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15 October 2012, Volume 7 Issue 29 Previous Issue    Next Issue

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Peripheral nerve regeneration research Why is it getting so “cool”? Stefano Geuna 2012, 7 (29):  2245-2246.  Abstract ( 225 )   PDF (95KB) ( 735 )   Save More than twenty years ago, when I first started working on plasticity and regeneration in the peripheral nervous system, I had the feeling of being part of a little, though lively, scientific community that was rarther isolated in the world of neuroscience which appeared to me as almost only focused on central nervous system. Since then, things have progressively changed very much and, today, interest in the regeneration in the peripheral nervous system, and especially in its main component. i.e. the peripheral nerves (Geuna S, Raimondo S, Ronchi G, et al. Histology of the peripheral nerve and changes occurring during nerve regeneration. Int Rev Neurobiol. 2009;87:27-46.), is sprading tremendouslty among both basic and clinical neuroscientists. Related Articles | Metrics

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Use of hybrid chitosan membranes and human mesenchymal stem cells from the Wharton jelly of umbilical cord for promoting nerve regeneration in an axonotmesis rat model Andrea Gärtner, Tiago Pereira, Maria João Simões, Paulo AS Armada-da-Silva, Miguel L França, Rosa Sousa, Simone Bompasso, Stefania Raimondo, Yuki Shirosaki, Yuri Nakamura, Satoshi Hayakawa, Akiyoshi O 2012, 7 (29):  2247-2258.  Abstract ( 202 )   PDF (416KB) ( 1322 )   Save Many studies have been dedicated to the development of scaffolds for improving post-traumatic nerve regeneration. The goal of this study was to assess the effect on nerve regeneration, associating a hybrid chitosan membrane with non-differentiated human mesenchymal stem cells isolated from Wharton’s jelly of umbilical cord, in peripheral nerve reconstruction after crush injury. Chromosome analysis on human mesenchymal stem cell line from Wharton’s jelly was carried out and no structural alterations were found in metaphase. Chitosan membranes were previously tested in vitro, to assess their ability in supporting human mesenchymal stem cell survival, expansion, and differentiation. For the in vivo testing, Sasco Sprague adult rats were divided in 4 groups of 6 or 7 animals each: Group 1, sciatic axonotmesis injury without any other intervention (Group 1-Crush); Group 2, the axonotmesis lesion of 3 mm was infiltrated with a suspension of 1 250 -1 500 human mesenchymal stem cells (total volume of 50 μL) (Group 2-CrushCell); Group 3, axonotmesis lesion of 3 mm was enwrapped with a chitosan type III membrane covered with a monolayer of non-differentiated human mesenchymal stem cells (Group 3-CrushChitIIICell) and Group 4, axonotmesis lesion of 3 mm was enwrapped with a chitosan type III membrane (Group 4-CrushChitIII). Motor and sensory functional recovery was evaluated throughout a healing period of 12 weeks using sciatic functional index, static sciatic index, extensor postural thrust, and withdrawal reflex latency. Stereological analysis was carried out on regenerated nerve fibers. Results showed that infiltration of human mesenchymal stem cells, or the combination of chitosan membrane enwrapment and human mesenchymal stem cell enrichment after nerve crush injury provide a slight advantage to post-traumatic nerve regeneration. Results obtained with chitosan type III membrane alone confirmed that they significantly improve post-traumatic axonal regrowth and may represent a very promising clinical tool in peripheral nerve reconstructive surgery. Yet, umbilical cord human mesenchymal stem cells, that can be expanded in culture and induced to form several different types of cells, may prove, in future experiments, to be a new source of cells for cell therapy, including targets such as peripheral nerve and muscle. Related Articles | Metrics

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Role of inflammatory cytokines in peripheral nerve injury Federica Fregnan, Luisa Muratori, Anabel Rodriguez Simões, Maria Giuseppina Giacobini-Robecchi, Stefania Raimondo 2012, 7 (29):  2259-2266.  Abstract ( 365 )   PDF (185KB) ( 832 )   Save 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. Related Articles | Metrics

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Emerging issues in peripheral nerve repair Stefano Geuna, Pierluigi Tos, Bruno Battiston 2012, 7 (29):  2267-2272.  Abstract ( 302 )   PDF (125KB) ( 974 )   Save It is today widely acknowledged that nerve repair is now more than a matter of perfect microsurgical reconstruction only and that, to further improve clinical outcome, the involvement of different scientific disciplines is required. This evolving reconstructive/regenerative approach is based on the interdisciplinary and integrated pillars of tissue engineering such as reconstructive microsurgery, transplantation and biomaterials. In this paper, some of the most promising innovations for the tissue engineering of nerves, emerging from basic science investigation, are critically overviewed with special focus on those approaches that appear today to be more suitable for clinical translation. Related Articles | Metrics

