A soft, scalable and adaptable multi-contact cuff electrode for targeted peripheral nerve modulation.

BACKGROUND: Cuff electrodes target various nerves throughout the body, providing neuromodulation therapies for motor, sensory, or autonomic disorders. However, when using standard, thick silicone cuffs, fabricated in discrete circular sizes, complications may arise, namely cuff displacement or nerve compression, due to a poor adaptability to variable nerve shapes and sizes encountered in vivo. Improvements in cuff design, materials, closing mechanism and surgical approach are necessary to overcome these issues. METHODS: In this work, we propose a microfabricated multi-channel silicone-based soft cuff electrode with a novel easy-to-implant and size-adaptable design and evaluate a number of essential features such as nerve-cuff contact, nerve compression, cuff locking stability, long-term integration and stimulation selectivity. We also compared performance to that of standard fixed-size cuffs. RESULTS: The belt-like cuff made of 150 µm thick silicone membranes provides a stable and pressure-free conformal contact, independently of nerve size variability, combined with a straightforward implantation procedure. The adaptable design and use of soft materials lead to limited scarring and demyelination after 6-week implantation. In addition, multi-contact designs, ranging from 6 to 16 electrodes, allow for selective stimulation in models of rat and pig sciatic nerve, achieving targeted activation of up to 5 hindlimb muscles. CONCLUSION: These results suggest a promising alternative to classic fixed-diameter cuffs and may facilitate the adoption of soft, adaptable cuffs in clinical settings.

Regenerative Peripheral Nerve Interfaces (RPNIs) in Animal Models and Their Applications: A Systematic Review.

Regenerative Peripheral Nerve Interfaces (RPNIs) encompass neurotized muscle grafts employed for the purpose of amplifying peripheral nerve electrical signaling. The aim of this investigation was to undertake an analysis of the extant literature concerning animal models utilized in the context of RPNIs. A systematic review of the literature of RPNI techniques in animal models was performed in line with the PRISMA statement using the MEDLINE/PubMed and Embase databases from January 1970 to September 2023. Within the compilation of one hundred and four articles employing the RPNI technique, a subset of thirty-five were conducted using animal models across six distinct institutions. The majority (91%) of these studies were performed on murine models, while the remaining (9%) were conducted employing macaque models. The most frequently employed anatomical components in the construction of the RPNIs were the common peroneal nerve and the extensor digitorum longus (EDL) muscle. Through various histological techniques, robust neoangiogenesis and axonal regeneration were evidenced. Functionally, the RPNIs demonstrated the capability to discern, record, and amplify action potentials, a competence that exhibited commendable long-term stability. Different RPNI animal models have been replicated across different studies. Histological, neurophysiological, and functional analyses are summarized to be used in future studies.

Selective chronic recording in small nerve fascicles of sciatic nerve with carbon nanotube yarns in rats.

Objective. The primary challenge faced in the field of neural rehabilitation engineering is the limited advancement in nerve interface technology, which currently fails to match the mechanical properties of small-diameter nerve fascicles. Novel developments are necessary to enable long-term, chronic recording from a multitude of small fascicles, allowing for the recovery of motor intent and sensory signals.Approach. In this study, we analyze the chronic recording capabilities of carbon nanotube yarn electrodes in the peripheral somatic nervous system. The electrodes were surgically implanted in the sciatic nerve's three individual fascicles in rats, enabling the recording of neural activity during gait. Signal-to-noise ratio (SNR) and information theory were employed to analyze the data, demonstrating the superior recording capabilities of the electrodes. Flat interface nerve electrode and thin-film longitudinal intrafascicular electrode electrodes were used as a references to assess the results from SNR and information theory analysis.Main results. The electrodes exhibited the ability to record chronic signals with SNRs reaching as high as 15 dB, providing 12 bits of information for the sciatic nerve, a significant improvement over previous methods. Furthermore, the study revealed that the SNR and information content of the neural signals remained consistent over a period of 12 weeks across three different fascicles, indicating the stability of the interface. The signals recorded from these electrodes were also analyzed for selectivity using information theory metrics, which showed an information sharing of approximately 1.4 bits across the fascicles.Significance. The ability to safely and reliably record from multiple fascicles of different nerves simultaneously over extended periods of time holds substantial implications for the field of neural and rehabilitation engineering. This advancement addresses the limitation of current nerve interface technologies and opens up new possibilities for enhancing neural rehabilitation and control.

