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Statement of the Problem: Healing of the inferior alveolar nerve injury during dental procedures is one of the biggest concerns of dentists. There are still debates on different treatment modalities. Purpose: This study aimed to compare the effect of 940nm and 810nm diode lasers on the repair of the inferior alveolar sensory nerve. Materials and Method: In this single-blinded randomized clinical trial, 39 patients with inferior alveolar nerve injury were divided into three groups: 1. 810nm laser irradiated, 2. 940nm laser irradiated, and 3. No laser irradiation (control group). All patients were treated in 12 sessions (3 days per week) and evaluated using a complete clinical neurosensory test (CNT), including brushstroke, 2-point discrimination, pinprick nociception, and thermal discrimination before and after treatment. Results: The mean dysesthesia of the patient treated with 810nm diode laser was significantly lower than the control group in all sessions (the 1st (p= 0.003), 3rd (p=0.008), 7th (p= 0.006), and 12th sessions (p= 0.005)). The 810nm laser resulted in more satisfaction in patients than the control group in almost all sessions (1st (p< 0.001), 7th (p= 0.028), and 12th (p= 0.006)). More patient satisfaction was seen in the 1st and 3rd sessions in the 810nm laser than in the 980nm laser (p< 0.001 and p= 0.003, respectively). Conclusion: 810nm diode laser can be better than 940nm in repairing inferior alveolar sensory nerve damage. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate spontaneous neural regeneration and functional recovery after resection of various lengths of the hypoglossal (XII) nerve in adult rats. Twelve weeks after XII nerve resection at lengths ranging from 0.0 to 15.8 mm, the tongue deviation angle of rats was measured to evaluate the severity of paralysis; thereafter, the XII neurons in the XII nucleus were labeled with Fluoro-Gold (FG), which was injected into the tongue to visualize regenerated XII neurons re-innervating the tongue muscles. In the XII nerve-resected rats, the regenerative rates, that is, the percentage of the total number of FG-positive neurons on the injured side relative to that on the uninjured side, were divided into two groups; the regenerative rates were more than 77% and less than 6%, respectively. Upon comparing the two groups, the boundary resection length was approximately 10.0 mm. Moreover, the former and latter groups demonstrated tongue deviation angles less than or greater than 15°, respectively. The critical nerve gap length for spontaneous neural regeneration was approximately 10.0 mm in XII nerve-resected adult rats, and nerve regeneration occurred in both morphological and functional aspects after resection at less than the critical length. • Spontaneous regeneration occurred in rat relatively long-gap nerve resection models. • Morphological and functional regeneration occurred in the nerve-resected rats. • A critical nerve gap length exists for spontaneous nerve regeneration. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries result in significant loss of motor and sensory function, and the slow rate of nerve regeneration can prolong recovery time. Thus, approaches that promote axonal regeneration are critical to improve the outcomes for patients with peripheral nerve injuries. In this study, we investigated the effects of Ficus carica L. (fig) and Vaccinium macrocarpon Ait. (cranberry), which are rich in phytochemicals with demonstrable and diverse medicinal properties, on nerve regeneration in a mouse model of sciatic nerve crush. Our investigation revealed that fig extract, but not cranberry extract, prevented the decline in muscle weight and nerve conduction velocity induced by nerve crush. The fig extract also mitigated motor function impairment, myelin thinning, and axon diameter reduction, indicating its potential to promote nerve regeneration. Furthermore, the fig extract enhanced macrophage infiltration into the nerve tissue, suggesting that it could ameliorate nerve injury by promoting tissue repair via increased macrophage infiltration. The study provides valuable insights into the potential of the fig extract as a novel agent promoting nerve regeneration. Further investigation into the mechanisms underlying the action of fig extracts is needed to translate these findings into clinical applications for patients with peripheral nerve injuries. [ABSTRACT FROM AUTHOR]

The combination of cellular and noncellular treatments has been postulated to improve nerve regeneration through a processed nerve allograft. This study aimed to evaluate the isolated effect of treatment with purified exosome product (PEP), mesenchymal stem cells (MSCs), and tacrolimus (FK506) alone and in combination when applied in decellularized allografts. A three-dimensional in vitro -compartmented cell culture system was used to evaluate the length of regenerating neurites from the neonatal dorsal root ganglion into the adjacent peripheral nerve graft. Decellularized nerve allografts were treated with undifferentiated MSCs, 5% PEP, 100 ng/mL FK506, PEP and FK506 combined, or MSCs and FK506 combined (N = 9/group) and compared with untreated nerve autografts (positive control) and nerve allografts (negative control). Neurite extension was measured to quantify nerve regeneration after 48 hours, and stem cell viability was evaluated. Stem cell viability was confirmed in all MSC-treated nerve grafts. Treatments with PEP, PEP + FK506, and MSCs + FK506 combined were found to be superior to untreated allografts and not significantly different from autografts. Combined PEP and FK506 treatment resulted in the greatest neurite extension. Treatment with FK506 and MSCs was significantly superior to MSC alone. The combined treatment groups were not found to be statistically different. Although all treatments improved neurite outgrowth, treatments with PEP, PEP + FK506, and MSCs + FK506 combined had superior neurite growth compared with untreated allografts and were not found to be significantly different from autografts, the current gold standard. Purified exosome product, a cell-free exosome product, is a promising adjunct to enhance nerve allograft regeneration, with possible future avenues for clinical translation. [ABSTRACT FROM AUTHOR]

