Neural implants provide effective treatment and diagnosis options for diseases where pharmaceutical therapies are missing or ineffective. These active implantable medical devices (AIMDs) are designed to remain implanted and functional over decades. A key factor for achieving reliability and longevity are cleaning procedures used during manufacturing to prevent failures associated with contaminations. The Implantable Devices Group (IDG) at University College London (UCL) pioneered an approach which involved a cocktail of reagents described as "Leslie's soup". This process proved to be successful but no extensive evaluation of this method and the cocktail's ingredients have been reported so far. Our study addressed this gap by a comprehensive analysis of the efficacy of this cleaning method. Surface analysis techniques complemented adhesion strengths methods to identify residues of contaminants like welding flux, solder residues or grease during typical assembly processes. Quantitative data prove the suitability of "Leslie's soup" for cleaning of ceramic components during active implant assembly when residual ionic contaminations were removed by further treatment with isopropanol and deionised water. Solder and flux contaminations were removed without further mechanical cleaning. The adhesive strength of screen-printed metalisation layers increased from 12.50 ± 3.83 MPa without initial cleaning to 21.71 ± 1.85 MPa. We conclude that cleaning procedures during manufacturing of AIMDs, especially the understanding of applicability and limitations, is of central importance for their reliable and longevity.

Objective. Micro-fabricated neural interfaces based on polyimide (PI) are achieving increasing importance in translational research. The ability to produce well-defined micro-structures with properties that include chemical inertness, mechanical flexibility and low water uptake are key advantages for these devices. Approach. This paper reports the development of the transverse intrafascicular multichannel electrode (TIME) used to deliver intraneural sensory feedback to an upper-limb amputee in combination with a sensorized hand prosthesis. A failure mode analysis on the explanted devices was performed after a first-in-human study limited to 30 d. Main results. About 90% of the stimulation contact sites of the TIMEs maintained electrical functionality and stability during the full implant period. However, optical analysis post-explantation revealed that 62.5% of the stimulation contacts showed signs of delamination at the metallization-PI interface. Such damage likely occurred due to handling during explantation and subsequent analysis, since a significant change in impedance was not observed in vivo. Nevertheless, whereas device integrity is mandatory for long-term functionality in chronic implantation, measures to increase the bonding strength of the metallization-PI interface deserve further investigation. We report here that silicon carbide (SiC) is an effective adhesion-promoting layer resisting heavy electrical stimulation conditions within a rodent animal trial. Optical analysis of the new electrodes revealed that the metallization remained unaltered after delivering over 14 million pulses in vivo without signs of delamination at the metallization-PI interface. Significance. Failure mode analysis guided implant stability optimization. Reliable adhesion of thin-film metallization to substrate has been proven using SiC, improving the potential transfer of micro-fabricated neural electrodes for chronic clinical applications. (Document number of Ethical Committee: P/905/CE/2012; Date of approval: 2012–10-04)

Transversal intrafascicular multichannel electrodes (TIME) have been developed to interface with peripheral nerves after upper limb amputation. Intended use is the electrical stimulation of the median and ulnar nerve to deliver sensory feedback during phantom limb pain treatment and artificial hand control. Miniaturized electrode arrays were developed on polyimide substrates with thin film metallization using sputtered iridium oxide as electrode coating. Here, we report on the essential requirements including biocompatibility, mechanical and stimulation stability that have been investigated before permission was granted by the legal authorities to conduct subchronic first-in-man clinical trials. Explants have been investigated to identify possible first failure points and optimize the devices for chronic implantation.

