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      Effect of Delayed Peripheral Nerve Repair on Nerve Regeneration, Schwann Cell Function and Target Muscle Recovery


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          Despite advances in surgical techniques for peripheral nerve repair, functional restitution remains incomplete. The timing of surgery is one factor influencing the extent of recovery but it is not yet clearly defined how long a delay may be tolerated before repair becomes futile. In this study, rats underwent sciatic nerve transection before immediate (0) or 1, 3, or 6 months delayed repair with a nerve graft. Regeneration of spinal motoneurons, 13 weeks after nerve repair, was assessed using retrograde labeling. Nerve tissue was also collected from the proximal and distal stumps and from the nerve graft, together with the medial gastrocnemius (MG) muscles. A dramatic decline in the number of regenerating motoneurons and myelinated axons in the distal nerve stump was observed in the 3- and 6-months delayed groups. After 3 months delay, the axonal number in the proximal stump increased 2–3 folds, accompanied by a smaller axonal area. RT-PCR of distal nerve segments revealed a decline in Schwann cells (SC) markers, most notably in the 3 and 6 month delayed repair samples. There was also a progressive increase in fibrosis and proteoglycan scar markers in the distal nerve with increased delayed repair time. The yield of SC isolated from the distal nerve segments progressively fell with increased delay in repair time but cultured SC from all groups proliferated at similar rates. MG muscle at 3- and 6-months delay repair showed a significant decline in weight (61% and 27% compared with contra-lateral side). Muscle fiber atrophy and changes to neuromuscular junctions were observed with increased delayed repair time suggestive of progressively impaired reinnervation. This study demonstrates that one of the main limiting factors for nerve regeneration after delayed repair is the distal stump. The critical time point after which the outcome of regeneration becomes too poor appears to be 3-months.

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          Contributing factors to poor functional recovery after delayed nerve repair: prolonged denervation.

          The effects of prolonged denervation, independent from those of prolonged axotomy, on the recovery of muscle function were examined in a nerve cross-anastomosis paradigm. The tibialis anterior muscle was denervated for various durations by cutting the common peroneal nerve before a freshly cut tibial nerve was cross-sutured to its distal stump. Nerve regeneration and muscle reinnervation were quantified by means of electrophysiological and histochemical methods. Progressively fewer axons reinnervated the muscle with prolonged denervation; for example, beyond 6 months the mean (+/- SE) motor unit number was 15 +/- 4, which was far fewer than that after immediate nerve suture (137 +/- 21). The poor regeneration after prolonged denervation is not due to inability of the long-term denervated muscle to accept reinnervation because each regenerated axon reinnervated three- to fivefold more muscle fibers than normal. Rather, it is due to progressive deterioration of the intramuscular nerve sheaths because the effects of prolonged denervation were simulated by forcing regenerating axons to grow outside the sheaths. Fewer regenerated axons account for reinnervation of less than 50% of the muscle fibers in each muscle and contribute to the progressive decline in muscle force. Reinnervated muscle fibers failed to fully recover from denervation atrophy: muscle fiber cross-sectional area being 1171 +/- 84 microns2 as compared to 2700 +/- 47 microns2 after immediate nerve suture. Thus, the primary cause of the poor recovery after long-term denervation is a profound reduction in the number of axons that successfully regenerate through the deteriorating intramuscular nerve sheaths. Muscle force capacity is further compromised by the incomplete recovery of muscle fibers from denervation atrophy.
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            Median and ulnar nerve injuries: a meta-analysis of predictors of motor and sensory recovery after modern microsurgical nerve repair.

