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Microelectrode Array
... Implantable microelectrode arrays (MEAs) based on microfabrication methods continue to evolve, and possible applications continue to grow in both the central and peripheral nervous systems [1]. Advances in microfabrication methods enable the manufacturing of heterogeneous arrays for distinct Fabrication and characterization of polyimide-based 'smooth' titanium nitride microelectrode arrays for neural stimulation and recording neural structures with improved functionalities. ...
Objective. As electrodes are required to interact with sub-millimeter neural structures, innovative microfabrication processes are required to enable fabrication of microdevices involved in such stimulation and/or recording. This requires the development of highly integrated and miniaturized systems, comprising die-integration-compatible technology and flexible microelectrodes. To elicit selective stimulation and recordings of sub-neural structures, such microfabrication process flow can beneficiate from the integration of titanium nitride (TiN) microelectrodes onto a polyimide substrate. Finally, assembling onto cuffs is required, as well as electrode characterization. Approach. Flexible TiN microelectrode array integration and miniaturization was achieved through microfabrication technology based on microelectromechanical systems (MEMS) and complementary metal-oxide semiconductor processing techniques and materials. They are highly reproducible processes, granting extreme control over the feature size and shape, as well as enabling the integration of on-chip electronics. This design is intended to enhance the integration of future electronic modules, with high gains on device miniaturization. Main results. (a) Fabrication of two electrode designs, (1) 2 mm long array with 14 TiN square-shaped microelectrodes (80 × 80 µm²), and (2) an electrode array with 2 mm × 80 µm contacts. The average impedances at 1 kHz were 59 and 5.5 kΩ, respectively, for the smaller and larger contacts. Both designs were patterned on a flexible substrate and directly interconnected with a silicon chip. (b) Integration of flexible microelectrode array onto a cuff electrode designed for acute stimulation of the sub-millimeter nerves. (c) The TiN electrodes exhibited capacitive charge transfer, a water window of −0.6 V to 0.8 V, and a maximum charge injection capacity of 154 ± 16 µC cm⁻². Significance. We present the concept, fabrication and characterization of composite and flexible cuff electrodes, compatible with post-processing and MEMS packaging technologies, which allow for compact integration with control, readout and RF electronics. The fabricated TiN microelectrodes were electrochemically characterized and exhibited a comparable performance to other state-of-the-art electrodes for neural stimulation and recording. Therefore, the presented TiN-on-polyimide microelectrodes, released from silicon wafers, are a promising solution for neural interfaces targeted at sub-millimeter nerves, which may benefit from future upgrades with die-electronic modules.
In order to provide high-quality visual information to patients with implanted retinal prosthetic devices, the number of microelectrode should be large. As the number of microelectrodes is increased, the dimensions of the microelectrode are also decreased, which in turn results in increased interface impedance of the microelectrodes and decreased dynamic range of injection current. In addition, the reduced maximum limit of injection current may not be sufficiently large to stimulate the ganglion cells in the retina. In order to improve the trade-off between the number of microelectrodes and the current injection limit, a 3D microelectrode structure can be used as an alternative. Due to the advancement of microfabrication technology, the fabrication of highly-accurate 3D structures with small dimensions is possible. This paper presents a comprehensive electrical characterization of 2D and 3D microelectrodes. Microelectrodes that differ in shape and diameter are compared to evaluate the feasibility of use in high-resolution retinal prostheses. Their electrode–electrolyte interface impedances and charge injection limits are quantitatively analyzed. Also, in vitro animal experiments using rd1 mice are performed to observe the evoked neural responses by increasing the stimulation current amplitude from 10 to 100 μA. This research can be used to define requirements for further retinal prosthetic device research.
In order to implement a nanowire-integrated device, well-aligned arrays of a silicon nanowires are necessary for scalable and repeatable mass production. Especially for biomedical applications in neural engineering, device flexibility robust to mechanical bending, without compromising the electrical performance, is a key issue to be resolved. In this paper, a simple fabrication method and the large-scale integration of silicon-nanowire arrays is proposed by combining top–down fabrication with nanowire transfer on flexible substrate for applications in high-resolution neural stimulation microelectrodes. The arrayed silicon nanowires are fabricated on a p-type, (111)-oriented, single-crystalline-silicon substrate by a top-down process that includes silicon dry etching, silicon wet etching, and wet oxidation. After the fabrication of nanowire arrays, the device is transferred to flexible substrate using polyimide coating, electrode formation, and substrate removal. In order to verify the feasibility of the proposed method, a silicon-nanowire field-effect transistor (FET) switch is implemented and evaluated. The results of the proposed method show an excellent potential for high-resolution neural stimulation microelectrodes.
The Argus® II retinal prosthesis system (Second Sight Medical Products) is the first prosthetic vision device to obtain regulatory approval in both Europe and the USA. As such it has entered the commercial market as a treatment for patients with profound vision loss from end-stage outer retinal disease, predominantly retinitis pigmentosa. To date, over 100 devices have been implanted worldwide, representing the largest group of patients currently treated with visual prostheses. The system works by direct stimulation of the relatively preserved inner retina via epiretinal microelectrodes, thereby replacing the function of the degenerated photoreceptors. Visual information from a glasses-mounted video camera is converted to a pixelated image by an external processor, before being transmitted to the microelectrode array at the macula. Elicited retinal responses are then relayed via the normal optic nerve to the cortex for interpretation. We reviewed the animal and human studies that led to the development of the Argus® II device. A sufficiently robust safety profile was demonstrated in the phase I/II clinical trial of 30 patients. Improvement of function in terms of orientation and mobility, target localisation, shape and object recognition, and reading of letters and short unrehearsed words have also been shown. There remains a wide variability in the functional outcomes amongst the patients and the factors contributing to these performance differences are still unclear. Future developments in terms of both software and hardware aimed at improving visual function have been proposed. Further experience in clinical outcomes is being acquired due to increasing implantation.
