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Treatment of digital nerve injuries, particularly in case of a gap, is challenging. Recovery of finger sensitivity is often incomplete and can impair personal and occupational activity. The need for better nerve regeneration has given rise to alternative treatments such as nerve conduits. This study aimed to evaluate the safety and efficacy of a conduit of freeze-dried inverted human umbilical cord vessel for regeneration in digital nerve section. Twenty-three patients with a mean nerve gap of 6.11 mm (range 2-30 mm and static 2-point discrimination (s2PD) 15 mm underwent surgical repair of digital nerve section using a nerve regeneration conduit. The primary endpoint was recovery of sensitivity after conduit implantation. Secondary endpoints comprised progression of pain, functional symptoms, pressure threshold, hand-specific symptoms and disabilities, and restored innervation. Mean follow-up was 10.1 ± 4.1 months (range 1-14 months). Sensitivity recovered progressively in the months following implantation. There was a mean decrease of 8.54 mm in s2PD between baseline and last follow-up (p 0.001). Complete innervation recovered in 83.3% of cases at last follow-up. Pressure threshold and hand-related quality of life improved significantly and symptoms due to nerve sectioning (pain, cold intolerance, hypoesthesia, hyperesthesia) resolved almost completely. There were no safety issues related to the nerve conduit. These results indicate that freeze-dried inverted human umbilical vessels can be a safe and effective option as conduit for digital nerve regeneration.

The aim of this study was to verify the effects of ultrasound on dorsal root ganglion (DRG) neurons at the injury site in a rat model of sciatic nerve crush injury. We evaluated the mRNA expression of neurotrophic and pro-inflammatory factors by quantitative reverse transcription polymerase chain reaction 7 and 14 d post-injury. We also evaluated the protein levels of brain-derived neurotrophic factor (BDNF) 7 and 14 d post-injury. Axon regeneration and motor function analyses were performed 21 days after injury to confirm the facilitative effect of ultrasound on nerve regeneration. In the ultrasound group, BDNF and interleukin-6 mRNA expression of the DRG was significantly reduced 7 d post-injury. Compared with the sham group, the BDNF protein expression of the DRG in the ultrasound group remained at a higher level 14 d post-injury. Motor function, myelinated fiber density and myelin sheath thickness were significantly higher in the ultrasound group than in the sham group 21 d post-injury. These results indicate that ultrasound therapy at the injury site promotes nerve regeneration and modulates gene and protein expression in the DRG of a rat model of a sciatic nerve crush injury.

In order to understand the biological processes underlying dopaminergic neurons (DpN) regeneration in a 6-hydroxydopamine(6-OHDA)-induced adult zebrafish-based Parkinson's disease model, this study investigated the specific phases of neuroregeneration in a time-based manner. Bromodeoxyuridine (BrdU) was administered 24 h before the harvest of brain tissues at day three, five, seven, nine, 12 and 14 postlesion. Potential migration of proliferative cells was tracked over 14 days postlesion through double-pulse tracking [BrdU and 5-ethynyl-2'-deoxyuridine (EdU)] of cells and immunohistostaining of astrocytes [glial fibrillary acidic protein (GFAP)]. Gene expression of foxa2 and nurr1 (nr4a2a) at day three, nine, 14, 18, 22 and 30 postlesion was quantified using qPCR. Protein expression of foxa2 at day three, seven, 14 and 22 postlesion was validated using the western blot technique. Double labelling [EdU and tyrosine hydroxylase (TH)] of proliferative cells was performed to ascertain their fate after the neuroregeneration processes. It was found that whilst cell proliferation remained unchanged in the area of substantial DpN loss, the ventral diencephalon (vDn), there was a transient increase of cell proliferation in the olfactory bulb (OB) and telencephalon (Tel) seven days postlesion. BrdU-immunoreactive (ir)/ EdU-ir cells and activated astrocytes were later found to be significantly increased in the vDn and its nearby area (Tel) 14 days postlesion. There was a significant but transient downregulation of foxa2 at day three and nine postlesion, and nr4a2a at day three, nine and 14 postlesion. The expression of both genes remained unchanged in the OB and Tel. There was a transient downregulation of foxa2 protein expression at day three and seven postlesion. The significant increase of EdU-ir/ TH-ir cells in the vDn 30 days postlesion indicates maturation of proliferative cells (formed between day five-seven postlesion) into DpN. The present findings warrant future investigation of critical factors that govern the distinctive phases of DpN regeneration.

We generated a rat model of sciatic nerve crush injury and characterized the effects of curcumin on sciatic nerve recovery by using behavioral experiments, hematoxylin-eosin staining, toluidine blue staining, and immunohistochemical. Proteomic analysis using tandem mass tagging was performed to determine differentially expressed proteins (DEPs), and GO and KEGG pathway analyses of overlapping DEPs was conducted, following which, qPCR, western blotting, and immunofluorescence were further performed to validate the proteins of interest. Finally, a Schwann cell injury model was used to verify the effect of curcumin on potential targets. The rat model was successfully established and curcumin improved the sciatic nerve function index of rats with sciatic nerve injury (SNI) and increased the number and diameter of myelinated axons in the sciatic nerve. In the Sham group versus the Injured group and in the Injured group versus the Curcumin group, we identified a total of 4,175 proteins, of which 953 were DEPs, and 218 were known overlapping DEPs. Ten associated pathways, such as calcium signaling pathway, biosynthesis of antibiotics, and long-term potentiation, were identified. The 218 overlapping DEPs were primarily involved in negative regulation of apoptotic process, biological processes, cytoplasm cellular component, and protein binding molecular function based on GO annotation. Curcumin promoted increased expression of ApoD and inhibited the expression of Cyba in vivo and in vitro. These results indicated that curcumin promoted sciatic nerve repair through regulation of various proteins, targets, and pathways. Cyba and ApoD may be potential targets of curcumin in the treatment of SNI.

