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The professional practice of biomedical engineering can lead to severe consequences. These potential consequences do not differ from those expected in the exercise of the medical profession. Hence, the ethical framework of biomedical engineers (BMEs) should not differ substantially from the ethical framework of medical doctors (MDs). In medicine, an element that is perceived as symbolic but essential in the formation of the ethical conscience of MDs is the “Hippocratic Oath”. The “Hippocratic Oath”, or its modern adaptation, the “Physician's Pledge”, is a brief not legally binding solemn declaration of ethical commitments that medical students take as a rite of passage in their final year or just after graduation. In other healthcare professions, such as nursing or pharmacy, sometimes the “Hippocratic Oath” is also taken. However, in its different versions, the “Hippocratic Oath” contains aspects that would not apply to the field of biomedical engineering and, therefore, its adoption without adaptations would be inappropriate. We have drafted a “Biomedical Engineer’s Pledge” aiming at strengthening the ethical awareness of future biomedical engineers. It consists of a preamble sentence, ten promises, and a concluding sentence. Top priority is given to the first promise, which combines the fundamental principles of beneficence and non-maleficence.

International audience; When implantable recording devices for brain or neural electrical activity are designed, the number of available materials for electrodes is quite limited. The material must be biocompatible with respect to ISO10993, its electrochemical properties must remain stable and the response of cells or tissues can be mitigated, especially on the glial scar. This involves electrode characterization pre- implantation and impedance spectroscopy during chronic implantation, in order to evaluate both electrode properties and performance. This study was aimed at a comparison of the long-term behavior of a nanostructured boron-doped diamond (BDD) with a nanostructured Platinum Iridium (PtIr) electrode. Firstly, a batch of cortical grids with bare and modified contacts (2 mm in diameter) was engineered for implantation. Secondly a miniature swine model was developed.This study highlighted the predominant role of electrode surface roughness on the quality of recordings. Rough PtIr contacts and BDD coated ones showed comparable behavior after three-month implantation with a slight increase of the modulus of the impedance and a tissue capsule. Nevertheless, immunohistochemistry analysis did not exhibit either a toxic or irritation reaction. With regard to biocompatibility, promising long term results are shown for both materials.

OBJECTIVE Hand amputation is a highly disabling event, which significantly affects quality of life. An effective hand replacement can be achieved if the user, in addition to motor functions, is provided with the sensations that are naturally perceived while grasping and moving. Intraneural peripheral electrodes have shown promising results toward the restoration of the sense of touch. However, the long-term usability and clinical relevance of intraneural sensory feedback have not yet been clearly demonstrated. METHODS To this aim, we performed a 6-month clinical study with 3 transradial amputees who received implants of transverse intrafascicular multichannel electrodes (TIMEs) in their median and ulnar nerves. After calibration, electrical stimulation was delivered through the TIMEs connected to artificial sensors in the digits of a prosthesis to generate sensory feedback, which was then used by the subjects while performing different grasping tasks. RESULTS All subjects, notwithstanding their important clinical differences, reported stimulation-induced sensations from the phantom hand for the whole duration of the trial. They also successfully integrated the sensory feedback into their motor control strategies while performing experimental tests simulating tasks of real life (with and without the support of vision). Finally, they reported a decrement of their phantom limb pain and a general improvement in mood state. INTERPRETATION The promising results achieved with all subjects show the feasibility of the use of intraneural stimulation in clinical settings. ANN NEUROL 2019;85:137-154.

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., Journal of Neural Engineering, 17 (4), ISSN:1741-2560, ISSN:1741-2552

Additional file 1. This file includes 9 Tables / Figures numbered S1 to S9 that give further details on obtained isolated movements (Figure S1, Table S2), electrodes’ configurations (Tables S3-S4, Figure S5), the ranges of scanned current amplitudes (Table S6), the modified MRC scale (Table S7), EMG processing details (Figure S8) and a possible fascicular organization (Figure S9).

International audience; 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.

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.

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. 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 first-in-human study limited to 30 days was performed. 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 mechanical damage 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 in vivo. 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. 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.

