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Peripheral nerve injuries (PNI) can have several etiologies, such as trauma and iatrogenic interventions, that can lead to the loss of structure and/or function impairment. These changes can cause partial or complete loss of motor and sensory functions, physical disability, and neuropathic pain, which in turn can affect the quality of life. This review aims to revisit the concepts associated with the PNI and the anatomy of the peripheral nerve is detailed to explain the different types of injury. Then, some of the available therapeutic strategies are explained, including surgical methods, pharmacological therapies, and the use of cell-based therapies alone or in combination with biomaterials in the form of tube guides. Nevertheless, even with the various available treatments, it is difficult to achieve a perfect outcome with complete functional recovery. This review aims to enhance the importance of new therapies, especially in severe lesions, to overcome limitations and achieve better outcomes. The urge for new approaches and the understanding of the different methods to evaluate nerve regeneration is fundamental from a One Health perspective. In vitro models followed by in vivo models are very important to be able to translate the achievements to human medicine.

Grafting of C7 from the nonparalyzed to the paralyzed side in patients with arm paralysis resulted in greater improvements in power, spasticity, and function at 12 months than rehabilitation therapy alone, and functional connection to the ipsilateral cerebral hemisphere developed.

Peripheral nerve injury (PNI), one of the most common concerns following trauma, can result in a significant loss of sensory or motor function. Restoration of the injured nerves requires a complex cellular and molecular response to rebuild the functional axons so that they can accurately connect with their original targets. However, there is no optimized therapy for complete recovery after PNI. Supplementation with exogenous growth factors (GFs) is an emerging and versatile therapeutic strategy for promoting nerve regeneration and functional recovery. GFs activate the downstream targets of various signaling cascades through binding with their corresponding receptors to exert their multiple effects on neurorestoration and tissue regeneration. However, the simple administration of GFs is insufficient for reconstructing PNI due to their short half‑life and rapid deactivation in body fluids. To overcome these shortcomings, several nerve conduits derived from biological tissue or synthetic materials have been developed. Their good biocompatibility and biofunctionality made them a suitable vehicle for the delivery of multiple GFs to support peripheral nerve regeneration. After repairing nerve defects, the controlled release of GFs from the conduit structures is able to continuously improve axonal regeneration and functional outcome. Thus, therapies with growth factor (GF) delivery systems have received increasing attention in recent years. Here, we mainly review the therapeutic capacity of GFs and their incorporation into nerve guides for repairing PNI. In addition, the possible receptors and signaling mechanisms of the GF family exerting their biological effects are also emphasized.

Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons. The axons emerge from the stump of the viable nerve attached to the neuronal soma. The SCs downregulate myelin-associated genes and concurrently, upregulate growth-associated genes that include neurotrophic factors as do the injured neurons. However, the gene expression is transient and progressively fails to support axon regeneration within the SC-containing endoneurial tubes. Moreover, despite some preference of regenerating motor and sensory axons to “find” their appropriate pathways, the axons fail to enter their original endoneurial tubes and to reinnervate original target organs, obstacles to functional recovery that confront nerve surgeons. Several surgical manipulations in clinical use, including nerve and tendon transfers, the potential for brief low-frequency electrical stimulation proximal to nerve repair, and local FK506 application to accelerate axon outgrowth, are encouraging as is the continuing research to elucidate the molecular basis of nerve regeneration.

