Functional Recovery Of Peripheral Nerve Research Articles

Evaluating the Effectiveness of the Experimental Use of the Collagen Conduit Filled With Dermal hydrogel to Repair a Peripheral Nerve Defect

Background: Current studies show that hollow conduits in combination with various synthetic and biological fillers significantly accelerate functional recovery of peripheral nerves. One of such fillers can be a hydrogel based on the extracellular matrix of the dermis, which contains surface ligands capable of providing topographic and biological signals for nerve regeneration.Objective: To evaluate the effectiveness of rat sciatic nerve regeneration using a collagen conduit filled with dermal hydrogel in an in vivo experiment.Materials and methods: We evaluated the effectiveness of the NeuraGen® collagen conduit filled with dermal hydrogel and compared it with that of an autograft and the NeuraGen® hollow collagen conduit in experimental treatment of rat sciatic nerve defects larger than 1 cm. Male Wistar rats underwent sciatic nerve resection. We calculated the Sciatic Functional Index (SFI) and ratio of the calf circumference in an operated limb to that in an intact limb on days 30, 60, and 90 after implantation. We performed electrophysiological tests and explanted samples for hematoxylin-eosin staining on day 90 of the experiment.Results: When assessing the SFI and electrophysiological parameters, the group of animals with autografts and the group with the NeuraGen® collagen conduits filled with dermal hydrogel demonstrated similar results. We observed muscle atrophy, low SFI scores, and low velocity and short duration of the action potential in the group with the hollow NeuraGen® collagen conduits. Histological analysis of explanted samples of the collagen conduits filled with dermal hydrogel demonstrated areas of glial proliferation and the absence of pronounced degeneration of nerve fibers throughout the implant compared with autografts, indicating functional regeneration of nerve fibers.Conclusions: Evaluation of the effectiveness of rat sciatic nerve regeneration showed that the NeuraGen® collagen conduit filled with dermal hydrogel provides functional and morphological integration with the nerve compared with an autograft. Our findings can be used for further development and improvement of nerve conduits.

Composite Hydrogel Conduit Incorporated with Platelet-Rich Plasma Improved the Regenerative Microenvironment for Peripheral Nerve Repair.

Peripheral nerve regeneration and functional recovery remain major challenges in clinical practice. Nerve guidance conduits (NGCs) which can regulate the regenerative microenvironment are beneficial for peripheral nerve repair. Platelet-rich plasma (PRP) can secrete multiple growth factors to regulate the regenerative microenvironment. However, current administration methods of PRP are rapidly activated followed by the burst release of growth factors, causing low therapeutic efficiency in vivo. To overcome these disadvantages, a composite nerve conduit was fabricated by incorporating PRP into a gelatin methacrylate (GelMA) and sodium alginate (SA) hydrogel. The GelMA/SA-3/PRP-20 NGCs possess optimal mechanical properties, degradation rate, and superior biological performance. Importantly, GelMA/SA-3/PRP-20 NGCs achieved the sustained release of two major growth factors (VEGF-A, PDGF-BB) from PRP. Moreover, the GelMA/SA-3/PRP-20 NGCs significantly promoted the migration of Schwann cells and the neovascularization of endothelial cells in vitro. While bridging 10 mm rat sciatic nerve defects, the GelMA/SA-3/PRP-20 NGCs promoted axonal regeneration and functional recovery of peripheral nerves. Therefore, the GelMA/SA-3/PRP-20 NGCs could regulate the regenerative microenvironment by sustained release of growth factors from PRP and shed new light on the clinical application of PRP in peripheral nerve repair.

Exploring the Physicochemical, Electroactive, and Biodelivery Properties of Metal Nanoparticles on Peripheral Nerve Regeneration.

Despite the advances in the regeneration/rehabilitation field of damaged tissues, the functional recovery of peripheral nerves (PNs), especially in a long gap injury, is considered a great medical challenge. Recent progress in nanomedicine has provided great hope for PN regeneration through the strategy of controlling cell behavior by metal nanoparticles individually or loaded on scaffolds/conduits. Despite the confirmed toxicity of metal nanoparticles due to long-term accumulation in nontarget tissues, they play a role in the damaged PN regeneration based on the topography modification of scaffolds/conduits, enhancing neurotrophic factor secretion, the ion flow improvement, and the regulation of electrical signals. Determining the fate of neural progenitor cells would be a major achievement in PN regeneration, which seems to be achievable by metal nanoparticles through altering cell vital approaches and controlling their functions. Therefore, in this literature, an attempt was made to provide an overview of the effective activities of metal nanoparticles on the PN regeneration, until the vital clues of the PN regeneration and how they are changed by metal nanoparticles are revealed to the researcher.