Significant improvements in sensory recovery after innervated breast reconstruction have been reported. However, surgical approaches and sensory testing methods have been widely variable. This systematic review aimed to synthesize neurotization techniques and outcomes in breast reconstruction surgery.A comprehensive literature search of the MEDLINE, Embase, Web of Science, and Cochrane databases was conducted to identify all studies reporting outcomes of neurotization in innervated breast reconstruction. Data extracted from each study included neurotization techniques, operative times, sensory methods and outcomes, and patient-reported outcomes.A total of 1,350 articles were identified, and 23 articles were included for analysis. Nerve coaptation was performed in 536 breasts and 419 patients, with techniques consisting of direct coaptation (65.1% of flaps), coaptation with nerve conduit (26.3%), and coaptation with nerve allograft (8.6%). The neural component of operating time ranged from 8 to 38 min, and the pooled neurotization success rate among nine studies that reported this outcome was 90.6% (95% CI: 83.6%-96.0%). Overall, innervated breasts achieved earlier and superior sensory recovery that was more uniformly distributed throughout the flap compared to non-innervated breasts. Despite high heterogeneity between studies, all included studies supported neurotized breast reconstruction to improve the rate, quality, and magnitude of sensory recovery.Neurotization during breast reconstruction may be worth the investment of additional operating time to increase the prospect of high-quality sensory recovery. Further investigation with standardized sensory testing methods and patient-reported outcome tools is needed to definitively support neurotization as a standard of care in breast reconstruction surgery.

The precise mechanism through which excessive tension confers poor outcomes in nerve gap repair is yet to be elucidated. Furthermore, the effect of tension on gene expression in regenerating nerves has not been characterized. This study investigated differential gene expression in transected nerves repaired under high and minimal tension.Male Lewis rats underwent right sciatic nerve transection with either minimal-tension or high-tension repair. Fourteen weeks postoperatively, segments of the right sciatic nerves were harvested along with equal-length segments from the contralateral, healthy nerve to serve as internal controls (naïve nerve). Differentially expressed genes (DEGs) and differentially regulated biochemical pathways between the samples were identified.Seventeen animals were studied. The gene expression profiles of naïve nerve and minimal-tension repair demonstrated minimal within-group variation, whereas that of high-tension repair demonstrated heterogeneity. Relative to naïve nerve, high-tension repair samples had 4276 DEGs (1941 upregulated and 2335 downregulated) and minimal-tension repair samples had 3305 DEGs (1479 upregulated and 1826 downregulated). High-tension repair samples had 360 DEGs relative to minimal-tension repair samples (68 upregulated and 292 downregulated). Upregulated biological pathways in all repaired nerves included steroid biosynthesis, extracellular matrix-receptor interaction, and ferroptosis. Finally, upregulated pathways in high-tension repair samples relative to minimal-tension repair samples included tumor necrosis factor signaling, interleukin-17 signaling, cytokine-cytokine receptor interaction, and mitogen-activated protein kinase signaling.The improved outcomes achieved with minimal-tension nerve repair may take root in a favorable gene expression profile. Future elucidation of biochemical pathways in nerve regeneration may identify potential therapeutic targets to optimize primary nerve repair outcomes.

Nerve injuries and neurodegenerative disorders are very serious and costly medical challenges. Damaged nerve tissue may not be able to heal and regain its function, and scar tissue may restrict nerve cell regeneration. In recent years, new electroactive biomaterials have attracted widespread attention in the neural tissue engineering field. Bacterial cellulose (BC) due to its unique properties such as good mechanical properties, high water retention, biocompatibility, high crystallinity, large surface area, high purity, very fine network, and inability to absorb in the human body due to cellulase deficiency, can be considered a promising treatment for neurological injuries and disorders that require long-term support. However, BC lacks electrical activity, but can significantly improve the nerve regeneration rate by combining with conductive structures. Electrical stimulation has been shown to be an effective means of increasing the rate and accuracy of nerve regeneration. Many factors, such as the intensity and pattern of electrical current, have positive effects on cellular activity, including cell adhesion, proliferation, migration and differentiation, and cell-cell/tissue/molecule/drug interaction. This study discusses the importance and essential role of BC-based biomaterials in neural tissue regeneration and the effects of electrical stimulation on cellular behaviors.

Nerve injuries are common after trauma and can be life-altering for patients. Electrodiagnostic studies are the gold standard for diagnosing and prognosticating nerve injuries. However, most surgeons are not trained in the interpretation of these studies; rather, they rely on the interpretation provided by the electrodiagnostician, who in turn is unlikely to be trained in nerve reconstruction. This discrepancy between the interpretation of these studies and the management of nerve injuries can lead to suboptimal surgical planning and patient outcomes. This review aims to provide a framework for surgeons to take a more active role in collaborating with their colleagues in electrodiagnostic medicine in the interpretation of these studies, with an ultimate goal of improved patient care. The basics of nerve conduction studies, electromyography, and relevant terminology are reviewed. The relationship between the concepts of demyelination, axon loss, Wallerian degeneration, nerve regeneration, collateral sprouting, and clinical function are explained within the framework of the Seddon and Sunderland nerve injury classification system. The natural evolution of each degree of nerve injury over time is illustrated, and management strategies are suggested.

Axon regeneration in response to injury has been documented in many animals over several hundred years. In contrast, how neurons respond to dendrite injury has been examined only in the last decade. So far, dendrite regeneration after injury has been documented in invertebrate model systems, but has not been assayed in a vertebrate. In this study, we use zebrafish motor neurons to track neurons after dendrite injury. We address two major gaps in our knowledge of dendrite regeneration: 1) whether post-synaptic dendrites can regenerate and 2) whether vertebrate dendrites can regenerate. We find that motor neurons survive laser microsurgery to remove one or all dendrites. Outgrowth of new dendrites typically initiated one to three days after injury, and a new, stable dendrite arbor was in place by five days after injury. We conclude that zebrafish motor neurons have the capacity to regenerate a new dendrite arbor.

