The Effect of Elbow Extension on the Biomechanics of the Osseoligamentous Structures of the Forearm.

PURPOSE: To investigate the hypothesis that elbow extension alters the biomechanics of forearm rotation including force transmission in the distal and proximal radioulnar joints (DRUJ and PRUJ) and the interosseous ligament (IOL). METHODS: A cadaver model with a custom-designed jig was used to measure forearm pronosupination ranges, transmitted forces and contact areas across the PRUJ and DRUJ, and tension in the 3 main components of the IOL's central band. Testing with applied loads was undertaken throughout pronosupination with the elbow fully flexed (n = 15) and fully extended (n = 11). RESULTS: Elbow extension-flexion affected the range of forearm pronosupination, shifting the arc of rotation such that the forearm supinated maximally with the elbow flexed and pronated maximally with the elbow extended. Elbow extension also increased transmitted forces across the DRUJ and PRUJ while also increasing contact areas within the DRUJ and PRUJ. Elbow extension significantly increased tension in the central band of the IOL when the forearm was maximally pronated. CONCLUSIONS: Maximum supination occurred with the elbow flexed. Maximum pronation occurred with it extended. Elbow position altered forearm biomechanics, including force transmission across the PRUJ and DRUJ and transmitted tension in the IOL. CLINICAL RELEVANCE: The interplay of osseoligamentous forearm structures is such that we would anticipate surgical alteration of any one of them to have effects upon function of the others.

Polymer scaffolds with preferential parallel grooves enhance nerve regeneration.

We have modified the surface topography of poly ɛ-caprolactone (PCL) and polylactic acid (PLA) blended films to improve cell proliferation and to guide the regeneration of peripheral nerves. Films with differing shaped grooves were made using patterned silicon templates, sloped walls (SL), V-shaped (V), and square-shaped (SQ), and compared with nongrooved surfaces with micropits. The solvent cast films were tested in vitro using adult adipose-derived stem cells differentiated to Schwann cell-like cells. Cell attachment, proliferation, and cell orientation were all improved on the grooved surfaces, with SL grooves giving the best results. We present in vivo data on Sprague-Dawley rat sciatic nerve injury with a 10-mm gap, evaluating nerve regeneration at 3 weeks across a polymer nerve conduit modified with intraluminal grooves (SL, V, and SQ) and differing wall thicknesses (70, 100, 120, and 210 µm). The SL-grooved nerve conduit showed a significant improvement over the other topographical-shaped grooves, while increasing the conduit wall thickness saw no positive effect on the biological response of the regenerating nerve. Furthermore, the preferred SL-grooved conduit (C) with 70 µm wall thickness was compared with the current clinical gold standard of autologous nerve graft (Ag) in the rat 10-mm sciatic nerve gap model. At 3 weeks postsurgery, all nerve gaps across both groups were bridged with regenerated nerve fibers. At 16 weeks, features of regenerated axons were comparable between the autograft (Ag) and conduit (C) groups. End organ assessments of muscle weight, electromyography, and skin reinnervation were also similar between the groups. The comparable experimental outcome between conduit and autograft, suggests that the PCL/PLA conduit with inner lumen microstructured grooves could be used as a potential alternative treatment for peripheral nerve repair.

Senescence in adipose-derived stem cells and its implications in nerve regeneration.

Adult mesenchymal stem cells, specifically adipose-derived stem cells have self-renewal and multiple differentiation potentials and have shown to be the ideal candidate for therapeutic applications in regenerative medicine, particularly in peripheral nerve regeneration. Adipose-derived stem cells are easily harvested, although they may show the effects of aging, hence their potential in nerve repair may be limited by cellular senescence or donor age. Cellular senescence is a complex process whereby stem cells grow old as consequence of intrinsic events (e.g., DNA damage) or environmental cues (e.g., stressful stimuli or diseases), which determine a permanent growth arrest. Several mechanisms are implicated in stem cell senescence, although no one is exclusive of the others. In this review we report some of the most important factors modulating the senescence process, which can influence adipose-derived stem cell morphology and function, and compromise their clinical application for peripheral nerve regenerative cell therapy.

Chemical surface modification of poly-ε-caprolactone improves Schwann cell proliferation for peripheral nerve repair.

