Review Accepted after revision: October 27, 2014 Published online: March 21, 2015

Cells Tissues Organs DOI: 10.1159/000369336

Adipose-Derived Stem Cells for Nerve Repair: Hype or Reality? Paul J. Kingham a Adam J. Reid c Mikael Wiberg a, b a

Section for Anatomy, Department of Integrative Medical Biology, and b Section for Hand and Plastic Surgery, Department of Surgical and Perioperative Science, Umeå University, Umeå, Sweden; c Blond McIndoe Laboratories, Institute of Inflammation and Repair, The University of Manchester, Manchester, UK

Abstract Peripheral nerve injury is a relatively commonly occurring trauma which seriously compromises the quality of life for many individuals. There is a major need to devise new treatment strategies, and one possible approach is to develop cellular therapies to bioengineer new nerve tissue and/or modulate the endogenous regenerative mechanisms within the peripheral nervous system. In this short review we describe how stem cells isolated from adipose tissue could be a suitable element of this approach. We describe the possible mechanisms through which the stem cells might exert a positive influence on peripheral nerve regeneration. These include their ability to differentiate into cells resembling Schwann cells and their secretion of a plethora of neurotrophic growth factors. We also review the literature describing the effects of these cells when tested using in vivo peripheral nerve injury models. © 2015 S. Karger AG, Basel

© 2015 S. Karger AG, Basel 1422–6405/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/cto

Introduction

Peripheral nerve injury results in impaired sensory and motor functions and often leads to long-term disability for the patient. Although peripheral nerve axons are able to regenerate and form functional connections with their targets, several factors, including the type of injury (for example crush vs. axotomy), the location of the injury (proximal vs. distal) and the time delay before treatment, determine the extent of functional outcomes after repair [Scheib and Höke, 2013]. Injury-activated endogenous changes at the cellular and molecular level (occurring during the process known as Wallerian degeneration) enable the neurons to switch from an electrically

Abbreviations used in this paper

ADSCs BDNF DRG GDNF GFAP MRI NGF

adipose-derived stem cells brain-derived neurotrophic factor dorsal root ganglion glial cell-derived neurotropic factor glial fibrillary acidic protein magnetic resonance imaging nerve growth factor

Dr. Paul J. Kingham Section for Anatomy, Department of Integrative Medical Biology Umeå University SE–901 87 Umeå (Sweden) E-Mail paul.kingham @ umu.se

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Key Words Differentiation · Growth factors · Nerve regeneration · Schwann cells · Stem cells

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Stem cells possess the ability to self-renew and generate differentiated progeny. Pluripotent embryonic stem cells can differentiate to cells of all lineages, whereas adult stem cells are multipotent and have a more restricted differentiation potential. A limited number of studies have shown the benefits of embryonic stem cells for treatment of peripheral nerve injuries [Craff et al., 2007; Cui et al., 2008], but ethical issues surrounding these cells means they are not a popular option. This might in the future be addressed by current developments in the area of induced pluripotent stem cells [Xu et al., 2011]. Adult stem cells have been more extensively studied for peripheral nerve repair and the earliest reports most commonly used stem cells isolated from the bone marrow [reviewed in Oliveira et al., 2013]. Adipose tissue is another source of multipotent stem cells which are capable of differentiating into many cell lineages, including neurons and glia [Erba et al., 2010b]. The quantity of adipose-derived stem cells (ADSCs) which can be harvested from adipose tissue has been reported to be significantly greater than the cell numbers which can be obtained from other adult tissues [Strem et al., 2005]. The cells can be harvested with minimally invasive surgical techniques and the isolation procedure is relatively simple, involving four steps: washing of the adipose tissue, enzymatic digestion, centrifugation and removal of red blood cells. The resultant stromal vascular fraction includes preadipocytes, endothelial cells, macrophages, fibroblasts and the stem cells of interest, which readily adhere to tissue plastic substrates and proliferate more rapidly than the other cells resulting in their progressive purification. The simplicity of this process and the development of in-operating room systems for the standardization of isolation have made ADSCs an attractive option for use in a variety of tissue engineering and regenerative medicine applications [Gimble et al., 2013]. In the following sections we review the recent advances in understanding the potential of these cells for treatment of the injured peripheral nervous system.