The cat sartorius (SA) can be divided functionally into an anterior (SAa), knee extensor portion and a medial (SAm), knee flexor portion; it can be further subdivided anatomically by multiple nerve branches into parallel longitudinal columns that terminate in a distributed insertion at the knee with a continuous range of moment arms. Thus, SA may be controlled by a discrete number of motoneuron task groups reflecting a small number of central command signals or by a continuum of activation patterns associated with a continuum of moment arms. To resolve this question, the activation patterns across the width of the SA were recorded with an electrode array during three kinematically different movements — treadmill locomotion, scratching and paw shaking, in awake, unrestrained cats. Uniformity of activation along the longitudinal axis was also examined because individual muscle fibers do not extend the length of the SA. In addition, the cutaneous reflex responses were recorded throughout all regions of the SA during locomotion. Two fascial surface-patch arrays, each carrying 4–8 pairs of bipolar EMG electrodes, were sutured to the inner surface of the SA, one placed proximally and the other more distally. Each array sampled separate sites across the anterior to medial axis of SA. During locomotion, two basic EMG patterns were observed: the two burst-per-step-cycle pattern typical of SAa and the single burst pattern typical of SAm. There was an abrupt transition in the pattern of activation recorded in the two parts of SA during locomotion, and no continuum in the activation pattern was observed. Stimulation of both sural and saphenous cutaneous nerves during locomotion produced reflex responses that were uniformly distributed throughout SA, in contrast to the regional differences noted during unperturbed walking. Similarly, during scratching and paw shaking all parts of the SA were active simultaneously but with regional differences in EMG amplitude. The abrupt functional border between SAa and SAm coincided with the division of the SA into a knee flexor vs. a knee extensor. In all cases, the quantitative and qualitative differences in SAa and SAm EMGs were uniformly recorded throughout the entire extent of SAa or SAm; i.e., there was no segregation of activity within either SAa or SAm. Furthermore, the time course of EMG from each proximal recording site was nearly identical to the corresponding distal site, indicating no segregation of function along the longitudinal axis of SA. These results indicate that SAa and SAm constitute the smallest functional modules that can be recruited in SA. The functional subdivision of the SA motor nucleus is reflected in the central pattern generators for these movements to permit a task-dependent recruitment of any combination of SAa and SAm. Our data indicate that the number of task groups even in an anatomically and functionally complex muscle like the SA is small and appears to be related to the kinematic conditions under which the muscle operates.
We propose a novel fabrication process to make flexible microneedle electrode array. The process includes creation of a silicon microneedle electrode array using a silicon-on-insulator substrate followed by its release using parylene films as the support material. The proposed structure provides flexibility of a parylene thin film and rigidity of a silicon structure. Using tissue-penetration tests and impedance spectroscopy, we demonstrate that such a structure is promising in invasive neural electrical stimulation and recording.
Retinal implants have been developed to treat blindness causing retinal degenerations such as Retinitis pigmentosa (RP). The retinal stimulators are covering only a small portion of the retina usually in its center. To restore not only central vision but also a useful visual field retinal stimulators need to cover a larger area of the retina. However, large area retinal stimulators are much more difficult to implant into an eye. Some basic questions concerning this challenge should be answered in a series of experiments.
Large area retinal stimulators were fabricated as flexible multielectrode arrays (MEAs) using silicon technology with polyimide as the basic material for the substrate. Electrodes were made of gold covered with reactively sputtered iridium oxide. Several prototype designs were considered and implanted into enucleated porcine eyes. The prototype MEAs were also used as recording devices.
Large area retinal stimulator MEAs were fabricated with a diameter of 12 mm covering a visual angle of 37.6[degree sign] in a normal sighted human eye. The structures were flexible enough to be implanted in a folded state through an insertion nozzle. The implants could be positioned onto the retinal surface and fixated here using a retinal tack. Recording of spontaneous activity of retinal neurons was possible in vitro using these devices.
Large flexible MEAs covering a wider area of the retina as current devices could be fabricated using silicon technology with polyimide as a base material. Principal surgical techniques were established to insert such large devices into an eye and the devices could also be used for recording of retinal neural activity.
A light switchable microelectrode array for retinal prosthesis, which is performed with the photosensitive conductivity of hydrogenated amorphous silicon (a-Si:H) and of more advantages over the two major current retinal prosthetic categories, is characterized. Sensitivity to different visible wavelengths and light intensities are verified as well. Preliminary impedance test invitro shows appropriate impedance for neuron stimulation applications. It is indicated that such device provides a promising potential to restore a certain degree of visual function.
There is a growing interest in the development of a retinal prosthesis device based on a number of successful experiments that have demonstrated electrical stimulation of retinal tissue. An introcular retinal prosthesis test device is currently under development at NRL/JHU. The general approach and technology development issues are discussed as well as some neurophysiology interface issues. The final device will enable acute human experiments in an operating room environment.
Patients with spinal cord injury lack the connections between brain and spinal cord circuits that are essential for voluntary movement. Clinical systems that achieve muscle contraction through functional electrical stimulation (FES) have proven to be effective in allowing patients with tetraplegia to regain control of hand movements and to achieve a greater measure of independence in daily activities. In existing clinical systems, the patient uses residual proximal limb movements to trigger pre-programmed stimulation that causes the paralysed muscles to contract, allowing use of one or two basic grasps. Instead, we have developed an FES system in primates that is controlled by recordings made from microelectrodes permanently implanted in the brain. We simulated some of the effects of the paralysis caused by C5 or C6 spinal cord injury by injecting rhesus monkeys with a local anaesthetic to block the median and ulnar nerves at the elbow. Then, using recordings from approximately 100 neurons in the motor cortex, we predicted the intended activity of several of the paralysed muscles, and used these predictions to control the intensity of stimulation of the same muscles. This process essentially bypassed the spinal cord, restoring to the monkeys voluntary control of their paralysed muscles. This achievement is a major advance towards similar restoration of hand function in human patients through brain-controlled FES. We anticipate that in human patients, this neuroprosthesis would allow much more flexible and dexterous use of the hand than is possible with existing FES systems.