The application of collagen in the repair of peripheral nerve defect.

Collagen is a natural polymer expressed in the extracellular matrix of the peripheral nervous system. It has become increasingly crucial in peripheral nerve reconstruction as it was involved in regulating Schwann cell behaviors, maintaining peripheral nerve functions during peripheral nerve development, and being strongly upregulated after nerve injury to promote peripheral nerve regeneration. Moreover, its biological properties, such as low immunogenicity, excellent biocompatibility, and biodegradability make it a suitable biomaterial for peripheral nerve repair. Collagen provides a suitable microenvironment to support Schwann cells’ growth, proliferation, and migration, thereby improving the regeneration and functional recovery of peripheral nerves. This review aims to summarize the characteristics of collagen as a biomaterial, analyze its role in peripheral nerve regeneration, and provide a detailed overview of the recent advances concerning the optimization of collagen nerve conduits in terms of physical properties and structure, as well as the application of the combination with the bioactive component in peripheral nerve regeneration.

Surface-Anchored Graphene Oxide Nanosheets on Cell-Scale Micropatterned Poly(d,l-lactide-co-caprolactone) Conduits Promote Peripheral Nerve Regeneration.

Regeneration and functional recovery of peripheral nerves remain formidable due to the inefficient physical and chemical cues in the available nerve guidance conduits (NGCs). Introducing micropatterns and bioactive substances into the inner wall of NGCs can effectively regulate the behavior of Schwann cells, the elongation of axons, and the phenotype of macrophages, thereby aiding the regeneration of injured nerve. In this study, linear micropatterns with ridges and grooves of 3/3, 5/5, 10/10, and 30/30 μm were created on poly(d,l-lactide-co-caprolactone) (PLCL) films following with surface aminolysis and electrostatic adsorption of graphene oxide (GO) nanosheets. The GO-modified micropatterns could significantly accelerate the collective migration of Schwann cells (SCs) and migration of SCs from their spheroids in vitro. Moreover, the SCs migrated directionally along the stripes with a fastest rate on the 3/3-GO film that had the largest cell adhesion force. The neurites of N2a cells were oriented along the micropatterns, and the macrophages tended to differentiate into the M2 type on the 3/3-GO film judged by the higher expression of Arg 1 and IL-10. The systematic histological and functional assessments of the regenerated nerves at 4 and 8 weeks post-surgery in vivo confirmed that the 3/3-GO NGCs had better performance to promote the nerve regeneration, and the CMAP, NCV, wet weight of gastrocnemius muscle, positive S100β and NF200 area percentages, and average myelinated axon diameter were more close to those of the autograft group at 8 weeks. This type of NGCs thus has a great potential for nerve regeneration.

Intraoperative single administration of neutrophil peptide 1 accelerates the early functional recovery of peripheral nerves after crush injury.

Neutrophil peptide 1 belongs to a family of peptides involved in innate immunity. Continuous intramuscular injection of neutrophil peptide 1 can promote the regeneration of peripheral nerves, but clinical application in this manner is not convenient. To this end, the effects of a single intraoperative administration of neutrophil peptide 1 on peripheral nerve regeneration were experimentally observed. A rat model of sciatic nerve crush injury was established using the clamp method. After model establishment, a normal saline group and a neutrophil peptide 1 group were injected with a single dose of normal saline or 10 μg/mL neutrophil peptide 1, respectively. A sham group, without sciatic nerve crush was also prepared as a control. Sciatic nerve function tests, neuroelectrophysiological tests, and hematoxylin-eosin staining showed that the nerve conduction velocity, sciatic functional index, and tibialis anterior muscle fiber cross-sectional area were better in the neutrophil peptide 1 group than in the normal saline group at 4 weeks after surgery. At 4 and 8 weeks after surgery, there were no differences in the wet weight of the tibialis anterior muscle between the neutrophil peptide 1 and saline groups. Histological staining of the sciatic nerve showed no significant differences in the number of myelinated nerve fibers or the axon cross-sectional area between the neutrophil peptide 1 and normal saline groups. The above data confirmed that a single dose of neutrophil peptide 1 during surgery can promote the recovery of neurological function 4 weeks after sciatic nerve injury. All the experiments were approved by the Medical Ethics Committee of Peking University People's Hospital, China (approval No. 2015-50) on December 9, 2015.

