Surgical repair of peripheral nerve injury

Magnification, use of fine interfascicular grafts for repair, and development of intraoperative electrophysiologic measurements of function have had a substantial impact on this field in the last 10 to 20 years. Basic surgical principles established during and since World War II remain the foundation for surgical repair of peripheral nerve injury but have been complemented nicely by these more recent advances. Selection of patients for surgery, as well as the timing of such, has been reviewed with emphasis on the differences between suspected transections and lesions in continuity, as well as comments on serious peripheral entrapments and tumors affecting nerve. The importance of not only preoperative electromyographic studies but also the intraoperative use of stimulation and stimulation and recording of nerve action potentials (NAPs) for lesions in continuity has been stressed. Operative techniques such as neurolysis, NAP recordings, suture, split repair, and interfascicular graft repair have been reviewed and some commentary on results provided. There has been a gradual evolution of centers in this country and abroad for care of the more serious surgical nerve problems. It is anticipated that in the future, such centers will be able to provide improved data concerning results with civilian nerve injuries.     

Craniocerebral injury promotes the repair of peripheral nerve injury

The increase in neurotrophic factors after craniocerebral injury has been shown to promote fracture healing. Moreover, neurotrophic factors play a key role in the regeneration and repair of peripheral nerve. However, whether craniocerebral injury alters the repair of peripheral nerve injuries remains poorly understood. Rat injury models were established by transecting the left sciatic nerve and using a free-fall device to induce craniocerebral injury. Compared with sciatic nerve injury alone after 6–12 weeks, rats with combined sciatic and craniocerebral injuries showed decreased sciatic functional index, increased recovery of gastrocnemius muscle wet weight, recovery of sciatic nerve ganglia and corresponding spinal cord segment neuron morphologies, and increased numbers of horseradish peroxidase-labeled cells. These results indicate that craniocerebral injury promotes the repair of peripheral nerve injury.     

Role of inflammatory cytokines in peripheral nerve injury

Inflammatory events occurring in the distal part of an injured peripheral nerve have, nowadays, a great resonance. Investigating the timing of action of the several cytokines in the important stages of Wallerian degeneration helps to understand the regenerative process and design pharmacologic intervention that promotes and expedites recovery. The complex and synergistic action of inflammatory cytokines finally promotes axonal regeneration. Cytokines can be divided into pro-and anti-inflammatory cytokines that upregulate and downregulate, respectively, the production of inflammatory mediators. While pro-inflammatory cytokines are expressed in the first phase of Wallerian degeneration and promote the recruitment of macrophages, anti-inflammatory cytokines are expressed after this recruitment and downregulate the production of all cytokines, thus determining the end of the process. In this review, we describe the major inflammatory cytokines involved in Wallerian degeneration and the early phases of nerve regeneration. In particular, we focus on interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor-β, interleukin-10 and transforming growth factor-β.     

Role of neuregulin-1 in peripheral nerve injury

Peripheral nerve injury in humans often leads to permanent functional deficits. Schwann cells play an important role in the recovery of peripheral nerve injury by ensheathing axons and providing various neurotrophic factors. Neuregulin-1 (NRG-1) provides axonal signals, which allow dedifferentiation and rapid proliferation of Schwann cells. Subsequently, NRG-1 promotes axonal myelination and influences myelin thickness. Moreover, NRG-1 plays a critical role in synapse formation in the neuromuscular junction. These effects, together, suggest that NRG-1 promotes recovery of peripheral nerve injury.     

Site-specific subtypes of macrophages recruited after peripheral nerve injury

After partial ligation of mouse sciatic nerve, the subtypes of macrophages were examined in the injured nerve and dorsal root ganglia (DRGs). Many M1 macrophages, which were inducible nitric oxide synthase (iNOS)-positive and arginase-1 (Arg-1)-negative, and neutrophils infiltrated the injured nerve. In contrast, almost all macrophages infiltrating the ipsilateral side of DRGs after the nerve injury were iNOS?/Arg-1?, M2 type. The infiltration of M1 and M2 macrophages was first observed in the injured nerve and ipsilateral DRGs on days 1 and 2, respectively. In addition, the macrophage infiltration preceded the activation of microglia in the ipsilateral dorsal horn of spinal cord. Thus, infiltrating macrophages after peripheral nerve injury may play unique roles dependent on the location in the development of neuropathic pain.     