The polarity of nerve grafts does not interfere with axon growth. Our goal was to investigate whether axons can regenerate in a retrograde fashion within sensory pathways and then extend into motor pathways, leading to muscle reinnervation. Fifty-four rats were randomized into four groups. In Group 1, the ulnar nerve was connected end-to-end to the superficial radial nerve after neurectomy of the radial nerve in the axilla. In Group 2, the ulnar nerve was connected end-to-end to the radial nerve distal to the humerus; the radial nerve then was divided in the axilla. In Group 3, the radial nerve was divided in the axilla, but no nerve reconstruction was performed. In Group 4, the radial nerve was crushed in the axilla. Over 6 months, we behaviorally assessed the recovery of toe spread in the right operated-upon forepaw by lifting the rat by its tail and lowering it onto a flat surface. Six months after surgery, rats underwent reoperation, nerve transfers were tested electrophysiologically, and the posterior interosseous nerve (PIN) was removed for histological evaluation. Rats in the crush group recovered toe spread between 5 and 8 days after surgery. Rats with nerve transfers demonstrated electrophysiological and histological findings of nerve regeneration but no behavioral recovery. Ulnar nerve axons regrew into the superficial radial nerve and then into the PIN to reinnervate the extensor digitorum communis. We were unable to demonstrate behavioral recovery because rats cannot readapt to cross-nerve transfer. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of the study was to analyze the apoptosis of neurons and the differences in expression of Bcl-2 and Bax protein in the neurons in the corresponding spinal cord segment after the repair of the tibial nerve (TN) and common peroneal nerve (CPN) in rats. MATERIALS AND METHODS: 126 healthy male Sprague-Dawley (SD) rats aged 7-8 weeks were randomly divided into group A (control group), group B (TN was cut and sutured), and group C (CPN was cut and sutured), with 42 rats in each group. The spinal cord tissues of rats in different groups were stained with hematoxylin-eosin (HE) on the 1st, 3rd, 7th, 14th, 21st, and 28th day after surgery; the number of neurons in anterior horn of spinal cord, axon density (AD), axon passage rate (APR), and recovery rate (RR) of muscle cell cross-sectional area (MCCA) were calculated; and differences in the expression of Bcl-2 and Bax proteins in the three groups of rats were analyzed by immunohistochemistry. RESULTS: The results showed that there was no statistically significant difference in the muscle wet weight (MWW) RR of the three groups of rats on the 14th day after the surgery (p>0.05), and the MWW RRs of rats in groups B and C were higher at the 28th day after surgery in contrast to group A (p<0.05). The number of motor neurons in the anterior horn of spinal cord in group B was higher than that in group C at the 3rd, 7th, 14th, and 21st day after surgery (p<0.05); the MWW RR, MCCA, and CSARR of rats in group B were lower than those in group C (p<0.05); the proximal AD, distal AD, and APR in group B were higher than those of group C on the 14th and 28th day after the surgery (p<0.05); and there were no positive staining results in the spinal cord tissue of rats in group A after staining. The expressions of Bcl-2 and Bax in group B were higher observably than the expressions in group C (p<0.05), which indicated that the recovery ability of TN was stronger than that of the CPN; the expression of Bcl-2 and Bax in TN was notably higher than that of the CPN. CONCLUSIONS: The expression of Bcl-2 and Bax was related to cell apoptosis and nerve regeneration after nerve injury. It provided a reference basis for clinical diagnosis and treatment of peripheral nerves. [ABSTRACT FROM AUTHOR]

The hypothesis of this study was that trigeminal nerve stimulation (TNS) or peripheral nerve stimulation (PNS) could improve functional outcomes of peripheral nerve injury in a rat forelimb model when compared to control rats not receiving electrical stimulation (ES). While PNS is known to improve outcomes after nerve surgery, the role of TNS has not been explored. Lewis rats were trained to perform a reach and grasp task before receiving a 2 mm gap repair of the ulnar and median nerves and randomized into four treatment groups: (1) sham injury, (2) nerve injury with sham ES, (3) nerve injury with PNS, and (4) nerve injury with TNS. Functional motor (median pull force and percent success in motor task) and sensory metrics (forelimb paw withdrawal thresholds) were collected both pre-injury and throughout rehabilitation. Nerves stained using Gomori's trichrome were assessed quantitatively and qualitatively. The sham ES group did not recover their pre-injury baseline functional outcomes. In contrast, the TNS and PNS groups fully recovered following injury, with no difference in functional outcomes between the pre-injury baseline and the final week of rehabilitation (P > 0.05, all). Histomorphology results demonstrated no quantitative difference, but qualitative differences in architecture were evident. Electrical stimulation of the trigeminal nerve or the injured nerve improved the functional outcomes of nerve regeneration in rodents. Histomorphology results of nerves from the TNS group support the proposed central mechanisms. This is an important step in translating this therapy as an adjunct, non-invasive treatment for high, mixed nerve injuries in humans. [ABSTRACT FROM AUTHOR]