Limb Amputations in Cancer: Modern Perspectives, Outcomes, and Alternatives.

PURPOSE OF REVIEW: This review summarizes current findings regarding limb amputation within the context of cancer, especially in osteosarcomas and other bony malignancies. We seek to answer the question of how amputation is utilized in the contemporary management of cancer as well as explore current advances in limb-sparing techniques. RECENT FINDINGS: The latest research on amputation has been sparse given its extensive history and application. However, new research has shown that rotationplasty, osseointegration, targeted muscle reinnervation (TMR), and regenerative peripheral nerve interfaces (RPNI) can provide patients with better functional outcomes than traditional amputation. While limb-sparing surgeries are the mainstay for managing musculoskeletal malignancies, limb amputation is useful as a palliative technique or as a primary treatment modality for more complex cancers. Currently, rotationplasty and osseointegration have been valuable limb-sparing techniques with osseointegration continuing to develop in recent years. TMR and RPNI have also been of interest in the modern management of patients requiring full or partial amputations, allowing for better control over myoelectric prostheses.

Surgical treatments for postamputation pain: study protocol for an international, double-blind, randomised controlled trial.

BACKGROUND: Painful conditions such as residual limb pain (RLP) and phantom limb pain (PLP) can manifest after amputation. The mechanisms underlying such postamputation pains are diverse and should be addressed accordingly. Different surgical treatment methods have shown potential for alleviating RLP due to neuroma formation - commonly known as neuroma pain - and to a lesser degree PLP. Two reconstructive surgical interventions, namely targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI), are gaining popularity in postamputation pain treatment with promising results. However, these two methods have not been directly compared in a randomised controlled trial (RCT). Here, we present a study protocol for an international, double-blind, RCT to assess the effectiveness of TMR, RPNI, and a non-reconstructive procedure called neuroma transposition (active control) in alleviating RLP, neuroma pain, and PLP. METHODS: One hundred ten upper and lower limb amputees suffering from RLP will be recruited and assigned randomly to one of the surgical interventions (TMR, RPNI, or neuroma transposition) in an equal allocation ratio. Complete evaluations will be performed during a baseline period prior to the surgical intervention, and follow-ups will be conducted in short term (1, 3, 6, and 12 months post-surgery) and in long term (2 and 4 years post-surgery). After the 12-month follow-up, the study will be unblinded for the evaluator and the participants. If the participant is unsatisfied with the outcome of the treatment at that time, further treatment including one of the other procedures will be discussed in consultation with the clinical investigator at that site. DISCUSSION: A double-blind RCT is necessary for the establishment of evidence-based procedures, hence the motivation for this work. In addition, studies on pain are challenging due to the subjectivity of the experience and the lack of objective evaluation methods. Here, we mitigate this problem by including different pain evaluation methods known to have clinical relevance. We plan to analyse the primary variable, mean change in NRS (0-10) between baseline and the 12-month follow-up, using the intention-to-treat (ITT) approach to minimise bias and keep the advantage of randomisation. The secondary outcomes will be analysed on both ITT and per-protocol (PP). An adherence protocol (PP population) analysis will be used for estimating a more realistic effect of treatment. TRIAL REGISTRATION: ClincialTrials.gov NCT05009394.

Regenerative Peripheral Nerve Interfaces Effectively Prevent Neuroma Formation After Sciatic Nerve Transection in Rats.