Poly-ε-caprolactone (PCL) is a biodegradable and biocompatible polymer used in tissue engineering for various clinical applications. Schwann cells (SCs) play an important role in nerve regeneration and repair. SCs attach and proliferate on PCL films but cellular responses are weak due to the hydrophobicity and neutrality of PCL. In this study, PCL films were hydrolysed and aminolysed to modify the surface with different functional groups and improve hydrophilicity. Hydrolysed films showed a significant increase in hydrophilicity while maintaining surface topography. A significant decrease in mechanical properties was also observed in the case of aminolysis. In vitro tests with Schwann cells (SCs) were performed to assess film biocompatibility. A short-time experiment showed improved cell attachment on modified films, in particular when amino groups were present on the material surface. Cell proliferation significantly increased when both treatments were performed, indicating that surface treatments are necessary for SC response. It was also demonstrated that cell morphology was influenced by physico-chemical surface properties. PCL can be used to make artificial conduits and chemical modification of the inner lumen improves biocompatibility.

Localization of mitochondrial carnitine/acylcarnitine translocase in sensory neurons from rat dorsal root ganglia.

The carnitine/acylcarnitine transporter is a transport system whose function is essential for the mitochondrial ß-oxidation of fatty acids. Here, the presence of carnitine/acylcarnitine carrier (CACT) in nervous tissue and its sub-cellular localization in dorsal root ganglia (DRG) neurons have been investigated. Western blot analysis using a polyclonal anti-CACT antibody produced in our laboratory revealed the presence of CACT in all the nervous tissue extracts analyzed. Confocal microscopy experiments performed on fixed and permeabilized DRG neurons co-stained with the anti-CACT antibody and the mitochondrial marker MitoTracker Red clearly showed a mitochondrial localization for the carnitine/acylcarnitine transporter. The transport activity of CACT from DRG extracts reconstituted into liposomes was about 50 % in respect to liver extracts. The experimental data here reported represent the first direct evidence of the expression of the carnitine/acylcarnitine transporter in sensory neurons, thus supporting the existence of the ß-oxidation pathway in these cells.

Adipose-derived stem cells and nerve regeneration: promises and pitfalls.

In order to improve the outcome of nerve regeneration following peripheral trauma injuries, the development of bioengineered nerve grafts has attracted great attention in the field of tissue engineering. Adult stem cells constitute the ideal alternative to Schwann cells (SCs) as transplantable cells in bioartificial nerve grafts. Among the various sources of stem cells with potential applications for regenerative medicine, the adipose tissue has been proven to be one of the most promising. Adipose-derived stem cells (ASCs) are easily obtained, rapidly expanded, show low immunogenicity, and can be differentiated into SCs in vitro. This chapter will focus on recent advances in the use of differentiated and undifferentiated ASCs for peripheral nerve regeneration, with a critical attention for the clinical exploitability of ASC in nerve repair strategies.

Long term peripheral nerve regeneration using a novel PCL nerve conduit.

The gold standard in surgical management of a peripheral nerve gap is currently autologous nerve grafting. This confers patient morbidity and increases surgical time therefore innovative experimental strategies towards engineering a synthetic nerve conduit are welcome. We have developed a novel synthetic conduit made of poly ε-caprolactone (PCL) that has demonstrated promising peripheral nerve regeneration in short-term studies. This material has been engineered to permit translation into clinical practice and here we demonstrate that histological outcomes in a long-term in vivo experiment are comparable with that of autologous nerve grafting. A 1cm nerve gap in a rat sciatic nerve injury model was repaired with a PCL nerve conduit or an autologous nerve graft. At 18 weeks post surgical repair, there was a similar volume of regenerating axons within the nerve autograft and PCL conduit repair groups, and similar numbers of myelinated axons in the distal stump of both groups. Furthermore, there was evidence of comparable re-innervation of end organ muscle and skin with the only significant difference the lower wet weight of the muscle from the PCL conduit nerve repair group. This study stimulates further work on the potential use of this synthetic biodegradable PCL nerve conduit in a clinical setting.

Baclofen modulates the expression and release of neurotrophins in schwann-like adipose stem cells.

