Artificial and non-artificial nerve grafts are the gold standard in peripheral nerve reconstruction in cases with extensive loss of nerve tissue, particularly where a direct end-to-end suture or an autologous nerve graft is inauspicious. Different materials are marketed and approved by the US Food and Drug Administration (FDA) for peripheral nerve graft reconstruction. The most frequently used materials are collagen and poly(DL-lactide-ε-caprolactone). Only one human nerve allograft is listed for peripheral nerve reconstruction by the FDA. All marketed nerve grafts are able to demonstrate sufficient nerve regeneration over small distances not exceeding 3.0 cm. A key question in the field is whether nerve reconstruction on large defect lengths extending 4.0 cm or more is possible. This review gives a summary of current clinical and experimental approaches in peripheral nerve surgery using artificial and non-artificial nerve grafts in short and long distance nerve defects. Strategies to extend nerve graft lengths for long nerve defects, such as enhancing axonal regeneration, include the additional application of Schwann cells, mesenchymal stem cells or supporting co-factors like growth factors on defect sizes between 4.0 and 8.0 cm.

In the period 1991 - 1993, 931 casualties with 1435 injured peripheral nerves were surgically treated at the Clinic for Neurosurgery of the Military Medical Academy. The statistical analyses of these series was done according to the type of the injured nerves, the age and sex of the wounded. The cause of injuries, associated and combined injuries, distribution of single and multiple lesions of certain nerves, as well as employed surgical procedures were analyzed.

Electrospinning can be used to mimic the architecture of an acellular nerve graft, combining microfibers for guidance, and pores for cellular infiltration. We made electrospun nerve guides, from polycaprolactone (PCL) or poly-L-lactic acid (PLLA), with aligned fibers along the insides of the channels and random fibers around them. We bridged a 10 mm rat sciatic nerve defect with the guides, and, in selected groups, added a cell transplant derived from autologous stromal vascular fraction (SVF). For control, we compared to hollow silicone tubes; or autologous nerve grafts. PCL nerve guides had a high degree of autotomy (8/43 rats), a negative indicator with respect to future usefulness, while PLLA supported axonal regeneration, but did not outperform autologous nerve grafts. Transplanted cells survived in the PLLA nerve guides, but axonal regeneration was not enhanced as compared to nerve guides alone. The inflammatory response was partially enhanced by the transplanted cells in PLLA nerve grafts; Schwann cells were poorly distributed compared to nerve guide without cells. Tailor-made electrospun nerve guides support axonal regeneration in vivo, and can act as vehicles for co-transplanted cells. Our results motivate further studies exploring novel nerve guides and the effect of stromal cell-derived factors on nerve generation.

One of the major challenges in the development of a larger and longer nerve conduit for peripheral nerve repair is the limitation in oxygen and nutrient diffusion within the tissue after transplantation preventing Schwann cell and axonal migration. This restriction is due to the slow neovascularization process of the graft starting from both nerve endings. To overcome this limitation, we propose the design of a living tissue-engineered nerve conduit made of an internal tube with a three-dimensional structure supporting axonal migration, which is inserted inside a hollow external tube that plays the role of an epineurium and is strong enough to be stitched to the severed nerve stumps. The internal tube is made of a rolled living fibroblast sheet and can be seeded with endothelial cells to promote the formation of a network containing capillary-like structures which allow rapid inosculation with the host nerve microvasculature after grafting. Human nerve conduits were grafted in immunodeficient rats to bridge a 15 mm sciatic nerve gap. Human capillaries within the pre-vascularized nerve conduit successfully connected to the host circulation 2 weeks after grafting. Twenty-two weeks after surgery, rats transplanted with the nerve conduits had a similar motor function recovery compared to the autograft group. By promoting rapid vascularization of the internal nerve tube from both ends of the nerve stumps, this endothelialized nerve conduit model displays a favorable environment to enhance axonal migration in both larger caliber and longer nerve grafts.