Corneal nerve wounding often causes abnormalities in the cornea and even blindness in severe cases. In this study, we construct a dorsal root ganglion-corneal stromal cell (DRG-CSC, DS) co-culture 3D model to explore the mechanism of corneal nerve regeneration. Firstly, this model consists of DRG collagen grafts sandwiched by orthogonally stacked and orderly arranged CSC-laden plastic compressed collagen. Nerve bundles extend into the entire corneal stroma within 14 days, and they also have orthogonal patterns. This nerve prevents CSCs from apoptosis in the serum withdrawal medium. The conditioned medium (CM) for CSCs in collagen scaffolds contains NT-3, IL-6, and other factors. Among them, NT-3 notably promotes the activation of ERK-CREB in the DRG, leading to the growth of nerve bundles, and IL-6 induces the upregulation of anti-apoptotic genes. Then, LM22B-10, an activator of the NT-3 receptor TrkB/TrkC, can also activate ERK-CREB to enhance nerve growth. After administering LM22B-10 eye drops to regular and diabetic mice with corneal wounding, LM22B-10 significantly improves the healing speed of the corneal epithelium, corneal sensitivity, and corneal nerve density. Overall, the DS co-culture model provides a promising platform and tools for the exploration of corneal physiological and pathological mechanisms, as well as the verification of drug effects in vitro. Meanwhile, we confirm that LM22B-10, as a non-peptide small molecule, has future potential in nerve wound repair. STATEMENT OF SIGNIFICANCE: The cornea accounts for most of the refractive power of the eye. Corneal nerves play an important role in maintaining corneal homeostasis. Once the corneal nerves are damaged, the corneal epithelium and stroma develop lesions. However, the mechanism of the interaction between corneal nerves and corneal cells is still not fully understood. Here, we construct a corneal stroma-nerve co-culture in vitro model and reveal that NT-3 expressed by stromal cells promotes nerve growth by activating the ERK-CREB pathway in nerves. LM22B-10, an activator of NT-3 receptors, can also induce nerve growth in vitro. Moreover, it is used as eye drops to enhance corneal epithelial wound healing, corneal nerve sensitivity and density of nerve plexus in corneal nerve wounding model in vivo.

Schwann cells play an important role in peripheral myelination, and dysfunction of these cells leads to axonal damage. Schwann cells degenerate following peripheral nerve injury. Immature Schwann cells proliferate, differentiate, and support axonal regeneration and extension during recovery. There are a lot of intracellular signals involved in the myelination process. Although serum- and glucocorticoid-inducible kinase (SGK

Decellularized nerve allograft is an alternative to autologous nerve graft for nerve defects but has shown inferior clinical outcomes. Mesenchymal stem cells can play a key role in improving nerve regeneration of decellularized nerve allografts. The purpose of this study was to compare different mesenchymal stem cell seeding methods and to find the most efficient way to attach cells to nerve grafts for peripheral nerve regeneration. Wharton's jelly mesenchymal stem cells were collected from human umbilical cords and were seeded in the acellular nerve graft in five different ways as follows: PBS injection, fibrin glue drop, Matrigel drop, bioreactor, and Matrigel injection. A 6-mm sciatic nerve defect of Sprague-Dawley rats was bridged using mesenchymal stem cells-laden acellular nerve grafts according to the five seeding methods. Two days after implantation, the nerve tissue was biopsied and analyzed by the immunofluorescence staining of nuclei. The number of Wharton's jelly mesenchymal stem cells (+ h Nuclei) was counted in the inside, outside, and the total area of the graft sections under 200X magnification. The highest efficiency of mesenchymal stem cell attachment inside the graft and the highest total number of attached mesenchymal stem cells was observed in the group using Matrigel injection (p0.0001). This study showed mesenchymal stem cells can be more effectively attached to decellularized nerve graft using the injection method with Matrigel than other static or dynamic seeding methods in vivo.

Long non-coding RNAs (lncRNAs) have been linked to immunological modulation. Unfortunately, little is known about the processes of immune control in shrimp. In crustaceans such as Litopenaeus vannamei, a prominent aquaculture species, the X-organ-sinus gland complex (XO-SG) in the eyestalk is an essential neuroendocrine regulatory organ. Eyestalk ablation is commonly employed in aquaculture to accelerate ovarian maturation in shrimp. It does, however, have a negative impact on the shrimps' immunocompetence and causes death. As a result, we used RNA-seq to profile the transcriptomes of L. vannamei hemocytes infected with Vibrio parahaemolyticus after the eyestalk ablation. Following strict transcript screening procedures, 2307 lncRNAs were identified from L. vannamei hemocytes in this study. Pearson correlation analysis was finally used to uncover 535 DElncRNAs and 1566 DEmRNA targets. According to the Venn diagram analysis, 326 non-eyestalk regulatory lncRNAs (NElncRNAs) with a target of 1014 non-eyestalk regulatory genes (NEmRNAs), 47 eyestalk negative regulatory lncRNAs (ENRlncRNAs) with a target of 95 eyestalk negative regulatory genes (ENRmRNAs), and 162 eyestalk positive regulatory lncRNAs (EPRlncRNAs) with a target of 457 eyestalk positive regulatory genes (EPRmRNAs) were screened. The bioinformatics analysis revealed that lncRNAs were associated with Axon regeneration, Rap1 signaling pathway, Thyroid hormone signaling pathway, TGF-beta signaling pathway, and PI3K-Akt signaling pathway, implying that lncRNAs may play a role in the regulation of the neuroendocrine-immune (NEI) system. Furthermore, several lncRNAs targeting HSP70, YWHAZ, FER2, HIF1α, and Notch were discovered and verified by qRT-PCR. These findings showed that regulation of lncRNAs in hemocytes which were controlled by the eyestalk might be one of the impact variables in controlling the differential expression of mRNAs associated with immune response in L. vannamei infected with V. parahaemolyticus.

The most essential principle in managing facial nerve (FN) injury is proper diagnosis and early treatment. This study evaluated local application of different concentrations and injection intervals of Cerebrolysin hydrogel (CBLH) for facial nerve axotomy (FNA) treatment. We hypothesized that local application of CBLH may provide a sustained release of Cerebrolysin and enhance neural regeneration.The authors implemented a randomized, controlled, blinded animal study. The sample was composed of the right FN. Functionally, eye-blink reflex was evaluated 2 and 4 weeks postoperatively. All rats were euthanized after 4 weeks, and nerve regeneration was evaluated histopathologically and immunohistochemically (IHC) with antibody against neurofilament (anti-NF) and S100 proteins. Descriptive and correlation statistics were computed, and the P value was set at .05.The sample was composed of 72 adult male rats equally allocated into 8 groups. Groups I and V served as control groups and were injected with phosphate buffered saline once and four times, respectively. Rest of the groups were injected with 5%, 10%, and 15% CBLH once in groups II, III, IV and weekly in groups VI, VII, and VIII. CBLH showed statistically significant FN regeneration by enhancing Schwann and axonal growth compared to control group especially with single injection of 10%, 15%, and 5% 4-time injections, where the P value was less than .001. Significant improvement of eye-blink reflex was correlated with structural improvement associated with CBLH.Finally, CBLH enhanced nerve regeneration and rehabilitation after FNA in rats. Therefore, it could be considered as an alternative treatment of FNA. More experimental and clinical trials should be considered to detect the effectiveness of CBLH in neural regeneration.