We attempt to investigate the expression pattern of GDF11 in the sciatic nerves after injury. Thirty-six healthy male Sprague Dawley (SD) rats were divided into three groups at random and were labelled as: day 1, day 4, and day 7 post-surgery. The sciatic nerve crush model was established on the left-hind limb, while the right limb was untreated, and served as the control. Nerve samples were collected at post-injury day 1, day 4 and day 7. Nerve samples collected from the proximal and distal stump of the injury site underwent immunofluorescence staining with GDF11, NF200 and CD31. GDF11 mRNA expression was analyzed by qRT-PCR. CCK-8 assay, after si-GDF11 transfection in Schwann cells (RSC96) was applied to verify its effect in cell proliferation rate. GDF11 was abundantly expressed in axons stained with NF200 and Schwann cells stained with S100. However, no GDF11 expression was observed in vascular endothelial tissues stained with CD31. From day 4 onwards, the level of GDF11 showed an increasing trend, up to a twofold level at day 7 after injury. Proliferation rate of RSC96 cells showed a significant decrease after the down-regulation of GDF11 by siRNAs compared to the control group. GDF11 may play a role in the proliferation of Schwann cell during nerve regeneration process. [ABSTRACT FROM AUTHOR]

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Aligned electrospun fibers provide topographical cues and local therapeutic delivery to facilitate robust peripheral nerve regeneration. mRNA delivery enables transient expression of desired proteins that promote axonal regeneration. However, no prior work delivers mRNA from electrospun fibers for peripheral nerve regeneration applications. Here, we developed the first aligned electrospun fibers to deliver pseudouridine-modified (Ψ) neurotrophin-3 (NT-3) mRNA (ΨNT-3mRNA) to primary Schwann cells and assessed NT-3 secretion and bioactivity. We first electrospun aligned poly(L-lactic acid) (PLLA) fibers and coated them with the anionic substrates dextran sulfate sodium salt (DSS) or poly(3,4-dihydroxy-L-phenylalanine) (pDOPA). Cationic lipoplexes containing ΨNT-3mRNA complexed to JetMESSENGER® were then immobilized to the fibers, resulting in detectable ΨNT-3mRNA release for 28 days from all fiber groups investigated (PLLA+mRNA, 0.5DSS4h+mRNA, and 2pDOPA4h+mRNA). The 2pDOPA4h+mRNA group significantly increased Schwann cell secretion of NT-3 for 21 days compared to control PLLA fibers (p < 0.001-0.05) and, on average, increased Schwann cell secretion of NT-3 by ≥ 2-fold compared to bolus mRNA delivery from the 1µgBolus+mRNA and 3µgBolus+mRNA groups. The 2pDOPA4h+mRNA fibers supported Schwann cell secretion of NT-3 at levels that significantly increased dorsal root ganglia (DRG) neurite extension by 44% (p < 0.0001) and neurite area by 64% (p < 0.001) compared to control PLLA fibers. The data show that the 2pDOPA4h+mRNA fibers enhance the ability of Schwann cells to promote neurite growth from DRG, demonstrating this platform's potential capability to improve peripheral nerve regeneration. Aligned electrospun fibers enhance axonal regeneration by providing structural support and guidance cues, but further therapeutic stimulation is necessary to improve functional outcomes. mRNA delivery enables the transient expression of therapeutic proteins, yet achieving local, sustained delivery remains challenging. Previous work shows that genetic material delivery from electrospun fibers improves regeneration; however, mRNA delivery has not been explored. Here, we examine mRNA delivery from aligned electrospun fibers to enhance neurite outgrowth. We show that immobilization of NT-3mRNA/JetMESSENGER® lipoplexes to aligned electrospun fibers functionalized with pDOPA enables local, sustained NT-3mRNA delivery to Schwann cells, increasing Schwann cell secretion of NT-3 and enhancing DRG neurite outgrowth. This study displays the potential benefits of electrospun fiber-mediated mRNA delivery platforms for neural tissue engineering. [Display omitted] [ABSTRACT FROM AUTHOR]

The aim of the study was to analyze the efficacy of retrograde innervation of single-stage free latissimus dorsi (LD) flap for facial reanimation by the distal stump of thoracodorsal nerve (TDN). After the main trunk of TDN was split in half to preserve the function of transverse branch, the proximal stump was coapted with the contralateral facial nerve, and the distal stump was coapted with the ipsilateral masseteric nerve, or vice versa. The length of each nerve stump and the time required for voluntary and spontaneous muscle contraction after surgical treatment were reviewed. Among a total of 30 patients, there was no statistically significant difference in the successful recovery ratio of voluntary smile (antegrade, 86.7%; retrograde, 92.3%; p = 0.323) and of spontaneous smile (antegrade, 61.5%; retrograde, 100.0%; p = 0.079). There was no significant difference in the speed of nerve regeneration of voluntary smile (antegrade, 1.32 cm/month; retrograde, 1.14 cm/month; p = 0.213) and of spontaneous smile (antegrade, 0.91 cm/month; retrograde, 1.09 cm/month, p = 0.120). Within the limitations of the study, it seems that retrograde innervation of neurovascular muscle grafts has the potential to serve as a relevant alternative to other established options of neurovascular muscle transfer, because it provides comparable results in terms of rehabilitation success. [ABSTRACT FROM AUTHOR]

