Current concepts in end-to-side neurorrhaphy

In peripheral nerve injury,end-to-side neurorrhaphy involves coaptation of the distal stump of a transected nerve to the trunk of an adjacent donor nerve.It has been proposed as an alternative technique when the proximal stump of an injured nerve is unavailable or the nerve gap is too long to be bridged by a nerve graft.Experimental and clinical data suggests that end-to-side neurorrhaphy can provide satisfactory functional recovery for the recipient nerve,without any deterioration of the donor nerve function.The most accepted mechanism of nerve regeneration following end-to-side neurorrhaphy is collateral sprouting.The source of the regenerating axons traveling in the epineurium of the donor nerve is thought to be the proximal Ranvier’s nodes at the site of end-to-side neurorrhaphy,however,histologic evidence is still lacking.Partial neurotomy of the donor nerve may enhance regeneration of motor neurons through end-to-side neurorrhaphy and reinnervation of motor targets.

Axonal regeneration from the spinal cord to peripheral nerve induced by end-to-side neurorrhaphy Evidence from acetylcholinesterase staining and Fluorogold retrograde tracing

BACKGROUND： In recent years, surgeons have advocated root or trunk repair of avulsed nerve roots for overall recovery. However, donor nerves pose a major problem, because they do not contain adequate numbers of axons. Moreover, the procedures lead to nerve deficits in the donor nerve following transplantation. OBJECTIVE： To observe whether axonal regeneration occurs by end-to-side neurorrhaphy in the peripheral nerve and spinal cord. DESIGN, TIME AND SETTING： A neuroanatomical, randomized, controlled, animal study was performed at Functional Anatomy Lab in Nagoya University School of Medicine from May 2002 to July 2003. MATERIALS： Fluorogold was purchased from Fluorochrome, LLC, USA. BX50 light microscope and fluorescent microscope were purchased from Olympus, Japan. METHODS： A total of 21 rats were randomly divided into three groups, and the posterior avulsion injury model （C6-8） of the brachial plexus was performed. In the ventral root graft group, the avulsed C7 ventral roots were reanastomosed to the small anterior lateral aspect window of the spinal cord via nerve grafts. In the dorsal root graft group, the C7 dorsal roots were reanastomosed at the small pia mater window of the posterior lateral aspect of the spinal cord via nerve grafts. In the control group, the avulsed nerve roots were not repaired. MAIN OUTCOME MEASURES： The nerve grafts were collected from the ventral and dorsal root graft groups, and the C7 proximal nerve end was collected from the control group. Acetylcholinesterase staining was performed on the tissue. Fluorogold retrograde tracing technique was applied to determine the origin of the regenerating axons. RESULTS： Results showed that acetylcholine-positive axons existed in nerve grafts of the ventral and dorsal root graft groups. However, axons were not found in the avulsed nerve roots of the control group. Fluorogold retrograde tracing confirmed the presence of fluorogold-containing neurons in the ventral and dorsal horn of the ventral and dorsal root graft groups. Fluorogold-positive neurons were not observed in the control group. CONCLUSION： End-to-side neurorrhaphy induced axonal regeneration from the spinal cord to the peripheral nervous system.

Study on functions of regenerated axons in end-to-side neurorrhaphy

Objective: To probe the possibility of functional sensory endings regeneration after end-to-side neurorrhaphy. Methods: Fifteen New Zealand rabbits were used in this study. The left greater auricular nerve served as the donor nerve. A nerve ed taken from the right ear served as the receptive nerve which anastomosed to the donor nerve by means of end-to-side method and the other end implanted into the denervated skin flap. Normal skin and denervated skin flap without nerve implantation served as control groups, 5 animals in each group. The single nerve fibre recording technique was used to investigate the number, distribution and types of regenerated discharging nerve fibers 4 mouths after operation. Results: The inductive discharges of nerve fibres wave observed in all types of regenerated sensory nerves, the total discharging fibers was about 58% of that in normal skin. Few discharging fibers were observed in denervated skin flap without nerve implantation. Conclusion: End-to-side neurorrhaphy can regenerate functional axons.

