IntroductionRobust, biocompatible ceramic electrical interconnects are essential for bridging the gap between macro-scale components, such as helically wound leads and connectors, and thin-film polyimide electrodes in neural interfaces. While screen-printed thick-film structures have been utilized for decades, there is a need to broaden the design space and improve reliability through thin-film techniques. This study evaluates various surface configurations to identify the optimal combination of mechanical adhesion, electrical insulation, and functional longevity.MethodsAll samples were fabricated on 96% pure alumina (Al2O3) substrates. Mechanical stability was evaluated via tensile shear tests, comparing thin-film platinum (Pt) with different adhesion promoters (SixNy, SiO2), laser-patterned Pt thin-films, and bare Pt thin-film against reference Al2O3 substrates. Electrical insulation was assessed by performing electrochemical impedance spectroscopy and DC resistance measurements for degradation monitoring. The evaluated layer stacks with PDMS encapsulation included bare thin-film Pt, thick-film Pt/Au with Overglaze, a SiO2 layer, a SixNy layer, and a layer of pulsed laser deposition (PLD) Al2O3. All samples underwent accelerated aging in phosphate buffered saline (PBS) at 60°C (acceleration factor ∼ 4.92 vs. 37°C).ResultsTensile shear strength decreased over the aging period across all groups. However, the integration of adhesion promoters increased mechanical stability compared to bare sputtered Pt, with SixNy coating bringing adhesion levels close to the Al2O3 reference samples. Electrically, SixNy-, PLD-Al2O3, and laser-patterned samples maintained higher insulation impedances over time than PDMS on bare Pt and SiO2. DC resistance measurements indicate good capabilities in protecting the conductors from degradation.DiscussionThe findings demonstrate that the addition of adhesion promoters enhances both the longevity of the mechanical bond and stability of the electrical insulation in ion-rich environments. These results provide guidance for selecting optimal ceramic interconnects for chronic peripheral-nerve implants, balancing reliability, manufacturability, and cost.

Objective: Decades of studies have enabled a constant optimization of thin-film-based neural implants, with technologies designed to adapt to the biological surroundings through biocompatible and miniaturized materials. Careful assessment of these materials is essential prior to photolithographic fabrication of multilayered devices, as delamination from adhesion mismatches between neighboring layers can compromise recording or stimulation and lead to channel crosstalk or device failure. Multi-layer interactions are therefore closely examined to tailor devices for long-term stability, yet post-implantation examinations still reveal failure modes that are not fully addressed and understood. Here, we propose an in vitro investigation of polyimide (PI), a widely used substrate material, in a simplified single layer configuration, to isolate substrate-related effects and evaluate long-term stability under combined conditions that cover not only the implantation period, but also post-implantation steps. Methods: Accelerated ageing was used to mimic processes occurring in the brain during implantation while aged samples were also exposed to aldehyde-based fixation and storage conditions commonly encountered during post-mortem processing. Surface morphology was assessed using Scanning Electron Microscopy (SEM). Chemical microstructure was analyzed in a dual approach using Time-of-Flight-Secondary-Ion Mass-Spectroscopy (ToF-SIMS) and Fourier Transform Infrared Spectroscopy (FTIR). Conclusion: PI remains morphologically and chemically stable under the harshest conditions, in both implantation scenarios and subsequent post-implantation steps. Significance: These findings provide critical validation for the use of PI as a durable substrate in long-term neural interfaces. They further indicate that damage observed after implantation may arise from factors beyond intrinsic PI degradation, helping prevent misinterpretation during post-implantation analysis.

Limb loss causes severe sensorimotor deficits and often necessitates prosthetic devices, particularly in lower-limb amputees. Although direct neural recording from residual nerves offers a biomimetic route for prosthetic control, low signal amplitudes and challenges in nerve interfacing have limited adoption. Intraneural multichannel electrodes provide a potential solution by enabling access to motor signals from muscles lost after amputation. Here, we report intraneural recordings from two transfemoral amputees using transversal intrafascicular multichannel electrodes implanted in distal branches of the sciatic nerve. We identified multiunit activity associated with volitional phantom movements of the knee, ankle, and toes, exhibiting joint- and direction-specific modulation distributed across electrodes. A Spiking Neural Network-based decoder outperformed conventional methods in predicting attempted movements, with further gains achieved by integrating intraneural and intermuscular signals. Motor and sensory maps showed minimal overlap, indicating early segregation within the sciatic nerve. These findings pave the way for bidirectional, neurally-controlled prosthetic systems.