Neurotrophins are a group of polypeptides that specifically influence neuronal activity during development and adult life in the central and peripheral nervous system (PNS). In particular, Schwann cells (SC) in the PNS exert a neurotrophic role following up-regulation of several growth factors, including nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). Also SC-like cells derived from adipose tissue (dASC), which have molecular and functional properties similar to SC, can produce and secrete NGF and BDNF. Interestingly, gamma-aminobutyric acid (GABA) and its receptors have been also suggested as modulators of development and myelination in PNS. Therefore, it was interesting to investigate whether the stimulation of the GABA-B receptor may regulate the expression of neurotrophins in SC and dASC. Our findings demonstrated that the specific GABA-B receptors agonist baclofen influences the expression and the secretion NGF and BDNF. In particular, 2 and 24 h of baclofen exposure lead to increased neurotrophins expression in both SC and dASC, as measured by western blot. Moreover, enzyme-linked immunosorbent assay showed that also the levels of released neurotrophins were modified after baclofen treatments. The possibility to modulate the neurotrophic potential of adult stem cell, acting on functional GABAergic receptors, could represent a novel pharmacological approach to improve nerve regeneration.

Extracellular matrix molecules enhance the neurotrophic effect of Schwann cell-like differentiated adipose-derived stem cells and increase cell survival under stress conditions.

Since the first reports of induction of adipose-derived stem cells (ASC) into neuronal and glial cell phenotypes, expectations have increased regarding their use in tissue engineering applications for nerve repair. Cell adhesion to extracellular matrix (ECM) is a basic feature of survival, differentiation, and migration of Schwann cells (SC) during nerve regeneration, and fibronectin and laminin are two key molecules of this process. Interaction between ECM and SC-like differentiated ASC (dASC) could potentially improve the neurotrophic potential of the stem cells. We have investigated the effect of ECM molecules on SC-like dASC in terms of proliferation, adhesion, and cell viability. Fibronectin and laminin did not affect the proliferation of dASC when compared with cell adherent tissue culture plastic, but significantly improved viability and cell attachment when dASC were exposed to apoptotic conditions. To assess the influence of the ECM molecules on dASC neurotrophic activity, dASC were seeded onto ECM-coated culture inserts suspended above dorsal root ganglia (DRG) sensory neurons. Neurite outgrowth of DRG neurons was enhanced when dASC were seeded on fibronectin and laminin when compared with controls. When DRG neurons and dASC were in direct contact on the various surfaces there was significantly enhanced neurite outgrowth and coculture with laminin-conditioned dASC produced the longest neurites. Compared with primary SCs, dASC grown on laminin produced similar levels of neurite outgrowth in the culture insert experiments but neurite length was shorter in the direct contact groups. Anti ß1 integrin blocking antibody could inhibit baseline and dASC evoked neurite elongation but had no effect on outgrowth mediated by laminin-conditioned dASC. ECM molecules had no effect on the levels of nerve growth factor and brain-derived neurotrophic factor secretion from dASC. The results of the study suggest that ECM molecules can significantly improve the potential of dASC for nerve regeneration.

Isolation of adult stem cells and their differentiation to Schwann cells.

Peripheral nerve injuries are an economic burden for society in general and despite advanced microsurgical reconstruction of the damaged nerves the functional result is unsatisfactory with poor sensory recovery and reduced motor functions (Wiberg and Terenghi, Surg Technol Int 11:303-310, 2003). In the treatment of nerve injuries transplantation of a nerve graft is often necessary, especially in nerve gap injuries.Schwann cells (SC) are the key facilitators of peripheral nerve regeneration and are responsible for the formation and maintenance of the myelin sheath around axons in peripheral nerve fibers. They are essential for nerve regeneration after nerve injuries as they produce extracellular matrix molecules, integrins, and trophic factors providing guidance and trophic support for regenerating axons (Wiberg and Terenghi, Surg Technol Int 11:303-310, 2003; Bunge, J Neurol 242:S19-21, 1994; Ide, Neurosci Res 25:101-121, 1996; Mahanthappa et al. J Neurosci 16:4673-4683, 1996). However, the use of ex vivo cultured SC within conduits is limited in its clinical application because of the concomitant donor site morbidity and the slow growth of these cells in vitro (Tohill et al. Tissue Eng 10:1359-1367, 2004).Mesenchymal stem cells (MSC or bone marrow stromal cells) and adipose-derived stem cells (ASC) are easily accessible non-hematopoietic stem cells that have proven essential for research purposes due to their plasticity and ability to differentiate into several functional cell types. This alternative source of cells is relatively simple to isolate and expand in culture. We have demonstrated that MSC and ASC can trans-differentiate along a SC lineage with functional properties and growth factor synthesis activities similar to those of native SC and could provide nerve fiber support and guidance during nerve regeneration.