End-to-side neurorrhaphy repairs peripheral nerve injury：sensory nerve induces motor nerve regeneration

End-to-side neurorrhaphy is an option in the treatment of the long segment defects of a nerve.It involves suturing the distal stump of the disconnected nerve（recipient nerve） to the side of the intimate adjacent nerve（donor nerve）.However,the motor-sensory specificity after end-to-side neurorrhaphy remains unclear.This study sought to evaluate whether cutaneous sensory nerve regeneration induces motor nerves after end-to-side neurorrhaphy.Thirty rats were randomized into three groups：（1） end-to-side neurorrhaphy using the ulnar nerve（mixed sensory and motor） as the donor nerve and the cutaneous antebrachii medialis nerve as the recipient nerve;（2） the sham group：ulnar nerve and cutaneous antebrachii medialis nerve were just exposed;and（3） the transected nerve group：cutaneous antebrachii medialis nerve was transected and the stumps were turned over and tied.At 5 months,acetylcholinesterase staining results showed that 34% ± 16% of the myelinated axons were stained in the end-to-side group,and none of the myelinated axons were stained in either the sham or transected nerve groups.Retrograde fluorescent tracing of spinal motor neurons and dorsal root ganglion showed the proportion of motor neurons from the cutaneous antebrachii medialis nerve of the end-to-side group was 21% ± 5%.In contrast,no motor neurons from the cutaneous antebrachii medialis nerve of the sham group and transected nerve group were found in the spinal cord segment.These results confirmed that motor neuron regeneration occurred after cutaneous nerve end-to-side neurorrhaphy.

Early muscle reinnervation by means of end-to-side neurorrhaphy in an experimental model

Aim:The aim of the study was to provide early muscular reinnervation to avoid muscle atrophy and functional loss in an experimental model.Methods:Fifty rats were divided into five groups.In group 0(control group)only nerve dissection was performed.Total peroneal nerve section was performed in the remaining groups.Immediate end-to-end neurorrhaphy(EEN)was made in group 1.In group 2,an end-to-side neurorrhaphy(ESN)was performed from the tibial nerve to the peroneal nerve.In group 3,a direct EEN,plus an ESN,were used as a nerve graft as a bridge from the donor nerve(tibial);all nerve coaptations were performed through an epineural window.In group 4,only a neurotomy was made without any type of reconstruction.Results:Neural diameters were similar in groups 0,1,and 3(38±1μm,31±6μm,32±3μm).Neural fibers in group 3 had an 18%increase in the number of axons(P<0.001)when compared to group 0.Group 2(28±1μm)and group 4(19±3μm)had diminished diameters with a lower index of muscle regeneration.Animals in group 4 presented with'clawed'lower extremities and had difficulty with ambulation.Neural graft diameters was similar in groups 2 and 3(33±4μm,31±3μm),but axon density was significantly higher in group 3(53±6μm,39±8μm)(P<0.001).Axon density was 36%higher when the combination of EEN and ESN with a neural graft through an epineural window was performed.Conclusion:This study revealed that the combination of EEN and ESN repairs with the addition of a neural graft provides a lower index of muscle fiber destruction,and can be a reliable method for reconstruction in high neural injuries.