The loss of hand function is one of the most devastating impairments for individuals with paralysis. While current neurotechnologies can partially restore prehensile control, they fall short of enabling independent finger movements — an essential requirement for full hand dexterity. Achieving this level of precision demands highly selective activation of individual muscles or muscle groups. In this first-in-human study, we explored a novel approach in an individual with chronic tetraplegia. Our method combined targeted surgery to isolate functionally relevant branches of the median and radial nerves with custom intrafascicular electrodes to interface with them. By precisely stimulating motor fibers within these nerves, we successfully restored independent movement in four fingers, including the thumb. The combination of these movements allowed the recreation of the lateral, hook, and palmar grasps with smoothly modulated forces. Furthermore, the participant regained the ability to perform functional tasks, such as pouring water from a bottle. These findings hold significant promise for individuals with hand paralysis, paving the way for neurotechnologies that can bypass spinal cord injuries and restore fine motor control.

Limb loss leads to severe sensorimotor deficits and requires the use of a prosthetic device, especially in lower-limb amputees. While direct recording from residual nerves offers a biomimetic route for an effective prosthetic control, the low amplitude and noisy nature of these neural signals together with the challenge of establishing a reliable nerve interfacing, have hindered its adoption. Intraneural multichannel electrodes could potentially establish an effective interface with the nerve fibers, enabling access to motor signals even from muscles lost after the amputation. In this study, we report the direct neural recordings of two transfemoral amputees using transversal intrafascicular multichannel electrodes (TIME) implanted in the tibial nerves. We observed multiunit activity associated with volitional phantom movements of the knee, ankle and toes flexion and extension, with joint- and direction-specific neural modulation in both participants. The motor signals were distributed across all the electrodes, showing both single-joint and multi-joint selectivity, as well as direction selectivity for limb flexion and extension. After characterizing the neural evoked activity, we developed a Spiking Neural Network (SNN)-based decoder that outperform conventional motor decoders in predicting attempted phantom leg movements. Decoding accuracy improved further by including a broader signal bandwidth that captured both intraneural (ENG) and inter-muscular (imEMG) activity. Finally, comparing motor maps (recording) with sensory maps (stimulation) revealed a minimal overlap, suggesting early segregation of motor and sensory fibers within the tibial nerve before the knee bifurcation. Our findings demonstrate the feasibility to record motor signal and decode lower-limb movements directly from the nerves in amputees using intraneural interfaces. This paves the way for bidirectional, neurally-controlled prosthetic limbs combining natural control with somatosensory feedback through a single implanted interface.

Microelectrode arrays (MEAs), a widely used class of neural implants, are susceptible to in vivo degradation despite using biocompatible materials like polyimide (PI). While PI has been extensively studied for its biostability, the role of oxidative stress, particularly from hydrogen peroxide (H2O2), a reactive oxygen species (ROS) released during foreign body reactions (FBR), remains underexplored. This study investigates the effects of in vivo environments, with a particular focus on H2O2 exposure, on the PI layer of MEAs. Scanning Electron Microscopy (SEM) and Time of Flight-Secondary Ion Mass Spectroscopy (ToF-SIMS) are used to study the structural and molecular changes, respectively. The findings indicate that reactive accelerated aging (RAA) mimicking in vivo conditions do not alter PI at the molecular level. Surface modifications, primarily due to oxidative degradation, were observed; however, the underlying material remained intact, confirming PI's durability for long-term implantable devices.

The functionality of neural implants relies on their capability to operate in a wet, chemically reactive, and dynamic environment over extended time frames, which determines their biostability. Failure mechanisms such as delamination, insulation breakage, or metal corrosion are common examples that must be prevented. In this study, we investigate the effects of reactive oxygen species (ROS) and physiological saline solution on polyimide (PI), a widely used substrate in neural applications that directly interfaces with the host tissue. To understand the processes that could influence PI degradation over time, we subjected PI-based samples to accelerated ageing conditions and observed not only the effects of storage media but also the impact that handling conditions could potentially have on the outcome. Scanning Electron Microscopy (SEM) indicated a possible connection between degradation of the PI substrate and experimental conditions rather than chemical variables alone. Furthermore, Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) and Fourier Transform Infrared Spectroscopy (FTIR) confirmed the infiltration of chemicals at the molecular level without any significant unexpected results. This research offers valuable insights into how PI films can deteriorate over time under the influence of different storage conditions and emphasizes the necessity of standardized protocols within the scientific community to accurately distinguish degradation originating from different factors.