BackgroundFunctional Electrical Stimulation (FES) is used for decades in rehabilitation centers. For patients with a spinal cord injury (SCI), FES can prevent muscular atrophy, reduce spasticity and/or restore limb movements. To this last aim, FES external devices can be used, but elicit imprecise movements. FES implanted devices used neuromuscular stimulation and required implantation of one electrode for each site (muscle) to stimulate, an heavy surgical procedure and 10 times more electrical charges than nerve stimulation. Moreover, complications related to the numerous implanted components could appear over time. The purpose of this work is to evaluate whether a multi-contact nerve cuff electrode can selectively activate forearm and hand muscles and restore functional movements in patient with a complete tetraplegia.MethodsA 12-contacts cuff electrode was designed to selectively activate, without damage it, multi fascicular peripheral nerve (1). Six subjects rwith at least one extensor or one flexor muscle stimulable by surface electrical stimulation, have been enrolled into the study. During the surgical procedure, radial or median nerve was stimulated through up to 35 different configurations of stimulation at an intensity up to 2.1 mA (25 Hz, pulse width 250 µs, inter-pulse 100 µs). Surface electrodes were positioned upon the forearm to record compound muscle action potentials elicited by nerve electrical stimulation. Recruitments curves and videos were recorded.ResultsThe multicontact cuff electrode allowed us to selectively activate group of muscles to produce multiple, independent and functional hand and forearm movements in persons with tetraplegia. A surface electrical stimulation did not allow all those movements.

Background/objective Changes in brain metabolism has been investigated thoroughly during unilateral cervical chronic vagal stimulation in epileptic or depressive patients. Bilateral stimulation of the abdominal vagus (aVNS) has received less attention despite the reduction in body weight and an altered feeding behavior in obese animals that could be clinically relevant in obese individuals. Our study aims to examine the changes in brain glucose metabolism (CMRglu) induced by aVNS in obese adult miniature pigs. Dopamine (DAT) and serotonin transporters (SERT) were also quantified to further understand the molecular origins of the alterations in brain metabolism. Subjects/methods Pairs of stimulating electrodes were implanted during laparoscopy on both abdominal vagal trunks in 20 obese adult’s miniature pigs. Half of the animals were permanently stimulated while the remaining were sham stimulated. Two months after the onset of stimulation, dynamic 18FDG PET and 123I-ioflupane SPECT were performed. Food intake, resting energy expenditure and fat deposition were also assessed longitudinally. Results Food intake was halved and resting energy expenditure was increased by 60% in aVNS group compared to sham. The gain in body weight was also 38% less in aVNS group compared to sham. Brain metabolic connectivity increased between numerous structures including striatum, mid-brain, amygdala and hippocampus. On the contrary, increased CMRglu were restricted to the thalamus, the periaqueducal grey and the amygdala. DAT binding potential was decreased by about one third in the striatum while SERT was about doubled in the midbrain. Conclusions Our findings demonstrated that aVNS reduced weight gain as a consequence of diminished daily food intake and increased resting energy expenditure. These changes were associated with enhanced connectivity between several brain areas. A lower striatal DAT together with a doubled mid-brain SERT were likely causative for these changes. Electronic supplementary material The online version of this article (10.1186/s12967-019-1831-5) contains supplementary material, which is available to authorized users.

Additional file 1: Table S1. Abbreviation list of the 39 regions used in the VOI evaluation based on the Saikali et al. (1) pig atlas. The order and definition of the regions were extracted from Hammers et al. (2) human brain atlas and were tentatively applied to the pig atlas.

International audience; ObjectiveThe aim of the paper is to objectively demonstrate that amputees implanted with intraneural interfaces are truly able to feel a sensation in the phantom hand by recording “phantom” somatosensory evoked potentials from the corresponding brain areas.MethodsWe implanted four transverse intrafascicular multichannel electrodes, available with percutaneous connections to a multichannel electrical stimulator, in the median and ulnar nerves of two left trans-radial amputees. Two channels of the implants that were able to elicit sensations during intraneural nerve stimulation were chosen, in both patients, for recording somatosensory evoked potentials.ResultsWe recorded reproducible evoked responses by stimulating the median and the ulnar nerves in both cases. Latencies were in accordance with the arrival of somatosensory information to the primary somatosensory cortex.ConclusionOur results provide evidence that sensations generated by intraneural stimulation are truly perceived by amputees and located in the phantom hand. Moreover, our results strongly suggest that sensations perceived in different parts of the phantom hand result in different evoked responses.SignificanceSomatosensory evoked potentials obtained by selective intraneural electrical stimulation in amputee patients are a useful tool to provide an objective demonstration of somatosensory feedback in new generation bidirectional prostheses.