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Direct muscle neurotization after end-to-end and end-to-side neurorrhaphy An experimental study in the rat forelimb model Igor Papalia, Giulia Ronchi, Luisa Muratori, Alessandra Mazzucco, Ludovico Magaudda, Stefano Geuna 2012, 7 (29):  2273-2278.  Abstract ( 235 )   PDF (233KB) ( 890 )   Save The need for the continuous research of new tools for improving motor function recovery after nerve injury is justified by the still often unsatisfactory clinical outcome in these patients. It has been previously shown that the combined use of two reconstructive techniques, namely end-to-side neurorrhaphy and direct muscle neurotization in the rat hindlimb model, can lead to good results in terms of skeletal muscle reinnervation. Here we show that, in the rat forelimb model, the combined use of direct muscle neurotization with either end-to-end or end-to-side neurorrhaphy to reinnervate the denervated flexor digitorum muscles, leads to muscle atrophy prevention over a long postoperative time lapse (10 months). By contrast, very little motor recovery (in case of end-to-end neurorrhaphy) and almost no motor recovery (in case of end-to-side neurorrhaphy) were observed in the grasping activity controlled by flexor digitorum muscles. It can thus be concluded that, at least in the rat, direct muscle neurotization after both end-to-end and end-to-side neurorrhaphy represents a good strategy for preventing denervation-related muscle atrophy but not for regaining the lost motor function. Related Articles | Metrics

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Sensory reinnervation of free flaps in reconstruction of the breast and the upper and lower extremities Nektarios Sinis, Androniki Lamia, Helml Gudrun, Thomas Schoeller, Frank Werdin 2012, 7 (29):  2279-2285.  Abstract ( 230 )   PDF (304KB) ( 1216 )   Save There is long-standing debate about sensate versus non-sensate free microvascular flaps among microsurgeons. The principle of connecting not only the vascular supply, but also sensitive nerves, in free tissue transfer is attractive. However, increased operating time and partial spontaneous innervation led to the common decision to restrict microsurgical tissue transfer to the vascular anastomosis and to leave the nerves “untreated”. Nevertheless, in special cases such as breast reconstruction or extremity reconstruction, the question about sensory nerve coaptation of the flaps remains open. We present our experience with free microvascular tissue transfer for breast and extremity reconstruction and compare the data with previous literature and conclude that most free flap surgeries do not benefit from nerve coaptation. Related Articles | Metrics

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Platelet-rich plasma gel in combination with Schwann cells for repair of sciatic nerve injury Fagang Ye, Haiyan Li,Guangxi Qiao, Feng Chen, Hao Tao, Aiyu Ji, Yanling Hu 2012, 7 (29):  2286-2292.  Abstract ( 204 )   PDF (359KB) ( 933 )   Save Bone marrow mesenchymal stem cells were isolated from New Zealand white rabbits, culture-expanded and differentiated into Schwann cell-like cells. Autologous platelet-rich plasma and Schwann cell-like cells were mixed in suspension at a density of 1 × 106 cells/mL, prior to introduction into a poly (lactic-co-glycolic acid) conduit. Fabricated tissue-engineered nerves were implanted into rabbits to bridge 10 mm sciatic nerve defects (platelet-rich plasma group). Controls were established using fibrin as the seeding matrix for Schwann cell-like cells at identical density to construct tissue-engineered nerves (fibrin group). Twelve weeks after implantation, toluidine blue staining and scanning electron microscopy were used to demonstrate an increase in the number of regenerating nerve fibers and thickness of the myelin sheath in the platelet-rich plasma group compared with the fibrin group. Fluoro-gold retrograde labeling revealed that the number of Fluoro-gold-positive neurons in the dorsal root ganglion and the spinal cord anterior horn was greater in the platelet-rich plasma group than in the fibrin group. Electrophysiological examination confirmed that compound muscle action potential and nerve conduction velocity were superior in the platelet-rich plasma group compared with the fibrin group. These results indicate that autologous platelet-rich plasma gel can effectively serve as a seeding matrix for Schwann cell-like cells to construct tissue-engineered nerves to promote peripheral nerve regeneration. Related Articles | Metrics

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Chemoattractive capacity of different lengths of nerve fragments bridging regeneration chambers for the repair of sciatic nerve defects Jiren Zhang, Yubo Wang, Jincheng Zhang 2012, 7 (29):  2293-2296.  Abstract ( 219 )   PDF (348KB) ( 693 )   Save A preliminary study by our research group showed that 6-mm-long regeneration chamber bridging is equivalent to autologous nerve transplantation for the repair of 12-mm nerve defects. In this study, we compared the efficacy of different lengths (6, 8, 10 mm) of nerve fragments bridging 6-mm re-generation chambers for the repair of 12-mm-long nerve defects. At 16 weeks after the regeneration chamber was implanted, the number, diameter and myelin sheath thickness of the regenerated nerve fibers, as well as the conduction velocity of the sciatic nerve and gastrocnemius muscle wet weight ratio, were similar to that observed with autologous nerve transplantation. Our results dem-onstrate that 6-, 8- and 10-mm-long nerve fragments bridging 6-mm regeneration chambers effec-tively repair 12-mm-long nerve defects. Because the chemoattractive capacity is not affected by the length of the nerve fragment, we suggest adopting 6-mm-long nerve fragments for the repair of pe-ripheral nerve defects. Related Articles | Metrics