Objective: The disordered growth of nerve stumps after amputation leading to the formation of neuromas is an important cause of postoperative pain in amputees. This severely affects the patients' quality of life. Regenerative peripheral nerve interfaces (RPNIs) are an emerging method for neuroma prevention, but its postoperative nerve growth and pathological changes are yet to be studied. Methods: The rat sciatic nerve transection model was used to study the effectiveness of RPNI in this experiment. The RPNI (experimental) group (n = 11) underwent RPNI implantation after sciatic nerve transection, while the control group (n = 11) only underwent sciatic nerve transection. Autotomy behavior, ultrasonography, and histopathology were observed for 2 months postoperatively. Results: Compared to the control group, the incidence and size of the neuromas formed and the incidence and extent of autotomy were significantly reduced in the RPNI group. The axon density in the stump and degree of stump fibrosis were also significantly reduced in the RPNI group. Conclusion: RPNI effectively prevented the formation of neuromas.

A finite element model of the mechanical interactions between peripheral nerves and intrafascicular implants.

Objective.Intrafascicular peripheral nerve implants are key components in the development of bidirectional neuroprostheses such as touch-enabled bionic limbs for amputees. However, the durability of such interfaces is hindered by the immune response following the implantation. Among the causes linked to such reaction, the mechanical mismatch between host nerve and implant is thought to play a decisive role, especially in chronic settings.Approach.Here we focus on modeling mechanical stresses induced on the peripheral nerve by the implant's micromotion using finite element analysis. Through multiple parametric sweeps, we analyze the role of the implant's material, geometry (aspect-ratio and shape), and surface coating, deriving a set of parameters for the design of better-integrated implants.Main results.Our results indicate that peripheral nerve implants should be designed and manufactured with smooth edges, using materials at most three orders of magnitude stiffer than the nerve, and with innovative geometries to redistribute micromotion-associated loads to less delicate parts of the nerve such as the epineurium.Significance.Overall, our model is a useful tool for the peripheral nerve implant designer that is mindful of the importance of implant mechanics for long term applications.

Tutorial: a guide to techniques for analysing recordings from the peripheral nervous system.

The nervous system, through a combination of conscious and automatic processes, enables the regulation of the body and its interactions with the environment. The peripheral nervous system is an excellent target for technologies that seek to modulate, restore or enhance these abilities as it carries sensory and motor information that most directly relates to a target organ or function. However, many applications require a combination of both an effective peripheral nerve interface (PNI) and effective signal processing techniques to provide selective and stable recordings. While there are many reviews on the design of PNIs, reviews of data analysis techniques and translational considerations are limited. Thus, this tutorial aims to support new and existing researchers in the understanding of the general guiding principles, and introduces a taxonomy for electrode configurations, techniques and translational models to consider.

Surgically Implanted Electrodes Enable Real-Time Finger and Grasp Pattern Recognition for Prosthetic Hands.

Currently available prosthetic hands are capable of actuating anywhere from five to 30 degrees of freedom (DOF). However, grasp control of these devices remains unintuitive and cumbersome. To address this issue, we propose directly extracting finger commands from the neuromuscular system. Two persons with transradial amputations had bipolar electrodes implanted into regenerative peripheral nerve interfaces (RPNIs) and residual innervated muscles. The implanted electrodes recorded local electromyography with large signal amplitudes. In a series of single-day experiments, participants used a high speed movement classifier to control a virtual prosthetic hand in real-time. Both participants transitioned between 10 pseudo-randomly cued individual finger and wrist postures with an average success rate of 94.7% and trial latency of 255 ms. When the set was reduced to five grasp postures, metrics improved to 100% success and 135 ms trial latency. Performance remained stable across untrained static arm positions while supporting the weight of the prosthesis. Participants also used the high speed classifier to switch between robotic prosthetic grips and complete a functional performance assessment. These results demonstrate that pattern recognition systems can use intramuscular electrodes and RPNIs for fast and accurate prosthetic grasp control.