Thin-film electrode arrays play an important role when large integration densities of stimulating or recording channels are required in neural interfaces. To fabricate such ultra-light-weighted and flexible implantable neural electrodes, polyimide (PI) has been used successfully as substrate and insulation material. Advantages are that PI can be processed in a standard cleanroom facility, its high chemical resistance and low moisture uptake. The disadvantage is that it allows the PI surface to come in contact with various contaminants from the photolithography steps as well as desorbed impurities from process chambers. This can lead to delamination of the PI to subsequent deposited layers. In this study, PI film surfaces were treated with oxygen (O2) plasma in reactive ion etching (RIE) and plasma enhanced chemical vapor deposition (PECVD) chambers to remove residues and activate the surface by functional groups. Results obtained from various surface analysis techniques have revealed that an O2-plasma recipe developed in the PECVD machine could replace the standard recipe in RIE. The developed O2-plasma recipe in PECVD comes with the advantage that batch processing of the wafers during plasma treatment is possible which includes processing of five 4" size wafers at once compared to the one wafer process in RIE. In both cases, hydrophobic recovery starts after six, respectively seven hours giving enough time initiating subsequent layer depositions.

Direct stimulation of peripheral nerves with implantable electrodes successfully provided sensory feedback to amputees while using hand prostheses. Longevity of the electrodes is key to success, which we have improved for the polyimide-based transverse intrafascicular multichannel electrode (TIME). The TIMEs were implanted in the median and ulnar nerves of three trans-radial amputees for up to six months. We present a comprehensive assessment of the electrical properties of the thin-film metallization as well as material status post explantationem . The TIMEs stayed within the electrochemical safe limits while enabling consistent and precise amplitude modulation. This lead to a reliable performance in terms of eliciting sensation. No signs of corrosion or morphological change to the thin-film metallization of the probes was observed by means of electrochemical and optical analysis. The presented longevity demonstrates that thin-film electrodes are applicable in permanent implant systems.

Artificial communication with the brain through peripheral nerve stimulation shows promising results in individuals with sensorimotor deficits. However, these efforts lack an intuitive and natural sensory experience. In this study, we design and test a biomimetic neurostimulation framework inspired by nature, capable of “writing” physiologically plausible information back into the peripheral nervous system. Starting from an in-silico model of mechanoreceptors, we develop biomimetic stimulation policies. We then experimentally assess them alongside mechanical touch and common linear neuromodulations. Neural responses resulting from biomimetic neuromodulation are consistently transmitted towards dorsal root ganglion and spinal cord of cats, and their spatio-temporal neural dynamics resemble those naturally induced. We implement these paradigms within the bionic device and test it with patients (ClinicalTrials.gov identifier NCT03350061). He we report that biomimetic neurostimulation improves mobility (primary outcome) and reduces mental effort (secondary outcome) compared to traditional approaches. The outcomes of this neuroscience-driven technology, inspired by the human body, may serve as a model for advancing assistive neurotechnologies.

Micro-machined peripheral nerve interfaces have entered translational research successfully. Polyimide-based interface substrates showed chemical inertness, mechanical flexibility and low water uptake. They allow neural interface with a thicknesses of ten micrometer reducing the probability of severe inflammatory reactions. To realize device thicknesses in this range, photolithographic processes are used to deposit thin-film metallization in the range of a few hundred nanometers. In order to prove long-term stability within chemical safe stimulation limits, in vitro stimulation of sputtered iridium oxide film stimulation contact sites was performed. After 4.5 billion pulses, first electrochemical changes occurred indicated by a decrease in impedance magnitude and simultaneously an increase of the cathodic charge storage capacity. Both scenarios indicated a change in the effective surface area. These contact sites were used for an optical in depth analysis using white light interferometry and scanning electron microscopy in combination with a focused ion beam, which confirmed crack formation and delamination. However, for all other contact sites further stimulation up to 6.5 billion pulses was applied. This amount was estimated about 6.6 years of stimulation in chronic human application with a conservative approach assuming daily work with each stimulation contact. The outcome of the long-term stimulation indicates stability for chronic stimulation studies in humans with life-times reasonably long for first translational studies on larger subject cohorts.