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Stress and strain analysis on the anastomosis site sutured with either epineurial or perineurial sutures after simulation of sciatic nerve injury Guangyao Liu, Qiao Zhang, Yan Jin, Zhongli Gao 2012, 7 (29):  2299-2304.  Abstract ( 217 )   PDF (294KB) ( 894 )   Save The magnitude of tensile stress and tensile strain at an anastomosis site under physiological stress is an important factor for the success of anastomosis following suturing in peripheral nerve injury treatment. Sciatic nerves from fresh adult cadavers were used to create models of sciatic nerve injury. The denervated specimens underwent epineurial and perineurial suturing. The elastic modulus (40.96 ± 2.59 MPa) and Poisson ratio (0.37 ± 0.02) of the normal sciatic nerve were measured by strain electrical measurement. A resistance strain gauge was pasted on the front, back, left, and right of the edge of the anastomosis site after suturing. Strain electrical measurement results showed that the stress and strain values of the sciatic nerve following perineurial suturing were lower than those following epineurial suturing. Scanning electron microscopy revealed that the sciatic nerve fibers were disordered following epineurial compared with perineurial suturing. These results indicate that the effect of perineurial suturing in sciatic nerve injury repair is better than that of epineurial suturing. References | Related Articles | Metrics

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Heme oxygenase-1 inhibits neuropathic pain in rats with diabetic mellitus Qian Kong, Kang Liu, Lingxi Wu, Long Wang 2012, 7 (29):  2305-2311.  Abstract ( 237 )   PDF (225KB) ( 881 )   Save A diabetes mellitus model was established through single intraperitoneal injection of streptozotocin into rats. Seven days later, model rats were intraperitoneally administered zinc protoporphyrin, a heme oxygenase-1 inducer, and cobalt protoporphyrin, a heme oxygenase-1 inhibitor, once every two days, for 5 successive weeks. After administration, the paw withdrawal mechanical threshold of diabetic mellitus rats significantly decreased, the myelin sheath of the sciatic nerve thickened or showed vacuole defects, the number of spinal dorsal horn neurons reduced, some neurons degenerated and were necrotic, and heme oxygenase-1 was visible in the cytoplasm of spinal dorsal horn neurons. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling demonstrated that the number of apoptotic neurons increased, which could be inhibited by cobalt protoporphyrin, however, zinc protoporphyrin led to an opposite effect. Our experimental findings indicate that heme oxygenase-1 attenuates neuropathic pain in diabetic mellitus rats through amelioration of peripheral neuropathy and inhibition of spinal dorsal horn neuron apoptosis. Related Articles | Metrics

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X-ray repair cross-complementing gene 1 Arg399Gln polymorphism and glioma risk among Asians A meta-analysis based on 2 326 cases and 3 610 controls Liang Zhang, Zhiqun Qiu, Jiaohua Luo, Weiqun Shu 2012, 7 (29):  2313-2319.  Abstract ( 199 )   PDF (189KB) ( 1067 )   Save OBJECTIVE: Previous reports have demonstrated that X-ray repair cross-complementing gene 1 (XRCC1) Arg399Gln polymorphism is a possible risk factor for several cancers. Published data on the association of XRCC1 Arg399Gln polymorphism with glioma susceptibility have generated conflicting results. This study is designed to precisely estimate the relationship. DATA RETRIEVAL: A computer-based online retrieval of Medline, EMBASE, OVID, Sciencedirect, and Chinese National Knowledge Infrastructure was performed to search papers regarding association of XRCC1 Arg399Gln polymorphisms with glioma published up to April 2012. SELECTION CRITERIA: Two investigators selected data independently. Meta analysis was then performed for the selected studies using STATA 11.0 software after strict selection. Heterogeneity test, sensitivity analysis and publication bias assessments were then conducted. MAIN OUTCOME MEASURES: Association of XRCC1 Arg399Gln polymorphism with glioma risk. RESULTS: A total of nine case-controlled studies comprising 2 326 cases and 3 610 controls were selected for final analysis. The overall data failed to indicate a significant association of XRCC1 Arg399Gln polymorphism with glioma risk (Gln/Gln vs. Arg/Arg: odds ratio (OR) = 1.11; 95% confidence interval (CI) = 0.94–1.31; dominant model: OR = 1.06; 95%CI = 0.95–1.18; recessive model: OR = 1.04; 95%CI = 0.81–1.34). However, subgroup analysis regarding ethnicity showed an increased risk among Asians (Gln/Gln vs. Arg/Arg: OR = 1.70; 95%CI = 1.17–2.46; dominant model: OR = 1.40; 95%CI = 1.10–1.78; recessive model: OR = 1.46; 95%CI = 1.04–2.05) but not Caucasians or mixed ethnicities. CONCLUSION: XRCC1 Arg399Gln polymorphism might modify the susceptibility to glioma among Asians but not Caucasians. Further large and well-designed studies are needed to confirm this conclusion. Related Articles | Metrics