Metformin Enhances Functional Recovery of Peripheral Nerve in Rats with Sciatic Nerve Crush Injury

BackgroundThe aim of this study was to explore the effect of metformin by inducing autophagy for enhancing functional recovery of peripheral nerve in rats with sciatic nerve crush injury.Material/MethodAutophagy was determined by electron microscopy, immunofluorescence, and Western blot analysis. Motor function recovery was studied by the footprint intensity method. Axonal growth and regeneration were detected through Western blot while axonal remyelination was analysed through immunocytochemistry. Sensory and functional recovery were assessed by reflexive motor function analysis.ResultsThe present study deciphered the role of autophagy induction by metformin in motor functions and peripheral nerve regeneration following sciatic nerve crush injury in rats. The process was detected by measuring autophagosomes and the expression of microtubule-associated protein 1A/1B-light chain 3 upon metformin treatment of sciatic nerve crush-injured rats. Neurobehavioral recovery by metformin was tested by CatWalk gait analysis, and we quantified expression of myelin basic protein MBP and neurofilament NF200 at the damage sight by immunoblotting. In metformin-treated injured rats, autophagy was upregulated, by which the number of dead cells was decreased. Motor function was also recovered after metformin treatment, which was accompanied by upregulation of MBP and NF200 through autophagy induction. Surprisingly, the motor regenerative capability was reduced by treatment with 3-methyl adenine (an autophagy inhibitor) in nerve-injured rats.ConclusionsOur study revealed that pharmacological induction of autophagy has an important and active role in the regeneration of nerve and motor function regain.

Local Administration of Methylprednisolone Laden Hydrogel Enhances Functional Recovery of Transected Sciatic Nerve in Rat.

To determine the effects of methylprednisolone-laden hydrogel loaded into a chitosan conduit on the functional recovery of peripheral nerve using a rat sciatic nerve regeneration model was assessed. 10-mm sciatic nerve defect was bridged using a chitosan conduit (CHIT/CGP-Hydrogel) filled with CGP-hydrogel. In authograft group (AUTO) a segment of sciatic nerve was transected and reimplanted reversely. In methylprednisolone treated group (CHIT/MP) the conduit was filled with methylprednisolone-laden CGP-hydrogel. The regenerated fibers were studied within 16 weeks after surgery. The behavioral, functional and electrophysiological studies confirmed faster recovery of the regenerated axons in methylprednisolone treated group compared to CHIT/Hydrogel group (p<0.05). The mean ratios of gastrocnemius muscles weight were measured. There was statistically significant difference between the muscle weight ratios of CHIT/MP and CHIT/Hydrogel groups (p<0.05). Morphometric indices of regenerated fibers showed number and diameter of the myelinated fibers were significantly higher in CHIT/MP than in CHIT/Hydrogel group. Methylprednisolone-laden hydrogel when loaded in a chitosan conduit resulted in improvement of functional recovery and quantitative morphometric indices of sciatic nerve.

Guided Regeneration of Nerve Repair by Means of Local Administration of Insulin-Like Growth Factor I In Streptozotocin Induced Diabetes In Rats

The aim was to evaluate the effect of locally administered insulin-like growth factor (IGF I) on functional recovery of peripheral nerve in diabetic rats. Sixty male healthy white Wistar rats were divided into four experimental groups (n = 15), randomly: In transected group (TC), left sciatic nerve was transected and stumps were fixed in the adjacent muscle. In treat - ment group defect was bridged using a silicone conduit (SIL/IGF) and filled with 10 µL IGF I (100 ng/kg). In silicone graft group (SIL), the graft was filled with phosphate-buffered saline alone. In sham-operated group (SHAM), sciatic nerve was exposed and manipulated. Each group was subdivided into three subgroups of five animals each and regenerated nerve fibers were studied 4, 8 and 12 weeks after surgery. Behavioral testing, sciatic nerve functional study, gastrocnemius muscle mass and morphometric indices confirmed faster recovery of regenerated axons in SIL/IGF than in SIL group (p < 0.05). In immunohistochemistry, location of reactions to S-100 in SIL/IGF was clearly more positive than that in SIL group. When loaded in a silicone graft, IGF I accelerated and improved functional recovery and morphometric indices of sciatic nerve in diabetic rats.