We aimed to investigate the effects of erythropoietin, acetyl-l-carnitine, and their combination on nerve regeneration in experimental peripheral nerve injury. Rats were randomly divided into five groups – sham-operated (S), sciatic nerve crush injury (C), C + acetyl-l-carnitine (ALCAR), C + erythropoietin (EPO), and C + EPO + ALCAR. ALCAR (50 mg/kg/day) was administered intraperitoneally, and EPO (5000 U/kg) was injected subcutaneously for 10 days. Functional recovery was evaluated using walking track analysis (sciatic functional index [SFI]), somatosensory evoked potentials (SEPs), thiobarbituric acid reactive substance (TBARS) assay, and caspase-3 and S100 immunoreactivities. In SFI analyses, delayed functional recovery was observed in the C group, whereas the functional recovery of rats treated with EPO and ALCAR significantly improved. The latencies of the SEP components were significantly prolonged in C group. In the treatment groups (C + EPO, C + ALCAR, and C + EPO + ALCAR), all recorded values of SEP components significantly decreased. TBARS levels in C group were significantly higher than those in the S group. EPO and ALCAR administration significantly decreased TBARS levels. Caspase-3 immunoreactivity was increased in the C group, whereas it was decreased in the treatment groups. S100 immunolabelling was significantly decreased in the C group. EPO and ALCAR administration caused an increase in the amount of S100-positive cells in all treatment groups. EPO and ALCAR administration could accelerate sciatic nerve repair by reducing apoptosis and lipid peroxidation and promoting myelinization. Although both EPO and ALCAR had positive effects on nerve healing, their combined efficacy had no statistically significant effect on peripheral nerve regeneration. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries are commonly encountered within clinical settings because of accidental trauma. This study aimed to examine the therapeutic effect of bee honey on peripheral nerve crush injury through a histological and physiological perspective. In this study, forty Wistar rats were divided into four groups. Rats were subjected to surgical operations to expose the sciatic nerve. Animals of the first group were operated without inducing any lesion to the nerve. The other three groups were subjected to induction of nerve crush injury. Two groups of them were treated with honey solution locally and intraperitoneally respectively. The other group served as injured nontreated group. Two physiological tests were performed to examine the living animals' nerve functions. At the end of the experimental period, the rats were sacrificed, and samples from the sciatic nerve and gastrocnemius muscle were obtained for histological, immunohistochemical and ultrastructural examination. Physiological indicators and structural investigations demonstrated considerable amelioration of the function and structure of nerves and muscles in the two treated groups compared with the injured nontreated group. The findings indicate that the bee honey has a curative effect on the peripheral nerve crush injury in the rat model. [ABSTRACT FROM AUTHOR]

Within the field of peripheral nerve surgery, the use of fibrin glue as an alternative to conventional microsurgical suture repair is becoming increasingly popular. Advantages of fibrin glue for nerve reconstruction include technical ease of use, less tissue manipulation, and shorter operation times. Although fibrin glue seems a promising alternative to conventional microsurgical repair, further insight into the outcomes of nerve recovery is essential. To summarize the current literature on the use of fibrin glue for peripheral nerve repair and compare these results with outcomes following conventional suture repair. A systematic search in Embase, MEDLINE, Web of Science, Cochrane, and Google Scholar databases was performed. The search included animal, cadaveric, and human studies assessing outcomes following peripheral nerve repair using fibrin glue. Data on outcomes were subdivided into functional outcomes, electrophysiology, histopathology, biomechanical outcomes, and operation times. We calculated standardized mean differences and combined these in a random effects model to estimate the overall effect. From a total of 2057 references, 37 animal, two cadaveric, and four human studies were included. Fibrin glue repairs resulted in similar functional and electrophysiology outcomes and shorter operation times than suture repairs. However, fibrin glue alone resulted in lower strength and more dehiscence. No dehiscence was reported when fibrin glue was combined with one or two sutures. Yet, we also found that methodological details were poorly reported in animal studies, resulting in an unclear risk of bias. This should be taken into consideration when interpreting the results. The results indicate that nerve regeneration may be similar in fibrin glue repairs and suture repairs. Combining fibrin glue with one or two positional sutures allows for a precise realignment of the nerve fibers and seems to provide sufficient strength to prevent dehiscence. [ABSTRACT FROM AUTHOR]

Neuronal loss and axonal degeneration after spinal cord injury or peripheral injury result in the loss of sensory and motor functions. Nerve regeneration is a complicated and medical challenge that requires suitable guides to bridge nerve injury gaps and restore nerve function. Due to the hostility of the microenvironment in the lesion, multiple conditions should be fulfilled to achieve improved functional recovery. Many nerve conduits have been fabricated using various natural and synthetic polymers. The design and material of the nerve guide conduits were carefully reviewed. A detailed review was conducted on the fabrication method of the nerve guide conduit for nerve regeneration. The typical fabrication methods used to fabricate nerve conduits are dip coating, solvent casting, micropatterning, electrospinning, and additive manufacturing. The advantages and disadvantages of the fabrication methods were reported, and research to overcome these limitations was reviewed. Extensive reviews have focused on the biological functions and in vivo performance of polymeric nerve conduits. In this paper, we emphasize the fabrication method of nerve conduits by polymers and their properties. By learning from the existing candidates, we can advance the strategies for designing novel polymeric systems with better properties for nerve regeneration. [ABSTRACT FROM AUTHOR]