Both of the surface topographical features and distribution of biochemical cues can influence the cell-substrate interactions and thereby tissue regeneration in vivo. However, they have not been combined simultaneously onto a biodegradable scaffold to demonstrate the synergistic role so far. In this study, a proof-of-concept study is performed to prepare micropatterns and peptide gradient on the inner wall of a poly (D,L-lactide-co-caprolactone) (PLCL) guidance conduit and its advantages in regeneration of peripheral nerve in vivo. After linear ridges/grooves of 20/40 μm in width are created on the PLCL film, its surface is aminolyzed in a kinetically controlled manner to obtain the continuous gradient of amino groups, which are then transferred to CQAASIKVAV peptide density gradient via covalent coupling of glutaraldehyde. The Schwann cells are better aligned along with the stripes, and show a faster migration rate toward the region of higher peptide density. Implantation of the nerve guidance conduit made of the PLCL film having both the micropatterns and peptide gradient can significantly accelerate the regeneration of sciatic nerve in terms of rate, function recovery and microstructures, and reduction of fibrosis in muscle tissues. Moreover, this nerve conduit can also benefit the M2 polarization of macrophages and promote vascularization in vivo., Graphical abstract Dual gradient of nerve-affinitive CQAASIKVAV peptides and linear ridges/grooves on the inner surface of biodegradable guidance conduit synergistically promote the regeneration of sciatic nerve in terms of rate, function recovery and microstructures, and reduction of fibrosis in muscle tissues in vivo.Image 1, Highlights • CQAASIKVAV peptide gradient and micropatterns are integrated on inner surface of a nerve regeneration conduit. • Cell alignment and migration are promoted toward the region of a higher peptide density. • The peptide gradient and micropatterns can synergistically accelerate the regeneration of sciatic nerve in vivo.

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.

Acute peripheral nerve injuries are common and can cause physical disabilities with sensory and functional sequelae; they therefore require surgery. The aim of this study was to conduct a systematic review to assess the clinical applicability of end-to-side neurorrhaphy in peripheral nerve reconstruction, based on available evidence. We carried out a systematic review of the literature using MEDLINE/PubMed, EMBASE, Cochrane Library, Web of Science, Scielo and Scopus through March 16, 2021. Most of the selected studies were qualitative and employed nonrandomized groups of patients, without standardized scales for assessing outcomes, which made statistical analysis difficult. Efficacy varied from 24% to 81%. Factors for better outcome included the type of injury, type of injured nerve (sensory, motor or mixed), presence of an epineural window, topography, injury extension1.3 cm, and intervention within 2 weeks of injury. Clinical studies so far lack scientific evidence on end-to-side neurorrhaphy in peripheral nerve lesions.

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 (p0.05). 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 (p0.05) with an active remyelination process (p0.05) 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.

Neurons of the mammalian central nervous system fail to regenerate. Substantial progress has been made toward identifying the cellular and molecular mechanisms that underlie regenerative failure and how altering those pathways can promote cell survival and/or axon regeneration. Here, we summarize those findings while comparing the regenerative process in the central versus the peripheral nervous system. We also highlight studies that advance our understanding of the mechanisms underlying neural degeneration in response to injury, as many of these mechanisms represent primary targets for restoring functional neural circuits.

The goal of this systematic review and meta-analysis was to compare nerve conduits and nerve graft for peripheral nerve regeneration. This type of lesion frequently causes disability due to pain, paresthesia and motor deficit. On the PICO process, "P" corresponded to patients with peripheral digital nerve lesions of any age, gender or ethnicity, "I" to interventions with nerve conduits or nerve graft, "C" to the control group with no treatment, placebo or receiving other treatment, and "O" to outcome assessment of nerve regeneration. Initial search found in 3859 studies, including 2001 duplicates. The remaining 1858 studies were selected by title and/or abstract; 1798 articles were excluded, leaving 60 articles for full-text review. Thirty-nine of these 60 reports were excluded as not meeting our inclusion criteria, and 21 articles were ultimately included in the systematic review. For patients older than 40 years, there was a greater mean improvement on S2PD and M2PD tests with grafting, which seemed to be the better surgical technique, positively impacting prognosis. On the M2PD test, there was significantly greater improvement in 11-17.99 mm defects with grafting (P 0.001); this finding should guide surgical strategy in peripheral nerve regeneration, to ensure better outcomes.

Hh signaling has been shown to be activated in intact and injured peripheral nerve. However, the role of Hh signaling in peripheral nerve is not fully understood. In the present study, we observed that Hh signaling responsive cells [Gli1(+) cells] in both the perineurium and endoneurium. In the endoneurium, Gli1(+) cells were classified as blood vessel associated or non-associated. After injury, Gli1(+) cells around blood vessels mainly proliferated to then accumulate into the injury site along with endothelial cells. Hh signaling activity was retained in Gli1(+) cells during nerve regeneration. To understand the role of Hedgehog signaling in Gli1(+) cells during nerve regeneration, we examined mice with Gli1(+) cells-specific inactivation of Hh signaling (Smo cKO). After injury, Smo cKO mice showed significantly reduced numbers of accumulated Gli1(+) cells along with disorganized vascularization at an early stage of nerve regeneration, which subsequently led to an abnormal extension of the axon. Thus, Hh signaling in Gli1(+) cells appears to be involved in nerve regeneration through controlling new blood vessel formation at an early stage.

Introduction A bioabsorbable collagen conduit (Renerve™) filled with collagen filaments is currently approved as an artificial nerve conduit in Japan and is mainly used for connecting and repairing peripheral nerves after traumatic nerve injury. However, there are few reports on its applications for reconstructing and repairing the facial nerve. The present study evaluated the efficacy of the conduit on promoting nerve regeneration in a murine model with a nerve defect at the buccal branch of the facial nerve. Methods Under inhalational anesthesia and microscopic guidance, the buccal branch of the left facial nerve in an 8-week-old Lewis rat was exposed, and a 7 mm gap was created in the nerve. The gap was then connected with either the nerve conduits (NC group) or an autologous nerve graft (the autograft group). At 13 weeks after the procedure, we compared the histological and physiological regenerations in the both groups. Results We found compound muscle action potential amplitude is significantly larger in the autograft group (2.8 ± 1.4 mV) than in NC group (1.3 ± 0.5 mV) (p, Highlights • The facial nerve regenerative efficacy of a nerve conduit was evaluated in a rat model. • Reinnervation was confirmed at 13 weeks postoperatively. • This study demonstrated the efficacy of the conduit for facial nerve reconstruction.