Vascular endothelial growth factor promotes anatomical and functional recovery of injured peripheral nerves in the avascular cornea

Peripheral nerve injury is a major neurological disorder that can cause severe motor and sensory dysfunction. Neurogenic effects of vascular endothelial growth factor (VEGF) have been found in the central nervous system, and we examined whether VEGF could promote anatomical and functional recovery of peripheral nerves after injury using an avascular corneal nerve injury model. We found that VEGF enhanced neurite elongation in isolated trigeminal ganglion neurons in a dose-dependent manner. This effect was suppressed by neutralizing antibodies for VEGF receptor (VEGFR) 1 and 2 or neuropilin receptor 1 or by VEGFR2 inhibitors (SU 1498 and Ki 8751). In vivo, mice receiving sustained VEGF via implanted pellets showed increased corneal nerve regeneration after superficial injury compared with those receiving vehicle. VEGF injected subconjunctivally at the time of injury accelerated reinnervation, the recovery of mechanosensation, and epithelial wound healing. Endogenous VEGF expression was up-regulated in the corneal epithelium and stroma after wounding. Thus, VEGF can mediate peripheral neuron growth but requires the activation of multiple VEGF receptor types. In addition, VEGF can accelerate the return of sensory and trophic functions of damaged peripheral nerves. Wounding induces the expression of VEFG, which may modulate physiological nerve repair.

Effects of Low Power Laser on Pain Response and Axonal Regeneration in Rat Models with Sciatic Nerve Crush Injury

This study purposed to examine the effect of low power laser on pain response and axonal regeneration. In order to prepare peripheral nerve injury models, we crushed the sciatic nerve of Sprague-Dawley rats and treated them with low power laser for 21 days. The rats were divided into 4 groups: normal group(n=10); control group(n=10) without any treatment after the induction of sciatic nerve crush injury; experimental group I(n=10) treated with low power laser(0.21<TEX>$mJ/mm^2$</TEX>) after the induction of sciatic nerve crush injury; and experimental group II(n=10) treated with low power laser(5.25<TEX>$mJ/mm^2$</TEX>) after the induction of sciatic nerve crush injury. We measured spontaneous pain behavior(paw withdrawal latency test) and mechanical allodynia(von Frey filament test) for evaluating pain behavioral response, and measured the sciatic function index for evaluating the functional recovery of peripheral nerve before the induction of sciatic nerve crush injury and on day 1, 7, 14 and 21 after the induction. After the experiment was completed, changes in the H & E stain and toluidine blue stain were examined histopathologically, and changes in MAG(myelin associated glycoprotein) and c-fos were examined immunohistologically. According to the results of this study, when low power laser was applied to rat models with sciatic nerve crush injury for 21 days and the results were examined through pain behavior evaluation and neurobehavioral, histopathological and immunohistological analyses, low power laser was found to affect pain response and axonal regeneration in both experimental group I and experimental group II. Moreover, the effect on pain response and axonal regeneration was more positive in experimental group I to which output 0.21<TEX>$mJ/mm^2$</TEX> was applied than in experimental group II to which 5.25<TEX>$mJ/mm^2$</TEX> was applied.