This study was performed to investigate the effect of platelet-rich fibrin membrane (PRFM), alone and with topical tacrolimus application, on regeneration of the crushed facial nerve (FN). Thirty healthy 7-week-old albino rats were used. The left FN was damaged by crushing in all rats. Three random groups of rats were formed: group 1, untreated; group 2, treated with PRFM; group 3, treated with PRFM plus topical tacrolimus. Functional recovery and histological and immunohistochemical evaluations were performed 4 and 8 weeks later. Anti-S100 was used to detect myelin sheath. At 4 weeks, blinking reflex recovery was more rapid in group 3 than in groups 2 and 1 (4.30 ± 0.48, 3.40 ± 0.52, and 2.20 ± 0.42, respectively); the difference was statistically significant (P = 0.001). Histologically, group 3 showed more apparent normal FN structures than the other groups. Immunohistochemical caspase-3 evaluation of the axon area revealed a significant difference between group 2 (PRFM alone; 8.67 ± 0.029) and group 3 (PRFM plus topical tacrolimus; 4.42 ± 0.028) (P = 0.001). Group 3 showed the greatest positive staining in the myelin sheath. Based on the results of this animal study, clinical studies should be performed to determine whether the combination of PRF and tacrolimus also improves the outcome of nerve regeneration in humans. [ABSTRACT FROM AUTHOR]

Development of multifunctional tube-filling materials is required to improve the performances of the existing nerve guidance conduits (NGCs) in the repair of long-gap peripheral nerve (PN) injuries. In this study, composite nanofiber yarns (NYs) based on poly(p-dioxanone) (PPDO) biopolymer and different concentrations of carbon nanotubes (CNTs) were manufactured by utilizing a modified electrospinning apparatus. We confirmed the successful incorporation of CNTs into the PPDO nanofibers of as-fabricated composite NYs. The PPDO/CNT NYs exhibited similar morphology and structure in comparison with pure PPDO NYs. However, the PPDO/CNT NYs showed obviously enhanced mechanical properties and electrical conductivity compared to PPDO NYs. The biological tests revealed that the addition of CNTs had no negative effects on the cell growth, and proliferation of rabbit Schwann cells (rSCs), but it better maintained the phenotype of rSCs. We also demonstrated that the electrical stimulation (ES) significantly enhanced the differentiation capability of human adipose-derived mesenchymal stem cells (hADMSCs) into SC-like cells (SCLCs) on the PPDO/CNT NYs. More importantly, a unique combination of ES and chemical induction was found to further enhance the maturation of hADMSC-SCLCs on the PPDO/CNT NYs by notably upregulating the expression levels of SC myelination-associated gene markers and increasing the growth factor secretion. Overall, this study showed that our electrically conductive PPDO/CNT composite NYs could provide a beneficial microenvironment for various cell activities, making them an attractive candidate as NGC-infilling substrates for PN regeneration applications. The morphology, microstructure, and bioelectrical properties of conductive PPDO/CNT NYs have been explored for guiding or controlling cell behaviors. The PPDO/CNT NYs exhibited improved mechanical properties and increased electrical conductivity compared to the CNT-free PPDO NYs. They also presented an obviously enhanced biocompatibility by effectively maintaining the phenotype of rSCs. In addition, when hADMSCs were seeded and cultured on the conductive PPDO/CNT NYs, CI was demonstrated to promote the SC-related growth factor secretion of hADMSCs, and ES was demonstrated to improve the phenotypic maturation of hADMSCs into myelinating SCLCs. Moreover, the combination of CI and ES was found to further synergistically enhance the maturation of hADMSC-SCLCs. The achievement of conductive PPDO/CNT NYs shows potential for application as NGC-infilling substrates for PN regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

Acellular nerve allografts (ANA) recellularized with mesenchymal stem cells (MSC) or Schwann cells (SC) are, at present, a therapeutic option for peripheral nerve injuries (PNI). This study aimed to evaluate the regenerative and functional capacity of a recellularized allograft (RA) compared with autograft nerve reconstruction in PNI. Fourteen ovines were randomly included in two groups (n=7). A peroneal nerve gap 30 mm in length was excised, and nerve repair was performed by the transplantation of either an autograft or a recellularized allograft with SC-like cells. Evaluations included a histomorphological analysis of the ANA, MSC pre differentiated into SC-like cells, at one year follow-up functional limb recovery (support and gait), and nerve regeneration using neurophysiological tests and histomorphometric analysis. All evaluations were compared with the contralateral hindlimb as the control. The nerve allograft was successfully decellularized and more than 70% of MSC were pre differentiated into SC-like cells. Functional assessment in both treated groups improved similarly over time (p <0.05). Neurophysiological results (latency, amplitude, and conduction velocity) also improved in both treated groups at twelve months. Histological results demonstrated a less organized arrangement of nerve fibers (p <0.05) with an active remyelination process (p <0.05) in both treated groups compared with controls at twelve months. ANA recellularized with SC-like cells proved to be a successful treatment for nerve gaps. Motor recovery and nerve regeneration were satisfactorily achieved in both graft groups compared with their contralateral nontreated nerves. This approach could be useful for the clinical therapy of PNI. [ABSTRACT FROM AUTHOR]