A novel Parylene-based shape-transferring technique was developed to fabricate 3-D microelectrodes, which fulfilled the requirements of the high-density microelectrode array (MEA) used in retinal prosthesis. A process combining anisotropic and isotropic etching was utilized to form the 3-D silicon-tip array whose shape was transferred to the Parylene C film as a flexible and biocompatible substrate. Platinum was chosen as the electrode material owing to its high charge delivery capacity and chemical inertness in the physiological environment. An aluminum-photoresist dual-layer lift-off process was employed for platinum patterning on the substrate with high tips. To avoid the cracking problem existing in the platinum-Parylene C structure, a gold intermediate layer was introduced to retard the tendency. To test the superiority of the present 3-D flexible MEA compared with the planar one, electrical properties of MEAs were characterized both in vitro and in vivo . The experimental results showed that the impedance of the 3-D electrode was about 72.7% of the planar one at 1 kHz with the same footprint in vitro , and 71.5% in vivo . The preliminary surgical experiment validated the feasibility of the 3-D MEA in retinal prosthesis.
Reduced upper airway muscle activity during sleep is fundamental to obstructive sleep apnea (OSA) pathogenesis. Hypoglossal nerve stimulation (HGNS) counteracts this problem, with potential to reduce OSA severity.
To examine safety and efficacy of a novel HGNS system (HGNS, Apnex Medical, Inc.) in treating OSA.
Twenty-one patients, 67% male, age (mean ± SD) 53.6 ± 9.2 years, with moderate to severe OSA and unable to tolerate continuous positive airway pressure (CPAP).
Each participant underwent surgical implantation of the HGNS system in a prospective single-arm interventional trial. OSA severity was defined by apnea-hypopnea index (AHI) during in-laboratory polysomnography (PSG) at baseline and 3 and 6 months post-implant. Therapy compliance was assessed by nightly hours of use. Symptoms were assessed using the Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), Calgary Sleep Apnea Quality of Life Index (SAQLI), and the Beck Depression Inventory (BDI).
HGNS was used on 89% ± 15% of nights (n = 21). On these nights, it was used for 5.8 ± 1.6 h per night. Nineteen of 21 participants had baseline and 6-month PSGs. There was a significant improvement (all P < 0.05) from baseline to 6 months in: AHI (43.1 ± 17.5 to 19.5 ± 16.7), ESS (12.1 ± 4.7 to 8.1 ± 4.4), FOSQ (14.4 ± 2.0 to 16.7 ± 2.2), SAQLI (3.2 ± 1.0 to 4.9 ± 1.3), and BDI (15.8 ± 9.0 to 9.7 ± 7.6). Two serious device-related adverse events occurred: an infection requiring device removal and a stimulation lead cuff dislodgement requiring replacement.
HGNS demonstrated favorable safety, efficacy, and compliance. Participants experienced a significant decrease in OSA severity and OSA-associated symptoms.
NAME: Australian Clinical Study of the Apnex Medical HGNS System to Treat Obstructive Sleep Apnea. Registration Number: NCT01186926. URL: http://clinicaltrials.gov/ct2/show/NCT01186926.
Brain changes in response to nerve damage or cochlear trauma can generate pathological neural activity that is believed to be responsible for many types of chronic pain and tinnitus. Several studies have reported that the severity of chronic pain and tinnitus is correlated with the degree of map reorganization in somatosensory and auditory cortex, respectively. Direct electrical or transcranial magnetic stimulation of sensory cortex can temporarily disrupt these phantom sensations. However, there is as yet no direct evidence for a causal role of plasticity in the generation of pain or tinnitus. Here we report evidence that reversing the brain changes responsible can eliminate the perceptual impairment in an animal model of noise-induced tinnitus. Exposure to intense noise degrades the frequency tuning of auditory cortex neurons and increases cortical synchronization. Repeatedly pairing tones with brief pulses of vagus nerve stimulation completely eliminated the physiological and behavioural correlates of tinnitus in noise-exposed rats. These improvements persisted for weeks after the end of therapy. This method for restoring neural activity to normal may be applicable to a variety of neurological disorders.
A light-sensitive, externally powered microchip was surgically implanted subretinally near the macular region of volunteers blind from hereditary retinal dystrophy. The implant contains an array of 1500 active microphotodiodes ('chip'), each with its own amplifier and local stimulation electrode. At the implant's tip, another array of 16 wire-connected electrodes allows light-independent direct stimulation and testing of the neuron-electrode interface. Visual scenes are projected naturally through the eye's lens onto the chip under the transparent retina. The chip generates a corresponding pattern of 38 × 40 pixels, each releasing light-intensity-dependent electric stimulation pulses. Subsequently, three previously blind persons could locate bright objects on a dark table, two of whom could discern grating patterns. One of these patients was able to correctly describe and name objects like a fork or knife on a table, geometric patterns, different kinds of fruit and discern shades of grey with only 15 per cent contrast. Without a training period, the regained visual functions enabled him to localize and approach persons in a room freely and to read large letters as complete words after several years of blindness. These results demonstrate for the first time that subretinal micro-electrode arrays with 1500 photodiodes can create detailed meaningful visual perception in previously blind individuals.
In chronic heart failure (CHF), reduced vagal activity correlates with increased mortality and acute decompensation. Experimentally, chronic vagus nerve stimulation (VNS) improved left ventricular (LV) function and survival; clinically, it is used for the treatment of drug-refractory epilepsy. We assessed safety and tolerability of chronic VNS in symptomatic CHF patients, using a novel implantable nerve stimulation system. The secondary goal was to obtain preliminary data on clinical efficacy.