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.brs.2017.04.126; International audience; Background :Abdominal bilateral vagal stimulation reduces food intake in animals. However, the classical square wave, mA range current generator is poorly effective to evoke action potentials on A∂ and C neurons that represent the majority of vagal neurons at the abdominal level.Objective/Hypothesis :(i) To ascertain the capability of very high-frequency stimulation schemes (pulsons) to trigger action potentials in abdominal vagal neurons in anaesthetized pigs. (ii) To compare these stimulation schemes with classical ones using PET imaging of brain metabolism and food intake behaviour in conscious pigs.Methods :The current thresholds for pulsons (S2 & S3) and millisecond pulses (S1) required to trigger action potentials were calculated in 5 anaesthetized pigs using single fibre recording. Similar stimulation protocols were compared chronically to sham stimulation in 24 pigs. After two weeks of chronic stimulation, food intake and brain metabolism were investigated. The electrical characteristics and histology of the vagus nerve were also studied.Results :S3 stimulation required a lower amount of charges to trigger an action potential. Chronically applied S2 & S3 activated the dorsal vagal complex and increased the metabolism of its afferent cortical structures. They also reduced energy intake together with a reduced ingestion of high fat and high sugar diets. All these effects were not observed for the S1 group. The vagal histology for the S1, S2 and S3 groups was not different from that of the sham.Conclusions :These findings demonstrate that pulsons applied bilaterally on the abdominal vagus reduced food intake as a consequence of the activation of the brainstem and higher-order brain areas.

This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0847/-/DC1.; Acute vagal stimulation modifies glucose and insulin metabolism, but the effect of chronic bilateral vagal stimulation is not known. Our aim was to quantify the changes in whole body and organ-specific insulin sensitivities, 12 weeks after permanent, bilateral, vagal stimulation performed at the abdominal level in adult mini-pigs. In 15 adult mini-pigs, stimulating electrodes were placed around the dorsal and ventral vagi using laparoscopy and connected to a dual channel stimulator placed subcutaneously. Animals were divided into three groups based on stimulation and body weight i.e. lean non-stimulated, obese non-stimulated and obese-stimulated. Twelve weeks after surgery, glucose uptake and insulin sensitivity were measured using PET during an isoglycemic clamp. Mean whole body insulin sensitivity was lower by 34% (P

International audience; OBJECTIVE: The goal of this study was to evaluate the long-term behavior of the surface electrode through electrochemical characterization and follow up of implanted parylene/platinum microelectrodes.APPROACH: To this aim, we designed and manufactured specific planar electrodes for cortical implantation for a rat model. This work was included in the INTENSE® project, one of the goals of which was to prove the feasibility of selective neural recording or stimulation with cuff electrodes around the vagus nerve.MAIN RESULTS: After a 12-week implantation on a rat model, we can report that these microelectrodes have withstood in-vivo use. Regarding the biocompatibility of the electrodes (materials and manufacturing process), no adverse effect was reported. Indeed, after the three months implantation, we characterized limited tissue reaction beneath the electrodes and showed an increase and a stabilization of their impedance. Interestingly, the follow up of the electrochemical impedance combined with electrical stimulation highlighted a drop of the impedance up to 60% @1kHz after ten minutes of electrical stimulation at 110Hz.

International audience; A wearable, 56-channel stimulator was developed and successfully tested to drive multichannel intrafascicular electrodes. It is able to safely elicit sensory afferent signals through the activation of 4 Time-4H intrafascicular electrodes. The STIMEP embeds not only the pulse generator but also a software that ensures: i) real time control by a hand-prosthesis, ii) embedded procedures for sensation mapping interfaced with a PC software, iii) impedance follow-up, iv) real-time safety management.

Événement(s) lié(s) : - (NER); International audience; This paper describes the fabrication and the packaging of a flexible parylene-based multi-contact electrode embedded in a silicone-based cuff. This type of electrode is well suited for peripheral nerve recording and offers improved spatial selectivity. We conducted mechanical and electrical tests for assessing the reliability by using an accelerated lifetime protocol. Test structures made with platinum sandwiched with parylene C were designed. The accelerated lifetime soaking tests in phosphate buffered saline (PBS) solution at 67 degrees C showed a longer life time (approximatively 4.5 years) with a dehydration bake introduction in the process flow and a parylene thickness increase. A specific test bench was developed for the mechanical cycling and for evaluating the mechanical robustness of the thin film devices.