周围神经损伤修复与再生中的基因治疗

背景：周围神经损伤后功能恢复不够理想。基因治疗为其功能修复提供了新的方法。 目的：从功能基因、转染载体选择、基因翻译因子生物学效应3方面进行综述,为周围神经损伤的基因治疗研究提供参考。 方法：由第一作者应用计算机检索PubMed和中国期刊全文数据库(CNKI)2006/2010相关文献。在标题、摘要、关键词中以“peripheral nerve injury, gene therapy, virus vector”或“周围神经损伤、基因治疗、病毒载体”为检索词进行检索。选择与周围神经损伤的基因治疗有关的文献,同一领域文献则选择近期发表及发表在权威杂志的文章。 结果与结论：共检索到35篇文章,按纳入和排除标准对文献进行筛选,保留20篇文章进行综述。目前,周围神经损伤的基因治疗技术已经日趋成熟,如转基因的腺病毒表达的骨形态发生蛋白7和Ad-32Ep65-Flag基因等,有望成为临床修复周围神经损伤的重要手段。     

Tissue engineering for the repair of peripheral nerve injury

Peripheral nerve injury is a common clinical problem and affects the quality of life of patients. Traditional restoration methods are not satisfactory. Researchers increasingly focus on the field of tissue engineering. The three key points in establishing a tissue engineering material are the biological scaffold material, the seed cells and various growth factors. Understanding the type of nerve injury, the construction of scaffold and the process of repair are necessary to solve peripheral nerve injury and promote its regeneration. This review describes the categories of peripheral nerve injury, fundamental research of peripheral nervous tissue engineering and clinical research on peripheral nerve scaffold material, and paves a way for related research and the use of conduits in clinical practice.     

神经导管生物材料修复周围神经损伤的动物实验

目的：通过动物体内神经导管生物材料移植实验,观察、测定再生神经功能恢复的程度和神经再生的数目。方法：应用计算机检索中国期刊全文数据库1996/2010文献,检索词为“神经导管,神经损伤,导管材料,生物材料”。纳入有关神经导管材料在周围神经损伤修复中应用的动物实验。结果：现有的任何材料都不能制备出理想的神经导管。在生物可降解前提下,往往天然材料具有更好的生物相容性,而合成高聚物可以通过调节组分的比例和相对分子质量及相对分子质量分布等条件,从而调节降解时间和材料的机械性能以及物理性能。外周神经修复理想的导管首先需要选择合适的生物材料和组装技术,制成具有良好物理特性(通透性、柔韧性、降解性等)的导管,尤其是对于较大的神经缺损通透性和柔韧性更为重要。结论：在单腔中空导管中填充不同材料能促进神经的再生,联合应用几种不同的填充物质可能更加有利于神经修复。关键词：神经导管;神经损伤;导管材料;修复;生物材料doi:10.3969/j.issn.1673-8225.2010.29.030     

A novel bioactive nerve conduit for the repair of peripheral nerve injury

The use of a nerve conduit provides an opportunity to regulate cytokines, growth factors and neurotrophins in peripheral nerve regeneration and avoid autograft defects. We constructed a poly-D-L-lactide(PDLLA)-based nerve conduit that was modified using poly{(lactic acid)-co-[(glycolic acid)-alt-(L-lysine)]} and β-tricalcium phosphate. The effectiveness of this bioactive PDLLA-based nerve conduit was compared to that of PDLLA-only conduit in the nerve regeneration following a 10-mm sciatic nerve injury in rats. We observed the nerve morphology in the early period of regeneration, 35 days post injury, using hematoxylin-eosin and methylene blue staining. Compared with the PDLLA conduit, the nerve fibers in the PDLLA-based bioactive nerve conduit were thicker and more regular in size. Muscle fibers in the soleus muscle had greater diameters in the PDLLA bioactive group than in the PDLLA only group. The PDLLA-based bioactive nerve conduit is a promising strategy for repair after sciatic nerve injury.     