Cortical plasticity and nerve regeneration after peripheral nerve injury

With the development of neuroscience, substantial advances have been achieved in peripheral nerve regeneration over the past decades. However, peripheral nerve injury remains a critical public health problem because of the subsequent impairment or absence of sensorimotor function. Uncomfortable complications of peripheral nerve injury, such as chronic pain, can also cause problems for families and society. A number of studies have demonstrated that the proper functioning of the nervous system depends not only on a complete connection from the central nervous system to the surrounding targets at an anatomical level, but also on the continuous bilateral communication between the two. After peripheral nerve injury, the interruption of afferent and efferent signals can cause complex pathophysiological changes, including neurochemical alterations, modifications in the adaptability of excitatory and inhibitory neurons, and the reorganization of somatosensory and motor regions. This review discusses the close relationship between the cerebral cortex and peripheral nerves. We also focus on common therapies for peripheral nerve injury and summarize their potential mechanisms in relation to cortical plasticity. It has been suggested that cortical plasticity may be important for improving functional recovery after peripheral nerve damage. Further understanding of the potential common mechanisms between cortical reorganization and nerve injury will help to elucidate the pathophysiological processes of nerve injury, and may allow for the reduction of adverse consequences during peripheral nerve injury recovery. We also review the role that regulating reorganization mechanisms plays in functional recovery, and conclude with a suggestion to target cortical plasticity along with therapeutic interventions to promote peripheral nerve injury recovery.

Safety and efficacy of a nerve matrix membrane as a collagen nerve wrapping: a randomized, single-blind, multicenter clinical trial

A new nerve matrix membrane derived from decellularized porcine nerves has been shown to retain the major extracellular matrix components, and to be effective in preventing adhesion between the nerve anastomosis sites and the surrounding tissues in a rat sciatic nerve transection model, thereby enhancing regeneration of the nerve. The effectiveness of the membrane may be attributed to its various bioactive components. In this prospective, randomized, single-blind, parallel-controlled multicenter clinical trial, we compared the safety and efficacy of the new nerve matrix membrane with a previously approved bovine tendon-derived type I collagen nerve wrapping. A total of 120 patients with peripheral nerve injury were recruited from Beijing Jishuitan Hospital, The First Bethune Hospital of Jilin University, and Yantai Yuhuangding Hospital, China. The patients were randomly assigned to undergo end-to-end and tension-free neurorrhaphy with nerve matrix membrane(n = 60, 52 male, 8 female, mean age 41.34 years, experimental group) or tendon-derived collagen nerve wrapping(n = 60, 42 male, 18 female, mean age 40.17 years, control group). Patients were followed-up at 14 ± 5, 30 ± 7, 90 ± 10 and 180 ± 20 days after the operation. Safety evaluation included analyses of local and systemic reactions, related laboratory tests, and adverse reactions. Efficacy evaluation included a static 2-point discrimination test, a moving 2-point discrimination test, and a Semmes–Weinstein monofilament examination. Sensory nerve function was evaluated with the British Medical Research Council Scale and Semmes–Weinstein monofilament examination. The ratio(percentage) of patients with excellent to good results in sensory nerve recovery 180 ± 20 days after the treatment was used as the primary effectiveness index. The percentages of patients with excellent to good results in the experimental and control groups were 98.00% and 94.44%, respectively, with no significant difference between the two groups. There were no significant differences in the results of routine blood tests, liver and renal function tests, coagulation function tests, or immunoglobulin tests at 14 and 180 days postoperatively between the two groups. These findings suggest that the novel nerve matrix membrane is similar in efficacy to the commercially-available bovine-derived collagen membrane in the repair of peripheral nerve injury, and it may therefore serve as an alternative in the clinical setting. The clinical trial was approved by the Institutional Ethics Committee of Beijing Jishuitan Hospital, China(approval No. 20160902) on October 8, 2016, the Institutional Ethics Committee of the First Bethune Hospital of Jilin University, China(approval No. 160518-088) on December 14, 2016, and the Institutional Ethics Committee of Yantai Yuhuangding Hospital, China(approval No. 2016-10-01) on December 9, 2016. The clinical trial was registered with the Chinese Clinical Trial Registry(registration number: Chi CTR2000033324) on May 28, 2020.