Peripheral nerve injury is a complex condition with a variety of signs and symptoms such as numbness, tingling, jabbing, throbbing, burning or sharp pain. Peripheral nerves are fragile in nature and can easily get damaged due to acute compression or trauma which may lead to the sensory and motor functions deficits and even lifelong disability. After lesion, the neuronal cell body becomes disconnected from the axon's distal portion to the injury site leading to the axonal degeneration and dismantlement of neuromuscular junctions of targeted muscles. In spite of extensive research on this aspect, complete functional recovery still remains a challenge to be resolved. This review highlights detailed pathophysiological events after an injury to a peripheral nerve and the associated factors that can either hinder or promote the regenerative machinery. In addition, it throws light on the available therapeutic strategies including supporting therapies, surgical and non-surgical interventions to ameliorate the axonal regeneration, neuronal survival, and reinnervation of peripheral targets. Despite the availability of various treatment options, we are still lacking the optimal treatments for a perfect and complete functional regain. The need for the present age is to discover or design such potent compounds that would be able to execute the complete functional retrieval. In this regard, plant-derived compounds are getting more attention and several recent reports validate their remedial effects. A plethora of plants and plant-derived phytochemicals have been suggested with curative effects against a number of diseases in general and neuronal injury in particular. They can be a ray of hope for the suffering individuals.

The peripheral nervous system has important regenerative capacities that regulate and restore peripheral nerve homeostasis. Following peripheral nerve injury, the nerve undergoes a highly regulated degeneration and regeneration process called Wallerian degeneration, where numerous cell populations interact to allow proper nerve healing. Recent studies have evidenced the prominent role of morphogenetic Hedgehog signaling pathway and its main effectors, Sonic Hedgehog (SHH) and Desert Hedgehog (DHH) in the regenerative drive following nerve injury. Furthermore, dysfunctional regeneration and/or dysfunctional Hedgehog signaling participate in the development of chronic neuropathic pain that sometimes accompanies nerve healing in the clinical context. Understanding the implications of this key signaling pathway could provide exciting new perspectives for future research on peripheral nerve healing.

Peripheral sensory neurons regenerate their axon after nerve injury to enable functional recovery. Intrinsic mechanisms operating in sensory neurons are known to regulate nerve repair, but whether satellite glial cells (SGC), which completely envelop the neuronal soma, contribute to nerve regeneration remains unexplored. Using a single cell RNAseq approach, we reveal that SGC are distinct from Schwann cells and share similarities with astrocytes. Nerve injury elicits changes in the expression of genes related to fatty acid synthesis and peroxisome proliferator-activated receptor (PPARα) signaling. Conditional deletion of fatty acid synthase ( Fasn ) in SGC impairs axon regeneration. The PPARα agonist fenofibrate rescues the impaired axon regeneration in mice lacking Fasn in SGC. These results indicate that PPARα activity downstream of FASN in SGC contributes to promote axon regeneration in adult peripheral nerves and highlight that the sensory neuron and its surrounding glial coat form a functional unit that orchestrates nerve repair. The contribution of satellite glia to peripheral nerve regeneration is unclear. Here, the authors show that satellite glia are transcriptionally distinct from Schwann cells, share similarities with astrocytes, and, upon injury, they contribute to axon regeneration via Fasn-PPARα signalling pathway.