A Microclip Peripheral Nerve Interface (µcPNI) for Bioelectronic Interfacing with Small Nerves.

Peripheral nerves carry sensory (afferent) and motor (efferent) signals between the central nervous system and other parts of the body. The peripheral nervous system (PNS) is therefore rich in targets for therapeutic neuromodulation, bioelectronic medicine, and neuroprosthetics. Peripheral nerve interfaces (PNIs) generally suffer from a tradeoff between selectivity and invasiveness. This work describes the fabrication, evaluation, and chronic implantation in zebra finches of a novel PNI that breaks this tradeoff by interfacing with small nerves. This PNI integrates a soft, stretchable microelectrode array with a 2-photon 3D printed microclip (µcPNI). The advantages of this µcPNI compared to other designs are: a) increased spatial resolution due to bi-layer wiring of the electrode leads, b) reduced mismatch in biomechanical properties with the nerve, c) reduced disturbance to the host tissue due to the small size, d) elimination of sutures or adhesives, e) high circumferential contact with small nerves, f) functionality under considerable strain, and g) graded neuromodulation in a low-threshold stimulation regime. Results demonstrate that the µcPNIs are electromechanically robust, and are capable of reliably recording and stimulating neural activity in vivo in small nerves. The µcPNI may also inform the development of new optical, thermal, ultrasonic, or chemical PNIs as well.

All-Polymer Printed Low-Cost Regenerative Nerve Cuff Electrodes.

Neural regeneration after lesions is still limited by several factors and new technologies are developed to address this issue. Here, we present and test in animal models a new regenerative nerve cuff electrode (RnCE). It is based on a novel low-cost fabrication strategy, called "Print and Shrink", which combines the inkjet printing of a conducting polymer with a heat-shrinkable polymer substrate for the development of a bioelectronic interface. This method allows to produce miniaturized regenerative cuff electrodes without the use of cleanroom facilities and vacuum based deposition methods, thus highly reducing the production costs. To fully proof the electrodes performance in vivo we assessed functional recovery and adequacy to support axonal regeneration after section of rat sciatic nerves and repair with RnCE. We investigated the possibility to stimulate the nerve to activate different muscles, both in acute and chronic scenarios. Three months after implantation, RnCEs were able to stimulate regenerated motor axons and induce a muscular response. The capability to produce fully-transparent nerve interfaces provided with polymeric microelectrodes through a cost-effective manufacturing process is an unexplored approach in neuroprosthesis field. Our findings pave the way to the development of new and more usable technologies for nerve regeneration and neuromodulation.

The future of upper extremity rehabilitation robotics: research and practice.

The loss of upper limb motor function can have a devastating effect on people's lives. To restore upper limb control and functionality, researchers and clinicians have developed interfaces to interact directly with the human body's motor system. In this invited review, we aim to provide details on the peripheral nerve interfaces and brain-machine interfaces that have been developed in the past 30 years for upper extremity control, and we highlight the challenges that still remain to transition the technology into the clinical market. The findings show that peripheral nerve interfaces and brain-machine interfaces have many similar characteristics that enable them to be concurrently developed. Decoding neural information from both interfaces may lead to novel physiological models that may one day fully restore upper limb motor function for a growing patient population.

DARPA investment in peripheral nerve interfaces for prosthetics, prescriptions, and plasticity.

BACKGROUND: Peripheral nerve interfaces have emerged as alternative solutions for a variety of therapeutic and performance improvement applications. The Defense Advanced Research Projects Agency (DARPA) has widely invested in these interfaces to provide motor control and sensory feedback to prosthetic limbs, identify non-pharmacological interventions to treat disease, and facilitate neuromodulation to accelerate learning or improve performance on cognitive, sensory, or motor tasks. In this commentary, we highlight some of the design considerations for optimizing peripheral nerve interfaces depending on the application space. We also discuss the ethical considerations that accompany these advances.