ADSC and Schwann Cell Differentiation

We were the first research group to show that ADSCs could be differentiated into a phenotype resembling Schwann cells [Kingham et al., 2007]. We found that by treating the ADSCs with a mixture of Schwann cell mitogenic and differentiating factors the cells were induced to express the glial cell markers S100B, glial fibrillary acidic protein (GFAP) and p75 neurotrophin receptor [Kingham et al., 2007] (fig. 1b). Other groups have also treated Kingham /Reid /Wiberg  

 

 

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excitable phenotype to one that actively rebuilds and extends its axon [Bosse, 2012]. However, the rate of regrowth is limited to 1–3 mm/day, this corresponding with the slow rate of anterograde transport of cytoskeletal molecules. Elongation and regeneration through the distal nerve stump is dependent on the growth-supportive milieu provided by the Schwann cells which proliferate and form the bands of Büngner to guide and direct the axons. Despite these intrinsic reactions, a prolonged period of axotomy results in motor neuron atrophy and cell death of primary sensory neurons [Fu and Gordon, 1995; Terenghi et al., 2011]. Any time delay to nerve repair also results in changes in the denervated distal nerve stump, which gradually loses its ability to support regeneration over the course of several months [Gordon et al., 2011; Jonsson et al., 2013]. It has been shown experimentally that even under the most optimal immediate nerve repair scenario only 50% of neurons regenerate their axons into the distal stump [Welin et al., 2008]. More proximal injuries which necessitate regeneration over long distances also result in significant target organ atrophy, which is often impossible to reverse. One of the greatest clinical challenges is to treat nerve defects in which there is a significant loss of tissue. For this, the most common approach is to bridge the proximal and distal nerve stumps with a nerve graft using a section of nerve taken from elsewhere in the body. There are a number of drawbacks to this, such as the limited availability of autologous nerves, size mismatches and the associated morbidities, including neuromas, loss of sensation and donor site tenderness. As an approach to overcome these problems, an active research field has become established in the development of alternative conduit structures [Bell and Haycock, 2012]. However, to date there are few clinically relevant alternatives to nerve grafts and all of the currently marketed conduits fail to fully replicate the biological properties of the nerve graft. Transplantation of cells has been widely proposed as a method to enhance the effectiveness of these alternative conduit structures (fig.  1a). In experimental models of peripheral nerve injury many research groups have shown that transplantation of Schwann cells enhances nerve regeneration [Rodrigues et al., 2012]. However, the use of Schwann cells clinically is limited by the inability to generate sufficient numbers of cells rapidly and the associated donor site morbidity. Stem cells have become a useful component of tissue engineering and regenerative medicine applications for a variety of clinical conditions and they might also have a role to play in replacing lost nerve tissue and as stimulators of axon regeneration.

a

b

Fig. 1. a Nerve conduits, made from various types of materials [re-

viewed in Bell and Haycock, 2012] are used to connect the proximal and distal stumps of injured nerves. Axon regeneration (blue bands) across the nerve tissue gaps can be enhanced by the addition of regenerative cells (green) such as ADSCs. b ADSCs treated with a specific mixture of glial growth factors [Kingham et al., 2007] assume a Schwann cell-like phenotype expressing GFAP (green), S100B (blue) and P75 (red) proteins. The merge immunostaining image shows that a majority of the cells express all 3 Schwann cell markers; the remaining cells are predominantly S100B and GFAP double positive. Scale bar: 40 μm.