            The aim of this study was to quantify variables that influence outcome after median and ulnar nerve transection injuries. The authors present a meta-analysis based on individual patient data on motor and sensory recovery after microsurgical nerve repair. From 130 studies found after literature review, 23 articles were ultimately included, giving individual data for 623 median or ulnar nerve injuries. The variables age, sex, nerve, site of injury, type of repair, use of grafts, delay between injury and repair, follow-up period, and outcome were extracted. Satisfactory motor recovery was defined as British Medical Research Council motor scale grade 4 and 5, and satisfactory sensory recovery was defined as British Medical Research Council grade 3+ and 4. For motor and sensory recovery, complete data were available for 281 and 380 nerve injuries, respectively. Motor and sensory recovery were significantly associated (Spearman r = 0.62, p 40 years: odds ratio, 4.3; 95 percent confidence interval, 1.6 to 11.2), site (proximal versus distal: odds ratio, 0.46; 95 percent confidence interval, 0.20 to 1.10), and delay (per month: odds ratio, 0.94; 95 percent confidence interval, 0.90 to 0.98) were significant predictors of successful motor recovery. In ulnar nerve injuries, the chance of motor recovery was 71 percent lower than in median nerve injuries (odds ratio, 0.29; 95 percent confidence interval, 0.15 to 0.55). For sensory recovery, age (odds ratio, 27.0; 95 percent confidence interval, 9.4 to 77.6) and delay (per month: odds ratio, 0.92; 95 percent confidence interval, 0.87 to 0.98) were found to be significant predictors. In this individual patient data meta-analysis, age, site, injured nerve, and delay significantly influenced prognosis after microsurgical repair of median and ulnar nerve injuries.
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              The basis for diminished functional recovery after delayed peripheral nerve repair.

              The postsurgical period during which neurons remain without target connections (chronic axotomy) and distal nerve stumps and target muscles are denervated (chronic denervation) deleteriously affects functional recovery. An autologous nerve graft and cross-suture paradigm in Sprague Dawley rats was used to systematically and independently control time of motoneuron axotomy, denervation of distal nerve sheaths, and muscle denervation to determine relative contributions of each factor to recovery failure. Tibial (TIB) nerve was cross-sutured to common peroneal (CP) nerve via a contralateral 15 mm nerve autograft to reinnervate the tibialis anterior (TA) muscle immediately or after prolonging TIB axotomy, CP autograft denervation, or TA muscle denervation. Numbers of motoneurons that reinnervated TA muscle declined exponentially from 99 ± 15 to asymptotic mean (± SE) values of 35 ± 1, 41 ± 10, and 13 ± 5, respectively. Enlarged reinnervated motor units fully compensated for reduced motoneuron numbers after prolonged axotomy and autograft denervation, but the maximal threefold enlargement did not compensate for the severe loss of regenerating nerves through chronically denervated nerve stumps and for failure of reinnervated muscle fibers to recover from denervation atrophy. Muscle force, weight, and cross-sectional area declined. Our results demonstrate that chronic denervation of the distal stump plays a key role in reduced nerve regeneration, but the denervated muscle is also a contributing factor. That chronic Schwann cell denervation within the nerve autograft reduced regeneration less than after the denervation of both CP nerve stump and TA muscle, argues that chronic muscle denervation negatively impacts nerve regeneration.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                7 February 2013
                : 8
                : 2
                : e56484
                [1 ]Department of Integrative Medical Biology, Section of Anatomy, Umeå University, Umeå, Sweden
                [2 ]Department of Surgical & Perioperative Science, Section of Hand and Plastic Surgery, Umeå University, Umeå, Sweden
                University of Edinburgh, United Kingdom
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: L. N. Novikov L. N. Novikova MW PK. Performed the experiments: SJ RW AMM PK. Analyzed the data: SJ RW AMM L. N. Novikov L. N. Novikova PK. Contributed reagents/materials/analysis tools: MW. Wrote the paper: SJ L. N. Novikov PK.

                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 3 August 2012
                : 10 January 2013
                Page count
                Pages: 13
                This study was supported by the Swedish Medical Research Council, European Union, Umeå University, County of Västerbotten, Åke Wibergs Stiftelse, Magnus Bergvalls Stiftelse, Clas Groschinskys Minnesfond and the Gunvor and Josef Aner Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Anatomy and Physiology
                Neurological System
                Nerve Tissue
                Peripheral Nervous System
                Cellular Neuroscience
                Molecular Neuroscience
                Neurobiology of Disease and Regeneration
                Anatomy and Physiology
                Neurological System
                Nerve Tissue



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