This multi-centre, open-label phase II, two-staged study (8-patient feasibility phase plus 24-patient safety and tolerability phase) enrolled 32 New York Heart Association (NYHA) class II-IV patients [age 56 ± 11 years, LV ejection fraction (LVEF) 23 ± 8%]. Right cervical VNS with CardioFit (BioControl Medical) implantable system started 2-4 weeks after implant, slowly raising intensity; patients were followed 3 and 6 months thereafter with optional 1-year follow-up. Overall, 26 serious adverse events (SAEs) occurred in 13 of 32 patients (40.6%), including three deaths and two clearly device-related AEs (post-operative pulmonary oedema, need of surgical revision). Expected non-serious device-related AEs (cough, dysphonia, and stimulation-related pain) occurred early but were reduced and disappeared after stimulation intensity adjustment. There were significant improvements (P < 0.001) in NYHA class quality of life, 6-minute walk test (from 411 ± 76 to 471 ± 111 m), LVEF (from 22 ± 7 to 29 ± 8%), and LV systolic volumes (P = 0.02). These improvements were maintained at 1 year.
This open-label study shows that chronic VNS in CHF patients with severe systolic dysfunction may be safe and tolerable and may improve quality of life and LV function. A controlled clinical trial appears warranted.
Similarities between the muscle synergies associated with the flexion reflex and locomotion in reduced preparations have suggested that spinal circuits subserving these two motor tasks might share common interneurons. To test this hypothesis in functionally complex muscles, we studied the interaction between low-threshold cutaneous afferents and the locomotor central pattern generator (CPG) during treadmill locomotion in awake, intact cats. Electrical stimuli were delivered via implanted nerve cuff electrodes at all phases of locomotion, and EMGs were recorded from fourteen intramuscular subregions in eight bifunctional thigh muscles (adductor femoris, biceps femoris, caudofemoralis, gracilis, semimembranosus, semitendinosus, tensor fasciae latae, and tenuissimus). In addition, the EMG patterns recorded during locomotion were compared with those recorded during two other centrally driven rhythmical behaviors, scratching and paw shaking, to determine whether the functional relationships among these intramuscular subregions were fixed or task dependent. Four of the five broad, bifunctional muscles studied (biceps femoris, gracilis, semimembranosus, and tensor fasciae latae) had functional subunits that could be differentially activated in one or more of the three movements studied; adductor femoris was consistently uniformly activated despite its distributed skeletal attachments. The pattern of recruitment of the intramuscular functional subunits was movement-specific. The locomotor CPG and cutaneous reflex pathways both similarly subdivided some bifunctional muscles, but not others, into intramuscular subregions. The results of the present study confirm that some combinations of muscle subregions and cutaneous nerves constitute simple reciprocal categories of flexors and extensors, as described originally by Sherrington (1910). "Typical" low threshold excitatory or inhibitory reflex responses were produced in muscles or muscle subregions that were recruited as "net" flexors of extensors, respectively. However, muscles with complex activation patterns during walking often had very individualized, complex reflex responses during locomotion that did not conform to the background locomotion synergies. All of the reflex responses observed were mediated by low threshold cutaneous afferents. These data indicate that there are multiple, low threshold, excitatory and inhibitory cutaneous reflex pathways that have highly specialized connections with flexor and extensor muscles and even their intramuscular subregions. It is also clear that the premotoneuronal circuits mediating these cutaneous reflex effects are not necessarily synonymous with those of the locomotor CPG. These two systems do interact powerfully, however, suggesting some convergence. The nature of the convergence between the CPG and the many independent subsets of spinal interneurons mediating cutaneous reflexes is specialized and muscle subregion-specific.
A novel type of nerve cuff electrode consisting of conductive segments embedded within a self-curling sheath of biocompatible insulation has been developed. This spiral nerve cuff is biased to self-wrap around peripheral nerves and possesses a 'self-sizing' property, presenting an alternative to present commercially available, fixed-size nerve cuffs that are manually wrapped around nerves and sutured shut ('split-cylinder' cuffs). Spiral cuff design and manufacture are described. The authors hypothesize that unlike traditional cuffs, the spiral cuff potentially can be implanted safely when sized to fit peripheral nerves snugly. Theoretical pressure analyzes of traditional and spiral cuffs that support this hypothesis are presented. These analyses are designed to predict the minimum CNR (cuff diameter/nerve diameter ratio) at which there is no interference with intraneural blood flow. Results of a preliminary experiment in which snug spiral cuffs were implanted on feline peripheral nerve support the prediction that they may be safe.
This book and its companion volume describe state-of-the-art advances in techniques associated with implantable neural prosthetic devices and their applications. Researchers, engineers, clinicians, students, and any specialist in this field will gain a deeper understanding of the neural prosthetic techniques currently available for a wide range of biomedical applications.
In part one of this two-volume sequence, Implantable Neural Prostheses 1: Devices and Applications, the focus is on implant designs and applications. Devices covered include sensory prosthetic devices such as cochlear implants, auditory midbrain implants, visual implants, spinal cord stimulators, and motor prosthetic devices including deep brain stimulators, Bions, and cardiac electro-stimulators. Readers will also understand the regulatory approval process in the U.S. and Europe for implantable medical devices.
The history of medicine has been substantially defined by a small number of monumental discoveries. Most of these breakthroughs have emerged from the biological sciences. One of the first great breakthroughs was the recognition by Koch in 1884 that pathogens could be transmitted from one living organism to another to cause disease. This profound concept led to a revolution in the approach to patient care that ultimately led to introduction of “sterile” techniques that greatly improved survivals of patients. This knowledge promoted the discovery of antibiotics 40 years later, which dramatically increased life expectancy throughout the more developed parts of the world. Another great milestone that has influenced medical care was the use of anesthesia for surgery, which was first introduced in 1846. Collectively, these three discoveries armed physicians with the knowledge and means to substantially reduce the prevalence of infectious disease, which was and still remains the leading cause of death throughout the world, and to perform a much wider range of surgeries with greatly improved survivals. The improved li- expectancies enabled the medical community to focus on a wider range of medical problems and solutions to disease.