rather than subcutaneous or epididymal fat, showed upregulation of all three glial cell markers consistent with the Schwann cell phenotype. Other protocols starting with ADSC-derived neurospheres have also been used to effectively induce a Schwann cell phenotype in the stem cells [Xu et al., 2008b; Radtke et al., 2009]. The growth factor treatment protocol can also be mimicked by coculturing ADSCs and primary Schwann cells [Liao et al., 2010]. Similarly, conditioned medium taken from degenerating sciatic nerves is capable of inducing Schwann celllike differentiation [Liu et al., 2013]. Further confirmation that ADSCs can be effectively differentiated into the Schwann cell phenotype is shown by their expression of specific peripheral myelin proteins [Mantovani et al., 2010] and their ability to form myelin structures with neurons in vitro [Xu et al., 2008a]. Thus, there is compelling evidence for differentiation of rodent adipose stem cells; however, the literature concerning human cells is more limited. Following our original protocol [Kingham et al., 2007], Tomita et al. [2013] showed that human cells adopted a spindle-like morphology but these morphological changes were not accompanied by changes in the expression of Schwann cell proteins. Interestingly, GFAP was found to be constitutively expressed by human ADSCs [Tomita et al., 2013]. Zavan et al. [2010] showed that proliferating glial-like cells could be isolated from human neurospheres. This method has been adapted and, with the inclusion of leukemia inhibitory factor in the differentiation medium, it was possible to increase the number of S100/GFAP-positive cells and the percentage of myelinating cells [Razavi et al., 2013]. A greater understanding of the mechanisms behind the induction of Schwann cell gene and protein expression is required to develop more effective differentiation protocols for human stem cells. However, irrespective of their ability to generate ‘bonafide’ Schwann cells, ADSCs are likely to elicit significant effects on the peripheral nervous system through their expression of a wide range of growth factor molecules.

adherent ADSC cultures under similar conditions and shown the expression of Schwann cell markers by immunocytochemistry and Western blotting [Jiang et al., 2008; Kaewkhaw et al., 2011]. The anatomical location of the adipose tissue depot appears to influence the effectiveness of the differentiation protocol. In the study by Kaewkhaw et al. [2011] only ADSCs isolated from perinephric fat,

Treatment of rat ADSCs with Schwann cell differentiating factors also enhances the ability of the stem cells to promote neurite outgrowth in vitro [Kingham et al., 2007; Jiang et al., 2008], which has been attributed to their expression of high levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) [Kaewkhaw et al., 2011]. ADSC-conditioned medium containing

Stem Cells for Nerve Repair

Cells Tissues Organs DOI: 10.1159/000369336

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ADSCs and Secreted Growth Factors

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Of particular note are the high expression levels of angiogenic molecules in the different systems. Functional assays examining in vitro angiogenic paracrine activity have shown that incubation of endothelial cells in conditioned medium taken from ADSCs evokes the formation of capillary-like tube structures much more efficiently than other stem cell types [Hsiao et al., 2012]. Analysis of the conditioned medium showed it contained high levels of vascular endothelial growth factor and insulin-like growth factor-1 [Hsiao et al., 2012]. More recent studies suggest that the angiogenic activity of ADSCs may be mediated by secreted extracellular vesicles [Lopatina et al., 2014]. We showed that stimulation of human ADSCs with growth factors increased the expression of vascular endothelial growth factor and angiopoietin-1, and promoted in vitro angiogenesis [Kingham et al., 2014]. Importantly, both molecules are also known to mediate axon regeneration [Hobson et al., 2000; Kosacka et al., 2006].

Evidence for ADSC Enhancement of in vivo Peripheral Nerve Regeneration and Repair

Early Time Point Effects Using a rat sciatic nerve transection model we showed that transplantation of Schwann cell-like differentiated ADSCs in fibrin nerve conduits enhances axonal regeneration (measured by immunohistochemistry for PGP9.5-expressing axons) and Schwann cell proliferation compared with empty conduits [di Summa et al., 2010]. In another study using polyhydroxybutyrate nerve conduits we implanted unstimulated rat ADSCs [Erba et al., 2010a]. Although these cells also evoked an increase in axon regeneration at the early time point, we were unable to detect any viable transplanted cells after 2 weeks. Furthermore, addition of stimulating growth factors to the conduit did not enhance regeneration suggesting that a pre-in vitro differentiation protocol is necessary for the cells to evoke the greatest response [Erba et al., 2010a]. We have shown that the Schwann cell-like differentiated ADSCs can be seeded onto various polyester-based scaffolds and retain their neurotrophic activity in coculture with dorsal root ganglion (DRG) neurons [Tse et al., 2010]. Following on from this, we transplanted these constructs in vivo to treat a gap defect in the rat sciatic nerve. The ADSCs modulated the nerve injury-evoked apoptotic signaling cascades in the DRG neurons. Cells increased antiapoptotic Bcl-2 mRNA expression, while decreasing proapoptotic Bax and the effector caspase-3 levels [Reid Kingham /Reid /Wiberg  