Mitochondrial involvement in sensory neuronal cell death and survival.

Peripheral nerve injuries (PNI) are continuing to be an ever-growing socio-economic burden affecting mainly the young working population and the current clinical treatments to PNI provide a poor clinical outcome involving significant loss of sensation. Thus, our understanding of the underlying factors responsible for the extensive loss of the sensory cutaneous subpopulation in the dorsal root ganglia (DRG) that occurs following injury needs to be improved. The current investigations focus in identifying visual cues of mitochondria-related apoptotic events in the various subpopulations of sensory cutaneous neurons. Sensory neuronal subpopulations were identified using FastBlue retrograde labelling following axotomy. Specialised fluorogenic probes, MitoTracker Red and MitoTracker Orange, were employed to visualise the dynamic changes of the mitochondrial population of neurons. The results reveal a fragmented mitochondrial network in sural neurons following apoptosis, whereas a fused elongated mitochondrial population is present in sensory proprioceptive muscle neurons following tibial axotomy. We also demonstrate the neuroprotective properties of NAC and ALCAR therapy in vitro. The dynamic mitochondrial network breaks down following oxidative exposure to hydrogen peroxide (H(2)O(2)), but reinitiates fusion after NAC and ALCAR therapy. In conclusion, this study provides both qualitative and quantitative evidence of the susceptibility of sensory cutaneous sub-population in apoptosis and of the neuroprotective effects of NAC and ALCAR treatment on H(2)O(2)-challenged neurons.

Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages.

Adult mesenchymal stem cells have self-renewal and multiple differentiation potentials, and play important roles in regenerative medicine. However, their use may be limited by senescence or age of the donor, leading to changes in stem cell functionality. We investigated morphological, molecular and functional differences between bone marrow-derived (MSC) and adipose-derived (ASC) stem cells isolated from neonatal, young and old rats compared to Schwann cells from the same animals. Immunocytochemistry, RT-PCR, proliferation assays, western blotting and transmission electron microscopy were used to investigate expression of senescence markers. Undifferentiated and differentiated ASC and MSC from animals of different ages expressed Notch-2 at similar levels; protein-38 and protein-53 were present in all groups of cells with a trend towards increased levels in cells from older animals compared to those from neonatal and young rats. Following co-culture with adult neuronal cells, dMSC and dASC from animals of all ages elicited robust neurite outgrowth. Mitotracker(®) staining was consistent with ultrastructural changes seen in the mitochondria of cells from old rats, indicative of senescence. In conclusion, this study showed that although the cells from aged animals expressed markers of senescence, aged MSC and ASC differentiated into SC-like cells still retain potential to support axon regeneration.

Differentiated adipose-derived stem cells promote myelination and enhance functional recovery in a rat model of chronic denervation.

Transplantation of autologous Schwann cells (SCs) is a promising approach for treating various peripheral nerve disorders, including chronic denervation. However, given their drawbacks, such as invasive biopsy and lengthy culture in vitro, alternative cell sources would be needed. Adipose-derived stem cells (ASCs) are a candidate, and in this study rat ASCs transdifferentiated into a SC phenotype (dASC) cocultured with dorsal root ganglion neurons were shown to associate with neurites and to express myelin basic protein (MBP)-positive myelin protein. Furthermore, dASCs transplanted into a chronically denervated rat common peroneal nerve survived for at least for 10 weeks, maintaining their differentiated state. Immunohistochemical analysis revealed that transplanted dASCs associated with regenerating axons, forming MBP-/protein zero-positive myelin sheaths. The cell survival and myelin expression assessed by double labelling with S100 and glial fibrillary acidic protein were similar between the dASC- and SC-transplanted nerves. Importantly, transplantation of dASCs resulted in dramatically improved motor functional recovery and nerve regeneration, with a level comparable to, or even superior to, transplantation of SCs. In conclusion, dASCs are capable of myelinating axons in vivo and enhancing functional outcome after chronic denervation.

The reinnervation pattern of wounds and scars after treatment with transforming growth factor ß isoforms.