Purpose: Wallerian degeneration (WD) is an antegrade degenerative process distal to peripheral nerve injury. Numerous genes are differentially regulated in response to the process. However, the underlying mechanism is unclear, especially the early response. We aimed at investigating the effects of sciatic nerve injury on WD via CLDN 14/15 interactions in vivo and in vitro.Methods: Using the methods of molecular biology and bioinformatics analysis, we investigated the molecular mechanism by which claudin 14/15 participate in WD. Our previous study showed that claudins 14 and 15 trigger the early signal flow and pathway in damaged sciatic nerves. Here, we report the effects of the interaction between claudin 14 and claudin 15 on nerve degeneration and regeneration during early WD.Results: It was found that claudin 14/15 were upregulated in the sciatic nerve in WD. Claudin 14/15 promoted Schwann cell proliferation, migration and anti-apoptosis in vitro. PKCα, NT3, NF2, and bFGF were significantly upregulated in transfected Schwann cells. Moreover, the expression levels of the β-catenin, p-AKT/AKT, p-c-jun/c-jun, and p-ERK/ERK signaling pathways were also significantly altered.Conclusion: Claudin 14/15 affect Schwann cell proliferation, migration, and anti-apoptosis via the β-catenin, p-AKT/AKT, p-c-jun/c-jun, and p-ERK/ERK pathways in vitro and in vivo. The results of this study may help elucidate the molecular mechanisms of the tight junction signaling pathway underlying peripheral nerve degeneration. [ABSTRACT FROM AUTHOR]

A surgical autograft remains the clinical gold-standard therapy for gap repair following peripheral nerve injury, however, challenges remain with achieving full recovery and reducing donor-site morbidity. Engineered Neural Tissue (EngNT) manufactured using differentiated CTX0E03 human stem cells (EngNT-CTX) has been developed as a potential 'off the shelf' allogeneic autograft replacement. Ensheathed within a collagen membrane developed to facilitate biomechanical integration, EngNT-CTX was used to bridge a critical-length (15 mm) sciatic nerve gap injury in athymic nude rats. The effectiveness of EngNT-CTX was compared to an autograft using outcome measures that assessed neuronal regeneration and functional recovery at 8 and 16 weeks. At both time points EngNT-CTX restored electrophysiological nerve conduction and functional reinnervation of downstream muscles to the same extent as the autograft. Histological analysis confirmed that more motor neurons had successfully regenerated through the repair in EngNT-CTX in comparison to the autograft at 8 weeks, which was consistent with the electrophysiology, with the number of motor neurons similar in both groups by 16 weeks. The total number of neurons (motor + sensory) was greater in autografts than EngNT-CTX at 8 weeks, indicating that more sensory fibres may have sprouted in those animals at this time point. In conclusion, this study provides evidence to support the effectiveness of EngNT-CTX as a replacement for the nerve autograft, as the functional regeneration assessed through histological and electrophysiological outcome measures demonstrated equivalent performance. Following injury a peripheral nerve has the capacity to regenerate naturally, however, in the case of severe damage where there is a gap the current gold-standard microsurgical intervention is an autograft. This is associated with serious limitations including tissue availability and donor-site morbidity. Tissue engineering aims to overcome these limitations by building a construct from therapeutic cells and biomaterials as a means to mimic and replace the autograft. In this study engineered neural tissue (EngNT) was manufactured using human stem cells (CTX) to bridge a critical-length gap injury. When compared to the autograft in an animal model the EngNT-CTX construct restored function to an equivalent or greater extent. [Display omitted] [ABSTRACT FROM AUTHOR]

Reliable and robust peripheral nerve regeneration after a nerve injury and repair remains an elusive goal. A variety of strategies have been proposed to mitigate the effects of Wallerian degeneration (through molecular therapies), enhance axonal regeneration across the repair site (through electrical stimulation and gene therapy), and explore alternatives to suture coaptation (through the fusion of transected ends). Although most of these techniques are in their infancy, animal data and some clinical trials have demonstrated promise for improving the restoration of function after these devastating injuries. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury and regeneration continue to be extensively studied through basic science research using animal models. A translational gap remains between basic science research and clinical application. The importance of peripheral nerve regeneration in basic science research depends on the design of the study, the outcome measures, and the time of regeneration selected. The purpose of this article is to provide an overview of the importance of the design and outcome measures of peripheral nerve basic science research, for hand surgeons to understand for potential clinical translation. [ABSTRACT FROM AUTHOR]

The gold standard reconstruction for facial reanimation is the functional muscle transfer. The reinnervation of a muscle is never complete, and clinical results are variable with 20% not achieving a satisfactory outcome. We hypothesise that this may be due to a mismatch between the characteristics of the donor nerve and transferred muscle. 81 YFP-16 and 14 YFP-H mice were studied in three intervention groups over three time periods. Two parameters were investigated: the number and surface area of reinnervated neuromuscular junctions and regenerating axons. An assessment was made of motor unit proportions. All cases of nerve repair and nerve graft, the neuromuscular junctions (NMJ) were completely reinnervated by regenerating axons. The number and calibre of the regenerating axons were significantly different from controls for both intervention groups. The motor units were smaller in both intervention groups. Reinnervation occurs after nerve repair or graft; however, the arbour was reinnervated by large numbers of much smaller axons. These axons showed some evidence of remodelling in the repair group, but not in the graft group. Neither group achieved the parameters of the control group. There were persistent qualitative changes to the morphology of both axons and junctions. Imaging documented both synkinesis and alterations that resemble those seen in ageing. Overall, the efficacy of reinnervation is very high with all NMJ reoccupied by regenerating axons. The way small axons are remodelled is different in the nerve repairs compared with the nerve grafts. [ABSTRACT FROM AUTHOR]