Role of microtubule dynamics in Wallerian degeneration and nerve regeneration after peripheral nerve injury

Wallerian degeneration,the progressive disintegration of distal axons and myelin that occurs after peripheral nerve injury,is essential for creating a permissive microenvironment for nerve regeneration,and involves cytoskeletal reconstruction.However,it is unclear whether microtubule dynamics play a role in this process.To address this,we treated cultured sciatic nerve explants,an in vitro model of Wallerian degeneration,with the microtubule-targeting agents paclitaxel and nocodazole.We found that paclitaxel-induced microtubule stabilization promoted axon and myelin degeneration and Schwann cell dedifferentiation,whereas nocodazole-induced microtubule destabilization inhibited these processes.Evaluation of an in vivo model of peripheral nerve injury showed that treatment with paclitaxel or nocodazole accelerated or attenuated axonal regeneration,as well as functional recovery of nerve conduction and target muscle and motor behavior,respectively.These results suggest that microtubule dynamics participate in peripheral nerve regeneration after injury by affecting Wallerian degeneration.This study was approved by the Animal Care and Use Committee of Southern Medical University,China(approval No.SMUL2015081) on October 15,2015.     

Roles of neural stem cells in the repair of peripheral nerve injury

Currently, researchers are using neural stem cell transplantation to promote regeneration after peripheral nerve injury, as neural stem cells play an important role in peripheral nerve injury repair. This article reviews recent research progress of the role of neural stem cells in the repair of peripheral nerve injury. Neural stem cells can not only differentiate into neurons, astrocytes and oligodendrocytes, but can also differentiate into Schwann-like cells, which promote neurite outgrowth around the injury. Transplanted neural stem cells can differentiate into motor neurons that innervate muscles and promote the recovery of neurological function. To promote the repair of peripheral nerve injury, neural stem cells secrete various neurotrophic factors, including brain-derived neurotrophic factor, fibroblast growth factor, nerve growth factor, insulin-like growth factor and hepatocyte growth factor. In addition, neural stem cells also promote regeneration of the axonal myelin sheath, angiogenesis, and immune regulation. It can be concluded that neural stem cells promote the repair of peripheral nerve injury through a variety of ways.     

Evaluation of artificial nerve conduit and autografts in peripheral nerve repair in the rat model of sciatic nerve injury

Objective: To investigate the therapeutic effect of artificial nerve conduit in the sciatic nerve injury and repair in the rat model.

Methods: A total of 60 adult male Sprague Dawley rats were evenly randomized into five groups to build the model of sciatic nerve injury and perform the injury repair experiment. The five groups were: group A which was treated with artificial nerve conduit, group B which was treated with common carotid artery (CCA) autograft, group C which was treated with sciatic nerve autograft, group D which was treated with sham operation, and group E as the normal control. The injury was repaired by direct coaptation of the nerve ends. Postoperatively, the rats’ behavior, motor nerve conduction velocity (MNCV), incubation period, amplitude, remaining rate of wet weight of the gastrocnemius muscle, the diameter and section area of the gastrocnemius cell, and the histological changes were assessed. The results were analyzed by one-way ANOVA and two-way ANOVA.

Results: Twelve days postoperatively, 36 rats in groups A, B, and C presented with denervated adermotrophia on the injured ankle. The electrophysiological indicators in groups D and E were constant and similar. The values of MNCV and amplitude were group C > group A > group B, with an increasing tendency. The values of the incubation period were group C < group A < group B with statistical difference (p < 0.05) and showed a decreasing tendency. The wet gastrocnemius muscle in groups D and E showed plump morphology with luster and elasticity. Groups A and C had similar atrophic gastrocnemius muscles and reduced flexibility while the phenomena were more severe in group B. Progressive decrease of the cell diameter and sectional area was observed in groups A, B, and C. The adhesion between the sciatic nerve and the surrounding area in groups A, B, and C had statistical significance (P < 0.05), with group B the most serious.

Conclusions: The results suggest that artificial nerve conduit facilitated functional and morphological regeneration of the nerve. It seemed more effective than CCA but inferior to sciatic nerve autograft in repairing sciatic nerve injury in the rat model.     