Methylene blue enhances polyethylene glycol-fusion repair of completely severed rat sciatic nerves

Complete transection of peripheral mixed nerves immediately produces loss of sensory perception,muscle contractions and voluntary behavior mediated by the severed distal axons.In contrast to natural regeneration(~1 mm/d)of proximal axons that may eventually reinnervate denervated targets,re-innervation is restored within minutes by PEG-fusion that consists of neurorrhaphy and a sequence of well specified hypo-and isotonic calcium-free or calcium-containing solutions,the anti-oxidant methylene blue(MB)and the membrane fusogen polyethylene glycol(PEG).In this study,we examined the relative efficacy of PEG-fusion with no MB(0%),0.5%MB,or 1%MB on the recovery of voluntary behaviors by female Sprague-Dawley rats with a complete mid-thigh severance of their sciatic nerve bathed in extracellular fluid or calcium-containing isotonic saline.The recovery of voluntary behaviors is the most relevant measure of success of any technique to repair peripheral nerve injuries.We assessed recovery by the sciatic functional index,a commonly used measure of voluntary hindlimb behaviors following complete sciatic transections.We reported that both 1%MB and 0.5%MB in sterile distilled water in our PEG-fusion protocol with neurorrhaphy significantly increased the rate and extent of behavioral recovery compared to PEG plus neurorrhaphy alone.Furthermore,0.5%MB was as effective as 1%MB in voluntary behavioral recovery as assessed by the sciatic functional index.Since sterile 1%MB is no longer clinically available,we therefore recommend that 0.5%MB be included in upcoming human clinical trials to evaluate the safety and efficacy of PEG-fusion.All animal procedures were approved by the University of Texas Institutional Animal Care and Use Committee(AUP-2019-00225)on September 9,2020.

Small gap anastomosis to repair peripheral nerve rupture using a nerve regeneration chamber constructed by scissoring and sleeve jointing autologous epineurium

A number of studies have shown how to eliminate the misorientated docking of the peripheral nerve bundle in the traditional epineurium or perineurium anastomosis, thus avoiding neuroma formation and axonal outgrowth from the coaptation sites, and seriously hindering neural function recovery. Based on the ＂peripheral nerve seJective regeneration theory＂, this experiment was designed to investigate the feasibility and benefits of a new small gap anastomosis repairing peripheral nerve rupture, by scissoring and sleeve jointing an autologous epineufium, in the proximal stump of the nerve, a 1 mm-long epineurium was annularly separated and removed, while a 3 mm-long epineurium was longitudinally incised in the distal stump after the epineurium was dissociated from proximal to distal. The epineuria of the two stumps and the longitudinal incision were sutured, leaving a 2 mm gap between the two nerve stumps. Results show that the experimental rats quickly recovered autonomic activities, and there were minimal adhesions at the outer surface of the epineudal tube to the surrounding tissue. The morphologJc changes to the sciatic nerve showed that connective tissue hyperplasia of the small gaps was significantly reduced, and nerve fibers were arranged orderly. No such changes were observed in the neurorrhaphy in situ group. Thus, the experiment confirmed that the new small gap anastomosis to repair peripheral nerve rupture by scissoring and sleeve jointing autologous epineurium is feasible, and that it is superior to epineurium neurorrhaphy in situ.

Does crossover innervation really affect the clinical outcome？ A comparison of outcome between unilateral and bilateral digital nerve repair

Digital nerve injuries are the mostly detected nerve injury in the upper extremity. However, since the clinical phenomenon of crossover innervation at some degree from uninjured digital nerve to the in- jured side occurs after digital nerve injuries is sustained, one could argue that this concept might even result in the overestimation of the outcome of the digital nerve repair. With this knowledge in mind, this study aimed to present novel, pure, focused and valuable clinical data by comparing the outcomes of bilateral and unilateral digital nerve repair. A retrospective review of 28 fingers with unilateral or bilateral digital nerve repair using end-to-end technique in 19 patients within 2 years was performed. Weber＇s two-point discrimination, sharp/dull discrimination, warm/cold sensation and Visual Analog Scale scoring were measured at final 12-month follow ups in all patients. There was no significant difference in recovery of sensibility after unilateral and bilateral digital nerve repairs. Though there is crossover innervation microscopically, it is not important in the clinical evaluation period. According to clinical findings from this study, crossover innervations appear to be negligible in the estimation of outcomes of digital neurorrhaphy.