Peripheral nerve defects (PND) often cause lifelong physical disability, and the available treatment options are often not satisfactory. PND are usually bridged with an autologous nerve transplant or a nerve guidance conduit (NGC), when coaptation as preferred technique is not possible. The aim of this experimental study was to determine the effectiveness of a novel NGC for regeneration in the treatment of PND.

There is a great demand for convenient and quantitative assessment of upper-limb traumatic peripheral nerve injuries (PNIs) beyond their clinical routine. This would contribute to improved PNI management and rehabilitation.

Peripheral nerve injury in the upper extremity is linked to high socioeconomic burden, yet cost-analyses are rare and from small cohorts. The objective of this study was to determine the costs and long-term socioeconomic effects of peripheral nerve injuries in the upper extremity in Germany.

To investigate the factors associated with sensory and motor recovery after the repair of upper limb peripheral nerve injuries.

Chronic constriction injury (CCI) of the sciatic nerve is a peripheral nerve injury widely used to induce mononeuropathy. This study used machine learning methods to identify the best gait analysis parameters for evaluating peripheral nerve injuries.

Peripheral nerve injury is one of the most debilitating pathologies that severely impair patients' life. Although many efforts have been made to advance in the treatment of such a complex disorder, successful strategies to ensure full recovery are still scarce. The aim of the present work was to develop flexible and mechanically resistant platforms intended to act as a support and guide for neural cells during the regeneration process of peripheral nerve injury. For this purpose, poly(lactic-co-glycolic acid) (PLGA)/poly(d,l-lactic acid) (PDLLA)/poly(ethylene glycol) 400 (PEG)-multichannel-based scaffolds (MCs) were prepared through a multistep process involving electrospun microfibers coated with a polymer blend solution and used as a sacrificial mold. In particular, scaffolds characterized by random (MCR) and aligned (MCA) multichannel were obtained. A design of experiments approach (DoE) was employed to identify a scaffold-optimized composition. MCs were characterized for morphological and mechanical properties, suturability, degradability, cell colonization, and in vivo safety. A new biodegradable, biocompatible, and safe microscale multichannel scaffold was developed as the result of an easy multistep procedure.

In the medical field, the use of 3-dimensional (3D) printing is increasing explosively and it is especially widespread in the clinical application of fabricating orthosis. Advantages of 3D-printed orthosis compared to conventional ones include its lower cost, easier modification, and faster fabrication. The 3D-printing technique makes it possible for physicians to easily create individual-tailored products. Recently, many kinds of orthosis through 3D printing have been studied and used. The knee orthosis, ankle-foot orthosis, wrist orthosis, hand orthosis, and foot orthotics are examples used in the rehabilitation fields of orthotics. We reported 3 cases of 3D-printed orthoses in patients with peripheral nerve injuries.

Peripheral nerve injuries are one of the most common and costly injuries especially in the young population. In this study, it is aimed to determine the histological role of epidermal growth factor (EGF) in nerve regeneration with an acute damage made on sciatic nerve in the rabbit model.

Due to the limitations in autogenous nerve grafting or Schwann cell transplantation, large gap peripheral nerve injuries require a bridging strategy supported by nerve conduit. Cell based therapies provide a novel treatment for peripheral nerve injuries. In this study, we first experimented an optimal scaffold material synthesis protocol, from where we selected the 10% GFD formula (10% GelMA hydrogel, recombinant human basic fibroblast growth factor and dental pulp stem cells (DPSCs)) to fill a cellulose/soy protein isolate composite membrane (CSM) tube to construct a third generation of nerve regeneration conduit, CSM-GFD. Then this CSM-GFD conduit was applied to repair a 15-mm long defect of sciatic nerve in a rat model. After 12 week post implant surgery, at histologic level, we found CSM-GFD conduit could regenerate nerve tissue like neuron and Schwann like nerve cells and myelinated nerve fibers. At physical level, CSM-GFD achieved functional recovery assessed by a sciatic functional index study. In both levels, CSM-GFD performed like what gold standard, the nerve autograft, could do. Further, we unveiled that almost all newly formed nerve tissue at defect site was originated from the direct differentiation of exogeneous DPSCs in CSM-GFD. In conclusion, we claimed that this third-generation nerve regeneration conduit, CSM-GFD, could be a promising tissue engineering approach to replace the conventional nerve autograft to treat the large gap defect in peripheral nerve injuries.