BACKGROUND: Wounds deprived of innervation fail to heal normally, and hypertrophic scars may be abnormally innervated. Manipulation of wounds alters the subsequent degree of scarring, and isoforms of transforming growth factor beta (TGFß) are well established in this role, whilst TGFß3 is undergoing clinical trials as an antiscarring agent for clinical use. It is unclear if treated wounds show changes in their innervation patterns as they mature into scars. METHODS: Mice underwent 1cm(2) full thickness skin excisions which were treated with TGFß1 or TGFß3. Wounds were harvested between 5 and 84 days (n=6 at each time point). Sections underwent histological scar assessment and immunohistochemical staining for protein gene product 9.5 (PGP9.5), a pan-neuronal marker, and the sensory neuropeptides calcitonin gene related peptide (CGRP) and substance P (SP). RESULTS: There was no difference in the reinnervation pattern between the peripheral and central parts of the wounds. Wounds treated with TGFß3 healed with dermal collagen organised more like normal skin, whereas TGFß1 treated wounds had abnormally orientated collagen within the scar compared to control treated wounds. Nerve fibre growth into the wounds followed a similar pattern in control and treated wounds, with only one significant difference during the healing process- at 42 days, the density of nerve fibres immunostained with PGP9.5 within the scar was greater than in control wounds. By 84 days, the density of PGP9.5, CGRP and SP immunopositive fibres were similar in control wounds and those treated with TGFß isoforms. CONCLUSIONS: Changes in reinnervation patterns of wounds treated with TGFß isoforms were only slightly different from those of control wounds, and by 84 days, the patterns were similar.

Expression of functional γ-aminobutyric acid type A receptors in Schwann-like adult stem cells.

γ-Aminobutyric acid (GABA) receptors are present in peripheral and central glia and modulate important physiological parameters of glial cells. Schwann cells (SC), the peripheral nervous system glial cells, play essential roles in nerve regeneration, but they are unsuitable for bioengineering of nerve repair. Increasing interest has been focused on adult stem cells derived from bone marrow (BM-MSC) or adipose tissue (ASC), which can be differentiated into SC-like phenotype and used as SC replacements. SC-like adult stem cells express GABA-B receptors that can modulate their proliferation. The aim of this study was to investigate GABA-A receptors functional expression in differentiated stem cells. BM-MSC and ASC were found to express GABA-A α2 and ß3, but not ß1 mRNA transcripts. Protein expression levels of GABA-A α2 and ß3 receptors were upregulated following SC-like differentiation as shown by Western blot studies. GABA-A receptor stimulation with muscimol increased the proliferation rate of SC, differentiated BM-MSC and differentiated ASC. In conclusion, GABA-A α2 and ß3 receptor subunits are present in BM-MSC and ASC and upregulated following glial differentiation. GABA-A subunits in differentiated stem cells and SC assemble in functional receptors modulating cell proliferation. Functional GABA-A and GABA-B receptors represent a possible pharmacological target to modulate SC-like stem cells physiology.

Neuregulin1 administration increases axonal elongation in dissociated primary sensory neuron cultures.

Neuregulin1 is a family of growth and differentiation factors involved in various functions of both peripheral and central nervous system including the regenerative processes that underlie regeneration of damaged peripheral nerves. In the present study we tested in vitro the effect of Neuregulin1 administration on dissociated rat dorsal root ganglion (DRG). Activity of neuregulin1 was compared to the activity of nerve growth factor in the same in vitro experimental model. Results showed that neurite outgrowth is enhanced by the addition of both neuregulin1 and nerve growth factor to the culture medium. While neuregulin1 was responsible for the growth of longer neurites, DRG neurons incubated with nerve growth factor showed shorter and more branched axons. Using enzyme-linked immunosorbent assay we also showed that the release of nerve growth factor, but not of brain derived neurotrophic factor is improved in DRG neuron treated with neuregulin1. On the other hand, the assay with growth factor blocking antibody, showed that effects exerted by neuregulin1 on neurite outgrowth is only partially due to the release of nerve growth factor. Taken together the results of this study provide a better understanding on the role of neuregulin1 in sensory neurons.

Sensory neurons of the human brachial plexus: a quantitative study employing optical fractionation and in vivo volumetric magnetic resonance imaging.