variation in expression of small ubiquitin-like modifiers in injured sciatic nerve of mice

Small ubiquitin-like modifiers (SUMOs) have been shown to regulate axonal regeneration, signal transduction, neuronal migration, and myelination, by covalently and reversibly attaching to the protein substrates during neuronal cell growth, development, and differentiation. It has not been reported whether SUMOs play a role in peripheral nerve injury and regeneration. To investigate any association between SUMOylation and potential neuroprotective effects during peripheral nerve injury and regeneration, C57/BL mice were randomly divided into sham and experimental groups. The sciatic nerve was exposed only in the sham group. The experimental group underwent neurotomy and epineurial neurorrhaphy. Real-time quantitative polymerase chain reaction and western blot assay results revealed different mRNA and protein expression levels of SUMO1, SUMO2, SUM03 and UBC9 in sciatic nerve tissue (containing both 5 mm of proximal and distal stumps at the injury site) at various time points after injury. Compared with the sham group, protein levels of SUM01 and SUMO2/3 increased in both their covalent and free states after sciatic nerve injury in the experimental group, especially in the covalent state. UBC9 protein levels showed similar changes to those of SUMO1 and SUMO2/3 in the covalent states. Immunohistochemical staining demonstrated that SUMO1 and SUMO2/3 immunopositivities were higher in the experimental group than in the sham group. Our results verified that during the repair of sciatic nerve injury, the mRNA and protein expression of SUMO1, SUMO2, SUMO3 and UBC9 in injured nerve tissues changed in varying patterns and there were clear changes in the expression of SUMO-related proteins. These findings reveal that SUMOs possibly play an important role in the repair of peripheral nerve injury. All animal protocols were approved by the Institutional Animal Care and Use Committee of Tianjin Fifth Central Hospital, China (approval No. TJWZXLL2018041) on November & 2018.

The role of peripheral nerve surgery in a tissue reinnervation

In modern neuroscience,the most relevant is the study of the problem of reinnervation of tissues after severe injuries.Complete restoration of lost physiological functions is still impossible with lesions of peripheral nerves with the formation of extensive diastasis between their proximal and distal sites.In this case,the standard neurorrhaphy cannot be carried out because of the eruption of the filaments during tension and convergence of the ends.To solve this problem,a technique was developed for autotransplantation of the nerve sections,which is still the gold standard for the reconstruction of extensive nerve defects.However,the presence of significant shortcomings led to the development of the doctrine of the direction of regeneration with the help of conduits.Currently,the use of nerve channels is the most promising technology for peripheral nerve repair after trauma.The most actively developing now is the direction of reinnervation,such as neurotization.Neurotization,in some way,combined all the methods of restoring nerves.The overall goal of all these methods—the restoration of extensive nerve defects—allows them to be combined into a new industry:reinnervating neurosurgery.

Sensory protection to enhance functional recovery following proximal nerve injuries:current trends

Proximal nerve injury can lead to devastating functional impairment.Because axonal regeneration is slow,timely reinnervation of denervated muscle does not occur.These denervated muscles atrophy and lose function.Sensory protection is a surgical technique thought to prevent denervated muscle impairment using local sensory nerves to provide trophic support to the muscle until motor nerves can regenerate,and neuromuscular junctions are reestablished.We performed a comprehensive literature search using multiple databases to find primary articles reporting on the outcomes and treatment of sensory protection.This paper reviews the three main approaches to sensory protection:(1)end-to-end neurorrhaphy,(2)end-to-side neurorrhaphy,and(3)direct muscle neurotization.It discusses the evidence supporting each technique and outlines goals for future investigations.