International audience; This paper describes the design, microfabrication, characterization and experimental validation of a 6-contact cuff electrode embedded in a parylene-based flexible support. This type of electrode is well suited for both peripheral nerve recording and stimulation and offers improved spatial selectivity as compared to conventional ring electrodes. Both measured and modeled impedance spectra are detailed. An experimental validation is performed on an earthworm with both multi-contact cuff (MCC) electrode recording and ring stimulation electrodes. Single fiber action potentials, elicited by the electrical stimulation, are well discriminated on the 6 contacts. Spontaneous activity is also recorded with burst of spikes.

In order to assess the signal to noise ratio and spatial selectivity of nanostructured microelectrodes, our consortium built an original assembly of surface macroelectrodes and deep microelectrode arrays. Acute and chronic assessments were achieved based on rodent and non human primate model. Eventually, we used this device to monitor by association of the surface and deep microelectrodes nominal behavior of the animals and induced epileptic seizure.

International audience; Phantom limb pain frequently follows amputation. Currently there is no fully effective treatment available. Our aim is to develop an innovative Human Machine Interface (HMI) where we apply multi-channel microstimulation to the nerve stump of an amputee subject to manipulate the phantom limb sensations and explore the possibility of using microstimulation as a treatment for phantom limb pain.

We present the results of a five-year patient follow-up after implantation of an original neuroprosthesis. The system is able to stimulate both epimysial and neural electrodes in such a way that the complete flexor-extensor chain of the lower limb can be activated without using of the withdrawal reflex. We demonstrate that standing and assisted walking are possible, and the results have remained stable for five years. Nevertheless, some problems were noted, particularly regarding the muscle response on the epimysial channels. Analysis of the electrical behaviour and thresholds indicated that the surgical phase is crucial because of the sensitivity of the functional responses to electrode placement. Neural stimulation proved to be more efficient and more stable over time. This mode requires less energy and provides more selective stimulation. This FES system can be improved to enable balanced standing and less fatiguing gait, but this will require feedback on event detection to trigger transitions between stimulation sequences, as well as feedback to the patient about the state of his lower limbs.

This paper presents an original electronic architecture to manage epimysial and neural stimulation using the same implantable device. All the muscles needed to achieve lower limb movements such as standing and walking can thus be activated. Mainly for surgical reasons, some muscles need to be stimulated through different inputs: epimysium or motor nerve. We developed an electronic solution, including the design of an application-specific integrated circuit, to meet the requirements of both types of stimulation. Five years after the successful implantation of the system, we were able to evaluate the system's performance. The patient is still using the system at home and no failure occurred during this 5-year period. We conclude that the electronic design not only provides a unique investigative tool for research, but that it can also be used to restore the motor function of the lower limb. This technology has an advantage over external stimulation because the patient can safely use the system at home. However, improvements such as lower power consumption, and thus greater autonomy, are needed. We further conclude that the modelling of the electrical behaviour of the electrodes is reliable and the estimated parameter values are homogeneous and consistent for the same type of electrode. Thus, the three parameters of the first-order model can be identified from an acute animal experiment and provide a means to optimize the design of the output stage of implanted stimulators.

International audience; The new generation of implanted neuroprostheses allows muscles to be controlled with fine accuracy, high selectivity and the repeatability of the muscle's response can be achieved. Thus, the closed loop control of such systems becomes possible. The SUAW project succeeded in the implantation of an advanced neuroprosthetic device on two patients, but the movement generation remains open loop and is tuned empirically. Nevertheless, the good results obtained give us the opportunity to envisage the system evolves towards closed loop control and automatic synthesis of the stimulation patterns generating the desired movement. To achieve this goal, some preliminary researches have to be carried out, beginning with a specific modelling that can be used in the context of Functional Electrical Stimulation (FES). The main issues concern muscle modelling including the interaction with the skeleton, fatigue, FES parameters as inputs, and the identification of dynamic parameters, and afterwards, the motion synthesis and the closed loop control based on this model. Besides, the scientific approach is the same as in robotics so that the theoretical tools used in the control theory are the same and directly applicable. This paper describes the results obtained in the previous project SUAW and how we attempt, through the new project DEMAR, to enhance the global performances of the system.