Major peripheral nerve injuries not only result in local deficits but may also cause distal atrophy of target muscles or permanent loss of sensation. Likewise, these injuries have been shown to instigate long-lasting central cortical reorganization.

Terminal Schwann cells (SCs) are nonmyelinating glia that are a prominent component of the neuromuscular junction (NMJ) where motor neurons form synapses onto muscle fibers. These cells play important roles not only in development and maintenance of the neuromuscular synapse but also restoring synaptic function after nerve damage. In response to muscle denervation, terminal SCs undergo dramatic changes in their gene expression patterns as well as in their morphology, such as extending elaborate processes into inter-junctional space. These SC processes serve as a path to guide axon terminal sprouts from nearby innervated junctions, promoting rapid reinnervation of denervated fibers. We studied the role of terminal SCs in synapse reformation by using two different fluorescent proteins to simultaneously label motor axons and SCs; we examined these junctions repeatedly in living animals using a fluorescence microscope. Here, we show that alterations in the patterns of muscle innervation following recovery from nerve injury can be explained by SC guidance of regenerating axons. In turn, this guidance leads to remodeling of the NMJ itself.

Following injury, primary sensory neurons undergo changes that drive central sensitization and contribute to the maintenance of persistent hypersensitivity. NR2B expression in the dorsal root ganglia (DRG) has not been previously examined in neuropathic pain models. Here, we investigated if changes in NR2B expression within the DRG are associated with hypersensitivities that result from peripheral nerve injuries. This was done by comparing the NR2B expression in the DRG derived from two modalities of the spared nerve injury (SNI) model, since each variant produces different neuropathic pain phenotypes. Using the electronic von Frey to stimulate the spared and non-spared regions of the hindpaws, we demonstrated that sural-SNI animals develop sustained neuropathic pain in both regions while the tibial-SNI animals recover. NR2B expression was measured at Day 23 and Day 86 post-injury. At Day 23 and 86 post-injury, sural-SNI animals display strong hypersensitivity, whereas tibial-SNI animals display 50 and 100% recovery from post-injury-induced hypersensitivity, respectively. In tibial-SNI at Day 86, but not at Day 23 the perinuclear region of the neuronal somata displayed an increase in NR2B protein. This retention of NR2B protein within the perinuclear region, which will render them non-functional, correlates with the recovery observed in tibial-SNI. In sural-SNI at Day 86, DRG displayed an increase in NR2B mRNA which correlates with the development of sustained hypersensitivity in this model. The increase in NR2B mRNA was not associated with an increase in NR2B protein within the neuronal somata. The latter may result from a decrease in kinesin Kif17, since Kif17 mediates NR2B transport to the soma's plasma membrane. In both SNIs, microglia/macrophages showed a transient increase in NR2B protein detected at Day 23 but not at Day 86, which correlates with the initial post-injury induced hypersensitivity in both SNIs. In tibial-SNI at Day 86, but not at Day 23, satellite glia cells (SGCs) displayed an increase in NR2B protein. This study is the first to characterize of cell-specific changes in NR2B expression within the DRG following peripheral nerve injury. We discuss how the observed NR2B changes in DRG can contribute to the different neuropathic pain phenotypes displayed by each SNI variant.