 

 

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NGF has been shown to activate the AMP-activated kinase pathway which is central to neuritogenesis [Tan et al., 2011]. Extracellular matrix molecules can potentiate the neurotrophic potential of stem cells. Neurite outgrowth of rat primary sensory neurons is enhanced when Schwann cell-like ADSCs are seeded on fibronectin and laminin [di Summa et al., 2013]. ADSCs themselves also produce a significant quantity of laminin which can activate Schwann cells to enhance myelination in a mutant mouse model [Carlson et al., 2011]. Pharmacological approaches have also been used to modulate the neurotrophic factor levels in ADSCs. For instance, the specific GABAB receptors agonist baclofen influences the expression and the secretion NGF and BDNF [Faroni et al., 2013a]. The cytokine CXCL5 is produced abundantly by ADSCs and is responsible for promoting neurite outgrowth from rat major pelvic ganglia and stimulating signaling cascades in Schwann cells [Zhang et al., 2011]. Coculture of Schwann cells and ADSCs synergistically upregulates the expression of NGF, BDNF and glial cellderived neurotropic factor (GDNF) [Dai et al., 2013]. Both undifferentiated stem cells and those treated with stimulating factors can induce neurite outgrowth, but only the later type can form myelin in vitro [Wei et al., 2010]. Importantly, stem cells seeded onto biomaterials used for nerve repair retain their ability to evoke neurite outgrowth [Tse et al., 2010; de Luca et al., 2013]. Human adipose stem cells stimulate neurite outgrowth of LAN-5 neuroblasts and PC12 cells via the release of both soluble molecules and contact-dependent processes [Lattanzi et al., 2011]. We have found that the stem cells isolated from the superficial layer of abdominal fat tissue have greater neurite outgrowth-enhancing properties than those taken from the deep layer, but we were unable to identify a specific neurotrophic factor accounting for this difference [Kalbermatten et al., 2011]. Stimulation of human ADSCs increases the secretion of NGF, BDNF and GDNF [Tomita et al., 2013; Kingham et al., 2014]. Oxidative stress activates the p38MAPK pathway in human ADSCs and stimulates the secretion of bone morphogenetic protein-2 and fibroblast growth factor-2, both of which enhance neurite outgrowth [Moriyama et al., 2012]. Conditioned medium from human ADSCs has also been shown to be neuroprotective in various in vitro model systems [Lu et al., 2011; Ribeiro et al., 2012]. With recent advances in protein detection and analysis it has become possible to characterize large numbers of proteins found in the ADSC secretome and as many as 68 proteins have been commonly identified across various different culture conditions [Kapur and Katz, 2013].

Later Time Points: Myelinated Fiber Counts, Electrophysiology and Functional Analysis Following on from our earlier work showing both the in vitro and short-term in vivo benefits of stimulating ADSCs towards a Schwann cell-like phenotype, we measured the effect of these cells on a variety of parameters at Stem Cells for Nerve Repair