BACKGROUND: Extensive neuron death following peripheral nerve trauma is implicated in poor sensory recovery. Translational research for experimentally proven neuroprotective drugs requires knowledge of the numbers and distribution of sensory neurons in the human upper limb and a novel noninvasive clinical measure of neuron loss. OBJECTIVE: To compare optical fractionation and volumetric magnetic resonance imaging (MRI) of dorsal root ganglia (DRG) in histological quantification and objective clinical assessment of human brachial plexus sensory neurons. METHODS: Bilateral C5-T1 DRG were harvested from 5 human cadavers for stereological volume measurement and sensory neuron counts (optical fractionator). MRI scans were obtained from 14 healthy volunteers for volumetric analysis of C5-T1 DRG. RESULTS: The brachial plexus is innervated by 425,409 (standard deviation 15,596) sensory neurons with a significant difference in neuron counts and DRG volume between segmental levels (P < .001), with C7 ganglion containing the most. DRG volume correlated with neuron counts (r = 0.75, P < .001). Vertebral artery pulsation hindered C5 and 6 imaging, yet high-resolution MRI of C7, C8, and T1 DRG permitted unbiased volume measurement. In accord with histological analysis, MRI confirmed a significant difference between C7, C8, and T1 DRG volume (P < .001), interindividual variability (CV = 15.3%), and sex differences (P = .04). Slight right-left sided disparity in neuron counts (2.5%, P = .04) was possibly related to hand dominance, but no significant volume disparity existed. CONCLUSION: Neuron counts for the human brachial plexus are presented. These correlate with histological DRG volumes and concur with volumetric MRI results in human volunteers. Volumetric MRI of C7-T1 DRG is a legitimate noninvasive proxy measure of sensory neurons for clinical study.

The CD44/integrins interplay and the significance of receptor binding and re-presentation in the uptake of RGD-functionalized hyaluronic acid.

We have studied the interplay between two endocytic receptors for a carrier structure bearing two complementary ligands. Hyaluronic acid (HA; three different molecular weights) was functionalized with an RGD-containing peptide; this ancillary ligand allows the macromolecule to bind to α(v) integrins in addition to the classical HA internalization receptor (CD44). The uptake of HA-RGD and of native HA was assessed in a phagocytic cell model (J774.2 murine macrophages), studying the kinetics of internalization and its mechanistic details. Indications of a synergic binding to integrins and CD44 emerged for HA-RGD; possibly, a first binding to integrins allows for a pre-concentration of the macromolecule on the cell surface, which is then followed by its binding to CD44. The endocytic mechanism and kinetics appeared then dominated by CD44, which has a much slower turnover than integrins. In this study we have demonstrated that the knowledge of the rate-determining steps of the internalization of a carrier is necessary for assessing its performance. In this case, the presence of multiple ligands on a carrier was beneficial in some respect (e.g. in improved binding/targeting), but may not be sufficient to overcome penetration barriers that arise from slow receptor re-presentation.

The nerve injury and the dying neurons: diagnosis and prevention.

Following distal nerve injury significant sensory neuronal cell death occurs in the dorsal root ganglia, while after a more proximal injury, such as brachial plexus injury, a sizeable proportion of spinal motoneurons also undergo cell death. This phenomenon has been undervalued for a long time, but it has a significant role in the lack of functional recuperation, as neuronal cells cannot divide and be replaced, hence the resulting nerve regeneration is usually suboptimal. It is now accepted that this cell death is due to apoptosis, as indicated by analysis of specific genes involved in the apoptotic signalling cascade. Immediate nerve repair, either by direct suturing or nerve grafting, gives a degree of neuroprotection, but this approach does not fully prevent neuronal cell death and importantly it is not always possible. Our work has shown that pharmacological intervention using either acetyl-L-carnitine (ALCAR) or N-acetyl-cysteine (NAC) give complete neuroprotection in different types of peripheral nerve injury. Both compounds are clinically safe and experimental work has defined the best dose, timing after injury and duration of administration. The efficacy of neuroprotection of ALCAR and NAC can be monitored non-invasively using MRI, as demonstrated experimentally and more recently by clinical studies of the volume of dorsal root ganglia. Translation to patients of this pharmacological intervention requires further work, but the available results indicate that this approach will help to secure a better functional outcome following peripheral nerve injury and repair.