Dietary interventions such as intermittent fasting and the ketogenic diet have demonstrated neuroprotective effects in various models of neurological insult. However, there has been a lack of evaluation of these interventions from a surgical perspective despite their potential to augment reparative processes that occur following nerve injury. Thus, we sought to analyze the effects of these dietary regimens on nerve regeneration and repair by critical appraisal of the literature. Following PRISMA guidelines, a systematic review was performed to identify studies published between 1950 and 2020 that examined the impact of either the ketogenic diet or intermittent fasting on traumatic injuries to the spinal cord or peripheral nerves. Study characteristics and outcomes were analyzed for each included article. A total of 1,890 articles were reviewed, of which 11 studies met inclusion criteria. Each of these articles was then assessed based on a variety of qualitative parameters, including type of injury, diet composition, timing, duration, and outcome. In total, seven articles examined the ketogenic diet, while four examined intermittent fasting. Only three studies examined peripheral nerves. Neuroprotective effects manifested as either improved histological or functional benefits in most of the included studies. Overall, we conclude that intermittent fasting and the ketogenic diet may promote neuroprotection and facilitate the regeneration and repair of nerve fibers following injury; however, lack of consistency between the studies in terms of animal models, diet compositions, and timing of dietary interventions preclude synthesis of their outcomes as a whole.

Delayed autologous nerve graft reconstruction is inevitable in devastating injuries. Delayed or prolonged repair time has deleterious effects on nerve grafts. We aimed improving and accelerating nerve graft reconstruction process in a rat long nerve defect model with loop nerve graft prefabrication particularly to utilize for injuries with tissue loss.

The composition and spatial structure of bioscaffold materials are essential for constructing tissue regeneration microenvironments. In this study, by using an electrospinning technique without any other additives, we successfully developed pure porcine decellularized nerve matrix (xDNME) conduits. The developed xDNME was composed of an obvious decellularized matrix fiber structure and effectively retained the natural components in the decellularized matrix of the nerve tissue. The xDNME conduit exhibited superior biocompatibility and the ability to overcome inter-species barriers. In vivo, after 12 weeks of implantation, xDNME significantly promoted the regeneration of rat sciatic nerve. The regenerated nerve fibers completely connected the two ends of the nerve defect, which were about 8 mm apart. The xDNME and xDNME-OPC groups showed myelin structures in the regenerated nerve fibers. In the xDNME group, the average thickness of the regenerated myelin sheath was 0.640 ± 0.013 μm, which was almost comparable to that in the autologous nerve group (0.646 ± 0.017 μm). Electrophysiological experiments revealed that both of the regenerated nerve fibers in the xDNME and xDNME-OPC groups had excellent abilities to transmit electrical signals. Respectively, the average conduction velocities of xDNME and xDNME-OPC were 8.86 ± 3.57 m/s and 6.99 ± 3.43 m/s. In conclusion, the xDNME conduits have a great potential for clinical treatment of peripheral nerve injuries, which may clinically transform peripheral nerve related regenerative medicine.

Autologous nerve grafting serves is considered the gold standard treatment for peripheral nerve defects; however, limited availability and donor area destruction restrict its widespread clinical application. Although the performance of allogeneic decellularized nerve implants has been explored, challenges such as insufficient human donors have been a major drawback to its clinical use. Tissue-engineered neural regeneration materials have been developed over the years, and researchers have explored strategies to mimic the peripheral neural microenvironment during the design of nerve catheter grafts, namely the extracellular matrix (ECM), which includes mechanical, physical, and biochemical signals that support nerve regeneration. In this study, polycaprolactone/silk fibroin (PCL/SF)-aligned electrospun material was modified with ECM derived from human umbilical cord mesenchymal stem cells (hUMSCs), and a dual-bionic nerve regeneration material was successfully fabricated. The results indicated that the developed biomimetic material had excellent biological properties, providing sufficient anchorage for Schwann cells and subsequent axon regeneration and angiogenesis processes. Moreover, the dual-bionic material exerted a similar effect to that of autologous nerve transplantation in bridging peripheral nerve defects in rats. In conclusion, this study provides a new concept for designing neural regeneration materials, and the prepared dual-bionic repair materials have excellent auxiliary regenerative ability and further preclinical testing is warranted to evaluate its clinical application potential.