16 weeks following a 1-cm rat sciatic nerve gap injury [di Summa et al., 2011]. Comparisons were made with bone marrow-derived stem cells treated under identical conditions and an autologous nerve graft group. The ADSCs were the most effective cell population in terms of improvement of the myelinated axonal diameter, evoked potentials in the gastrocnemius muscle and regeneration of the number of motoneurons, similar to the autografts [di Summa et al., 2011]. Schwann cell-like ADSCs can survive transplantation into a chronically denervated rat common peroneal nerve for at least 10 weeks, maintaining their differentiated state [Tomita et al., 2012]. Immunohistochemical staining showed that the transplanted cells actively contributed to the formation of myelin sheaths and the cells produced improvements in motor functional recovery comparable to, and in some parameters superior to, transplanted primary Schwann cells [Tomita et al., 2012]. Human ADSCs induced towards the Schwann cell-like phenotype also survived transplantation in the peripheral nerve of athymic nude rats [Tomita et al., 2013]. In a similar study, transdifferentiated ADSCs were combined with decellularized artery grafts to treat a rat facial nerve lesion [Sun et al., 2011]. After 8 weeks, functional evaluations showed that these cells were as effective as Schwann cells and significantly better than undifferentiated stem cells in a number of morphological and functional parameters. The transplanted cells maintained their Schwann cell-like phenotype and myelin-forming capabilities [Sun et al., 2011]. Interestingly, it appears that differentiated ADSCs have a greater propensity for survival compared with undifferentiated cells [Tomita et al., 2013]. This is rather surprising given the fact that differentiation of ADSCs leads to upregulation of P2X receptors, which sensitizes them to the toxic effects of adenosine 5′-triphosphate via elevated levels of calcium [Faroni et al., 2013b]. Other studies have shown the benefits of manipulating the phenotype of ADSCs in alternative ways. Neurosphere cells derived from human ADSCs can be combined with chitosan-coated nerve conduits to reduce the inflammatory cell reactions associated with glial scarring and thereby evoke improvements in morphological parameters and gait analysis in a rat model [Hsueh et al., 2014]. Neurally induced ADSCs injected onto acellular nerve matrices align to form bands of Büngner-like structures which when used to reconstruct 1-cm nerve gaps in the rat enhance repair as measured by electrophysiology, retrograde labeling and histology analysis [Zhang et al., 2010]. The number of regenerated myelinated nerve fibers is greater when using neurally induced ADSCs versus undifCells Tissues Organs DOI: 10.1159/000369336

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et al., 2011]. This suggests that in addition to stimulating early nerve regeneration the Schwann cell-like adipose stem cells can play a neuroprotective role. More recently we showed that human stem cells also exhibit these properties. In addition to effects on caspase levels in the DRG, transplantation of stimulated ADSCs enhanced expression of two regeneration-associated genes, GAP-43 (growth-associated protein-43) and activating transcription factor-3 in the spinal cord [Kingham et al., 2014]. We have not yet identified the molecules mediating these effects or how they might be able to affect neuronal cell bodies located a significant distance away from the site of cell transplantation, but it is most likely that there is some transfer of the various neurotrophic growth factors identified with in vitro experiments. The mechanism of ADSC effect on axon growth in vivo has been partially addressed using a Matrigel subcutaneous implantation system. GAP-43-positive nerve fiber length and quantity was increased in implants containing undifferentiated ADSCs and further boosted by using ADSCs treated with a neural induction medium [Lopatina et al., 2011]. The induced ADSCs expressed significantly elevated levels of BDNF and treatment of mice with a BDNF-neutralizing antibody abolished the potentiation of axon growth [Lopatina et al., 2011]. In another in vivo transplantation study, Marconi et al. [2012] showed that systemic administration of human ADSCs 1 week after sciatic nerve crush injury in mice increased early nerve fiber sprouting and reduced inflammatory infiltrates up to 3 weeks after injury. Interestingly, they found that the concentration of GDNF was significantly increased in the sciatic nerves in mice treated with ADSCs. This molecule was, however, not detected in the cells prior to their administration, suggesting that the stem cells induced the local production of GDNF by endogenous Schwann cells [Marconi et al., 2012]. Effects of ADSCs on early nerve regeneration can be monitored using magnetic resonance imaging (MRI) [Tremp et al., 2013]. Using a clinical 3-tesla MRI scanner, Tremp et al. [2013] were able to show a strong correlation between the length of regenerating axon front measured by MRI and the length measured by immunocytochemistry. Transplantation of rat ADSCs in this model showed significant enhancements in both measurements.

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has been shown to mimic the effects of the living cells by improving function, electrophysiological recordings and muscle mass measurements after nerve injury and repair in a rat sciatic nerve model [Raisi et al., 2014]. It might, therefore, in the future be possible to generate exosomes from allogeneic donors and bypass requirements for immunosuppression. In summary, there are now a large number of studies describing the use of stem cells for peripheral nerve repair. In a meta-analysis of these studies, including ADSCs and other adult stem cell types, Hundepool et al. [2014] produced forest plots of the 3 major outcome measurements (walking track analysis, muscle mass ratio and electrophysiology) and showed positive effects of stem cells on the regeneration of peripheral nerves at various different time points. Almost all these studies incorporate the short gap injury model in rat sciatic nerve and there is clearly a need to translate these studies to large animal preclinical models.