Estimations of topographically correct regeneration to nerve branches and skin after peripheral nerve injury and repair

Peripheral nerve injury is typically associated with long-term disturbances in sensory localization, despite nerve repair and regeneration. Here, we investigate the extent of correct reinnervation by back-labeling neuronal soma with fluorescent tracers applied in the target area before and after sciatic nerve injury and repair in the rat. The subpopulations of sensory or motor neurons that had regenerated their axons to either the tibial branch or the skin of the third hindlimb digit were calculated from the number of cell bodies labeled by the first and/or second tracer. Compared to the normal control side, 81% of the sensory and 66% of the motor tibial nerve cells regenerated their axons back to this nerve, while 22% of the afferent cells from the third digit reinnervated this digit. Corresponding percentages based on quantification of the surviving population on the experimental side showed 91%, 87%, and 56%, respectively. The results show that nerve injury followed by nerve repair by epineurial suture results in a high but variable amount of topographically correct regeneration, and that proportionally more neurons regenerate into the correct proximal nerve branch than into the correct innervation territory in the skin.     

Heat shock protein is a key therapeutic target for nerve repair in autoimmune peripheral neuropathy and severe peripheral nerve injury

Guillain-Barré syndrome (GBS) is an autoimmune peripheral neuropathy and a common cause of neuromuscular paralysis. Preceding infection induces the production of anti-ganglioside (GD) antibodies attacking its own peripheral nerves. In severe proximal peripheral nerve injuries that require long-distance axon regeneration, motor functional recovery is virtually nonexistent. Damaged axons fail to regrow and reinnervate target muscles. In mice, regenerating axons must reach the target muscle within 35 days (critical period) to reform functional neuromuscular junctions and regain motor function. Successful functional recovery depends on the rate of axon regeneration and debris removal (Wallerian degeneration) after nerve injury. The innate-immune response of the peripheral nervous system to nerve injury such as timing and magnitude of cytokine production is crucial for Wallerian degeneration. In the current study, forced expression of human heat shock protein (hHsp) 27 completely reversed anti-GD-induced inhibitory effects on nerve repair assessed by animal behavioral assays, electrophysiology and histology studies, and the beneficial effect was validated in a second mouse line of hHsp27. The protective effect of hHsp27 on prolonged muscle denervation was examined by performing repeated sciatic nerve crushes to delay regenerating axons from reaching distal muscle from 37 days up to 55 days. Strikingly, hHsp27 was able to extend the critical period of motor functional recovery for up to 55 days and preserve the integrity of axons and mitochondria in distal nerves. Cytokine array analysis demonstrated that a number of key cytokines which are heavily involved in the early phase of innate-immune response of Wallerian degeneration, were found to be upregulated in the sciatic nerve lysates of hHsp27 Tg mice at 1 day postinjury. However, persistent hyperinflammatory mediator changes were found after chronic denervation in sciatic nerves of littermate mice, but remained unchanged in hHsp27 Tg mice. Taken together, the current study provides insight into the development of therapeutic strategies to enhance muscle receptiveness (reinnervation) by accelerating axon regeneration and Wallerian degeneration.     

周围神经的诱导修复

在外伤性的损伤中约有2.8%的人造成周围神经的损伤(如车祸和工伤等),而其中65%的人伤势严重,而且他们大多数年龄在18～35周岁的青壮年男子,损伤后的周围神经需要在一定的时间内进行修复和重建,否则损伤神经所支配的器官或组织的功能将丧失.在周围神经的损伤中除了外伤性损伤外,还有自发性损伤、医源性损伤、压迫性综合征和系统性疾病等,而这些神经损伤或病变中诸多是显微外科所不能治愈的,神经的诱导修复和再生是最好的解决办法.目前周围神经的修复和再生的标准方法是自体神经移植(Autologous nerve graft, ANG),但是由于能够提供自体神经移植的捐赠部位十分有限,远远不能满足需要,有些较长或粗大的周围神经损伤不是一两个捐赠部位的神经所能解决的,而且捐赠部位的神经的损伤会造成新的功能的丧失.因此许多学者利用异体材料或人工合成材料来诱导周围神经的修复和再生进行了大量的研究,希望能够取代自体神经移植.本文就近几年的基质材料的选择、许旺细胞(Schwann cells,SCs)、生长因子和生物学评价等方面的进展作一综述.     

