via holes and regenerated through the distal nerve had a normal appearance. However. in a few cases decline of target reinnervation and loss of regenerated nerve fibers was found from 6 to 12 months postimplantation. Motor axons labeled by ChAT immunoreactivity regenerated scattered within minifascicles, although they were found at higher density at the periphery of the regenerated nerve. The number of ChAT-positive axons was markedly lower distally than proximally to the sieve electrode.

Purpose It is not known whether motor and sensory pathways associated with a missing or denervated limb remain functionally intact over periods of many months or years after amputation or chronic peripheral nerve transection injury. We examined the extent to which activity on chronically severed motor nerve fibers could be controlled by human amputees and whether distally referred tactile and proprioceptive sensations could be induced by stimulation of sensory axons in the nerve stumps. Methods Amputees undergoing elective stump procedures were invited to participate in this study. Longitudinal intrafascicular electrodes were threaded percutaneously and implanted in severed nerves of human amputees. The electrodes were interfaced to an amplifier and stimulator system controlled by a laptop computer. Electrophysiologic tests were conducted for 2 consecutive days after recovery from the surgery. Results It was possible to record volitional motor nerve activity uniquely associated with missing limb movements. Electrical stimulation through the implanted electrodes elicited discrete, unitary, graded sensations of touch, joint movement, and position, referring to the missing limb. Conclusions These findings indicate that both central and peripheral motor and somatosensory pathways retain significant residual connectivity and function for many years after limb amputation. This implies that peripheral nerve interfaces could be used to provide amputees with prosthetic limbs that have more natural feel and control than is possible with current myoelectric and body-powered control systems.

We studied the consequences of long-term implantation of a penetrating microelectrode array in peripheral nerve over the time course of 4-6 mo. Electrode arrays without lead wires were implanted to test the ability of different containment systems to protect the array and nerve during contractions of surrounding muscles. Treadmill walking was monitored and the animals showed no functional deficits as a result of implantation. In a different set of experiments, electrodes with lead wires were implanted for up to 7 mo and the animals were tested at 2-4 week intervals at which time stimulation thresholds and recorded sensory activity were monitored for every electrode. It was shown that surgical technique highly affected the long-term stimulation results. Results between measurement sessions were compared, and in the best case, the stimulation properties stabilized in 80% of the electrodes over the course of the experiment (162 days). The recorded sensory signals, however, were not stable over time. A histological analysis performed on all implanted tissues indicated that the morphology and fiber density of the nerve around the electrodes were normal.

One of the important goals of peripheral nerve electrode development is to design an electrode for selective recruitment of the different functions of a common nerve trunk. A challenging task is gaining selective access to central axon populations. In this paper, a simple electrode that takes advantage of the neural plasticity to reshape the nerve is presented. The flat interface nerve electrode (FINE) reshapes the nerve into a flat geometry to increase the surface area and move central axon populations close to the surface. The electrode was implanted acutely on the sciatic nerve of eight cats. The FINE can significantly reshape the nerve and fascicles (p

Restoration of motor function to individuals who have had spinal cord injuries or stroke has been hampered by the lack of an interface to the peripheral nervous system. A suitable interface should provide selective stimulation of a large number of individual muscle groups with graded recruitment of force. We have developed a new neural interface, the Utah Slanted Electrode Array (USEA), that was designed to be implanted into peripheral nerves. Its goal is to provide such an interface that could be useful in rehabilitation as well as neuroscience applications. In this study, the stimulation capabilities of the USEA were evaluated in acute experiments in cat sciatic nerve. The recruitment properties and the selectivity of stimulation were examined by determining the target muscles excited by stimulation via each of the 100 electrodes in the array and using force transducers to record the force produced in these muscles. It is shown in the results that groups of up to 15 electrodes were inserted into individual fascicles. Stimulation slightly above threshold was selective to one muscle group for most individual electrodes. At higher currents, co-activation of agonist but not antagonist muscles was observed in some instances. Recruitment curves for the electrode array were broader with twitch thresholds starting at much lower currents than for cuff electrodes. In these experiments, it is also shown that certain combinations of electrode pairs, inserted into an individual fascicle, excite fiber populations with substantial overlap, whereas other pairs appear to address independent populations. We conclude that the USEA permits more selective stimulation at much lower current intensities with more graded recruitment of individual muscles than is achieved by conventional cuff electrodes.

The functionality of prosthetic arms would be enhanced by incorporating cognitive feedback about tactile events, grasp force and hand position. This goal may best be met by interfacing directly with the peripheral nerves in the prosthesis user's residual limb. We are presently exploring a variety of interface designs based on arrays of fine wires. The efficacy of nerve fiber activation and the biocompatibility of the arrays are being studied by chronic implantation into the transected tibial nerve in the rabbit. A behavioral eye blink conditioning paradigm was implemented to assess the implant functionality over time. Our ultimate goal is to achieve stable activation of single tactile afferents. Results show that stable nerve activation with thresholds on the order of 2 nC/stimulus phase (100 /spl mu/s stimulus), can be achieved for a long period (at least 15 months has been verified in one animal that is still being observed). Using the eye blink test paradigm, it is not possible to verify if the behavioral threshold represents single fiber activation. However, in view of the low stimulus threshold, it is likely that only a few fibers are being activated.

A newly designed intrafascicular electrode for chronic neural recording was studied by implanting 12 electrodes in the radial nerves of 6 cats for 6 months. Action potentials were monitored at specified intervals throughout the experiment. The number and size of the signals recorded suggest that this type of electrode provides information that is appropriate for feedback control in functional electrical stimulation (FES) systems. Histology of the nerve revealed that the implants are biocompatible and that little damage is caused by the presence of the electrode.

An implantable neural interface capable of reliable long-term high-resolution recording from peripheral nerves has yet to be developed. Device design is challenging because extracellular axonal signals are very small, decay rapidly with distance from the axon, and in myelinated fibres are concentrated close to nodes of Ranvier, which are around 1 mum long and spaced several hundred micrometers apart. We present a finite element model examining the electrical behavior of axons in microchannels, and demonstrate that confining axons in such channels substantially amplifies the extracellular signal. For example, housing a 10-microm myelinated axon in a 1-cm-long channel with a 1000-microm(2) cross section is predicted to generate a peak extracellular voltage of over 10 mV. Furthermore, there is little radial signal decay within the channel, and a smooth axial variation of signal amplitude along the channel, irrespective of node location. Additional benefits include a greater extracellular voltage generated by large myelinated fibres compared to small unmyelinated axons, and the reduction of gain to unity at the end of the channel which ensures that there can be no crosstalk with electrodes in other channels nearby. A microchannel architecture seems well suited to the requirements of a peripheral nerve interface.

We have fabricated a soft silicone structure to support the regeneration of a sciatic nerve. The device consists of 70 parallel (120 x 110 mu m(2)) channels through which axons extend and then reconnect to the muscles on the other side of the device. Through histology and electrophysiology, we show that axons grow through the device and functionality of the muscle control is restored. Nerve functionality as demonstrated with stimulated electromyography (EMG) recordings is still intact at 9 months after implantation. Future work on this device will include electrodes for recording and stimulating the regenerating nerve.