In the growing field of brain-machine interface (BMI), the interface between electrodes and neural tissues plays an important role in the recording and stimulation of neural signals. To minimize tissue damage while retaining high sensitivity, a flexible and a smaller electrode with low impedance is required. However, it is a major challenge to reduce electrode size while retaining the conductive characteristics of the electrode. In addition, the mechanical mismatch between stiff electrodes and soft tissues creates damaging reactive tissue responses. Here, we demonstrate a neural probe structure based on graphene, ZnO nanowires, and conducting polymer that provides flexibility and low impedance performance. A hybrid Au and graphene structure was utilized to achieve both flexibility and good conductivity. Using ZnO nanowires to increase the effective surface area drastically decreased the impedance value and enhanced the signal to noise ratio (SNR). A Poly[3,4-ethylenedioxythiophene] (PEDOT) coating on the neural probe improved the electrical characteristics of the electrode while providing better bio-compatibility. In-vivo neural signal recordings showed that our neural probe can detect clearer signals.
Conventional wet electrodes require skin preparation and gel usage to maintain low interface impedance, which limit their applications in long-term monitoring of biopotentials such as electroencephalogram (EEG). To address this problem, microneedle electrode arrays (MNEAs) have been employed as dry electrodes, which could be capable of EEG monitoring without skin abrasion and gel electrolyte. However, most of them are usually based on rigid substrates that are not conformal to curved and moved human skin. Therefore, we develop a flexible parylene-based MNEA (P-MNEA) with silicon microneedles, which could provide not only conformal but also robust contact. Firstly, the microfabrication process is concretely illustrated and makes it repeatable. Then, penetration tests illustrate these microneedles are robust enough to penetrate into epidermis so that impedances of stratum corneum make limited contribution to interface impedance. Consequently, in vivo impedance results verify the priority of P-MNEA in long-time impedance stability. Meanwhile, competitive impedance density of 7.5 KΩ cm²@10 Hz is attained. Eventually, EEG recoding results as well as correlation and coherence analyses of P-MNEA indicate comparable performance to that of wet electrode. In brief, these results reveal promising prospect of P-MNEA in long-time EEG monitoring.
This paper demonstrates bidirectional selective recording and stimulation by using flexible and adjustable sling electrodes aiming at electroceuticals application in the future. The sling design enables helical implantations of sensing electrodes on a nerve with less pressure and tight contact. Neural signals are recorded from six sensing electrodes with different amplitudes and latencies, showing relatively selective recordings. In addition, selective stimulations are also conducted with monitoring muscle signals, showing different selectivity depending on spatial positions of stimulating electrodes. Overall our data shows that this sling design would be effective in bidirectional control in electroceuticals.
The development of high-resolution retinal prostheses fabricated from silicon wafers presents an interesting problem: how to electrically bridge the space between the flat silicon wafer and the curved retinal surface. One potential “bridge” is a microwire glass electrode. In this paper we present our results in evaluating microwire glass electrodes. We stimulated isolated rabbit retina (n=5) with a 0.0256 cm2 microwire electrode. The current and pulse duration were varied from 498 to 1660 μA and 0.1 to 3 ms, respectively. We found that short pulses produced more spikes per coulomb and longer pulses produced more spikes per milliamp. The optimal pulse duration range of 0.7–1 ms was identified as a compromise between the advantages of short and long pulses. Stimulation of isolated rabbit retina with microwire glass results in consistent neuronal spike formation at safe charge density, 20.7±4.3 μC/cm2. We also examined the response of retinas (n=6) to stimulation with a smaller microwire electrode, 0.0002 cm2. We found that less current was required (15 μA versus 756 μA) for a 1 ms pulse, but at the expense of greater charge density (75 μC/cm2 versus 29.5 μC/cm2). Nonetheless, a 128-fold reduction in area resulted in only a 2.7-fold increase in charge density required for a 1 ms pulse duration. The results presented here indicate that microwire glass can be used as a neural stimulating electrode to bridge the gap between flat microelectronic stimulator chips and curved neuronal tissue.
The cuff electrode provides a stable interface with the peripheral nerve, which has been widely utilized in both basic research and clinical practice over the past few decades. In this paper, we present a microfabricated, parylene-based self-locking cuff electrode. The cuff diameter can be adjusted to accommodate the nerve properly during implantation. This type of cuff electrodes is easy to implant and the cuff was made of the thin, flexible, and biocompatible parylene substrate. Moreover, the integrated parylene cable and pads facilitate the connection with external circuits. Electrochemical properties of electrode sites were characterized by impedance spectroscopy and cyclic voltammetry. The average impedance magnitude and average charge delivery capacity of the Pt electrodes are 8.3 k (Omega ) (at 1 kHz) and 2.8 mC/cm (^{mathrm {mathbf {2}}}) , respectively. Using the proposed cuff electrodes, the evoked compound action potentials of the rat sciatic nerve were successfully recorded. Electrical stimulation tests proved the feasibility of selective stimulation of tibial and peroneal fascicles within the rat sciatic nerve. This type of cuff electrodes induced only a benign foreign body reaction and did not damage the axons within the rat sciatic nerve over 11 weeks of an implantation period. [2014-0062]
We report a flexible electrocorticogram (ECoG) electrode array device with one directionally self-curling and -sticking properties, to solve the difficulty of the handling of thin (
Liquid Crystal Polymer (LCP) has been considered as an alternative biomaterial for implantable biomedical devices primarily for its low moisture absorption rate compared with conventional polymers such as polyimide, parylene and silicone elastomers. A novel retinal prosthetic device based on monolithic encapsulation of LCP is being developed in which entire neural stimulation circuitries are integrated into a thin and eye-conformable structure. Micromachining techniques for fabrication of a LCP retinal electrode array have been previously reported. In this research, however, for being used as a part of the LCP-based retinal implant, we developed advanced fabrication process of LCP retinal electrode through new approaches such as electroplating and laser-machining in order to achieve higher mechanical robustness, long-term reliability and flexibility. Thickened metal tracks could contribute to higher mechanical strength as well as higher long-term reliability when combined with laser-ablation process by allowing high-pressure lamination. Laser-thinning technique could improve the flexibility of LCP electrode.