&lt;i&gt;Morus alba&lt;/i&gt; Enhanced Functional Recovery After Sciatic Nerve Crush Injury

Problem statement: Traumatic nerve injury has been recognized as one of the problems commonly found in road traffic crashes. Therefore, searching for the effective substances for promoting the functional recovery of nerve after injury is in required. Accumulating lines of evidence show that free radicals generated after injury contribute the important role to retard functional recovery, thus the substance possessing anti-oxidant could facilitate functional recovery. Based on the effect of antioxidant to promote functional recovery of nerve after injury mentioned earlier, we hypothesized that Morus alba extract, a substance possessing anti-oxidant activity, should be able to facilitate the functional recovery of peripheral nerve after injury. Approach: To elucidate this issue, male Wistar rats, weighing 180-220 g, were orally given the aqueous extract of Morus alba at various doses ranging from 0.1, 1 and 10 mg kg-1 BW 5days before and 21 days after sciatic nerve injury. Motor, sensory and sensorimotor coordination were observed every 3 days for 3 weeks by using De Medinacelli method, foot reflex withdrawal test and rotarod test, respectively. Results: The low dose of the extract significantly improved both sensory and motor functions after crush injury. Although sensory function recovers more sooner than the motor function, it fails to show full recovery within weeks. Thus, the present study demonstrates the potential of M. alba extract to enhance functional recovery after crush injury. Conclusion: In conclusion, Morus alba may serve as functional food to promote nerve recovery after injury. However, further studies about the possible active ingredient (s) and underlying mechanism (s) are required.

Peripheral neuropathy in the twitcher mouse: accumulation of extracellular matrix in the endoneurium and aberrant expression of ion channels

Globoid cell leukodystrophy (GLD; Krabbe's disease), caused by a genetic galactosylceramidase deficiency, affects both the central and peripheral nervous systems (CNS and PNS). Allogenic hematopoietic stem-cell transplantation (HSCT) has been beneficial for clinical improvement of this disease. However, recent reports by Siddiqi et al. suggested that none of their transplanted patients achieved complete normalization of their peripheral nerve function, despite the well-documented remyelination of the CNS and PNS in the treated patients. We hypothesized that the PNS dysfunction in GLD is due to altered Schwann cell-axon interactions, resulting in structural abnormalities of the node of Ranvier and aberrant expression of ion channels caused by demyelination and that the persistence of this altered interaction is responsible for the dysfunction of the PNS after HSCT. Since there has not been any investigation of the Schwann cell-axonal relationship in twitcher mice, an authentic model of GLD, we first investigated structural abnormalities, focusing on the node of Ranvier in untreated twitcher mice, and compared the results with those obtained after receiving bone marrow transplantation (BMT). As expected, we found numerous supernumerary Schwann cells that formed structurally abnormal nodes of Ranvier. Similar findings, though at somewhat variable extent, were detected in mice treated with BMT. Activated supernumerary Schwann cells expressed GFAP immunoreactivity and generated Alcian blue-positive extracellular matrix (ECM) in the endoneurial space. The processes of these supernumerary Schwann cells often covered and obliterated the nodal regions. Furthermore, the distribution of Na(+) channel immunoreactivity was diffuse without the concentration at the nodes of Ranvier as seen in wild-type mice. Neither K(+) channels nor Neurexin IV/ Caspr/ Paranoidin (NCP-1) were detected in the twi/twi sciatic nerve. The results of our study suggest the importance of normalization of the Schwann cell-axon relationship for the functional recovery of peripheral nerves, when one considers therapeutic strategies for PNS pathology in GLD.

TUMOR NECROSIS FACTOR PROMOTES MOTOR FUNCTIONAL RECOVERY IN CRUSHED PERIPHERAL NERVE

The potential benefits of tumor necrosis factor pretreatment in promoting motor functional recovery of peripheral nerve following low load crush injury were examined. Using a specially designed crush device, rat sciatic nerve was subjected to a low load crush injury of 2-h duration. Recombinant murine tumor necrosis factor and saline were intraperitoneally injected into the experimental and control animals, respectively, prior to nerve crushing. Subsequent motor function was evaluated at intervals by measurement of the sciatic functional index. There was significantly ( P < 0.05 to < 0.01) more rapid recovery in the tumor necrosis factor pretreated group as compared to the controls between day 14 and day 28. The sciatic functional index in the tumor necrosis factor group improved to −69.3 ± 5.3 at day 14 and to nearly normal at day 21. In contrast, the sciatic functional index in the control group was −95.5 ± 3.1% at day 14 and did not approach normal until day 42. Histological results paralleled the functional findings. The results suggest that tumor necrosis factor pretreatment has the potential to attenuate neurostructural damage and promote motor functional recovery in rat peripheral nerve. Copyright © 1996 Elsevier Science Ltd.