Using biocompatible polymer nanofibrous conduits with a controlled drug delivery have attracted much attention for peripheral nerve regeneration. This work was aimed at preparing electrospun poly ( l -lactide-co- D , l -lactide) (PLDLLA) containing multi-walled carbon nanotubes (MWCNTs) and 4-aminopyridine (4-AP)-loaded molecularly imprinted nanoparticles (MIP4-AP) as well as evaluating their performance in in vitro and in vivo assessments. After synthesis of MIP4-AP based on poly (methacrylic acid) with imprinting factor of 1.78, it was incorporated into the PLDLLA/MWCNTs nanofibers to optimize. By adjusting the process variables, the average diameter and electrical conductivity of the nanofibrous sample were 92 nm and 2870 × 10−7 S cm−1, respectively. Afterward, 4-AP release of the optimum sample showed the presence of MIP4-AP leading to initial burst release decrease and plateau level postpone up to 96 h. Moreover, the culture results of PC12 as neuroblastoma cell line on optimal PLDLLA/MWCNTs/MIP4-AP nanofibrous sample revealed the highest cell proliferation without cytotoxicity compared to neat nanofibers. Eventually, the animal model experiment exhibited that the conductive conduit based on the optimum sample was able to repair the rat's sciatic nerve after four weeks in accordance with sciatic function index and histological studies.

Background We evaluated how artificial nerves filled with adipose-derived stem cell (ADSC) sheets could facilitate peripheral nerve regeneration. Methods We prepared ADSC sheets following previously described protocols. We transected the sciatic nerve in 12-week-old Wistar rats, fixed the nerve ends to the artificial conduit, and prepared three groups: (1) conduits alone (control group); (2) conduits filled with ADSCs (ADSCs group), and (3) conduits filled with ADSC sheets (ADSC sheet group). We assessed the subjects 4 and 12 weeks post-transplantation (n = 24). We investigated βIII-tubulin and anti-S100 expression at 4 and 12 weeks post-transplantation, in longitudinal- and cross-sections of the central portion in the regenerated tissues. The vascular endothelial growth factor A (VEGFA) and neuregulin-1 expressions were analyzed using real-time reverse-transcription polymerase chain reaction (real-time RT-PCR). We evaluated the tibialis anterior muscle wet weight (affected/healthy sides, %) and sciatic function index (SFI) 12 weeks post-transplantation. Results The ADSC sheet group comprised more S100-positive cells than the other groups. The regenerated axon length in the ADSC sheet group was markedly the longest among the studied groups. The immunostaining revealed a positive area in the regenerated tissue center in all groups, tending to be the largest in the ADSC sheet group. The muscle wet weight indicated that the ADSC sheet group exhibited significantly higher weight than the control. The mean SFI showed that the ADSC sheet group exhibited significantly better results than the control. The VEGFA expression was higher both in the ADSC and the ADSC sheet group than in the control. The neuregulin-1 expression was higher both in the ADSC and the ADSC sheet group than in the control. Conclusions The ADSC sheets could potentially support transplanting an adequate number of ADSCs at the target site. Compared with the conventional method of attaching ADSCs, the use of ADSC sheets promotes accelerated nerve regeneration.

Spinal cord injury (SCI) causes motor and sensory deficits and is currently considered an incurable disease. We have previously reported that administration of anti-High Mobility Group Box-1 monoclonal antibody (anti-HMGB1 mAb) preserved lesion area and improved locomotion recovery in mouse model of SCI. In order to further enhance the recovery, we here examined combinatorial treatment of anti-HMGB1 mAb and epothilone B (Epo B), which has been reported to promote axon regeneration. This combinatorial treatment significantly increased hindlimb movement compared with anti-HMGB1 mAb alone, although Epo B alone failed to increase functional recovery. These results are in agreement with that anti-HMGB1 mAb alone was able to decrease the lesion area spreading and increase the surviving neuron numbers around the lesion, whereas Epo B facilitated axon outgrowth only in combination with anti-HMGB1 mAb, suggesting that anti-HMGB1 mAb-dependent tissue preservation is necessary for Epo B to exhibit its therapeutic effect. Taken together, the combinatorial treatment can be considered as a novel and clinically applicable strategy for SCI.

Aquaporins (AQPs) are a highly conserved group of membrane proteins that play critical roles in water and small solute transport across epithelial and endothelial barriers. The aim of this study was to determine whether AQP5, a well-known water channel protein, also plays a role in corneal epithelial wound healing. AQP5 knockout (AQP5−/−) mice were generated using CRISPR/Cas9. A corneal wound healing model was established using epithelial debridement of corneas. The time to corneal epithelial and nerve regeneration was significantly delayed in the AQP5−/− mice. Reduction in Ki-67–positive cells and nerve growth factor (NGF) expression was confirmed in the AQP5−/− mice during healing. Epithelial and nerve regeneration rates were significantly increased in the AQP5−/− mice after treatment with NGF, which was accompanied by recovered levels of phosphorylated Akt. NGF treatment also improved the recovery of corneal nerve fiber density and sensitivity in the AQP5−/− mice. While the promotion of NGF induced corneal epithelial and nerve regeneration, Akt inhibitor reversed Akt reactivation. A significant impairment of corneal wound healing in the AQP5−/− mice resulted from distinct defects in corneal epithelial cell proliferation and nerve regeneration. These results provide evidence for the involvement of aquaporin in cell proliferation and suggest that AQP5 induction could be a potential therapy for accelerating the resurfacing of corneal defects.