Neural microprobes with 16 stimulation/recording channels are fabricated employing surface micromachining techniques. Each device integrates a flexible polyimide-based interconnection cable, the array of bonding pads, and 4 parallel shanks hosting the electrode sites, all constructed in a single 3 mask fabrication process. In order to provide the shanks with enough mechanical strength for insertion into the tissue, a 15 μm thick gold micro-needle is embedded inside each shank as the reinforcement structure. A polyimide shell encapsulates the micro-needles from electrode sites and the interconnection lines. The shanks are 4 mm long, 100 μm wide at the base, and 24 μm thick. The electrode sites measuring 20 μm × 20 μm are addressed through gold interconnection lines to reduce the electrodes impedances and consequently improve the signal to noise ratio of the recording signal. This paper presents the details of microprobe fabrication and the preliminary characterization results.
In this paper, we present a new process for fabricating tip-shaped polymer microstructure array coated by patterned metal layer. This new process involves three techniques including: micro-molding, patterned metal layer transfer, and electrochemical-based sacrificial layer. As we know, it is very difficult to remove the extra photoresist (PR) in the concave areas in traditional micro-fabrication technology, which hinders patterning metal layers on three-dimensional (3D) microstructures. The electrochemical-based sacrificial layer technique can effectively resolve this problem, which is verified by scanning electron microscopy (SEM) characterization. Comparative study between the 3D metal-coated polyimide microstructures fabricated with and without the electrochemical-based sacrificial layer step is also performed and SEM images proved the effect of the presented process. The applicability of the developed process is also demonstrated with the successful fabrication of a pyramid-shaped polyimide microelectrodes array for neural stimulation.
A 3D flexible multichannel microprobe array was designed, fabricated and tested. Since each probe had several recording pads, the probe array could be used to measure neural activity at various depths in the brain. They were batch fabricated with interconnections, using a specific folding process to fold the planar probe structures. This flexible probe array was inserted into a rat's brain without fracturing and was successfully used to measure neural signals.
Neural implants are technical systems that restore sensory or motor functions after injury and modulate neural behavior in neuronal diseases. Neural interfaces or prostheses have lead to new therapeutic options and rehabilitation approaches in the last 40 years. The interface between the nervous tissue and the technical material is the place that determines success or failure of the neural implant. Recording of nerve signals and stimulation of nerve cells take place at this neuro-technical interface. Polymers are the most common material class for substrate and insulation materials in combination with metals for interconnection wires and electrode sites. This work focuses on the neuro-technical interface and summarizes its fundamental specifications first. The most common polymer materials are presented and described in detail. We conclude with an overview of the different applications and their specific designs with the accompanying manufacturing processes from precision mechanics, laser structuring and micromachining that are introduced in either the peripheral or central nervous system. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2010
In implantable medical systems, low-impedance electrode-tissue interface is important for maintaining signal quality for recording
and effective charge transfer for stimulation. In this paper, we propose a novel hemispherical biocompatible and flexible
microelectrode arrays (MEAs) which were fabricated by the process of micro electrical mechanical system (MEMS). Compared with
conventional planar microelectrodes, the interface impedance of hemispherical microelectrodes decreased due to their increased
surface area. Parylene C thin film with good biocompatibility and flexibility was chemical vapor deposited as packaging material
for decreasing nerve tissue damage. Pt-black coatings were electroplated by applying current pulses in H2PtCl6 solution on electrode sites for the further decrease of interface impedance. Moreover, the geometrical and electrical properties
of these MEAs were demonstrated by using a scanning electron microscope (SEM) and an electrochemical workstation. Experimental
results showed that the interface impedance decreased by about 34% compared with conventional planar microelectrodes, and
significantly decreased by 84% with Pt-black coatings on electrode sites compared with those uncoated microelectrodes.
Purpose:
Sacral spinal nerve stimulation is a new therapeutic approach for patients with severe fecal incontinence owing to functional deficits of the external anal sphincter. It aims to use the morphologically intact anatomy to recruit residual function. This study evaluates the long-term results of the first patients treated with this novel approach applying two techniques of sacral spinal nerve stimulator implantation.
Methods:
Six patients underwent either of two techniques for electrode placement: one "closed" (electrodes placed through the sacral foramen) and one "open" (cuff electrodes placed after sacral laminectomy). Follow-up evaluation of their continence status ranged from 5 to 66 months.
Results:
Incontinence improved in all patients. The percentage of incontinent bowel movements decreased during chronic stimulation from a mean of 40.2 percent to 2.8 percent, and the Wexner score decreased from a mean of 17 to 2. The function of the striated anal sphincter improved during chronic stimulation: maximum squeeze pressure increased from a mean of 48.5 mmHg to 92.7 mmHg, and median squeeze pressure increased from a mean of 37.3 mmHg to 72.5 mmHg. No complications were encountered perioperatively or postoperatively. Two devices had to be removed because of intractable pain, in one patient at the site of the electrode after five months and in the other at the site of the impulse generator after 45 months.
Conclusion:
Long-term sacral spinal nerve stimulation persistently improves continence and increases striated anal sphincter function in patients with fecal incontinence owing to functional deficits, but in whom the striated anal sphincter is morphologically intact. Two different operative approaches can be applied effectively.
Cuff electrodes are effective for chronic electroneurogram (ENG) recording while minimizing nerve damage. However, the ENG signals are usually contaminated by electromyogram (EMG) activity from the surrounding muscles, stimulus artifacts produced by the electrical stimulation and noise generated in the first stage of the neural signal amplifier. This paper proposed a new cuff electrode to reduce the interference from EMG signals and stimulus artifacts. As a result, when an additional middle electrode was placed at the center of the cuff electrode, a significant improvement in the signal-to-interference ratio was achieved at 11% for the EMG signals and 12% for the stimulus artifacts when compared to a conventional tripolar cuff. Furthermore, a new low-noise amplifier was proposed to improve the signal-to-noise ratio. The circuit was designed based on a noise analysis to minimize the noise, and the results show that the total noise of the amplifier was below 1 μV for a cuff impedance of 1 kΩ and a frequency bandwidth of 300 to 5000 Hz.