The number of devices for electrical stimulation of nerve fibres implanted worldwide for medical applications is constantly increasing. Stimulation charge is one of the most important parameters of stimulation. High stimulation charge may cause tissue and electrode damage and also compromise the battery life of the electrical stimulators. Therefore, the objective of minimizing stimulation charge is an important issue. Delaying the second phase of biphasic stimulation waveform may decrease the charge required for fibre activation, but its impact on stimulation selectivity is not known. This information is particularly relevant when transverse intrafascicular multichannel electrode (TIME) is used, since it has been designed to provide for high selectivity. In this in vivo study, the rat sciatic nerve was electrically stimulated using monopolar and bipolar configurations with TIME. The results demonstrated that the inclusion of a 100-μs delay between the cathodic and the anodic phase of the stimulus allows to reduce charge requirements by around 30 %, while only slightly affecting stimulation selectivity. This study shows that adding a delay to the typical stimulation waveform significantly (\(P < 0.001\)) reduces the charge required for nerve fibres activation. Therefore, waveforms with the delayed discharge phase are more suitable for electrical stimulation of nerve fibres.

Many micromachined neural implants with multi-channel thin-film electrodes have been presented over the last decades. A transverse intrafascicular multi-channel electrode (TIME) was developed for translational research to treat phantom limb pain (PLP). Four TIME systems (latest electrode version) have been implanted for 30 days into the arm of an amputee. After finishing successfully the clinical trials the TEVIE-3H systems have been explanted. The material composition of the electrode contacts used for stimulation have been investigated with X-ray photoelectron spectroscopy (XPS). System integrity has been examined using focused ion beam (FIB) and pictures were acquired using the integrated scanning electron microscope (SEM). Both methods revealed that the metallization was still intact after explantation and that no delamination occurred. Crack formation without delamination was observed but it could not be determined if it originated while the implant was inside the body or during the explantation or during the cleaning of the implants.

This work evaluated the subchronic stimulation performance of an intraneural multichannel electrode (transverse intrafascicular multichannel electrode, TIME) in a large human-sized nerve. One or two TIMEs were implanted in the right median nerve above the elbow joint in four pigs for a period of 32 to 37 days (six TIMEs in total). The ability of the contact sites to recruit five muscles in the forelimb was assessed via their evoked electromyographic responses. Based on these responses, a selectivity index was defined. Four TIMEs were able to selectively recruit a subset of muscles throughout the implantation period. The required recruitment current significantly increased, while there was a tendency for the recruitment selectivity to decrease over time. Histological assessment showed that all TIMEs remained inside the nerve and that they were located between fascicles. The average thickness of the encapsulation of the electrode was estimated to be 115.4 ± 51.5 μm (mean ± SD). This study demonstrates the feasibility of keeping the TIME electrodes fixed and functional inside a large polyfascicular human-sized nerve in a subchronic setting.

Hand loss is a highly disabling event that markedly affects the quality of life. To achieve a close to natural replacement for the lost hand, the user should be provided with the rich sensations that we naturally perceive when grasping or manipulating an object. Ideal bidirectional hand prostheses should involve both a reliable decoding of the user's intentions and the delivery of nearly "natural" sensory feedback through remnant afferent pathways, simultaneously and in real time. However, current hand prostheses fail to achieve these requirements, particularly because they lack any sensory feedback. We show that by stimulating the median and ulnar nerve fascicles using transversal multichannel intrafascicular electrodes, according to the information provided by the artificial sensors from a hand prosthesis, physiologically appropriate (near-natural) sensory information can be provided to an amputee during the real-time decoding of different grasping tasks to control a dexterous hand prosthesis. This feedback enabled the participant to effectively modulate the grasping force of the prosthesis with no visual or auditory feedback. Three different force levels were distinguished and consistently used by the subject. The results also demonstrate that a high complexity of perception can be obtained, allowing the subject to identify the stiffness and shape of three different objects by exploiting different characteristics of the elicited sensations. This approach could improve the efficacy and "life-like" quality of hand prostheses, resulting in a keystone strategy for the near-natural replacement of missing hands.