Craniofacial pain is one of the most common chronic pain conditions, affecting more than one-fifth of the US population. While various medications and conservative treatment modalities are available for this condition, many patients have refractory symptoms. These patients suffer from social impairment, reduced quality of life, and increased financial burdens. The objective of this study was to examine the clinical outcomes of patients receiving a permanent, high-frequency electromagnetic coupling (HF-EMC) powered peripheral nerve stimulator (PNS) system for the treatment of chronic craniofacial neuropathic pain. This study was a multicenter, randomized, controlled clinical trial conducted under an investigational device exemption (IDE). This study was conducted in 7 clinical sites in the US. All patients in this randomized controlled trial (RCT) were permanently implanted with the Freedom® Peripheral Nerve Stimulator (PNS) System (Curonix LLC). All patients completed an initial 7-day therapy assessment period following the permanent implantation. The patients who successfully completed the initial 7-day therapy assessment period (>= 50% pain relief) were randomly assigned to either a patient group that received continued stimulation (the \"active\" arm) or a patient group whose treatment was discontinued for 3 months after the initial positive 7-day therapy assessment period (the \"deactivated\" stimulation arm). After the 3-month follow-up visit, the deactivated patients were reactivated. The primary efficacy outcome included the proportion of patients who experienced significant pain relief (>= 50%) 3 months after the permanent implant procedure. The visual analog scale (VAS), Brief Pain Inventory Facial (BPIF) questionnaire, and Short-Form McGill Pain Questionnaire 2 (MPQ-SF-2) were used to measure changes in pain. Additional functional outcome measures included the Patient Global Impression of Change (PGIC) and the 36-Item Short-Form Survey (SF-36). During the 7-day therapy assessment period, 56 out of 60 patients reported significant pain relief (>= 50%), representing a 93% responder rate. At 3 months, 69% of the active stimulation group experienced significant pain relief, while only 11% of the deactivated group reported significant pain relief. The mean VAS scores were reduced by 62% and 8.5% in the active and deactivated stimulation groups. When patients within the deactivated group were reactivated after 3 months, the reactivated patients reported similar reduction in pain scores to those reported by the active arm patients. Similar results were found for the functional outcome measures. After the reactivation, significant pain relief was maintained through the 12-month follow-up period. No SAEs were reported throughout the study for any of the patients. Limitations include the lack of true placebo due to the required use or nonuse of the external transmitter as control per the study design, the optional utilization of supra- or sub-threshold stimulation, and variations in patient follow-up due to the COVID-19 pandemic. This RCT operated under an IDE requiring regulatory FDA oversight. This study provides Level 1 evidence for PNS therapy. The positive outcomes of this study support an expanded PNS indication for the treatment of craniofacial pain. The study confirms that HF-EMC powered permanent PNS is an effective and safe intervention for refractory chronic craniofacial neuropathic pain.

Background Repairing large nerve defects remains challenging, and no definitive method has been established. We developed a nerve lengthening device for humans and achieved nerve defect repair through nerve lengthening in three cases. The purpose of this report is to describe the clinical course of three cases treated by nerve lengthening and to discuss its effectiveness in the treatment of nerve defects. Methods The target population included males and females aged 20–65 years with peripheral nerve injuries that cannot undergo primary suturing in the limbs were recruited. Three patients were included in this study. The nerve gaps were 13 mm, 15 mm and 100 mm, respectively. We developed a special nerve lengthening device. Starting from postoperative day 1, nerve lengthening was initiated on the proximal and distal ends at a rate of 0.5–1 mm daily (0.25 mm x 2–4 times) using the device. Monthly evaluations post-nerve suturing assessed nerve regeneration, pain, and adverse events. We observed postoperative courses for over 2 years. Results There were two radial nerve injury cases and one median nerve injury case. Functional recovery was observed in cases of shorter nerve defects repaired through nerve lengthening. However, significant functional restoration was not attainable for cases of longer nerve defects or those with prolonged post-injury intervals. Furthermore, in chronic cases, it was confirmed that this method could be used to gradually lengthened and repair severed nerves. There were no reports of pain or lengthening-related troubles during nerve lengthening. Conclusion It was found that good nerve regeneration can be achieved with short nerve defects. Compared to free nerve grafting, this new treatment is promising as it does not require the sacrifice of healthy nerves from the donor site or leave surgical scars. We demonstrated the potential of nerve lengthening as a new treatment option for nerve defects. This study is registered and published in the Japan Registry of Clinical Trials (Project No. jRCTs032180098, https://jrct.niph.go.jp/re/reports/detail/17847 ). Registration date: 28/01/2019.

Unlike other tissues in the body, peripheral nerve regeneration is slow and usually incomplete. Less than half of patients who undergo nerve repair after injury regain good to excellent motor or sensory function and current surgical techniques are similar to those described by Sunderland more than 60 years ago. Our increasing knowledge about nerve physiology and regeneration far outweighs our surgical abilities to reconstruct damaged nerves and successfully regenerate motor and sensory function. It is technically possible to reconstruct nerves at the fascicular level but not at the level of individual axons. Recent surgical options including nerve transfers demonstrate promise in improving outcomes for proximal nerve injuries and experimental molecular and bioengineering strategies are being developed to overcome biological roadblocks limiting patient recovery.