Nine spiral nerve cuff electrodes were implanted in two human subjects for up to three years with no adverse functional effects. The objective of this study was to look at the long term nerve and muscle response to stimulation through nerve cuff electrodes. The nerve conduction velocity remained within the clinically accepted range for the entire testing period. The stimulation thresholds stabilized after approximately 20 weeks. The variability in the activation over time was not different from muscle-based electrodes used in implanted functional electrical stimulation systems. Three electrodes had multiple, independent contacts to evaluate selective recruitment of muscles. A single muscle could be selectively activated from each electrode using single-contact stimulation and the selectivity was increased with the use of field steering techniques. The selectivity after three years was consistent with selectivity measured during the implant surgery. Nerve cuff electrodes are effective for chronic muscle activation and multichannel functional electrical stimulation in humans.
This paper reports on a new structure and fabrication technology for Parylene-based recording and stimulating penetrating microprobes with engineered mechanical stiffness, low cross-sectional area and sharp tips. Taking advantage of significant benefits from polymer microprobes is often prevented due to their troublesome insertion. This paper addresses this issue and describes a process that allows integrating vertical Parylene stiffeners in the shank without adding process complexity, increasing probe thickness and volume or compromising use in 2D/3D arrays. A metal mask formed around the tip allows for the local thinning down of Parylene, creating a sharp tip during an etch step. These features increase the stability of the probe while reducing both the load on the shank during implantation as well as the dimpling of the brain surface. Shanks 2 mm long, 20 μm thick and 380 μm wide were rendered stable enough for insertion into cadaver lamb brain through the pia by employing five stiffeners. Probes were fabricated in a three mask process with high yield (>;80%), and under soak-tests it was determined that they remain electrically functional over a period of three months.
Novel flexible parylene-based high-density electrode arrays have been developed for functional electrical stimulation in retinal and spinal cord prosthetics. These arrays are microfabricated according to a single-metal-layer process and a revolutionary dual-metal-layer process that promises to meet the needs of extremely high-density stimulation applications. While in many cases thin-film platinum electrodes in parylene C would be sufficient, high surface-area platinum electroplating has been shown to extend the lifetime of stimulated electrodes to more than 430 million pulses without failing. Iridium electrode arrays with higher charge delivery capacity have also been fabricated using a new high-temperature stabilized parylene variant, parylene HT. In addition, a new heat molding process has been implemented to conform electrode arrays to approximate the curvature of canine retinas, and a chronic implantation study of the mechanical effects of parylene-based electrode arrays on the retina over a 6-month follow-up period has provided excellent results. Retinal stimulation from these parylene-based electrode arrays in an isolated tiger salamander preparation was shown to be comparable to light stimulation in terms of generation of action potentials in the inner retina. Finally, electrode arrays have also been implanted and tested on the spinal cords of murine models, with the ultimate goal of facilitation of locomotion after spinal cord injury; these arrays provide a higher density and better spatial control of stimulation and recording than is typically possible using traditional fine-wire electrodes. Spinal cord stimulation typically elicited three muscle responses, an early (direct), a middle (monosynaptic), and a late (polysynaptic) response, classified based on latency after stimulation. Stimulation at different rostrocaudal levels of the cord yielded markedly different muscle responses, highlighting the need for such high-density arrays.
A novel structure for chronically implantable cortical electrodes using polyimide bio-polymer was devised, which provides both flexibility for micro-motion compliance between brain tissues and the skull and at the brain/implant interface, and enough stiffness for successful surgical implantation into the brain tissue. A 5–10 μm thick silicon backbone layer was attached to the tip of the electrode to enhance the structural stiffness. This stiff segment was then followed by a 1 mm flexible segment without a silicon backbone layer. The fabricated implants have three shanks with five recording sites ( μm) and two via holes ( μm) to promote tissue attachment on each shank. Each recording site was connected to the external circuitry via a 15-channel connector, which is especially designed to facilitate processing of neural signals to the external circuitry. In vitro cytotoxicity tests of prototype implants revealed no adverse toxic effects on cultured cells. The implant with a silicon backbone layer of 5–10 μm was robust enough to penetrate the rat’s pia without buckling, a major drawback with polymer. The averaged impedance value at 1 KHz was ∼2 MΩ.
Arm movement is well represented in populations of neurons recorded from the motor cortex. Cortical activity patterns have been used in the new field of brain-machine interfaces to show how cursors on computer displays can be moved in two- and three-dimensional space. Although the ability to move a cursor can be useful in its own right, this technology could be applied to restore arm and hand function for amputees and paralysed persons. However, the use of cortical signals to control a multi-jointed prosthetic device for direct real-time interaction with the physical environment ('embodiment') has not been demonstrated. Here we describe a system that permits embodied prosthetic control; we show how monkeys (Macaca mulatta) use their motor cortical activity to control a mechanized arm replica in a self-feeding task. In addition to the three dimensions of movement, the subjects' cortical signals also proportionally controlled a gripper on the end of the arm. Owing to the physical interaction between the monkey, the robotic arm and objects in the workspace, this new task presented a higher level of difficulty than previous virtual (cursor-control) experiments. Apart from an example of simple one-dimensional control, previous experiments have lacked physical interaction even in cases where a robotic arm or hand was included in the control loop, because the subjects did not use it to interact with physical objects-an interaction that cannot be fully simulated. This demonstration of multi-degree-of-freedom embodied prosthetic control paves the way towards the development of dexterous prosthetic devices that could ultimately achieve arm and hand function at a near-natural level.
To determine the threshold charges needed for eliciting visual perceptions through acute electrical stimulation of the human retina in patients suffering from retinitis pigmentosa, using an epiretinal microelectrode array.
In a multicentre study, 20 patients (average age 55 years) with visual acuities ranging from 4/200 to no light perception were included. The stimulation procedure was performed during a pars plana vitrectomy, for a maximum of 45 min, by using a microcontact film with IrO(x) electrodes connected by cable to a current generator. After repeated stimulation and threshold charge determination, the microelectrode array was removed.