Precise control of bionic limbs relies on robust decoding of motor commands from nerves or muscles signals and sensory feedback from artificial limbs to the nervous system by interfacing the afferent nerve pathways. Implantable devices for bidirectional communication with bionic limbs have been developed in parallel with research on physiological alterations caused by an amputation. In this perspective article, we question whether increasing our effort on bridging these technologies with a deeper understanding of amputation pathophysiology and human motor control may help to overcome pressing stalls in the next generation of bionic limbs.

Bioelectronic medicine is a promising venue for treatment of disabilities using implantable neural interfaces. Peripheral neurostimulation of residual nerves recently enabled multiple functional benefits in amputees. Despite the preliminary promising impact on patients' life, the over-time stability of implants and the related nerve reactions are unclear. To unveil the mechanisms and inform the design of better nerve-electrode interfaces, we engaged a multifaceted approach, merging functional responses from patients, their histological data, and corresponding computational modelling. Neurostimulation evoked different selective sensation locations and qualities over-time, with respective perceptual thresholds, that showed different degree of time stabilities dependent from the stimulating active sites. The histological analysis after explant showed mild tissue reactions, while electromechanically active sites and substrates remained conserved. Computational models, based on patients' histology, revealed the direct influence of the simulated tissue reaction to change of thresholds and type of perceived sensations. Novel insights of electrode biocompatibility was observed compared to animals and the increase of thresholds could be predicted computationally. This multifaced framework suggest that future intraneural implants should have easier implantation and higher biocompatibility counteracting the sensations changes through AI-based stimulations and electrode coatings.

Restoring dexterous hand control is critical for people with paralysis. Approaches based on surface or intramuscular stimulation provide limited finger control, generate insufficient force to recover functional movements, and require numerous electrodes. Here, we show that intrafascicular peripheral electrodes could produce functional grasps and sustained forces in three monkeys. We designed an intrafascicular implantable electrode targeting the motor fibers of the median and radial nerves. Our interface selectively and reliably activated extrinsic and intrinsic hand muscles, generating multiple functional grips, hand opening, and sustained contraction forces for up to 2 months. We extended those results to a behaving monkey with transient hand paralysis and used intracortical signals to control simple stimulation protocols that enabled this animal to perform a functional grasping task. Our findings show that just two intrafascicular electrodes can generate a rich portfolio of dexterous and functional hand movements with important implications for clinical applicability.

Peripheral Nerve Stimulation (PNS) is a promising approach in functional restoration following neural impairments. Although it proves to be advantageous in the number of implantation sites provided compared with intramuscular or epimysial stimulation and the fact that it does not require daily placement, as is the case with surface electrodes, the further advancement of PNS paradigms is hampered by the limitation of spatial selectivity due to the current spread and variations of nerve physiology. New electrode designs such as the Transverse Intrafascicular Multichannel Electrode (TIME) were proposed to resolve this issue, but their use was limited by a lack of innovative multichannel stimulation devices. In this study, we introduce a new portable multichannel stimulator-called STIMEP-and implement different stimulation protocols in rats to test its versatility and unveil the potential of its combined use with TIME electrodes in rehabilitation protocols. We developed and tested various stimulation paradigms in a single fascicle and thereafter implanted two TIMEs. We also tested its stimulation using two different waveforms. The results highlighted the versatility of this new stimulation device and advocated for the parameterizing of a hyperpolarizing phase before depolarization as well as the use of small pulse widths when stimulating with multiple electrodes.