Neural prostheses are limited by the availability of peripheral neural electrodes to record the user's intention or provide sensory feedback through functional electrical stimulation. Our objective was to compare the ability of the novel “transverse intrafascicular multi-channel electrode” (TIME) and an earlier generation “thin-film longitudinal intrafascicular electrode” (tfLIFE) to selectively stimulate nerve fascicles and activate forelimb muscles in pigs. TIME was designed to access a larger subpopulation of fascicles than tfLIFE and should therefore be able to selectively activate a larger number of muscles. Electrodes were implanted in the median nerve, and sequential electric stimulation was applied to individual contacts. The compound muscle action potentials of seven muscles were recorded to quantify muscle recruitment. As expected, TIME was able to recruit more muscles with higher selectivity than tfLIFE (significant difference when comparing the performance of an entire electrode); a similar activation current was used (no significant difference). Histological analysis revealed that electrodes were located between fascicles, which influenced the selectivity and activation current level. In conclusion, TIME is a viable neural interface for selective activation of multiple fascicles in human-sized nerves that may assist to pave the way for future neuroprosthesis applications.

The Transversal Intrafascicular Multichannel Electrode (TIME) is intended to be implanted transversally in the nerve and address several fascicles or subgroups of nerve fibres with one device. It has been already shown that TIME allows to achieve high selectivity of stimulation when using monopolar configuration, i.e. when current is delivered through one of the sites of the TIME against small needle electrode placed in the proximity of the nerve. Results of the current study suggest that using bipolar configuration, i.e. when current is delivered through one of the TIME sites against an other site of the same electrode, could allow to further enhance selectivity of stimulation. However, higher charge of the stimulation may be necessary to achieve similar level of muscle activation, as compared to the monopolar configuration.

Helium-spray testing poses a simple technique to investigate the hermeticity of joints and unsealed packages in general by sealing the device under test to a mass spectrometer by way of an O-ring seal, drawing a mild vacuum within the sample and exposing the outside to helium while measuring the leak rate through the joints, surfaces and seals. Military Standard 883 describes this test and establishes a pass-fail criterion, but fails to give distinct instructions on how to setup the test and to interpret the results. The aim of this study is therefore to explore the limits of spray testing unsealed packages by evaluating the standard deviation of the method in combination with the maximum achievable sensitivity as a function of the permeability of the O-ring material to helium gas. It could be shown (1) that nitrile O-rings exhibited the lowest permeability to He gas under steady state conditions, (2) the O-ring itself usually limits the detection rate and (3) that the achievable sensitivity lies in the range of 10-8 atm*cc*s-1 and, thus, may merely be used for gross leak detection.

Sputtered iridium oxide films (SIROFs) serve often as state of the art material when high charge injection capacities and robust coatings are desired. The main advantage above activated iridium oxide films (AIROFs) is that activation in-vivo is not needed since iridium oxide is already formed during the sputtering process. However, it is commonly accepted that SIROF coatings are in need of a hydration procedure to clean the surface and to transfer the stoichiometry into the favorable Ir3+ and Ir4+ oxidation states. This is usually done via cyclic voltammetry after fabrication of the devices, i.e. in-vitro. In order to implant such devices however, they have to be disinfected and sterilized. We report here on the influence of disinfection and sterilization in hot-steam on the hydration level of SIROF coatings. Therefore, samples were subjected to electrochemical impedance spectroscopy and cyclic voltammetry prior to disinfection and sterilization and afterwards. It could be observed that sterilization in hot-steam has a major impact on the hydration level of iridium oxide films. Subsequently, the different parameters of the sterilization procedure, i.e. vacuum pressure and temperature, were simulated to test whether the one or the other is responsible for the alteration. Finally, it could be shown that elevated temperatures decrease the charge storage capacity and increase the impedance of the coating.

When applied in the rat model the Transverse Intrafascicular Multi-channel Electrode (TIME) showed selective nerve fascicle recruitment. But results from the larger and poly-fasicular median nerves in pigs indicated that a single TIME could not reach the entire nerve and could only selectively recruit a subset of the nerve fascicles. The use of multiple TIME structures could offer a means to achieve highly selective fascicular stimulation while reaching a larger percentage of the fascicles in the nerve. This work investigates this approach using pairs of TIMEs implanted in the median nerves of anesthesized pigs (n=6). TIME structures were implanted at different angles relative to each other or in parallel with one another. Electrical stimuli was passed through each contact of each TIME and the resulting electromyograms were recorded from seven muscles innervated by the median nerve. The ability to recruit these muscles was used to assess the stimulation selectivity of each contact using a selectivity index comparing the root-mean-square of the the evoked EMG of individual muscles. Results showed a significant increase in the selectivity index, when using two TIMEs compared to one. The optimal improvement was observed when TIMEs were placed in parallel to each other in such a way that they interfaced non-overlapping nerve regions.