Nineteen of 20 patients stated in the postoperative interviews that they experienced one or more visual perceptions with close time correlation to single stimulation events. Minimum threshold charges needed to generate visual perceptions could be measured and verified in 15 patients. The charge level ranged from 20 to 768 nC with single or multiple electrodes. One patient suffered a retinal detachment during the procedure; this patient's retina was successfully reattached. There were no further adverse reactions observed during the 3-month follow-up.
Acute epiretinal stimulation of the human retina, using a microelectrode array, can elicit visual perceptions in blind patients with retinitis pigmentosa.
Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and depression, and it is currently under investigation for applications in Alzheimer's disease, anxiety, heart failure, and obesity. However, the mechanism(s) by which VNS has its effects are not clear, and the stimulation parameters for obtaining therapeutic outcomes appear highly variable. The purpose of this study was to quantify the excitation properties of the right cervical vagus nerve in adult dogs anesthetized with propofol and fentanyl. Input-output curves of the right cervical vagus nerve compound action potential and laryngeal muscle electromyogram were measured in response to VNS across a range of stimulation parameters: amplitudes of 0.02-50mA, pulsewidths of 10, 50, 100, 200, 300, 500, and 1,000μs, frequencies of 1-2Hz, and train lengths of 20 pulses with 3 different electrode configurations: monopolar cathode, proximal anode/distal cathode, and proximal cathode/distal anode. Electrode configuration and stimulation waveform (monophasic vs. asymmetric charge-balanced biphasic) did not affect the threshold or recruitment of the vagal nerve fibers that were activated. The rheobase currents of A- and B-fibers were 0.4mA and 0.7mA, respectively, and the chronaxie of both components was 180μs. Pulsewidth had little effect on the normalized threshold difference between activation of A- and B-fibers. The results provide insight into the complement of nerve fibers activated by VNS and guidance to clinicians for the selection of optimal stimulation parameters.
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.
Electronics that are capable of intimate, non-invasive integration with the soft, curvilinear surfaces of biological tissues offer important opportunities for diagnosing and treating disease and for improving brain/machine interfaces. This article describes a material strategy for a type of bio-interfaced system that relies on ultrathin electronics supported by bioresorbable substrates of silk fibroin. Mounting such devices on tissue and then allowing the silk to dissolve and resorb initiates a spontaneous, conformal wrapping process driven by capillary forces at the biotic/abiotic interface. Specialized mesh designs and ultrathin forms for the electronics ensure minimal stresses on the tissue and highly conformal coverage, even for complex curvilinear surfaces, as confirmed by experimental and theoretical studies. In vivo, neural mapping experiments on feline animal models illustrate one mode of use for this class of technology. These concepts provide new capabilities for implantable and surgical devices.
Visual sensations in patients with blindness and retinal degenerations may be restored by electrical stimulation of retinal neurons with implantable microelectrode arrays. A prospective trial was initiated to evaluate the safety and efficacy of a wireless intraocular retinal implant (EPIRET3) in six volunteers with blindness and RP.
The implant is a remotely controlled, fully intraocular wireless device consisting of a receiver and a stimulator module. The stimulator is placed on the retinal surface. Data and energy are transmitted via an inductive link from outside the eye to the implant. Surgery included removal of the lens, vitrectomy, and implantation of the EPIRET3 device through a corneal incision. The clinical outcome after implantation and explantation of the device was determined. The implant was removed after 4 weeks, according to the study protocol.
Implantation was successful in all six patients. While the anterior part was fixed with transscleral sutures, the stimulating foil was placed onto the posterior pole and fixed with retinal tacks. The implant was well tolerated, causing temporary moderate postoperative inflammation, whereas the position of the implant remained stable until surgical removal. In all cases explantation of the device was performed successfully. Adverse events were a sterile hypopyon effectively treated with steroids and antibiotics in one case and a retinal break in a second case during explantation requiring silicone oil surgery.
The EPIRET3 system can be successfully implanted and explanted in patients with blindness and RP. The surgical steps are feasible, and the postoperative follow-up disclosed an acceptable range of adverse events.
A novel fabrication technique has been developed for creating high density (6.25 electrodes/mm(2)), out of plane, high aspect ratio silicon-based convoluted microelectrode arrays for neural and retinal prostheses. The convoluted shape of the surface defined by the tips of the electrodes could compliment the curved surfaces of peripheral nerves and the cortex, and in the case of retina, its spherical geometry. The geometry of these electrode arrays has the potential to facilitate implantation in the nerve fascicles and to physically stabilize it against displacement after insertion. This report presents a unique combination of variable depth dicing and wet isotropic etching for the fabrication of a variety of convoluted neural array geometries. Also, a method of deinsulating the electrode tips using photoresist as a mask and the limitations of this technique on uniformity are discussed.
Helical electrodes were implanted around the left and right common peroneal nerves of cats. Three weeks after implantation one nerve was stimulated for 4-16 hours using charge-balanced, biphasic, constant current pulses. Compound action potentials (CAP) evoked by the stimulus were recorded from over the cauda equina before, during and after the stimulation. Light and electron microscopy evaluations were conducted at various times following the stimulation. The mere presence of the electrode invariably resulted in thickened epineurium and in some cases increased peripheral endoneurial connective tissue beneath the electrodes. Physiologic changes during stimulation included elevation of the electrical threshold of the large axons in the nerve. This was reversed within one week after stimulation at a frequency of 20 Hz, but often was not reversed following stimulation at 50-100 Hz. Continuous stimulation at 50 Hz for 8-16 hours at 400 microA or more resulted in neural damage characterized by endoneurial edema beginning within 48 hours after stimulation, and early axonal degeneration (EAD) of the large myelinated fibers, beginning by 1 week after stimulation. Neural damage due to electrical stimulation was decreased or abolished by reduction of the duration of stimulation, by stimulating at 20 Hz (vs. 50 Hz) or by use of an intermittent duty cycle. These results demonstrate that axons in peripheral nerves can be irreversely damaged by 8-16 hours of continuous stimulation at 50 Hz. However, the extent to which these axons may subsequently regenerate is uncertain. Therefore, protocols for functional electrical stimulation in human patients probably should be evaluated individually in animal studies.