Spinal cord injury (SCI) is one kind of severe diseases with high mortality and morbidity worldwide, and lacks effective therapeutic interventions currently, which leads to not only permanent neurological impairments but also heavy social and economic burden. Recent studies have proved that circRNAs are highly expressed in neural tissues, regulating the neuronal and synaptic functions. What's more, significantly altered circRNAs expression profiles are closely associated with the pathophysiology of SCI. In this review, we summarize the current advance on the role of circRNAs in SCI, which may provide a better understanding of pathogenesis and therapeutic strategies of SCI. The Translational potential of this article The Translational potential of this article is that A further understanding of circRNAs in the pathogenesis of SCI will promote the circRNA-based clinical applications.

Surgical intervention is necessary following nerve trauma. Tubular prostheses can guide growing axons and inserting substances within these prostheses can be positive for the regeneration, making it an alternative for the current standard tools for nerve repair. Our aim was to investigate the effects of fibrin glue BthTL when combined with a synthetic TNF mimetic-action peptide on nerve regeneration. Male Wistar rats suffered left sciatic nerve transection. For repairing, we used empty silicon tubes (n = 10), tubes filled with fibrin glue BthTL (Tube + Glue group, n = 10) or tubes filled with fibrin glue BThTL mixed with TNF mimetic peptide (Tube + Glue + Pep group, n = 10). Animals were euthanized after 45 days. We collected nerves to perform immunostaining (neurofilament, GAP43, S100-β, NGFRp75 and Iba-1), light and transmission electron microscopy (for counting myelinated, unmyelinated and degenerated fibers; and for the evaluation of morphometric aspects of regenerated fibers) and collagen staining. All procedures were approved by local ethics committee (protocol 063/17). Tube + Glue + Pep group showed intense inflammatory infiltrate, higher Iba-1 expression, increased immunostaining for NGFRp75 receptor (which characterizes Schwann cell regenerative phenotype), higher myelin thickness and fiber diameter and more type III collagen deposition. Tube + Glue group showed intermediate results between empty tube and Tube + Glue + Pep groups for anti-NGFRp75 immunostaining, inflammation and collagen; on fiber counts, this group showed more degenerate fibers and fewer unmyelinated axons than others. Empty tube group showed superiority only in GAP43 immunostaining. A combination of BthTL glue and TNF mimetic peptide induced greater axonal regrowth and remyelination.

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.

Sensory disturbance in the orofacial region owing to trigeminal nerve injury is caused by dental treatment or accident. Commercially available therapeutics are ineffective for the treatment of sensory disturbance. Additionally, the therapeutic effects of rapamycin, an allosteric inhibitor of mammalian target of rapamycin (mTOR), which negatively regulates autophagy, on the sensory disturbance are not fully investigated. Thus, we investigated the therapeutic effects of rapamycin on the sensory disturbance in the mandibular region caused by inferior alveolar nerve (IAN) transection (IANX) in rats. The expression levels of the phosphorylated p70S6K, a downstream molecule of mTOR, in the proximal and distal stumps of the transected IAN were significantly reduced by rapamycin administration to the injured site. Conversely, the increments of both Beclin 1 and microtubule-associated protein-1 light chain 3-II protein levels in the proximal and distal stumps of the transected IAN was induced by rapamycin administration. Immunohistochemical analyses revealed that Beclin 1 was located in Schwann cells in the proximal stump of the IAN. Accumulation of myelin protein zero and myelin basic protein in the proximal and distal stumps of the IAN was significantly reduced by rapamycin administration. Rapamycin administration facilitated axon regeneration after IANX and increased the number of brain-derived neurotrophic factor positive neurons in the trigeminal ganglion. Thus, recovery from sensory disturbance in the lower lip caused by IANX was markedly facilitated by rapamycin. These findings suggest that rapamycin administration is a promising treatment for the sensory disturbance caused by IANX.

Patient experience of motor recovery from denervation paralysis is complex and textured. The Medical Research Council (MRC) system of grading muscle peak volitional force is widely used as a single measure of assessment. However, it is becoming clear that current motor function assessments are not reflecting the patient lived experience of muscle reinnervation. Therefore, this study aimed to engage international expert nerve surgeons in a classical Delphi process to achieve a consensus of opinion on the ideal clinical assessment of motor function. This was compared with patient-reported impairments of reinnervated muscle. Invitations to engage in the Delphi process were extended to expert peripheral nerve surgeons across two international specialist meetings. For comparison, patients who attended a "Nerve Injury Community Day" were invited to complete a questionnaire on patient-reported impairments of reinnervated muscle. Questions were designed on the basis of a literature review and the clinical experiences of a specialist nerve injury unit. A combination of direct yes/no, multiple choice, open-ended and Likert questions were employed throughout the questionnaires. Eighteen surgeons engaged with the Delphi process; 18 and 11 responded to the first and second rounds respectively. Thirty-one patients responded to the questionnaire. It was found that clinicians were strongly biased towards efferent assessments of muscular function, while patients strongly favoured muscular fatigue, co-contraction and pain when monitoring their own recovery. The findings suggest that current clinical assessments of muscular function are inadequate and should embody measurements of afferent muscular function to better reflect the lived experience of muscle reinnervation.

In adult mammals, axon regeneration is limited within the lesion site after injury to the optic nerve. Changes in the microenvironment of lesion sites play an important role in retinal ganglion cells (RGCs) axon regeneration along with other intrinsic factors. In this study, the effect of the lesion site on the microenvironment and axon growth was evaluated using a refined optic nerve crush (ONC) injury model, in which the injury range was extended compared to classical injury. The number of regenerated axons labeled anterogradely with cholera toxin B fragment (CTB) was significantly increased in the long-range crush injury (LI) group compared to the ONC group at distances of 500, 1000 and 1500 µm from the initial site of the injury. These data confirmed that RGC axons can regenerate inside the lesion site. Immunofluorescence and proteomic analysis showed that the microenvironment at the lesion site was highly heterogeneous. The levels of myelin-associated inhibitors, chondroitin-sulfate proteoglycans (CSPGs) and other axon growth inhibitors decreased inside the lesion site compared to the posterior segment of the optic nerve lesion site. The expression of multiple lysosome-related enzymes, metabolic inhibitors including cholesterol esterase, cathepsin B, D, Z and arylsulfatase B (ARSB) were significantly increased inside the lesion site for the LI group compared to the normal optic nerves. Our results suggest that the model of long range optic nerve injury is more useful towards understanding the lesion microenvironment and the endogenous regeneration of RGCs. Also, we showed that myelin and neurocan (a CSPG) are differently expressed in the optic nerve between the interior and posterior lesion sites and may explain why axons cannot reach the brain through the lesion site.