A Laminin Graft Replaces Neurorrhaphy in the Restorative Surgery of the Rat Sciatic Nerve

We investigated the role of laminin in functional recovery of a peripheral nerve injury using electrophysiological and behavioral approaches on the rat sciatic nerve in vivo. These studies were complemented by neurofilament protein immunocytochemistry on the sciatic nerve 20 days after an operation, in which an 8-mm piece of the nerve was removed and replaced by a graft of laminin, its neurite outgrowth-promoting peptide, a control peptide, collagen, or by resuturing of the removed piece of the nerve. Electrophysiological measurements of muscle strength 4 months after the sciatic nerve transection showed that a laminin graft was as effective as neurorrhaphy in supporting functional recovery of an injured peripheral nerve. A laminin graft also significantly reduced autotomy in the operated animals. Immunocytochemistry confirmed that both a laminin graft and resuturing supported growth of the 200-kDa neurofilament-positive axons into the distal stump of the nerve within 20 days of operation. A graft with a neurite outgrowth-promoting peptide of the B2 chain of laminin supported similar axon growth, whereas another peptide graft also derived from laminin or a collagen graft did not support axon growth. All grafts allowed Schwann cell growth into the distal stumps of the nerves, but neurites accompanied them only in the regeneration-supporting grafts and in the resutured nerves. The Schwann cells of the regenerating nerves expressed high levels of the neurite outgrowth-promoting domain of the B2 chain of laminin, whereas the Schwann cells of the degenerating nerves failed to express this domain in the distal stumps of the degenerating nerves. These results provide the first in vivo evidence for the functional role of laminin in peripheral nerve regeneration. As the neurite outgrowth-promoting domain of the B2 chain of laminin is as efficient as laminin or resuturing in supporting a short-term recovery of an injured sciatic nerve, this area may be a regeneration-promoting domain of this glycoprotein. More importantly, as grafting significantly reduces post-traumatic pain behavior in the operated animals, the laminin graft surgery may provide a useful method for clinical restoration of the injured peripheral nerves.

The functional recovery of peripheral nerves following defined acute crush injuries.

This study evaluates the effect of crushing load on functional recovery of the sciatic nerve. Male Sprague-Dawley rats were divided into five groups: sham operation, resected sciatic nerve, and 100 g (13 mm Hg/mm2), 500 g (50 mm Hg/mm2), and 15,000 g (1,000 mm Hg/mm2) of sciatic crush load (groups 1-5). In groups 3-5, a 5-mm segment of sciatic nerve was crushed for 10 min using a specially designed crushing device. Motor functional recovery was assessed from hind-limb walking tracks by calculating a sciatic functional index. There was no detectable functional deficit in the group receiving sham operations, while the resected sciatic nerve group exhibited complete dysfunction for the full duration of the experiment. All groups subjected to crush exhibited an initial deficit that gradually recovered to normal by day 14 (100-g crush), day 39 (500-g crush), and day 53 (15,000-g crush). Histological changes were also related to the initial crushing load and the length of the recovery period. Results indicate that the crushing device described is able to administer an adjustable, defined crush injury to the rat sciatic nerve, and that the functional deficit resulting from such an injury can be easily monitored with a sciatic functional index. The rate of recovery of crushed nerves was directly related to the initial load. All crushed nerves recovered in this experiment, even after the application of a 15,000-g load for 10 min.

The effects of polyamines and polyamine inhibitors on rat sciatic and facial nerve regeneration

The effects of exogenous polyamines and polyamine biosynthetic pathway inhibitors on regenerating nerves were examined in adult male rats following nerve transection and surgical repair. Several studies have demonstrated the efficacy of exogenous polyamines in promoting the functional recovery of peripheral nerves following crush or freeze injuries in the rat. In order to simulate clinical peripheral nerve surgery, we studied these effects after complete nerve transection and evaluated regeneration by counting axons. There was no statistical difference in axon number with and without polyamines and in the presence of inhibitors and inhibitors with end product addition. Our study suggests that the difference in recovery seen in previous studies is not mediated by a change in axon number.