To compare 2 different, commercially available fibrin glue products with nylon suture with regard to repair strength, muscle function, and axon regeneration after delayed nerve repair in an animal model. A total of 120 Lewis rats underwent transection of the sciatic nerve. On day 3 after transection, the nerves were reexposed. A primary repair was performed on 40 rats from each group using nylon suture, Tisseel fibrin glue, or Evicel fibrin glue. On days 0, 3, and 7 after repair, 10 rats from each group underwent burst strength testing. Seventy days after repair, 10 rats from each group underwent functional muscle testing and histomorphic analysis of the nerve, with the contralateral limb serving as the control. There was no significant difference in burst strength among the groups on days 0 and 3. On day 7, the burst strength of the Evicel and nylon suture groups was significantly greater than that of the Tisseel group. There were 5 total coaptation failures in both fibrin glue groups and none in the suture group. Seventy days after repair, tetanic muscle strength, muscle mass, axon inner diameter, and g-ratio were equivalent among all groups. Axon counts were equivalent between the nylon suture and Evicel groups, although in the nylon group axon counts were higher than for the Tisseel group. In an animal model with a 3-day delay in nerve repair, although dehiscences occurred, when the initial repair held, fibrin glue was not inferior to nylon suture with regard to repair strength and muscle recovery. Historical concerns regarding spontaneous fibrin glue–based nerve repair dehiscences are well-founded. However, when coaptation is maintained, commercially available fibrin glues support nerve regeneration. [ABSTRACT FROM AUTHOR]

The loss of continuity of the nerve structure interrupts the transmission of nerve impulses and leads to the disorganization of functional activities. Many methods, as the use of neurogenic factors, aid in the process of neural regeneration by accelerating or improving peripheral nerves neoformation. The adipose tissue is abundant in the human body, and it has presented promising results in the regeneration of peripheral nerves. We carried out a randomized controlled study in 9 months, using 45 male Wistar rats, 80 days old, and the sciatic nerve was chosen for analysis. The control animals were divided into three groups - Initial group (IG), Final group (FG), and denervated group (DG) - with seven animals each. The experimental groups, with twelve animals each, were polyethylene tube filled with fat (EGF) and polyethylene tube without filling (EGwf). All groups, except IG, were submitted to 10 sessions of hyperbaric oxygen treatment of 1h 45 min in alternating days. Functional evaluation by walking-track was assessed using the Catwalk XT® software and tissues were harvested and stained with 1% toluidine blue for histological analysis. Quantitative data were first analyzed with the Kolmogorov Smirnov normality test. Comparison between the four groups was analyzed by ANOVA followed by Tukey Test. We concluded that hyperbaric oxygen therapy had positive results on morphometric and functional parameters. However, no significant differences were found regarding the use of autologous fat graft. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries (PNI) are common and frequently afflict otherwise healthy individuals after traumatic or iatrogenic events. Adjuvant therapies to improve functional outcomes after surgical repair of PNI have been investigated extensively in preclinical studies; however, to date, none have been clinically proven to have a notable therapeutic effect. FK506 (tacrolimus), a US Food and Drug Administration–approved systemic immunosuppressant, has demonstrated promising neuro-regenerative properties in both animal studies and clinical reports, but its adverse effects when systemically administered have precluded its broader applicability for patients with PNI. Recent advances in bioengineered drug delivery systems have made local FK506 delivery to a site of PNI an intriguing method of promoting peripheral nerve regeneration, with promising results in preclinical translational investigations. This review summarizes the preclinical and clinical evidence for FK506's beneficial effect in promoting peripheral nerve regeneration when administered systemically and locally. [ABSTRACT FROM AUTHOR]

Objectives: Rodent models of optic nerve crush (ONC) have often been used to study degeneration and regeneration of retinal ganglion cells (RGCs) and their axons as well as the underlying molecular mechanisms. However, ONC results from different laboratories exhibit a range of RGC injury with varying degree of axonal damage. We developed instrumented tweezers to measure optic nerve (ON) crush forces in real time and studied the correlation between RGC axon loss and force-impulse, the product of force and duration, applied through the instrumented tweezers in mice. Methods: A pair of standard self-closing #N7 tweezers were instrumented with miniature foil strain gauges at optimal locations on both tweezers' arms. The instrumented tweezers were capable of recording the tip closure forces in the form of voltages, which were calibrated through load cells to corresponding tip closure forces over the operating range. Using the instrumented tweezers, the ONs of multiple mice were crushed with varied forces and durations and the axons in the immunostained sections of the crushed ONs were counted. Results: We found that the surviving axon density correlated with crush force, with longer duration and stronger crush forces producing consistently more axon damage. Discussion: The instrumented tweezers enable a simple technique for measurement of ONC forces in real-time for the first time. Using the instrumented tweezers, experimenters can quantify crush forces during ONC to produce consistent and predictable post-crush cell death. This should permit future studies a way to produce nerve damage more consistently than is available now. [ABSTRACT FROM AUTHOR]