Fully implantable neural recording and stimulation interfaces: Peripheral nerve interface applications.

BACKGROUND: Peripheral nerve interfacing has many applications ranging from investigation of neural signals to therapeutic intervention for varied diseases. This need has driven technological advancements in the field of electrode arrays and wireless systems for in-vivo electrophysiological experiments. Hence we present our fully implantable, programmable miniaturized wireless stimulation and recording devices. NEW METHOD: The method consists of technological advancements enabling implantable wireless recording up to 128 channels with a sampling rate of 50Khz and stimulation up to ±4 mA from 15 independent channels. The novelty of the technique consists of induction charging cages which enables freely moving small animals to undergo continuous electrophysiological and behavioral studies without any impediments. The biocompatible hermetic packaging technology for implantable capsules ensures stability for long-term chronic studies. RESULTS: Electromyographs wirelessly recorded from leg muscles of a macaque and a rat using implantable technology are presented during different behavioral task studies. The device's simultaneous stimulation and recording capabilities are reported when interfaced with the vagus and pelvic nerves. COMPARISON WITH EXISTING METHOD(S): The wireless interfacing technology has a large number of recording and stimulating channels without compromising on the signal quality due to sampling rates or stimulating current output capabilities. The induction charging technology along with transceiver and software interface allows experiments on multiple animals to be carried out simultaneously. CONCLUSIONS: This customizable technology using wireless power transmission, reduced battery size, and miniaturized electronics has paved way for a robust, fully implantable, hermetic neural interface system enabling the study of bioelectronic medical therapies.

Soft Conducting Elastomer for Peripheral Nerve Interface.

State-of-the-art intraneural electrodes made from silicon or polyimide substrates have shown promise in selectively modulating efferent and afferent activity in the peripheral nervous system. However, when chronically implanted, these devices trigger a multiphase foreign body response ending in device encapsulation. The presence of encapsulation increases the distance between the electrode and the excitable tissue, which not only reduces the recordable signal amplitude but also requires increased current to activate nearby axons. Herein, this study reports a novel conducting polymer based intraneural electrode which has Young's moduli similar to that of nerve tissue. The study first describes material optimization of the soft wire conductive matrix and evaluates their mechanical and electrochemical properties. Second, the study demonstrates 3T3 cell survival when cultured with media eluted from the soft wires. Third, the study presents acute in vivo functionality for stimulation of peripheral nerves to evoke force and compound muscle action potential in a rat model. Furthermore, comprehensive histological analyses show that soft wires elicit significantly less scar tissue encapsulation, less changes to axon size, density and morphology, and reduced macrophage activation compared to polyimide implants in the sciatic nerves at 1 month postimplantation.

On the development of optical peripheral nerve interfaces.

Limb loss and spinal cord injury are two debilitating conditions that continue to grow in prevalence. Prosthetic limbs and limb reanimation present two ways of providing affected individuals with means to interact in the world. These techniques are both dependent on a robust interface with the peripheral nerve. Current methods for interfacing with the peripheral nerve tend to suffer from low specificity, high latency and insufficient robustness for a chronic implant. An optical peripheral nerve interface may solve some of these problems by decreasing invasiveness and providing single axon specificity. In order to implement such an interface three elements are required: (1) a transducer capable of translating light into a neural stimulus or translating neural activity into changes in fluorescence, (2) a means for delivering said transducer and (3) a microscope for providing the stimulus light and detecting the fluorescence change. There are continued improvements in both genetically encoded calcium and voltage indicators as well as new optogenetic actuators for stimulation. Similarly, improvements in specificity of viral vectors continue to improve expression in the axons of the peripheral nerve. Our work has recently shown that it is possible to virally transduce axons of the peripheral nerve for recording from small fibers. The improvements of these components make an optical peripheral nerve interface a rapidly approaching alternative to current methods.