Complex prosthetic limbs, the bionic eye, or brain-computer interfaces implement microelectrode arrays to connect the nervous system to an electronic device. The aim is to partly restore lost body functions or to gather bioelectrical activity from the nervous system. Microelectrode arrays are fabricated to have specific electrical and mechanical properties to match the biological requirements of the intended application. Polyimide and parylene-C are favorable polymers for substrate and insulation layers in thin-film applications. This article reviews the materials and the mechanical and electrical properties of electrode arrays. It emphasizes the often ignored but crucial influence of adhesion of the thin-film layers on the device’s longevity and reliability. Adhesion promotion techniques using layers of silicon carbide (SiC) are also discussed. Even though the main focus is on thin-film devices fabricated using traditional methods of micromachining based on lithography, an alternative to thin films, laser-patterned silicone/metal foil microelectrode arrays, is also presented. Characterization as well as application examples of these devices are also presented.

Over the last three years, a novel type of intrafascicular electrode was developed to serve as a corrective neural prosthetic interface to be placed in the peripheral nerve stumps of upper limb amputees who suffer from phantom limb pain (PLP). In general, the presented interface is an advancement of the thin-film LIFE electrode that was successfully used in amputees a couple of years ago. Although the LIFE concept proved to be effective, the longitudinal orientation of the implant prevented distribution of spatial selective sites in more than one fascicle. Therefore, a transversal approach was developed. The work presented was developed within the European project "TIME" and will be implanted in the median and ulnar nerves of an amputee subject in Rome later this year (2012). The present paper will outline the design, assembly technologies and full electrochemical characterization of the TIME-3H electrode for sub-chronic (<;30 days) human implants.

Neural prostheses are technical systems that interface nerves to treat the symptoms of neurological diseases and to restore sensory of motor functions of the body. Success stories have been written with the cochlear implant to restore hearing, with spinal cord stimulators to treat chronic pain as well as urge incontinence, and with deep brain stimulators in patients suffering from Parkinson's disease. Highly complex neural implants for novel medical applications can be miniaturized either by means of precision mechanics technologies using known and established materials for electrodes, cables, and hermetic packages or by applying microsystems technologies. Examples for both approaches will be introduced and discussed. Electrode arrays for recording of electrocorticograms during presurgical epilepsy diagnosis have been manufactured using approved materials and a marking laser to achieve an integration density that is adequate in the context of brain machine interfaces, e.g. on the motor cortex. Microtechnologies have to be used for further miniaturization to develop polymer-based flexible and light weighted electrode arrays to interface the peripheral and central nervous system. Polyimide as substrate and insulation material will be discussed as well as several application examples for nerve interfaces like cuffs, filament like electrodes and large arrays for subdural implantation.

Phantom limb pain (PLP) is a chronic condition that develops in the majority of amputees. The underlying mechanisms are not completely understood, and thus, no treatment is fully effective. Based on recent studies, we hypothesize that electrical stimulation of afferent nerves might alleviate PLP by giving sensory input to the patient if nerve fibers can be activated selectively. The critical component in this scheme is the implantable electrode structure. We present a review of a novel electrode concept to distri bute highly selective electrode contacts over the complete cross section of a peripheral nerve to create a distributed activation of small nerve fiber ensembles at the fascicular level, the transverse intrafascicular multichannel nerve electrode (TIME). The acute and chronic implantations in a small animal model exhibited a good surface and structural biocompatibility as well as excellent selectivity. Implantation studies on large animal models that are closer to human nerve size and anatomical complexity have also been conducted. They proved implant stability and the ability to selectively activate nerve fascicles in a limited proximity to the implant. These encouraging results have opened the way forward for human clinical trials in amputees to investigate the effect of selective electrical stimulation on PLP.