Neurotrophic keratopathy is a degenerative disease in which damage to the corneal nerves leads to corneal hypoesthesia. Injuries to neurotrophic corneas are notoriously difficult to treat and have traditionally been approached with supportive management. However, recent progress in the field of corneal neurotization has given new direction for addressing nerve loss directly by stimulating new nerve growth onto the cornea from nearby sensory nerves transferred to the perilimbal region. Herein, we review the surgical techniques utilized in corneal neurotization, including direct transfers and the use of nerve grafts. Considerations in surgical approach, as well as factors that influence prognosis and outcomes of the surgical intervention are also discussed.

Made available in DSpace on 2021-06-25T10:37:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-04-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Denervation leads to severe atrophy of neuromuscular junction (NMJ) structure including decrease of the expression of fundamental proteins. Up to now, conventional suture has been the gold standard method used to correct this injury. Fibrin sealant is one of the alternatives proposed to optimize this method. This study verified if the association of fibrin sealant - Heterologous Fibrin Biopolymer (HFB) and a single suture stitch promotes return of morphology and NMJ structure to mature pattern after peripheral nerve injury. Forty Wistar rats were distributed into 4 groups: Sham-Control (SC), Denervated-Control (DC), Suture-Lesion (SL) and Suture-Lesion + HFB (SFS). In SC group only the right sciatic nerve identification was done. In DC, SL and SFS groups fixation of nerve stumps on musculature immediately after neurotmesis was performed. After seven days, stump reconnection with 3 stitches in SL and a single stitch associated with HFB in SFS were done. After sixty days right soleus muscles were prepared for nicotinic acetylcholine receptors (nAChRs) and nerve terminal confocal analyses, and for nAChRs (α1, ε e γ), S100, Agrin, LRP-4, MMP-3, Rapsyn western blotting analyses. SC group presented normal morphology. In DC group it was observed flattening of NMJ, fragmentation of nAChRs and tangled nerve terminals. The majority of the parameters of SL and SFS groups presented values in between SC and DC groups. There was an increase of relative planar area in these groups (SL and SFS) highlighting that there was less nAChRs fragmentation and the values of protein expression showed return of nAChRs to mature pattern. Use of HFB associated with a single suture stitch decreased surgical time, minimized suture injuries, did not alter nerve regeneration and presented potential to reestablish the NMJ apparatus. These consolidated results encourage surgeons to develop future clinical trials to install definitively this new approach both for reconstructive surgery and neurosurgery. Graduate Program in Surgery and Translational Medicine Medical School São Paulo State University (Unesp) Department of Structural and Functional Biology (Anatomy Sector) Institute of Biosciences São Paulo State University (Unesp) Center for the Studies of Venoms and Venomous Animals (CEVAP) São Paulo State University (Unesp) Herminio Ometto University Center (Uniararas) Graduate Program in Surgery and Translational Medicine Medical School São Paulo State University (Unesp) Department of Structural and Functional Biology (Anatomy Sector) Institute of Biosciences São Paulo State University (Unesp) Center for the Studies of Venoms and Venomous Animals (CEVAP) São Paulo State University (Unesp) FAPESP: 2017/06472-2

Summary Introduction 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. Method 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. Results 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. Discussion 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. Conclusion 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.

The wiring of visual circuits requires that retinal neurons functionally connect to specific brain targets, a process that involves activity-dependent signaling between retinal axons and their postsynaptic targets. Vision loss in various ophthalmological and neurological diseases is caused by damage to the connections from the eye to the brain. How postsynaptic brain targets influence retinal ganglion cell (RGC) axon regeneration and functional reconnection with the brain targets remains poorly understood. Here, we established a paradigm in which the enhancement of neural activity in the distal optic pathway, where the postsynaptic visual target neurons reside, promotes RGC axon regeneration and target reinnervation and leads to the rescue of optomotor function. Furthermore, selective activation of retinorecipient neuron subsets is sufficient to promote RGC axon regeneration. Our findings reveal a key role for postsynaptic neuronal activity in the repair of neural circuits and highlight the potential to restore damaged sensory inputs via proper brain stimulation.

Activated microglia/macrophages infiltration, astrocyte migration, and increased production of inhibitory chondroitin sulfate proteoglycans (CSPGs) are standard harmful events taking place after the spinal cord injuries (SCI). The gliotic scar, viz. the outcome of chronic SCI, constitutes a long-lasting physical and chemical barrier to axonal regrowth. In the past two decades, various research groups targeted the hostile host microenvironments of the gliotic scar at the injury site. To this purpose, biomaterial scaffolds demonstrate to provide a promising potential for nervous cell restoration. We here focused our efforts on two self-assembling peptides (SAPs), featuring different self-assembled nanostructures, and on different methods of drug loading to exploit the neuroregenerative potential of Chondroitinase ABC (ChABC), a thermolabile pro-plastic agent attenuating the inhibitory action of CSPGs. Enzymatic activity of ChABC (usually lasting less than 72 hours in vitro) released from SAPs was remarkably detected up to 42 days in vitro. ChABC was continuously released in vitro from a few days to 42 days as well. Also, injections of ChABC loaded SAP hydrogels favored host neural regeneration and behavioral recovery in chronic SCI in rats. Hence, SAP hydrogels showed great promise for the delivery of Chondroitinase ABC in future therapies targeting chronic SCI.

We report 2 patients who underwent strabismus surgery following corneal neurotization for neurotrophic keratopathy. Strabismus surgery in such cases presents unique challenges because of the potentially complicated motility problems arising from underlying neurologic or orbital processes. We consider the management of conjunctival incisions for strabismus surgery in these patients.