Conclusions

ADSCs have been shown to have positive effects in a large number of experimental peripheral nerve injury studies, but their definitive mechanism of action is still uncertain. ADSCs show multipotency and can be induced or differentiated into cells with properties resembling Schwann cells (fig. 1b) and other neural lineage phenotypes. ADSCs also secrete a plethora of growth factors which can modulate activity in the peripheral nervous system. From a clinical translation point of view it would be optimal to isolate ADSCs from the nerve-injured patient, minimally manipulate these cells and either transplant as quickly as possible or harness the cell secretome. If the cells are to be transplanted, then future studies need to address the best way to deliver them and create an environment to enable their long-term stable engraftment. If the cell secretome proves to be sufficient for enhancing regeneration, then identification of the optimal cell from the heterogenous mix of cells in the stromal vascular fraction should be addressed, together with finding methods to stabilize the factors and enable a prolonged activity.

Acknowledgements Work at Umeå University is supported by the Swedish Research Council, European Union, Umeå University, County of Västerbotten, Åke Wibergs Stiftelse, and the Clas Groschinskys Minnesfond. A.J.R. is supported by the National Institute for Health Research and the Academy of Medical Sciences.

Kingham /Reid /Wiberg  

 

 

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ferentiated cells in a rat sciatic nerve repair model, although the thickness of the myelin sheath and diameter of nerve fibers is greater when using the later cell type [Gu et al., 2012]. Scholz et al. [2011] also described the use of human ADSCs treated with a neural induction cocktail, although the phenotype of the differentiated cells was not characterized. The cells were transplanted in a silicone conduit to bridge a 13-mm sciatic nerve gap in athymic rats. In a novel approach, the effect of replacing differentiating medium in the conduits, 14 and 28 days after implantation, was investigated. Replenishment of the medium boosted the effects of the ADSCs on the sciatic functional index scores and reduced specific motor functional deficits [Scholz et al., 2011]. Furthermore, the group of animals receiving fresh medium also showed higher muscle masses and more distal nerve fibers 4 months after the repair [Scholz et al., 2011]. The authors concluded that the regeneration was enhanced by production of neurotrophic factors since they did not observe any evidence of histological differentiation or formation of synaptic contact with the growth cones; however, the definitive mechanism remains to be elucidated. Few studies have addressed the treatment of long nerve gaps, but a study by Wang et al. [2012] showed that Schwann cell-like ADSCs are effective inducers of regeneration across a 15-mm defect in the rat sciatic nerve, although the report described only very limited functional outcomes. Although there is now a significant number of reports describing the benefits of differentiated ADSCs in vivo, the clinical acceptance of ADSCs for nerve repair is more likely to be gained if minimally manipulated undifferentiated cells show efficacy. It is therefore encouraging that both uncultured omental adipose-derived stromal vascular fraction [Mohammadi et al., 2011] and ADSCs cultured for one passage [Mohammadi et al., 2013] can evoke better functional recoveries and reduction of muscle atrophy compared with no cell treatment groups after rat sciatic nerve injury. Unfortunately, in those studies a direct comparison with differentiated cells was not made. An alternative approach has been to use undifferentiated stem cells transplanted in coculture with Schwann cells, which gives better functional and morphological results than using ADSCs alone [Dai et al., 2013]. Another route to clinical translation might be to bypass the use of living cells and instead isolate exosomes/microvesicles from the cells. These particulate structures contain proteins and various types of nucleic acid molecules which can be transferred from the donor cell to target cells whose function is then modified [Sun et al., 2013]. Application of microvesicles derived from omental adipose stem cells

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Adipose-derived stem cells for nerve repair: hype or reality?

Peripheral nerve injury is a relatively commonly occurring trauma which seriously compromises the quality of life for many individuals. There is a maj...
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