A simple model of radial nerve injury in the rhesus monkey to evaluate peripheral nerve repair

Current research on bone marrow stem cell transplantation and autologous or xenogenic nerve transplantation for peripheral nerve regeneration has mainly focused on the repair of peripher-al nerve defects in rodents. In this study, we established a standardized experimental model of radial nerve defects in primates and evaluated the effect of repair on peripheral nerve injury. We repaired 2.5-cm lesions in the radial nerve of rhesus monkeys by transplantation of autografts, acellular allografts, or acellular allografts seeded with autologous bone marrow stem cells. Five months after surgery, regenerated nerve tissue was assessed for function, electrophysiology, and histomorphometry. Postoperative functional recovery was evaluated by the wrist-extension test. Compared with the simple autografts, the acellular allografts and allografts seeded with bone marrow stem cells facilitated remarkable recovery of the wrist-extension functions in the rhesus monkeys. This functional improvement was coupled with radial nerve distal axon growth, a higher percentage of neuron survival, increased nerve fiber density and diameter, increased myelin sheath thickness, and increased nerve conduction velocities and peak amplitudes of compound motor action potentials. Furthermore, the quality of nerve regeneration in the bone marrow stem cells-laden allografts group was comparable to that achieved with autografts. The wrist-extension test is a simple behavioral method for objective quantification of peripheral nerve regeneration.     

Use of nerve conduits for peripheral nerve injury repair A Web of Science-based literature analysis

OBJECTIVE: To identify global research trends in the use of nerve conduits for peripheral nerve injury repair. DATA RETRIEVAL: Numerous basic and clinical studies on nerve conduits for peripheral nerve injury repair were performed between 2002-2011. We performed a bibliometric analysis of the institutions, authors, and hot topics in the field, from the Web of Science, using the key words peripheral nerve and conduit or tube. SELECTION CRITERIA: Inclusion criteria: peer-reviewed published articles on nerve conduits for peripheral nerve injury repair, indexed in the Web of Science; original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items. Exclusion criteria: articles requiring manual searching or telephone access; documents not published in the public domain; and several corrected papers. MAIN OUTCOME MEASURES: (a) Annual publication output; (b) publication type; (c) publication by research field; (d) publication by journal; (e) publication by funding agency; (f) publication by author; (g) publication by country and institution; (h) publications by institution in China; (i) most-cited papers. RESULTS: A total of 793 publications on the use of nerve conduits for peripheral nerve injury repair were retrieved from the Web of Science between 2002-2011. The number of publications gradually increased over the 10-year study period. Articles constituted the main type of publication. The most prolific journals were Biomaterials, Microsurgery, and Journal of Biomedical Materials Research Part A. The National Natural Science Foundation of China supported 27 papers, more than any other funding agency. Of the 793 publications, almost half came from American and Chinese authors and institutions. CONCLUSION: Nerve conduits have been studied extensively for peripheral nerve regeneration; however, many problems remain in this field, which are difficult for researchers to reach a consensus.     

Interaction between Schwann cells and other cells during repair of peripheral nerve injury

Peripheral nerve injury(PNI) is common and, unlike damage to the central nervous system injured nerves can effectively regenerate depending on the location and severity of injury. Peripheral myelinating glia, Schwann cells(SCs), interact with various cells in and around the injury site and are important for debris elimination, repair, and nerve regeneration. Following PNI, Wallerian degeneration of the distal stump is rapidly initiated by degeneration of damaged axons followed by morphologic changes in SCs and the recruitment of circulating macrophages. Interaction with fibroblasts from the injured nerve microenvironment also plays a role in nerve repair. The replication and migration of injury-induced dedifferentiated SCs are also important in repairing the nerve. In particular, SC migration stimulates axonal regeneration and subsequent myelination of regenerated nerve fibers. This mobility increases SC interactions with other cells in the nerve and the exogenous environment, which influence SC behavior post-injury. Following PNI, SCs directly and indirectly interact with other SCs, fibroblasts, and macrophages. In addition, the inter-and intracellular mechanisms that underlie morphological and functional changes in SCs following PNI still require further research to explain known phenomena and less understood cell-specific roles in the repair of the injured peripheral nerve. This review provides a basic assessment of SC function post-PNI, as well as a more comprehensive evaluation of the literature concerning the SC interactions with macrophages and fibroblasts that can influence SC behavior and, ultimately, repair of the injured nerve.