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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.

ObjectiveTo describe the ultrasound (US) appearance of regenerative peripheral nerve interfaces (RPNIs) in humans, and correlate clinically and with histologic findings from rat RPNI.Materials and methodsPatients (≥ 18 years) who had undergone RPNI surgery within our institution between the dates of 3/2018 and 9/2019 were reviewed. A total of 21 patients (15 male, 6 female, age 21–82 years) with technically adequate US studies of RPNIs were reviewed. Clinical notes were reviewed for the presence of persistent pain after RPNI surgery. Histologic specimens of RPNIs in a rat model from prior studies were compared with the US findings noted in this study.ResultsThere was a variable appearance to the RPNIs including focal changes involving the distal nerve, nerve-muscle graft junction, and area of the distal sutures. The muscle grafts varied in thickness with accompanying variable echogenic changes. No interval change was noted on follow-up US studies. Diffuse hypoechoic swelling with loss of the fascicular structure of the nerve within the RPNI and focal hypoechoic changes at the nerve-muscle graft junction were associated with clinical outcomes. US findings corresponded to histologic findings in the rat RPNI.ConclusionUltrasound imaging can demonstrate various morphologic changes involving the nerve, muscle, and interface between these two biological components of RPNIs. These changes correspond to expected degenerative and regenerative processes following nerve resection and muscle reinnervation and should not be misconstrued as pathologic in all cases. N5 and N1 morphologic type changes of the RPNI were found to be associated with symptoms.

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 behaviour, 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.

Purpose of ReviewThis 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 FindingsThe 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.SummaryWhile 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.

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 ClinicalTrials.gov NCT05009394.

Intuitive and perceptual neuroprosthetic systems require a high degree of neural control and a variety of sensory feedback, but reliable neural interfaces for long‐term use that maintain their functionality are limited. Here, a novel hybrid bionic interface is presented, fabricated by integrating a biological interface (regenerative peripheral nerve interface (RPNI)) and a peripheral neural interface to enhance the neural interface performance between a nerve and bionic limbs. This interface utilizes a shape memory polymer buckle that can be easily implanted on a severed nerve and make contact with both the nerve and the muscle graft after RPNI formation. It is demonstrated that this interface can simultaneously record different signal information via the RPNI and the nerve, as well as stimulate them separately, inducing different responses. Furthermore, it is shown that this interface can record naturally evoked signals from a walking rabbit and use them to control a robotic leg. The long‐term functionality and biocompatibility of this interface in rabbits are evaluated for up to 29 weeks, confirming its promising potential for enhancing prosthetic control. A hybrid bionic interface that integrates a biological interface and a neural interface is developed, demonstrating simultaneous nerve and muscle graft contact. Chronic implantation in a rabbit model validates stable recording and stimulation. Long‐term implantation (29 weeks) is validated. Multiple signal acquisition possibilities and potential neuroprosthetic applications are highlighted, with an emphasis on future advancements in bionic interface technology.

Background Amputees suffer from symptomatic neuroma and phantom limb pain. Regenerative peripheral nerve interface (RPNI) has recently been regarded as an effective method to prevent neuroma after amputation. However, the verifications of RPNI efficacy are mostly based on subjective evaluation, lacking objective approaches. This study aims to unveil the effect of RPNI on preventing neuroma formation and provide evidence supporting the efficacy of RPNI based on ultrasound. Methods Amputees of lower limb at Peking University People’s Hospital from July 2020 to March 2022 were analyzed retrospectively. The clinical data collected consisted of general information, pathology of primary disease, history of limb-salvage treatment, amputation level of nerve, pain scales such as the Numerical Rating Scale (NRS) and the Manchester Foot Pain and Disability Index (MFPDI). Three months after amputation, the transverse diameter, anteroposterior diameter, and cross-sectional area of neuromas in stump nerves at the end of residual limbs were measured using ultrasound and compared to adjacent normal nerves. Results Fourteen patients were enrolled in the study, including 7 in the traditional amputation group (TA group) and 7 in the RPNI group. There was no significant difference in basic information and amputation sites between the two groups. The NRS and MFPDI scores of patients in RPNI group were significantly lower than those in TA group, and decreased with the follow-up time increasing, indicating that RPNI could reduce symptomatic neuroma pain. The comparison of preoperative ultrasound and postoperative pathology showed ultrasound could reflect the size of neuroma in vivo. Independent-sample t tests indicated that the ratios of anteroposterior diameter, transverse diameter and area of the cross section of both the neuroma and adjacent normal nerve obtained via ultrasound were significantly reduced in the RPNI group. Conclusion This study suggested that RPNI can effectively prevent the formation of symptomatic neuroma after amputation using ultrasound.

Background The treatment of neuromas with regenerative peripheral nerve interfaces (RPNI) has gained much attention in recent years. This systematic review compared the clinical outcomes of upper limb neuromas treated with free (fRPNI) versus vascularized RPNI (vRPNI). Methods This systematic review was performed in accordance with PRISMA guidelines. The PubMed database was searched for relevant studies published between August 2016 and May 2023. The search term “RPNI” was used. Data including patient demographics, type of RPNI performed, mean pain duration prior to RPNI, post-operative follow-up period, the reduction in neuroma pain scores after RPNI and post-operative complications were extracted independently by two authors and recorded using standard computer software for data processing. Results Of 43 papers identified, only four fulfilled the inclusion criteria. This provided data for upper limb neuromas in 32 patients where a total of 83 RPNIs (22 vascularized) were performed. The means for patient age, duration of neuroma pain, length of reported postoperative follow-up, and reduction in neuroma pain scores were 44.0 years, 3.6 years, 12.2 months and 86% respectively. Conclusions The current evidence suggests that either fRPNI or vRPNI may be useful for treating upper extremity neuromas, both prophylactically and secondarily. However, the heterogeneity and inconsistencies in data reporting are such that further studies are required to compare clinical outcomes between fRPNI and vRPNI to determine if one is superior to the other. Level of Evidence: Not gradable.

Causalgia and complex regional pain syndrome (CRPS) type II with nerve injury can be difficult to treat. Surgical peripheral nerve denervation for causalgia has been largely abandoned by pain clinicians because of a perception that this may aggravate a central component (anesthesia dolorosa). We selectively searched Pubmed, Cochrane, MEDLINE, EMBASE, CINAHL Plus, and Scopus from 1947 for articles, books, and book chapters for evidence of surgical treatments (nerve resection and amputation) and treatment related to autoimmunity and immune deficiency with CRPS. Reviews were found for the treatment of causalgia or CRPS type II ( = 6), causalgia relieved by nerve resection ( = 6), and causalgia and CRPS II treated by amputation ( = 8). Twelve reports were found of autoimmunity with CRPS, one paper of these on associated immune deficiency and autoimmunity, and two were chosen for discussion regarding treatment with immunoglobulin and one by plasma exchange. We document a report of a detailed and unique pathological examination of a CRPS type II affected amputated limb and related successful treatment with immunoglobulin. Nerve resection, with grafting, and relocation may relieve uncomplicated causalgia and CRPS type II in some patients in the long term. However, an unrecognized and treatable immunological condition may underly some CRPS II cases and can lead to the ultimate failure of surgical treatments.

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.