The specific patterns of revascularization of allograft nerves after the addition of vascularization remain unknown. The aim of this study was to determine the revascularization patterns of optimized processed allografts (OPA) after surgically induced angiogenesis to the wound bed in a rat sciatic nerve model. In 51 Lewis rats, sciatic nerve gaps were repaired with (i) autografts, (ii) OPA and (iii) OPA wrapped in a pedicled superficial inferior epigastric artery fascia flap (SIEF) to provide vascularization to the wound bed. At 2, 12, and 16 weeks, the vascular volume and vascular surface area in nerve samples were measured using micro CT and photography. Cross-sectional images were obtained and the number of vessels was quantified in the proximal, mid, and distal sections of the nerve samples. At 2 weeks, the vascular volume of SIEF nerves was comparable to control (P = 0.1). The vascular surface area in SIEF nerves was superior to other groups (P <0.05). At 12 weeks, vascularity in SIEF nerves was significantly higher than allografts (P <0.05) and superior compared to all other groups (P <0.0001) at 16 weeks. SIEF nerves had a significantly increased number of vessels compared to allografts alone in the proximal (P <0.05) and mid-section of the graft (P <0.05). Addition of surgical angiogenesis to the wound bed greatly improves revascularization. It was demonstrated that revascularization occurs primarily from proximal to distal (proximal inosculation) and not from both ends as previously believed and confirms the theory of centripetal revascularization. [ABSTRACT FROM AUTHOR]

Hypoglossal nerve-facial nerve 'side'-to-side neurorrhaphy is a new method for the treatment of potential incomplete facial paralysis after acoustic neuroma. However, there are differences in postoperative outcomes among patients. This study analysed preoperative factors that may influence the treatment outcomes of neurorrhaphy. We performed a retrospective study of 53 patients who were treated by neurorrhaphy for facial paralysis after acoustic neuroma resection. After a one-year follow-up period, the patients were divided into two groups according to facial functional outcome: better recovery or ordinary recovery. We analysed the following factors: gender, age, tumour size, and characteristics, tumour adhesion to the facial nerve, the duration of facial paralysis (DFP) and F wave appearance prior to neurorrhaphy (F wave). Univariate analysis showed significant differences between the two groups in DFP (P = 0.0002), tumour adhesion to the facial nerve (P = 0.0079) and F waves (P = 0.0048). Logistic regression analysis of these factors also showed statistical significance with P values of 0.042 for the DFP, 0.043 for F waves, and 0.031 for tumour adhesion to the facial nerve. Tumour adhesion to the facial nerve, F waves appearance and DFP prior to neurorrhaphy are the predominant factors that influence treatment outcomes. [ABSTRACT FROM AUTHOR]

Nerve transfers for peripheral nerve injuries can result in variable outcomes. We investigated the neuroprotective effect of epineurial lidocaine injection in the donor nerve prior to transection, with the hypothesis that proximal axon loss would be decreased with consequent increased neuroregeneration and functional recovery. A rat sciatic nerve model was used with 4 intervention groups: (1) lidocaine; (2) lidocaine/calcium gluconate (CG); (3) CG; or (4) saline (control). Behavioral testing and qualitative and quantitative histological evaluation was performed at 8 and 12 weeks. Histological assays included transmission electron microscopy, retrograde fluorogold labeling, and whole mount immunostaining. Functional assessments through the sciatic functional index and Basso, Beattie, and Bresnahan scale showed a statistically significant increase in recovery at 8 and 12 weeks with lidocaine treatment. Significantly higher axonal counts were obtained in the lidocaine-treated groups. Fragmentation and increased myelin damage was present in the CG and saline groups. Retrograde fluorogold labeling showed a statistically significant increase in the number of L4-6 dorsal root ganglion neurons in the lidocaine-treated groups. Whole mount immunostaining identified extension of the axonal growth cone past the nerve coaptation site in lidocaine-treated groups, but not in CG and saline groups. Our results suggest that epineurial lidocaine injection prior to donor nerve transection for nerve transfer has a neuroprotective effect, resulting in increased proximal axon counts and improved functional recovery. These findings may have direct clinical application because epineurial lidocaine can be used in surgery as a simple and inexpensive intervention for promoting improved clinical outcomes after nerve transfer. [ABSTRACT FROM AUTHOR]

Whole eye transplantation (WET) holds promise for vision restoration in devastating/disabling visual loss (congenital or traumatic) not amenable to surgical or neuroprosthetic treatment options. The eye includes multiple tissues with distinct embryonic lineage and differential antigenicity. Anatomically and immunologically, the eye is unique due to its avascular (cornea) and highly vascular (retina) components. Our goal was to establish technical feasibility, demonstrate graft viability, and evaluate histologic changes in ocular tissues/adnexae in a novel experimental model of WET that included globe, adnexal, optic nerve (ON), and periorbital soft tissues. Outbred Sprague-Dawley rats (n = 5) received heterotopic vascularized WET from donors. Each WET included the entire globe, adnexa, ON, and periorbital soft tissues supplied by the common carotid artery and external jugular vein. Viability and perfusion were confirmed by clinical examination, angiography and magnetic resonance imaging (MRI). Globe, adnexal, and periorbital tissues were analyzed for histopathologic changes, and the ON was examined for neuro-regeneration at study endpoint (30 days) or Banff Grade 3 rejection in the periorbital skin (whichever was earlier). Gross examination confirmed transplant viability and corneal transparency. Average operative duration was 64.0 ± 5.8 min. Average ischemia time was 26.0 ± 4.2 min. MRI revealed loss of globe volume by 36.0 ± 2.8% after transplantation. Histopathology of globe and adnexal tissues showed unique and differential patterns of inflammatory cell infiltration. The ON revealed a neurodegeneration pattern. The present study is the first in the literature to establish an experimental model of WET. This model holds significant potential in investigating mechanistic pathways, monitoring strategies or developing management approaches involving ocular viability, immune rejection, and ON regeneration after WET. [ABSTRACT FROM AUTHOR]