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)

Substrates and packages of active implantable medical devices are often fabricated from ceramics, such as alumina. Screen-printed PtAu paste is the state-of-the-art metallization for functional structures. Due to solid-state and liquid diffusion of Au during thermal exposure, solder times are limited. Otherwise, metal structures tend to delaminate. Moreover, it was shown that PtAu with solder fails after 37.4 years. We established a thin film metallization on the alumina process to overcome these disadvantages. We used sputtered platinum with an underlying adhesion layer made of tungsten-titanium to increase the adhesion strength of the alumina substrate. We avoided using gold in this work due to its high diffusion tendency. All used materials provided relatively low diffusion properties, which increases independence from joining techniques and mechanical longevity during use. Utilizing the Design of Experiment (DoE) methodology, we derived an optimal Pt thickness of 500 nm with 43 nm of WTi as an adhesion-promoting layer. After accelerated aging at 150 °C, corresponding to 125 years at body temperature (37 °C), the contact pad adhesion strength was 32.75 ± 7.08 MPa. This exceeded the safety limit of 17 MPa by far, set as a recommendation for robust screen-printing metallization processes. Soldering times of up to 120 s did not influence the adhesive strength. The new process reduced the minimum track distance to 50% of screen-printing values and is capable to be transferred into rapid prototyping techniques. It helps to make the assembly process independent of the manufacturing person in order to increase the yield of device fabrication and-most important in implantable device manufacturing-to make it more robust and thereby safer for the patient.

The applications of polyimide (PI) based thin-film electrodes in neural implants has been steadily increasing in the last decades. Beside the advantages of factors such as size reduction and chemical inertness, the adhesion between PI and metals lacks the necessary robustness for chronic implantation [1]. Adhesion promoters like silicon carbide (SiC) and titanium help increase the long-term stability [1-3]. However crack formation is still probable in thin-film metallization of active contact sites, which can lead to detrimental thin-film metal delamination. This work presents our process to integrate 3D groove structures into the active contact sites, thereby reducing the probability of crack formation. The contact sites were entirely covered with a sputtered iridium oxide film (SIROF) and showed more conformable electrochemical properties compared to regular planar SIROF contact sites.

Direct stimulation of peripheral nerves can successfully provide sensory feedback to amputees while using hand prostheses. Recent clinical studies have addressed this important limitation of current prostheses solutions using different implantable electrode concepts. Longevity of the electrodes is key to success. We have improved the long-term stability of the polyimide-based transverse intrafascicular multichannel electrode (TIME) that showed promising performance in clinical trials by integration of silicon carbide adhesion layers. The TIMEs were implanted in the median and ulnar nerves of three trans-radial amputees for up to six months. Here, we present the characterization of the electrical properties of the thin-film metallization as well as material status post explantationem for the first time. The TIMEs showed reliable performance in terms of eliciting sensation and stayed within the electrochemical safe limits maintaining a good working range with respect to amplitude modulation. After termination of the trials and explantation of the probes, no signs of corrosion or morphological change to the thin-film metallization was observed by means of electrochemical and optical analysis. Damage to the metallization was assigned exclusively to mechanical impacts during explantation and handling. The results indicate that thin-film metallization on polymer substrates is applicable in permanent implant system.

Lower limb amputation (LLA) destroys the sensory communication between the brain and the external world during standing and walking. Current prostheses do not restore sensory feedback to amputees, who, relying on very limited haptic information from the stump-socket interaction, are forced to deal with serious issues: the risk of falls, decreased mobility, prosthesis being perceived as an external object (low embodiment), and increased cognitive burden. Poor mobility is one of the causes of eventual device abandonment. Restoring sensory feedback from the missing leg of above-knee (transfemoral) amputees and integrating the sensory feedback into the sensorimotor loop would markedly improve the life of patients. In this study, we developed a leg neuroprosthesis, which provided real-time tactile and emulated proprioceptive feedback to three transfemoral amputees through nerve stimulation. The feedback was exploited in active tasks, which proved that our approach promoted improved mobility, fall prevention, and agility. We also showed increased embodiment of the lower limb prosthesis (LLP), through phantom leg displacement perception and questionnaires, and ease of the cognitive effort during a dual-task paradigm, through electroencephalographic recordings. Our results demonstrate that induced sensory feedback can be integrated at supraspinal levels to restore functional abilities of the missing leg. This work paves the way for further investigations about how the brain interprets different artificial feedback strategies and for the development of fully implantable sensory-enhanced leg neuroprostheses, which could drastically ameliorate life quality in people with disability.