Conductive self -electrical stimuli bioactive scaffolds could be used the potential for peripheral nerve regeneration with the maximum efficiency. To produce such conductive self-electrical stimuli bioactive scaffolds, chopped spun piezoelectric nanofibers of polyvinylidene fluoride/mesoporous silica nanoparticle (PVDF/MCM41) are prepared and incorporated in gellan/polyaniline/graphene (gellan/PAG) nanocomposites which have been previously prepared by incorporation of polyaniline/graphene (PAG) nanoparticles in gellan gel at 80 °C. Highly conductive binary doped polyaniline/graphene nanoparticles are prepared by chemical oxidative polymerization of aniline monomer using in-suite precipitation polymerization method in presence of graphene nanoparticles and sodium dodecyl sulfate. All intermediate and final products including spun PVDF/MCM41 nanofibers, PAG nanoparticles, and gellan-gelatin gel scaffolds containing PVDF/MCM41 nano spun fibers and PAG nanoparticles are characterized using different analysis methods. Chemical and structural analyses of PAG nanoparticles and PVDF/MCM41 nanofibers have been done using FTIR and XRD methods. The morphological structure of different samples is investigated using SEM. Morphological investigation and DLS results confirm fabrication of MCM41 nanoparticle with a completely spherical shape and the average size of 50 nm of which have been dispersed in electrospun PVDF nanofibers very well. Also, the preparation of PAG nanoparticle with high conductivity is verified with morphological and conductivity tests. MTT easy and biocompatibility test results indicate potential applicability of the prepared conductive self -stimuli nano-scaffold for nerve regeneration applications.

Purpose Biomaterials used to restore digital nerve continuity after injury associated with a defect may influence ultimate outcomes. An evaluation of matched cohorts undergoing digital nerve gap reconstruction was conducted to compare processed nerve allograft (PNA) and conduits. Based on scientific evidence and historical controls, we hypothesized that outcomes of PNA would be better than for conduit reconstruction. Methods We identified matched cohorts based on patient characteristics, medical history, mechanism of injury, and time to repair for digital nerve injuries with gaps up to 25 mm. Data were stratified into 2 gap length groups: short gaps of 14 mm or less and long gaps of 15 to 25 mm. Meaningful sensory recovery was defined as a Medical Research Council scale of S3 or greater. Comparisons of meaningful recovery were made by repair method between and across the gap length groups. Results Eight institutions contributed matched data sets for 110 subjects with 162 injuries. Outcomes data were available in 113 PNA and 49 conduit repairs. Meaningful recovery was reported in 61% of the conduit group, compared with 88% in the PNA group. In the group with a 14-mm or less gap, conduit and PNA outcomes were 67% and 92% meaningful recovery, respectively. In the 15- to 25-mm gap length group, conduit and PNA outcomes were 45% and 85% meaningful recovery, respectively. There were no reported adverse events in either treatment group. Conclusions Outcomes of digital nerve reconstruction in this study using PNA were consistent and significantly better than those of conduits across all groups. As gap lengths increased, the proportion of patients in the conduit group with meaningful recovery decreased. This study supports the use of PNA for nerve gap reconstruction in digital nerve reconstructions up to 25 mm. Type of study/level of evidence Therapeutic III.

The way thyroid hormone works in peripheral nerve regeneration has not been fully elucidated, although studies have shown that it has a strong positive effect on nerve regeneration. It is argued that its action is probably stronger than the neurotrophic factors that have been used for some time. It is hypothesized that the use of thyroid hormone in the nerve tubes has a beneficial effect on nerve regeneration to the extent that the results of its use are comparable to those of the autograft technique in bridging small nerve deficits. In this experimental study, we examined the effect of thyroid hormone and BDNF (Brain Derived Neurotrophic Factor) on the repair of 10 mm nerve defects when administered within silicone nerve tubes and compared the results with the autograft method. Thyroid hormone promotes nerve regeneration mainly by increasing its speed and its effect on the maturation of nerve fibers compared to the other groups where the nerve deficit was bridged by entubulation. Also, better organization and the absence of intraneural fibrosis, compared to the other groups, may argue for the action of thyroid hormone in regulating the inflammatory response. Functionally, the AG group showed better results compared to the other groups by the end of the study (16 weeks).

The time course of events following end-to-side nerve coaptation remains unclear. Re-innervation and effects on the donor nerve were assessed following short- and long-term end-to-side neurorrhaphy were investigated in a rat model. One hundred and our Sprague-Dawley female rats were randomized to fresh and pre degenerated repair groups with or without perineurotomy. The right peroneal nerve was sutured to the tibial nerve in an end-to-side manner. Histological and electro-physiological assessment of re-innervation and of the donor nerve was performed at two-three months and at nine-twelve months, post-operatively. The results demonstrated that end-to-side neurorrhaphy could attract axonal sprouts and successfully re-innervate the target muscles. The influence on donor nerve was minimal in late stages, although it did have early negative effect. Double labeling provided evidence that one of the mechanisms of this procedure is probably by collateral sprouting.

Development of a functional nerve conduit to replace autografts remains a significant challenge particularly considering the compositional complexity and structural hierarchy of native peripheral nerves. In the present study, a multiscale strategy was adopted to fabricate 3D biomimetic nerve conduit from Antheraea pernyi silk fibroin (ApF)/(Poly(L-lactic acid-co-caprolactone)) (PLCL)/graphene oxide (GO) (ApF/PLCL/GO) nanofibers via nanofiber dispersion, template-molding, freeze-drying and crosslinking. The resultant conduits exhibit parallel multichannels (ϕ = 125 µm) surrounded by biomimetic fibrous fragments with tailored degradation rate and improved mechanical properties in comparison with the scaffold without GO. In vitro studies showed that such 3D biomimetic nerve scaffolds had the ability to offer an effective guiding interface for neuronal cell growth. Furthermore, these conduits showed a similarity to autografts in vivo repairing sciatic nerve defects based on a series of analysis (walking track, triceps weight, morphogenesis, vascularization, axonal regrowth and myelination). The conduits almost completely degraded within 12 weeks. These findings demonstrate that the 3D hierarchical nerve guidance conduit (NGC) with fascicle-like structure have great potential for peripheral nerve repair.

International audience; Retinal regeneration efficiency from Mü ller glia varies tremendously among vertebrate species, being extremely limited in mammals. Efforts towards the identification of molecular mechanisms underlying Mü ller cell proliferative and neurogenic potential should help finding strategies to awake them and ensure regeneration in mammals. We provide here an update on the most recent and original progresses made in the field. These include remarkable discoveries regarding (i) unprecedented cross-species comparison of Mü ller cell transcriptome using single-cell technologies, (ii) the identification of new strategies to promote both the proliferative and the neurogenic potential of mammalian Mü ller cells, (iii) the role of the epigenome in regulating Mü ller glia plasticity, (iv) miRNA-based regulatory mechanisms of Mü ller cell response to injury, and (v) the influence of inflammatory signals on the regenerative process.

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.